bluuebunny/crossref_metadata_2025 huggingface dataset:
Coverage of Gingival Fenestration Using Modified Pouch and Tunnel Technique: A Novel Approach
Authors: Pendor Sunil , Baliga Vidya , Muthukumaraswamy A. , Dhadse Prasad V. , Ganji Kiran Kumar , Thakare Kaustubh
Published: July 2013

Gingival fenestration defects are a rare phenomenon. Gingival fenestration means the exposure of the tooth due to loss of the overlying bone and gingiva. Though treatment of mucosal fenestration occurring in association with chronic periapical inflammation has been reported previously, the occurrence and treatment of gingival fenestration have not been documented in great detail. This report describes the occurrence of a gingival fenestration that developed secondarily to a gutka chewing habit. Treatment of the fenestration along with coverage of an adjacent recession defect in a single-step procedure using a pouch and tunnel technique is described.
Factors That Influence Failure Behaviour and Remaining Useful Life of Mining Equipment Components
Authors: Ho Mark , Hodkiewicz Melinda
Published: July 2013

Mobile mining equipment often operates in harsh environments characterised by remote locations and highly variable rock and operating conditions. This research explores the hypothesis that the failure behaviour of mining equipment is influenced by the physical properties of the ore and waste. We describe a method of examining this relationship via data mining on maintenance records and apply it to the hydraulic cylinders of two classes of earthmoving mobile equipment. Failure data for the analysis are drawn from maintenance work orders from 14 sites mining for haematite iron, nickel sulphide, and coking and thermal coal. The results show that the distributions of the estimated life parameters for hydraulic cylinders on earthmoving equipment are distinctly different for haematite iron, coal, and nickel sulphide sites. Analysis of the relationship between selected physical properties identified the influence of rock impact hardness number, abrasion index, and absolute hardness of the ore as significant factors for these hydraulic cylinders. Their effects are significant when parameters are considered in combination, for example, rock impact hardness number and abrasion index, and vary according to the cylinder type and asset class. The engineering implications of these results are considered with respect to known failure modes of the cylinders.
BIBO Stabilization of Discrete-Time Stochastic Control Systems with Mixed Delays and Nonlinear Perturbations
Authors: Zhou Xia , Ren Yong , Zhong Shouming
Published: July 2013

The problem of bounded-input bounded-output (BIBO) stabilization in mean square for a class of discrete-time stochastic control systems with mixed time-varying delays and nonlinear perturbations is investigated. Some novel delay-dependent stability conditions for the previously mentioned system are established by constructing a novel Lyapunov-Krasovskii function. These conditions are expressed in the forms of linear matrix inequalities (LMIs), whose feasibility can be easily checked by using MATLAB LMI Toolbox. Finally, a numerical example is given to illustrate the validity of the obtained results.
Sinonasal Melioidosis in a Returned Traveller Presenting with Nasal Cellulitis and Sinusitis
Authors: Lim Rebecca Sin Mei , Flatman Sam , Dahm Markus C.
Published: July 2013

We illustrate a case involving a 51-year-old man who presented to a tertiary hospital with sepsis secondary to an abscess of the nasal vestibule and pustular eruptions of the nasal mucosa. Associated cellulitis extended across the face to the eye, and mucosal thickening of the sinuses was seen on computed tomography. The patient underwent incision and drainage and endoscopic sinus surgery. Blood cultures and swabs were positive for a gram-negative bacillus,Burkholderia pseudomallei. He had multiple risk factors including travel to an endemic area. The patient received extended antibiotic therapy in keeping with published national guidelines. Melioidosis is caused byBurkholderia pseudomallei, found in the soil in Northern Australia and Asia. It is transmitted via cutaneous or inhaled routes, leading to pneumonia, skin or soft tissue abscesses, and genitourinary infections. Risk factors include diabetes, chronic lung disease, and alcohol abuse. It can exist as a latent, active, or reactivated infection. A high mortality rate has been identified in patients with sepsis. Melioidosis is endemic in tropical Northern Australia and northeastern Thailand where it is the most common cause of severe community-acquired sepsis. There is one other report of melioidosis in the literature involving orbital cellulitis and sinusitis.
SpecificDioscoreaPhytoextracts Enhance Potency of TCL-Loaded DC-Based Cancer Vaccines
Authors: Chang Wei-Ting , Chen Hui-Ming , Yin Shu-Yi , Chen Yung-Hsiang , Wen Chih-Chun , Wei Wen-Chi , Lai Phoency , Wang Cheng-Hsin , Yang Ning-Sun
Published: July 2013

