bluuebunny/crossref_metadata_2025 huggingface dataset:
New Thrombotic Events in Ischemic Stroke Patients with Elevated Factor VIII
Authors: Gouse Brittany M. , Boehme Amelia K. , Monlezun Dominique J. , Siegler James E. , George Alex J. , Brag Katherine , Albright Karen C. , Beasley T. Mark , Leissinger Cindy , El Khoury Ramy , Martin-Schild Sheryl
Published: December 2014

Background. Heightened levels of Factor VIII (FVIII) have been associated with both arterial and venous thrombosis. While elevated FVIII is common during acute ischemic stroke (AIS), whether elevated FVIII confers an increased risk for recurrent thrombotic events (RTEs) following AIS has not been previously explored. Methods. Consecutive AIS patients who presented to our center between July 2008 and September 2013 and had FVIII measured during admission were identified from our stroke registry. Baseline characteristics and the occurrence of RTE (recurrent or progressive ischemic stroke, DVT/PE, and MI) were compared in patients with and without elevated FVIII levels. Results. Of the 298 patients included, 203 (68.1%) had elevated FVIII levels. Patients with elevated FVIII had higher rates of any in-hospital RTE (18.7% versus 8.4%, P=0.0218). This association remained after adjustment for baseline stroke severity and etiology (OR 1.01, 95% CI 1.00–1.01, P=0.0013). Rates of major disability were also higher in patients who experienced a RTE (17.8% versus 3.2%, P<0.0001). Conclusion. A significantly higher frequency of in-hospital RTEs occurred in AIS patients with elevated FVIII. The occurrence of such events was associated with higher morbidity. Further study is indicated to evaluate whether FVIII is a candidate biomarker for increased risk of RTEs following AIS.
Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature
Authors: Lopez Patricia , Kohler Sven , Dimri Seema
Published: December 2014

Interstitial lung disease (ILD) has been reported with the use of mammalian target of rapamycin inhibitors (mTORi). The clinical and safety databases of three Phase III trials of everolimus inde novokidney (A2309), heart (A2310), and liver (H2304) transplant recipients (TxR) were searched using a standardized MedDRA query (SMQ) search for ILD followed by a case-by-case medical evaluation. A literature search was conducted in MEDLINE and EMBASE. Out of the 1,473de novoTxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR) representing an incidence of 0.4%. Everolimus was discontinued in three of the four heart TxR, resulting in ILD improvement or resolution. Outcome was fatal in the kidney TxR (in whom everolimus therapy was continued) and in the liver TxR despite everolimus discontinuation. The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation.
Proteomic Analysis of Serum and Urine of HIV-Monoinfected and HIV/HCV-Coinfected Patients Undergoing Long Term Treatment with Nevirapine
Authors: Wongtrakul Jeerang , Thongtan Thananya , Roytrakul Sittiruk , Kumrapich Benjawan , Janphen Kanokwan , Praparattanapan Jutarat , Supparatpinyo Khuanchai , Smith Duncan R.
Published: December 2014

Nevirapine (NVP) is an effective nonnucleoside reverse transcriptase inhibitor (NNRTI) of particular interest as it is often used in resource limited countries. However, one of the main concerns with the use of NVP is hepatotoxicity and elevation of liver enzymes as a consequence of highly active antiretroviral therapy (HAART) containing NVP is more often reported in HIV patients coinfected with hepatitis C virus than in HIV-monoinfected patients. To discover possible markers of NVP induced hepatotoxicity, serum and urine samples from twenty-five HIV or HIV/HCV patients, all of whom had received NVP continuously for at least four months, and healthy controls were subjected to in-solution or in-gel proteomic analysis. A total of 83 differentially regulated proteins consisted of 34 proteins identified in serum by in-solution analysis, 2 proteins identified from serum in a 2D gel electrophoresis analysis, and 47 proteins identified in urine in an in-solution analysis. Three proteins, namely, haptoglobin, Rho-related BTB domain containing protein 3, and death-associated protein kinase 3, were selected for further validation by Western blot analysis and results showed that haptoglobin has potential for further development as an additional marker of NVP induced hepatotoxicity.
The Cloninger Type I/Type II Typology: Configurations and Personality Profiles in Socially Stable Alcohol Dependent Patients
Authors: Wennberg Peter , Berglund Kristina , Berggren Ulf , Balldin Jan , Fahlke Claudia
Published: December 2014