Dioscoreatuber phytoextracts can confer immunomodulatory activitiesex vivoand improve regeneration of bone marrow cellsin vivo. In present study, we evaluated specificDioscoreaphytoextracts for useex vivoas a bone-marrow-derived dendritic cell- (DC-) based vaccine adjuvant for cancer immunotherapy. FractionatedDioscoreaextracts (DsII) were assayed for their effect on maturation and functions of DCex vivoand antimelanoma activity of DC-based vaccinein vivo. The phytoextract from 50–75% ethanol-precipitated fraction ofDioscorea alatavar.purpureaTainung no. 5 tuber, designated as DsII-TN5, showed a strong augmentation of tumor cell lysate- (TCL-) loaded DC-mediated activation of T-cell proliferation. DsII-TN5 stimulated the expression of CD40, CD80, CD86, and IL-1βin TCL-loaded DCs and downregulated the expression of TGF-β1. DC vaccines prepared by a specific schema (TCL (2 h) + LPS (22 h)) showed the strongest antitumor activity. DsII-TN5 as a DC vaccine adjuvant showed strong antimelanoma activity and reduced myeloid-derived suppressor cell (MDSC) population in tested mice. DsII-TN5 can also activate DCs to enhance Th1- and Th17-related cytokine expressions. Biochemical analysis showed that DsII-TN5 consists mainly of polysaccharides containing a high level (53%) of mannose residues. We suggest that DsII-TN5 may have potential for future application as a potent, cost-effective adjuvant for DC-based cancer vaccines.
Phosphorylation of Tau Protein as the Link between Oxidative Stress, Mitochondrial Dysfunction, and Connectivity Failure: Implications for Alzheimer’s Disease
Authors: Mondragón-Rodríguez Siddhartha , Perry George , Zhu Xiongwei , Moreira Paula I. , Acevedo-Aquino Mariana C. , Williams Sylvain
Published: July 2013

Alzheimer’s disease (AD) is defined by the concurrence of abnormal aggregates composed of phosphorylated tau protein and of abnormal cellular changes including neurite degeneration, loss of neurons, and loss of cognitive functions. While a number of mechanisms have been implicated in this complex disease, oxidative stress remains one of the earliest and strongest events related to disease progression. However, the mechanism that links oxidative stress and cognitive decline remains elusive. Here, we propose that phosphorylated tau protein could be playing the role of potential connector and, therefore, that a combined therapy involving antioxidants and check points for synaptic plasticity during early stages of the disease could become a viable therapeutic option for AD treatment.
System Consolidation of Spatial Memories in Mice: Effects of Enriched Environment
Authors: Bonaccorsi Joyce , Cintoli Simona , Mastrogiacomo Rosa , Baldanzi Sigrid , Braschi Chiara , Pizzorusso Tommaso , Cenni Maria Cristina , Berardi Nicoletta
Published: July 2013

Environmental enrichment (EE) is known to enhance learning and memory. Declarative memories are thought to undergo a first rapid and local consolidation process, followed by a prolonged process of system consolidation, which consist in a time-dependent gradual reorganization of brain regions supporting remote memory storage and crucial for the formation of enduring memories. At present, it is not known whether EE can affect the process of declarative memory system consolidation. We characterized the time course of hippocampal and cortical activation following recall of progressively more remote spatial memories. Wild-type mice either exposed to EE for 40 days or left in standard environment were subjected to spatial learning in the Morris water maze and to the probe test 1, 10, 20, 30, and 50 days after learning. Following the probe test, regional expression of the inducible immediate early gene c-Fos was mapped by immunohistochemistry, as an indicator of neuronal activity. We found that activation of the medial prefrontal cortex (mPFC), suggested to have a privileged role in processing remote spatial memories, was evident at shorter time intervals after learning in EE mice; in addition, EE induced the progressive activation of a distributed cortical network not activated in non-EE mice. This suggests that EE not only accelerates the process of mPFC recruitment but also recruits additional cortical areas into the network supporting remote spatial memories.
Structure Transformation and Coherent Interface in Large Lattice‐Mismatched Nanoscale Multilayers
Authors: Xie J. Y. , Wang F. , Huang P. , Lu T. J. , Zhang L. F. , Xu K. W.
Published: July 2013

Nanoscale Al/W multilayers were fabricated by DC magnetron sputtering and characterized by transmission electron microscopy and high‐resolution electron microscopy. Despite the large lattice mismatch and significantly different lattice structures between Al and W, a structural transition from face‐centered cubic to body‐centered cubic in Al layers was observed when the individual layer thickness was reduced from 5 nm to 1 nm, forming coherent Al/W interfaces. For potential mechanisms underlying the observed structure transition and forming of coherent interfaces, it was suggested that the reduction of interfacial energy and high stresses induced by large lattice‐mismatch play a crucial role.
Modulation of the Expression of the Proinflammatory IL-8 Gene in Cystic Fibrosis Cells by Extracts Deriving from Olive Mill Waste Water
Authors: Lampronti Ilaria , Borgatti Monica , Vertuani Silvia , Manfredini Stefano , Gambari Roberto
Published: July 2013