Many attempts have been made to derive alcohol use typologies or subtypes of alcohol dependence and this study aimed at validating the type I/type II typology in a treatment sample of socially stable alcohol dependent males and females. A second aim was to compare the two types with respect to their temperament profiles. Data was part of a larger ongoing longitudinal study, the Gothenburg Alcohol Research Project, and included 269 alcohol dependent males and females recruited from three treatment centers. The results showed that type II alcoholism occurred as a more homogenous type than type I alcoholism, and type I alcoholism seemed too heterogeneous to be summarized into one single type. When adapting a strict classification, less than a third of the study population could be classified in accordance with the typology, suggesting that the typology is not applicable, at least in socially stable individuals with alcohol dependence. The results also showed that type II alcoholics showed higher levels of novelty seeking than did the individuals that were classified as type I alcoholics. Quite surprisingly, the individuals classified as type II alcoholics also showed higher levels of harm avoidance than did the individuals that were classified as type I alcoholics.
The Prevalence of Antinuclear Antibodies in Patients with Sarcoidosis
Authors: Kobak Senol , Yilmaz Hatice , Sever Fidan , Duran Arzu , Sen Nazime , Karaarslan Ahmet
Published: December 2014

Introduction. Sarcoidosis, which is a chronic inflammatory granulomatous disease, can mimic different rheumatologic diseases including connective tissue diseases. Antinuclear antibodies are the markers used for connective tissue diseases.Aim. To determine antinuclear antibody frequency and any possible correlation with clinical and laboratory data in sarcoidosis patients.Material and Method. Forty-two sarcoidosis patients, 45 rheumatoid arthritis patients, and 45 healthy volunteers who were followed up in rheumatology outpatient clinic were included in this study. Demographic, clinical, serological, and radiological data of all patients were recorded. Antinuclear antibodies were determined with indirect immunofluorescent method and 1/100 titration was accepted as positive. The cases that were ANA positive were evaluated with immunoblot method.Results. Average age of the 42 patients (10 males) with sarcoidosis was 45.2 (20–70 years), and average disease duration was 3.5 years. ANA positivity was detected in 12 (28.5%) patients with sarcoidosis (1/100 in 10 patients, 1/320 in two patients), in 19 of RA patients (42.2%), and in two of healthy volunteers in low titer (P<0.001). In the subgroup analysis made by immunblot test, one patient had anticentromere antibody, one had anti-Ro antibody, one had anti-Scl-70 antibody, one had anti-dsDNA antibody, and eight patients were negative. The two patients who had anticentromere and anti-Scl-70 antibodies had also Sjögren’s syndrome and scleroderma diagnosis, respectively.Discussion. The prevalence of ANA in patients with sarcoidosis was found to be significantly higher than healthy control group and lower than RA patients. This result shows that ANA may have an important role in the pathogenesis of sarcoidosis and also could be important in revealing the overlap syndromes of sarcoidosis-connective tissue diseases. Further studies with larger series are necessary in this subject.
The Filtering of the Posturographic Signals Shows the Age Related Features
Authors: Michalak Krzysztof Piotr , Przekoracka-Krawczyk Anna , Nawrot Paweł , Woźniak Piotr , Vieregge Peter
Published: December 2014

Objective. Lower frequencies of slow oscillations of the posturographic signals can be removed using high-pass filtering. This procedure releases postural reflexes possessing higher frequencies and lower amplitude range. Mutual dependence between thexandycomponents of posturographic signals was analyzed using principal component analysis (PCA). The posturographic signals of old patients with idiopathic gait disturbance were compared with the control group of similar age and with younger patients. There was also the analysis of the influence of the eyes state (open versus closed) and the head position (normal or bent back). The statistically significant differences in the mutual dependence betweenxandycomponents between the groups of patients were analyzed using MANOVA. The significant differences were observed mainly in the range of filter frequenciesf=0.1–1.5 Hz andf=2.2–5.5 Hz with a maximum effect at approximately4-5 Hz. A detailed post-hoc analysis is also presented. The differences in the higher frequency range suggest the main disturbance to be connected with the spinal reflexes. Visual and vestibular support appear insufficient for postural stability control in the idiopathic gait disturbance group. The results suggest that idiopathic gait disturbance is the final stage of the aging process of postural system.
Perampanel and Challenging Behaviour in Intellectual Disability and Epilepsy: A Management Dilemma
Authors: Dolton Emily , Choudry Ansar
Published: December 2014