A persistent recruitment of neutrophils in the bronchi of cystic fibrosis (CF) patients contributes to aggravate the airway tissue damage, suggesting the importance of modulating the expression of chemokines, including IL-8 during the management of the CF patients. Polyphenols rich extracts derived from waste water from olive mill, obtained by a molecular imprinting approach, have been investigated in order to discover compounds able to reduce IL-8 expression in human bronchial epithelial cells (IB3-1 cells), derived from a CF patient with a ΔF508/W1282X mutant genotype and stimulated with TNF-alpha. Initially, electrophoretic mobility shift assays (EMSAs) were performed to determine whether the different active principles were able to inhibit the binding between transcription factor (TF) NF-kappaB and DNA consensus sequences. Among different representative active principles present in the extract, three compounds were selected, apigenin, oleuropein, and cyanidin chloride, which displayed remarkable activity in inhibiting NF-kappaB/DNA complexes. Utilizing TNF-alpha-treated IB3-1 cells as experimental model system, we demonstrated that apigenin and cyanidin chloride are able to modulate the expression of the NF-kappaB-regulated IL-8 gene, while oleuropein showed no effect in regulating the expression of the gene IL-8.
The Improvement of Emotion and Attention Regulation after a 6-Week Training of Focused Meditation: A Randomized Controlled Trial
Authors: Menezes Carolina Baptista , de Paula Couto Maria Clara , Buratto Luciano G. , Erthal Fátima , Pereira Mirtes G. , Bizarro Lisiane
Published: July 2013

Self-regulatory trainings can be an effective complementary treatment for mental health disorders. We investigated the effects of a six-week-focused meditation training on emotion and attention regulation in undergraduates randomly allocated to a meditation, a relaxation, or a wait-list control group. Assessment comprised a discrimination task that investigates the relationship between attentional load and emotional processing and self-report measures. For emotion regulation, results showed greater reduction in emotional interference in the low attentional load condition in meditators, particularly compared to relaxation. Only meditators presented a significant association between amount of weekly practice and the reduction in emotion interference in the task and significantly reduced image ratings of negative valence and arousal, perceived anxiety and difficulty during the task, and state and trait-anxiety. For attention regulation, response bias during the task was analyzed through signal detection theory. After training, meditation and relaxation significantly reduced bias in the high attentional load condition. Importantly, there was a dose-response effect on general bias: the lowest in meditation, increasing linearly across relaxation and wait-list. Only meditators reduced omissions in a concentrated attention test. Focused meditation seems to be an effective training for emotion and attention regulation and an alternative for treatments in the mental health context.
ANTXR1, a Stem Cell-Enriched Functional Biomarker, Connects Collagen Signaling to Cancer Stem-like Cells and Metastasis in Breast Cancer
Authors: Chen Daohong , Bhat-Nakshatri Poornima , Goswami Chirayu , Badve Sunil , Nakshatri Harikrishna
Published: July 2013

Cancer stem-like cells are thought to contribute to tumor recurrence. The anthrax toxin receptor 1 (ANTXR1) has been identified as a functional biomarker of normal stem cells and breast cancer stem-like cells. Primary stem cell-enriched basal cells (CD49f+/EpCAM−/Lin−) expressed higher levels of ANTXR1 compared with mature luminal cells. CD49f+/EpCAM−, CD44+/EpCAM−, CD44+/CD24−, or ALDEFLUOR-positive subpopulations of breast cancer cells were enriched for ANTXR1 expression. CD44+/CD24−/ANTXR1+ cells displayed enhanced self-renewal as measured by mammosphere assay compared with CD44+/CD24−/ANTXR1− cells. Activation of ANTXR1 by its natural ligand C5A, a fragment of collagen VI α3, increased stem cell self-renewal in mammosphere assays and Wnt signaling including the expression of the Wnt receptor–lipoprotein receptor-related protein 6 (LRP6), phosphorylation of GSK3α/β, and elevated expression of Wnt target genes. RNAi-mediated silencing of ANTXR1 enhanced the expression of luminal-enriched genes but diminished Wnt signaling including reduced LRP6 and ZEB1 expression, self-renewal, invasion, tumorigenicity, and metastasis. ANTXR1 silencing also reduced the expression of HSPA1A, which is overexpressed in metastatic breast cancer stem cells. Analysis of public databases revealed ANTXR1 amplification in medullary breast carcinoma and overexpression in estrogen receptor-negative breast cancers with the worst outcome. Furthermore, ANTXR1 is among the 10% most overexpressed genes in breast cancer and is coexpressed with collagen VI. Thus, ANTXR1:C5A interactions bridge a network of collagen cleavage and remodeling in the tumor microenvironment, linking it to a stemness signaling network that drives metastatic progression. Cancer Res; 73(18); 5821–33. ©2013 AACR.
HOXB13 Mediates Tamoxifen Resistance and Invasiveness in Human Breast Cancer by Suppressing ERα and Inducing IL-6 Expression
Authors: Shah Nilay , Jin Kideok , Cruz Leigh-Ann , Park Sunju , Sadik Helen , Cho Soonweng , Goswami Chirayu Pankaj , Nakshatri Harikrishna , Gupta Rajnish , Chang Howard Y. , Zhang Zhe , Cimino-Mathews Ashley , Cope Leslie , Umbricht Christopher , Sukumar Saraswati
Published: July 2013