We describe a case of a patient with a diagnosis of moderate learning disability with challenging behaviour and treatment refractory epilepsy. Antiepileptics can increase challenging behaviour; however, antipsychotics can provoke seizures. This results in a difficult balance for patient care. Due to worsening seizures, the patient was prescribed perampanel. This increased her aggression and agitation resulting in admission. We trialled four antipsychotic drugs to reduce her challenging behaviour, two of which worsened her seizures. It was necessary to continue antiepileptic medication to maintain adequate seizure control. However, the resulting uncontrolled challenging behaviour persisted, meaning she was unable to return to her family home on discharge. This case emphasises the difficult scenario clinician’s encounter when balancing the use of antipsychotics and antiepileptics. The case demonstrates the significant functional loss due to challenging behaviour, balanced against controlling life threatening seizures.
Exploiting Unique Structural and Functional Properties of Malarial Glycolytic Enzymes for Antimalarial Drug Development
Authors: Alam Asrar , Neyaz Md. Kausar , Ikramul Hasan Syed
Published: December 2014

Metabolic enzymes have been known to carry out a variety of functions besides their normal housekeeping roles known as “moonlighting functions.” These functionalities arise from structural changes induced by posttranslational modifications and/or binding of interacting proteins. Glycolysis is the sole source of energy generation for malaria parasitePlasmodium falciparum, hence a potential pathway for therapeutic intervention. Crystal structures of severalP. falciparumglycolytic enzymes have been solved, revealing that they exhibit unique structural differences from the respective host enzymes, which could be exploited for their selective targeting. In addition, these enzymes carry out many parasite-specific functions, which could be of potential interest to control parasite development and transmission. This review focuses on the moonlighting functions ofP. falciparumglycolytic enzymes and unique structural differences and functional features of the parasite enzymes, which could be exploited for therapeutic and transmission blocking interventions against malaria.
Accumulation of Bile in the Gallbladder: Evaluation by means of Serial Dynamic Contrast-Enhanced Magnetic Resonance Cholangiography with Gadolinium Ethoxybenzyl Diethylenetriaminepentaacetic Acid
Authors: Tamada Tsutomu , Ito Katsuyoshi , Yasokawa Kazuya , Higaki Atsushi , Kanki Akihiko , Noda Yasufumi , Yamamoto Akira
Published: December 2014

The aim of this study was to evaluate the process of biliary excretion of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) into the biliary tract and to assess the accumulation patterns in the gallbladder using MR cholangiography obtained with Gd-EOB-DTPA which is a liver-specific hepatobiliary contrast agent. Seventy-five patients underwent Gd-EOB-DTPA enhanced MR imaging. Serial multiphasic hepatobiliary phase imaging was qualitatively reviewed to evaluate the process of the biliary excretion of contrast agent into the bile duct and the gallbladder. The accumulation pattern of contrast agent into gallbladder was classified into two groups (group 1 = orthodromic type and group 2 = delayed type). Furthermore, the results in differences of the presence of T1 hyperintense bile or sludge of gallbladder, gall stones, wall thickening of gallbladder, chronic liver disease, and liver cirrhosis between two groups were compared. Forty-eight of 75 patients (64%) were included in group 1, and remaining 27 (36%) were in group 2. The frequency of the presence of T1 hyperintense bile or sludge of gallbladder was significantly higher in patients with group 2 than that in patients with group 1 (P=0.041). MR cholangiography obtained with Gd-EOB-DTPA showed that there may be an association between the biliary accumulation pattern in the gallbladder and the pathological condition.
Characteristics and Prevention of the Debris Flows following Wenchuan Earthquake in Jushui River Basin, An County, China
Authors: Ge Yonggang , Zhang Jianqiang , Guo Xiaojun
Published: December 2014