Most breast cancers expressing the estrogen receptor α (ERα) are treated successfully with the receptor antagonist tamoxifen (TAM), but many of these tumors recur. Elevated expression of the homeodomain transcription factor HOXB13 correlates with TAM-resistance in ERα-positive (ER+) breast cancer, but little is known regarding the underlying mechanism. Our comprehensive evaluation of HOX gene expression using tiling microarrays, with validation, showed that distant metastases from TAM-resistant patients also displayed high HOXB13 expression, suggesting a role for HOXB13 in tumor dissemination and survival. Here we show that HOXB13 confers TAM resistance by directly downregulating ERα transcription and protein expression. HOXB13 elevation promoted cell proliferation in vitro and growth of tumor xenografts in vivo. Mechanistic investigations showed that HOXB13 transcriptionally upregulated interleukin (IL)-6, activating the mTOR pathway via STAT3 phosphorylation to promote cell proliferation and fibroblast recruitment. Accordingly, mTOR inhibition suppressed fibroblast recruitment and proliferation of HOXB13-expressing ER+ breast cancer cells and tumor xenografts, alone or in combination with TAM. Taken together, our results establish a function for HOXB13 in TAM resistance through direct suppression of ERα and they identify the IL-6 pathways as mediator of disease progression and recurrence. Cancer Res; 73(17); 5449–58. ©2013 AACR.
Pesticide Exposure and Inherited Variants in Vitamin D Pathway Genes in Relation to Prostate Cancer
Authors: Karami Sara , Andreotti Gabriella , Koutros Stella , Barry Kathryn Hughes , Moore Lee E. , Han Summer , Hoppin Jane A. , Sandler Dale P. , Lubin Jay H. , Burdette Laurie A. , Yuenger Jeffrey , Yeager Meredith , Freeman Laura E. Beane , Blair Aaron , Alavanja Michael C.R.
Published: July 2013

Background: Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin D's anticarcinogenic properties. We hypothesize that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants.

Methods: We evaluated interactions between 41 pesticides and 152 single-nucleotide polymorphisms (SNP) in nine vitamin D pathway genes among 776 prostate cancer cases and 1,444 male controls in a nested case–control study of Caucasian pesticide applicators within the Agricultural Health Study. We assessed Pinteraction values using likelihood ratio tests from unconditional logistic regression and a false discovery rate (FDR) to account for multiple comparisons.

Results: Five significant interactions (P < 0.01) displayed a monotonic increase in prostate cancer risk with individual pesticide use in one genotype and no association in the other. These interactions involved parathion and terbufos use and three vitamin D genes (VDR, RXRB, and GC). The exposure–response pattern among participants with increasing parathion use with the homozygous CC genotype for GC rs7041 compared with unexposed participants was noteworthy [low vs. no exposure: OR, 2.58, 95% confidence interval (CI), 1.07–6.25; high vs. no exposure: OR, 3.09, 95% CI, 1.10–8.68; Pinteraction = 3.8 × 10−3].

Conclusions: In this study, genetic variations in vitamin D pathway genes, particularly GC rs7041, an SNP previously linked to lower circulating vitamin D levels, modified pesticide associations with prostate cancer risk.

Impact: Because our study is the first to examine this relationship, additional studies are needed to rule out chance findings. Cancer Epidemiol Biomarkers Prev; 22(9); 1557–66. ©2013 AACR.
Mutual Regulation between Raf/MEK/ERK Signaling and Y-Box–Binding Protein-1 Promotes Prostate Cancer Progression
Authors: Imada Kenjiro , Shiota Masaki , Kohashi Kenichi , Kuroiwa Kentaro , Song YooHyun , Sugimoto Masaaki , Naito Seiji , Oda Yoshinao
Published: July 2013

Purpose: Y-box–binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial–mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer.

Experimental Design: Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses.

Results: EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor [HR, 7.947; 95% confidence interval (CI), 3.527–20.508; P < 0.0001].

Conclusion: We revealed the functional relationship between YB-1 and MAPK signaling and its biochemical relevance to the progression of prostate cancer. In addition, ERK2 expression was an independent prognostic factor. These findings suggest that both the ERK pathway and YB-1 may be promising molecular targets for prostate cancer diagnosis and therapeutics. Clin Cancer Res; 19(17); 4638–50. ©2013 AACR.
Accelerated Tumor Growth Mediated by Sublytic Levels of Antibody-Induced Complement Activation Is Associated with Activation of the PI3K/AKT Survival Pathway
Authors: Wu Xiaohong , Ragupathi Govind , Panageas Katherine , Hong Feng , Livingston Philip O.
Published: July 2013

Purpose: We addressed the possibility that low levels of tumor cell-bound antibodies targeting gangliosides might accelerate tumor growth.

Experimental Design: To test this hypothesis, we treated mice with a range of monoclonal antibody (mAb) doses against GM2, GD2, GD3, and CD20 after challenge with tumors expressing these antigens and tested the activity of the same mAbs in vitro. We also explored the mechanisms behind the complement-mediated tumor growth acceleration that we observed and an approach to overcome it.

Results: Serologically detectable levels of IgM-mAb against GM2 are able to delay or prevent tumor growth of high GM2 expressing cell lines both in vitro and in a SCID mouse model, whereas very low levels of this mAb resulted in slight but consistent acceleration of tumor growth in both settings. Surprisingly, this is not restricted to IgM mAb targeting GM2 but consistent against an IgG mAb targeting GD3 as well. These findings were mirrored by in vitro studies with antibodies against these antigens as well as GD2 and CD20 (with Rituxan), and shown to be complement-dependent in all cases. Complement-mediated accelerated growth of cultured tumor cell lines initiated by low mAb levels was associated with activation of the phosphoinositide 3-kinase (PI3K)/AKT survival pathway and significantly elevated levels of both p-AKT and p-PRAS40. This complement-mediated PI3K activation and accelerated tumor growth in vitro and in vivo are eliminated by PI3K inhibitors NVP-BEZ235 and Wortmannin. These PI3K inhibitors also significantly increased efficacy of high doses of these four mAbs.

Conclusion: Our findings suggest that manipulation of the PI3K/AKT pathway and its signaling network can significantly increase the potency of passively administered mAbs and vaccine-induced antibodies targeting a variety of tumor cell surface antigens. Clin Cancer Res; 19(17); 4728–39. ©2013 AACR.
Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors
Authors: Sessa Cristiana , Lorusso Patricia , Tolcher Anthony , Farace Françoise , Lassau Nathalie , Delmonte Angelo , Braghetti Antonio , Bahleda Rastislav , Cohen Patrick , Hospitel Marie , Veyrat-Follet Christine , Soria Jean-Charles
Published: July 2013

Purpose: The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies.

Experimental Design: Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated.

Results: Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients.

Conclusions: The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity. Clin Cancer Res; 19(17); 4832–42. ©2013 AACR.
Detection of Mutant Free Circulating Tumor DNA in the Plasma of Patients with Gastrointestinal Stromal Tumor Harboring Activating Mutations of CKIT or PDGFRA
Authors: Maier Jacqueline , Lange Thoralf , Kerle Irina , Specht Katja , Bruegel Melanie , Wickenhauser Claudia , Jost Philipp , Niederwieser Dietger , Peschel Christian , Duyster Justus , von Bubnoff Nikolas
Published: July 2013

Purpose: In gastrointestinal stromal tumor (GIST), there is no biomarker available that indicates success or failure of therapy. We hypothesized that tumor-specific v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (CKIT)- or platelet-derived growth factor receptor-α (PDGFRA)–mutant DNA fragments can be detected and quantified in plasma samples of patients with GIST.

Experimental Design: We prospectively collected 291 plasma samples from 38 subjects with GIST harboring activating mutations of CKIT or PDGFRA detected in tumor tissue, irrespective of current disease status or treatment. We used allele-specific ligation PCR to detect mutant free circulating DNA (fcDNA).

Results: We were able to detect fcDNA harboring the tumor mutation in 15 of 38 patients. Patients with active disease displayed significantly higher amounts of mutant fcDNA compared with patients in complete remission (CR). The amount of mutant fcDNA correlated with disease course. We observed repeated positive test results or an increase of mutant fcDNA in five patients with progressive disease or relapse. A decline of tumor fcDNA or conversion from positive to negative was seen in five patients responding to treatment. A negative to positive conversion was seen in two patients with relapse and one patient with progression. In two cases, we aimed to identify additional mutations and found four additional exchanges, including mutations not known from sequentially conducted tumor biopsies.

Conclusions: Our results indicate that fcDNA harboring tumor-specific mutations in the plasma of patients with GIST can be used as tumor-specific biomarker. The detection of resistance mutations in plasma samples might allow earlier treatment changes and obviates the need for repeated tumor biopsies. Clin Cancer Res; 19(17); 4854–67. ©2013 AACR.
Tumor Genetic Analyses of Patients with Metastatic Melanoma Treated with the BRAF Inhibitor Dabrafenib (GSK2118436)
Authors: Nathanson Katherine L. , Martin Anne-Marie , Wubbenhorst Bradley , Greshock Joel , Letrero Richard , D'Andrea Kurt , O'Day Steven , Infante Jeffrey R. , Falchook Gerald S. , Arkenau Hendrik-Tobias , Millward Michael , Brown Michael P. , Pavlick Anna , Davies Michael A. , Ma Bo , Gagnon Robert , Curtis Martin , Lebowitz Peter F. , Kefford Richard , Long Georgina V.
Published: July 2013

Purpose: Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently showed improved progression-free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. This study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib.

Experimental Design: Baseline (pretreatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array-based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available.