After analysing the catastrophic debris flows on August 18, 2012, and on July 9, 2013, in Jushui River basin, An County, the Wenchuan Earthquake seriously striken areas, it was found that they were characterized by the clay soil content of 0.1~1.2%, the density of 1.68~2.03 t/m3, the discharges of 62.2 m3/s to 552.5 m3/s, and the sediment delivery modulus of 1.0~9.4 × 104 m3/km2. Due to intense rainstorm, many large debris flows produced hazard chain, involved in flash flood, debris flow, dammed lake, and outburst flood, and rose Jushui River channel about 1~4 m as well as amplified flood. The hazards and losses mainly originated from the burying and scouring of debris flows, flood inundating, and river channel rise. The prevention of debris flows is facing the intractable problems including potential hazard identification, overstandard debris flow control, control constructions destructing, and river channel rapid rise. Therefore, the prevention measures for the basin, including hazard identification and risk assessment, inhabitants relocating, monitoring and alarming network establishing, emergency plans founding, and river channel renovating, and the integrated control mode for watershed based on regulating the process of debris flow discharge, were recommended for mitigation.
Intraoperative Full-Dose of Partial Breast Irradiation with Electrons Delivered by Standard Linear Accelerators for Early Breast Cancer
Authors: Barros Alfredo Carlos S. D. , Hanna Samir A. , Carvalho Heloísa A. , Martella Eduardo , Andrade Felipe Eduardo M. , Piato José Roberto M. , Bevilacqua José Luiz B.
Published: December 2014

Purpose. To assess feasibility, efficacy, toxicity, and cosmetic results of intraoperative radiotherapy (IORT) with electrons delivered by standard linear accelerators (Linacs) during breast conserving surgeries for early infiltrating breast cancer (BC) treatment.Materials and Methods. A total of 152 patients with invasive ductal carcinoma (T≤3.0 cm) at low risk for local relapses were treated. All had unicentric lesions by imaging methods and negative sentinel node. After a wide local excision, 21 Gy were delivered on the parenchyma target volume with electron beams. Local recurrences (LR), survival, toxicity, and cosmetic outcomes were analyzed.Results. The median age was 58.3 years (range 40–85); median follow-up was 50.7 months (range 12–101.5). There were 5 cases with LR, 2 cases with distant metastases, and 2 cases with deaths related to BC. The cumulative incidence rates of LR, distant metastases, and BC death were 3.2%, 1.5%, and 1.5%, respectively. Complications were rare, and the cosmetic results were excellent or good in most of the patients.Conclusions. IORT with electrons delivered by standard Linacs is feasible, efficient, and well tolerated and seems to be beneficial for selected patients with early infiltrating BC.
Intraoperative Boost Radiotherapy during Targeted Oncoplastic Breast Surgery: Overview and Single Center Experiences
Authors: Malter Wolfram , Kirn Verena , Richters Lisa , Fridrich Claudius , Markiefka Birgid , Bongartz Rudolf , Semrau Robert , Mallmann Peter , Kraemer Stefan
Published: December 2014

Breast-conserving surgery followed by whole-breast irradiation is the standard local therapy for early breast cancer. The international discussion of reduced importance of wider tumor-free resection margins than “tumor not touching ink” leads to the development of five principles in targeted oncoplastic breast surgery. IORT improves local recurrence risk and diminishes toxicity since there is less irradiation of healthy tissue. Intraoperative radiotherapy (IORT) can be delivered in two settings: an IORT boost followed by a conventional regimen of external beam radiotherapy or a single IORT dose. The data from TARGIT-A and ELIOT reinforce the conviction that intraoperative radiotherapy during breast-conserving surgery is a reliable alternative to conventional postoperative fractionated irradiation, but only in a carefully selected population at low risk of local recurrence. We describe our experiences with IORT boost (50 kV energy X-rays; 20 Gy) in combination with targeted oncoplastic breast surgery in a routine clinical setting. Our experiences demonstrate the applicability and reliability of combining IORT boost with targeted oncoplastic breast surgery in breast-conserving therapy of early breast cancer.
Certain Type Turbofan Engine Whole Vibration Model with Support Looseness Fault and Casing Response Characteristics
Authors: Wang H. F. , Chen G.
Published: December 2014