Results: All baseline patient samples had BRAFV600E/K confirmed. Baseline PTEN loss/mutation was not associated with best overall response to dabrafenib, but it showed a trend for shorter median PFS [18.3 (95% confidence interval, CI, 9.1–24.3) vs. 32.1 weeks (95% CI, 24.1–33), P = 0.059]. Higher copy number of CCND1 (P = 0.009) and lower copy number of CDKN2A (P = 0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high-level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors.

Conclusions: Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients. Clin Cancer Res; 19(17); 4868–78. ©2013 AACR.
A Dendritic Cell Vaccine Pulsed with Autologous Hypochlorous Acid-Oxidized Ovarian Cancer Lysate Primes Effective Broad Antitumor Immunity: From Bench to Bedside
Authors: Chiang Cheryl Lai-Lai , Kandalaft Lana E. , Tanyi Janos , Hagemann Andrea R. , Motz Gregory T. , Svoronos Nikolaos , Montone Kathleen , Mantia-Smaldone Gina M. , Smith Lori , Nisenbaum Harvey L. , Levine Bruce L. , Kalos Michael , Czerniecki Brian J. , Torigian Drew A. , Powell Daniel J. , Mick Rosemarie , Coukos George
Published: July 2013

Purpose: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells.

Experimental Design: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo.

Results: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate–pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC.

Conclusions: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers. Clin Cancer Res; 19(17); 4801–15. ©2013 AACR.
DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF-β–Driven Epithelial–Mesenchymal Transition
Authors: Chen Nanyue , Balasenthil Seetharaman , Reuther Jacquelyn , Frayna Aileen , Wang Ying , Chandler Dawn S. , Abruzzo Lynne V. , Rashid Asif , Rodriguez Jaime , Lozano Guillermina , Cao Yu , Lokken Erica , Chen Jinyun , Frazier Marsha L. , Sahin Aysegul A. , Wistuba Ignacio I. , Sen Subrata , Lott Steven T. , Killary Ann McNeill
Published: July 2013

Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation, and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum, with both Dear1−/− and Dear1+/− mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice. DEAR1 loss of function in the presence of TGF-β results in failure of acinar morphogenesis, upregulation of epithelial–mesenchymal transition (EMT) markers, anoikis resistance, migration, and invasion. Furthermore, DEAR1 blocks TGF-β–SMAD3 signaling, resulting in decreased nuclear phosphorylated SMAD3 by binding to and promoting the ubiquitination of SMAD3, the major effector of TGF-β–induced EMT. Moreover, DEAR1 loss increases levels of SMAD3 downstream effectors SNAIL1 and SNAIL2, with genetic alteration of DEAR1/SNAIL2 serving as prognostic markers of overall poor survival in a cohort of 889 cases of invasive breast cancer.

Significance: Cumulative results provide compelling evidence that DEAR1 is a critical tumor suppressor involved in multiple human cancers and provide a novel paradigm for regulation of TGF-β–induced EMT through DEAR1′s regulation of SMAD3 protein levels. DEAR1 loss of function has important therapeutic implications for targeted therapies aimed at the TGF-β–SMAD3 pathway. Cancer Discov; 3(10); 1172–89. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1083
Human Regulatory T Cells Kill Tumor Cells through Granzyme-Dependent Cytotoxicity upon Retargeting with a Bispecific Antibody
Authors: Choi Bryan D. , Gedeon Patrick C. , Herndon James E. , Archer Gary E. , Reap Elizabeth A. , Sanchez-Perez Luis , Mitchell Duane A. , Bigner Darell D. , Sampson John H.
Published: July 2013

A major mechanism by which human regulatory T cells (Treg) have been shown to suppress and kill autologous immune cells is through the granzyme-perforin pathway. However, it is unknown whether Tregs also possess the capacity to kill tumor cells using similar mechanisms. Bispecific antibodies (bscAb) have emerged as a promising class of therapeutics that activate T cells against tumor antigens without the need for classical MHC-restricted T-cell receptor (TCR) recognition. Here, we show that a bscAb targeting the tumor-specific mutation of the EGF receptor, EGFRvIII, redirects human CD4+CD25+FoxP3+ Tregs to kill glioblastoma cells. This activity was significantly abrogated by inhibitors of the granzyme-perforin pathway. Notably, analyses of human primary glioblastoma also displayed diffused infiltration of granzyme-expressing FoxP3+ T cells. Together, these data suggest that despite their known suppressive functions, tumor-infiltrating Tregs possess potent cytotoxic mechanisms that can be co-opted for efficient tumor cell lysis. Cancer Immunol Res; 1(3); 163–7. ©2013 AACR.
Delayed Neurovascular Dysfunction Is Alleviated by Hydrogen in Asphyxiated Newborn Pigs
Authors: Oláh Orsolya , Tóth-Szűki Valéria , Temesvári Péter , Bari Ferenc , Domoki Ferenc
Published: July 2013

Background: The neurovascular unit encompasses the functional interactions of cerebrovascular and brain parenchymal cells necessary for the metabolic homeostasis of neurons. Previous studies indicated marked but only transient (1-4 h) reactive oxygen species-dependent neurovascular dysfunction in newborn pigs after severe hypoxic/ischemic (H/I) stress contributing to the neuronal injury after birth asphyxia. Objectives: Our major purpose was to determine if neurovascular dysfunction would also occur later, at 24 h after a milder H/I stress. We also tested if the putative hydroxyl radical scavenger hydrogen (H2) exerted neurovascular protection. Methods: Anesthetized, ventilated piglets were assigned to three groups of 9 animals: time control, asphyxia/reventilation with air, and asphyxia/reventilation with air +2.1% H2 for 4 h. Asphyxia was induced by suspending ventilation for 8 min. Cerebrovascular reactivity (CR) of pial arterioles was determined using closed cranial window/intravital microscopy 24 h after asphyxia to the endothelium-dependent cerebrovascular stimulus hypercapnia, the neuronal function-dependent stimulus N-methyl-D-aspartate (NMDA), norepinephrine, and sodium nitroprusside. The brains were subjected to histopathology. Results: Hemodynamic parameters, blood gases, and core temperature did not differ significantly among the experimental groups. In the early reventilation period, the recovery of electroencephalographic activity was significantly better in H2-treated animals. Asphyxia/reventilation severely attenuated CR to hypercapnia and NMDA; however, reactivity to norepinephrine and sodium nitroprusside were unaltered. H2 fully or partially preserved CR to hypercapnia or NMDA, respectively. Histopathology revealed modest neuroprotection afforded by H2. Conclusions: Severe stimulus-selective delayed neurovascular dysfunction develops and persists even after mild H/I stress. H2 alleviates this delayed neurovascular dysfunction that can contribute to its neuroprotective effect.
Effects of Bronchodilators on Regional Lung Sound Distribution in Patients with Chronic Obstructive Pulmonary Disease
Authors: Mineshita Masamichi , Matsuoka Shin , Miyazawa Teruomi
Published: July 2013

Background: Bronchodilators have been reported to influence regional lung ventilation in patients with chronic obstructive pulmonary disease (COPD), which may change regional lung sound distribution. Vibration response imaging (VRI) is a lung imaging system for the assessment of breath sounds. Objective: To evaluate the effects of a short-acting β2-agonist (SABA) on the regional distribution of lung sounds in COPD patients. Methods: A double-blind crossover trial was performed to compare the treatment of COPD patients with an SABA (20 µg of inhaled procaterol) versus a placebo. The percentage of regional lung sound energy [quantitative lung data (QLD)] was evaluated with VRI. VRI, spirometry, and impulse oscillometry (IOS) were performed immediately before and 30 min after SABA administration. Results: Ten male patients (69.6 ± 14.2 years of age, percentage predicted forced expiratory volume in 1 s: 43.8 ± 16.9%) were evaluated. The use of an SABA produced significant functional improvements in the spirometric and IOS measurements. Among the homogeneous emphysema patients (n = 7), the upper-lung QLD decreased (from 24.2 ± 5.8 to 18.8 ± 6.1%, p < 0.05) and the lower-lung QLD increased (from 37.9 ± 12.7 to 46.1 ± 14.3%, p < 0.05) following SABA inhalation. However, the significant redistribution of the regional lung QLD to the lower-lung field was not observed in 2 of the 3 inhomogeneous emphysema patients. Conclusion: The additional use of an SABA by COPD patients improved their pulmonary function, which was accompanied by changes in regional lung air flow. The distribution of emphysematous lesions and the bronchial reactivity to SABA appeared to affect the redistribution of the lung sounds following bronchodilator administration.
Acne Cosmetica Revisited: A Case-Control Study Shows a Dose-Dependent Inverse Association between Overall Cosmetic Use and Post-Adolescent Acne
Authors: Singh Sanjay , Mann Baldeep Kaur , Tiwary Narendra K.
Published: July 2013

Background: Case-control studies to support the concept of acne cosmetica are lacking. Objective: To examine the association of post-adolescent acne with the use of cosmetics and cosmetic procedures. Methods: 910 post-adolescent patients with acne and an equal number of matched controls were studied for exposure to cosmetics and cosmetic procedures. A cumulative cosmetic exposure index was stratified into four quarters of increasing exposure. Results: Comparison of different cumulative exposure categories with the lowest exposure category (multivariate analysis, logistic regression) showed that the odds ratios, which were always <1, progressively declined as cosmetic exposure increased [odds ratios (95% confidence intervals): 0.679 (0.501-0.922), 0.355 (0.258-0.487), 0.307 (0.217-0.433)]. However, some individual cosmetics had odds ratios >1. Conclusion: Overall cosmetic use was negatively associated with post-adolescent acne. The term ‘acne cosmetica' is appropriate in the sense that some cosmetics may cause acne.
The Challenges for Cardiac Vascular Precursor Cell Therapy: Lessons from a Very Elusive Precursor
Authors: Roura Santiago , Gálvez-Montón Carolina , Bayes-Genis Antoni
Published: July 2013