Support looseness fault is a type of common fault in aeroengine. Serious looseness fault would emerge under larger unbalanced force, which would cause excessive vibration and even lead to rubbing fault, so it is important to analyze and recognize looseness fault effectively. In this paper, based on certain type turbofan engine structural features, a rotor-support-casing whole model for certain type turbofan aeroengine is established. The rotor and casing systems are modeled by means of the finite element beam method; the support systems are modeled by lumped-mass model; the support looseness fault model is also introduced. The coupled system response is obtained by numerical integral method. In this paper, based on the casing acceleration signals, the impact characteristics of symmetrical stiffness and asymmetric stiffness models are analyzed, finding that the looseness fault would lead to the longitudinal asymmetrical characteristics of acceleration time domain wave and the multiple frequency characteristics, which is consistent with the real trial running vibration signals. Asymmetric stiffness looseness model is verified to be fit for aeroengine looseness fault model.
Image Guidance in Radiation Therapy: Techniques and Applications
Authors: Goyal Shikha , Kataria Tejinder
Published: December 2014

In modern day radiotherapy, the emphasis on reduction on volume exposed to high radiotherapy doses, improving treatment precision as well as reducing radiation-related normal tissue toxicity has increased, and thus there is greater importance given to accurate position verification and correction before delivering radiotherapy. At present, several techniques that accomplish these goals impeccably have been developed, though all of them have their limitations. There is no single method available that eliminates treatment-related uncertainties without considerably adding to the cost. However, delivering “high precision radiotherapy” without periodic image guidance would do more harm than treating large volumes to compensate for setup errors. In the present review, we discuss the concept of image guidance in radiotherapy, the current techniques available, and their expected benefits and pitfalls.
The Meaning of Collaboration, from the Perspective of Iranian Nurses: A Qualitative Study
Authors: Zamanzadeh V. , Irajpour A. , Valizadeh L. , Shohani M.
Published: December 2014

Background. Interdisciplinary collaboration among nurses is a complex and multifaceted process, an essential element in nursing, which is crucial to maintain an efficient, safe, and viable medical setting. The aim of this study was to explore the meaning of concept of collaboration through conducting a qualitative research approach.Method. The present study is qualitatively conducted in a content analysis approach. The data collection process included 18 unstructured and in-depth interviews with nurses during 2012-2013 in educational medical centers of west and northwest of Iran. A purposive sampling method was used. All the interviews were recorded, transcribed, and finally analyzed using a qualitative content analysis with a conventional method.Result. Categories obtained from analysis of the data to explain the meaning of collaboration consist of (i) prerequisites of collaboration, (ii) actualization of collaboration, and (iii) achievement of a common goal.Conclusion. The results of the present study ended in the discovery of meaning of collaboration that confirm results of other related studies, hence clarifying and disambiguating the concept under study. These results also contribute to the development of collaboration theories and the relevant measurement tools.
Successful Use of Extracorporeal Membrane Oxygenation for Respiratory Failure Caused by Mediastinal Precursor T Lymphoblastic Lymphoma
Authors: Oto Masafumi , Inadomi Kyoko , Chosa Toshiyuki , Uneda Shima , Uekihara Soichi , Yoshida Minoru
Published: December 2014

Precursor T lymphoblastic lymphoma (T-LBL) often manifests as a mediastinal mass sometimes compressing vital structures like vessels or large airways. This case was a 40-year-old male who developed T-LBL presenting as respiratory failure caused by mediastinal T-LBL. He presented with persistent life threatening hypoxia despite tracheal intubation. We successfully managed this respiratory failure using venovenous (VV) ECMO. Induction chemotherapy was started after stabilizing oxygenation and the mediastinal lesion shrank rapidly. Respiratory failure caused by compression of the central airway by tumor is an oncologic emergency. VV ECMO may be an effective way to manage this type of respiratory failure as a bridge to chemotherapy.
Sciatic Nerve Palsy following Total Hip Replacement via Direct Anterior Approach after Recommencement of Warfarin for Prophylaxis in Atrial Fibrillation
Authors: Asopa Vipin , Al-Nammari Shafic , Spriggins Tony , Menz Tony , Bauze Adrian
Published: December 2014