There is compelling evidence that cardiovascular disorders arise and/or progress due mainly to endothelial dysfunction. Novel therapeutic strategies aim to generate new myocardial tissue using cells with regenerative potential, either alone or in combination with biomaterials, cytokines and advanced monitoring devices. Among the human adult progenitor cells used in such methods, those historically termed ‘endothelial progenitor cells' show promise for vascular growth and repair. Asahara et al. [Science 1997;275:964-967] initially described putative endothelial cell precursors in 1997. Subsequently, distinct cell populations termed endothelial colony-forming units-Hill, circulating angiogenic cells and endothelial colony-forming cells were identified that varied in terms of phenotype, vascular homeostasis contribution and purity. Notably, most of these cells are not genuine vascular precursor cells belonging to the endothelial lineage. This review provides a broad overview of the main properties of the endothelium, focusing on the basis governing its growth and repair. We discuss efforts to identify true vascular precursors, a matter of debate for the past 15 years, as well as recent methodological advances in identifying new hierarchies of more homogeneous, clonogenic and proliferative vascular endothelial-lineage precursors. Consideration of these issues provides insights that may help develop more effective therapies against human diseases that involve vascular deficits.
Naturopathic Reflex Therapies for the Treatment of Chronic Back and Neck Pain - Part 1: Neurobiological Foundations
Authors: Musial Frauke , Spohn Dorothee , Rolke Roman
Published: July 2013

Evidence from recent RCT's has shown that naturopathic reflex therapies such as massage, Gua Sha massage, cupping, wet packs, or rhythmic embrocation etc. are helpful in reducing symptoms of chronic pain. These bodily oriented therapies are likely able to influence chronic pain not only through brain mechanisms such as expectation or the feeling of well-being, but also through mechanisms at the level of the peripheral nociceptor and the spinal cord. However, the neurobiological basis of these effects has rarely been investigated even though the accumulating knowledge of the pathophysiology of chronic pain syndromes allows for developing specific hypotheses. This essay discusses specific reflex therapies (cupping, Gua Sha massage, classical massage, and rhythmic embrocation) and their possible mechanisms of action via ascending pathways to the brain.
Acute Appendicitis Following Appendectomy
Authors: Lin Chien-Hua , Ou Jing-Jim , Lee Yueh-Tsung , Wu Hurng-Sheng
Published: July 2013

SummaryBackground: Stump appendicitis is a rare delayed complication of appendectomy. Several diseases present with right lower abdominal pain, and therefore it is occasionally difficult to make a differential diagnosis, especially in patients with a history of appendectomy. In this paper we present our experiences with acute appendicitis following an appendectomy. Patients and Method: We selected five cases from January 2002 to December 2010. The clinical characteristics, imaging studies, treatment, and outcome were recorded. Results: All patients presented with abdominal pain (4 patients with fever). The mean duration of onset was 2 days. All patients had a history of ruptured appendicitis (2 patients showed a combination with generalized peritonitis). The mean duration since the previous appendectomy was 7.54 years. 4 patients underwent an abdominal ultrasound, and all patients underwent abdominal computed tomography, showing again a ruptured appendicitis. 4 of 5 patients had a stump appendicitis. All of the patients showed a good prognosis following surgery. Conclusions: The stump following an appendectomy should be shortened as much as possible. However, sometimes recurrent appendicitis with perforation will develop in patients with complete resection of the appendix. Stump appendicitis is associated with a history of ruptured appendicitis.
Team Resource Management im OP und in der Endoskopie
Authors: Lackner Christian K. , Moecke Heinzpeter , Burghofer Karin
Published: July 2013

Hintergrund: Klinischem Handeln ist implizit, dass die große Mehrzahl an risikoreichen und gleichzeitig prognoserelevanten Handlungen am Patienten nicht durch Einzelne erfolgt, sondern die Resultate einer Teamleistung (bisweilen ad hoc) sind. Methode: Publizierte Forschungsergebnisse zeigen nachvollziehbare Befunde, welche die Ursachen von Fehlermechanismen und -ketten darstellen und die Wirksamkeit von TRM(Team Resource Management)-Trainingsformaten belegen. Ergebnisse: Die Analyse der Literaturbefunde seit 2003 zeigt deutlich, dass die Ursache von prognose- oder zwischenfallrelevanten Fehlerketten in der klinischen Medizin zu mehr als 70% den Anwendern zuzuordnen ist. Die Implementierung und kontinuierliche Weiterentwicklung der Patientensicherheit im Bereich der Human Factors und die Anwendung der TRM-Leitsätze erfordert als Basis eine gute und breit akzeptierte Sicherheitskultur. Schlussfolgerungen: Initiativmaßnahmen wie regelmäßige realitätsnahe Simulationsteamtrainings, TRM-Formate und gut etablierte nichtpunitive Incident-Reporting-Systeme können hierbei effektiv zu einer stetigen und messbaren Verbesserung der Sicherheitskultur beitragen.