The occurrence of sciatic nerve palsy following posterior and anterolateral approaches to the hip has been well documented and is about 1-2%. To our knowledge, however, there are no reports of sciatic nerve palsy occurring secondary to the anterior approach to the hip for arthroplasty. We describe a case of sciatic nerve palsy secondary to haematoma formation following total hip replacement through the anterior approach. The recommencement of warfarin for prophylaxis against atrial fibrillation is thought to have been a contributing factor. Full recovery is rare following delayed diagnosis and early recognition of the signs of pain, parasthesia, and gradual loss of dorsiflexion and prompt drainage may reverse the condition. We advise caution with restarting warfarin following total hip arthroplasty.
Comparative Study of M5 Model Tree and Artificial Neural Network in Estimating Reference Evapotranspiration Using MODIS Products
Authors: Alipour Armin , Yarahmadi Jalal , Mahdavi Maryam
Published: December 2014

Reference evapotranspiration (ETO) is one of the major parameters affecting hydrological cycle. Use of satellite images can be very helpful to compensate for lack of reliable weather data. This study aimed to determine ETO using land surface temperature (LST) data acquired from MODIS sensor. LST data were considered as inputs of two data-driven models including artificial neural network (ANN) and M5 model tree to estimate ETO values and their results were compared with calculated ETO by FAO-Penman-Monteith (FAO-PM) equation. Climatic data of five weather stations in Khuzestan province, which is located in the southeastern Iran, were employed in order to calculate ETO. LST data extracted from corresponding points of MODIS images were used in training of ANN and M5 model tree. Among study stations, three stations (Amirkabir, Farabi, and Gazali) were selected for creating the models and two stations (Khazaei and Shoeybie) for testing. In Khazaei station, the coefficient of determination (R2) values for comparison between calculated ETO by FAO-PM and estimated ETO by ANN and M5 tree model were 0.79 and 0.80, respectively. In a similar manner, R2 values for Shoeybie station were 0.86 and 0.85. In general, the results showed that both models can properly estimate ETO by means of LST data derived from MODIS sensor.
Copper Oxide Nanomaterials Prepared by Solution Methods, Some Properties, and Potential Applications: A Brief Review
Authors: Tran Thi Ha , Nguyen Viet Tuyen
Published: December 2014

Cupric oxide (CuO), having a narrow bandgap of 1.2 eV and a variety of chemophysical properties, is recently attractive in many fields such as energy conversion, optoelectronic devices, and catalyst. Compared with bulk material, the advanced properties of CuO nanostructures have been demonstrated; however, the fact that these materials cannot yet be produced in large scale is an obstacle to realize the potential applications of this material. In this respect, chemical methods seem to be efficient synthesis processes which yield not only large quantities but also high quality and advanced material properties. In this paper, the effect of some general factors on the morphology and properties of CuO nanomaterials prepared by solution methods will be overviewed. In terms of advanced nanostructure synthesis, microwave method in which copper hydroxide nanostructures are produced in the precursor solution and sequentially transformed by microwave into CuO may be considered as a promising method to explore in the near future. This method produces not only large quantities of nanoproducts in a short reaction time of several minutes, but also high quality materials with advanced properties. A brief review on some unique properties and applications of CuO nanostructures will be also presented.
1 : 3 Resonance and Chaos in a Discrete Hindmarsh-Rose Model
Authors: Li Bo , He Zhimin
Published: December 2014

1 : 3 resonance of a two-dimensional discrete Hindmarsh-Rose model is discussed by normal form method and bifurcation theory. Numerical simulations are presented to illustrate the theoretical analysis, which predict the occurrence of a closed invariant circle, period-three saddle cycle, and homoclinic structure. Furthermore, it also displays the complex dynamical behaviors, especially the transitions between three main dynamical behaviors, namely, quiescence, spiking, and bursting.
Genetic Mutation of p53 and Suppression of the miR-17∼92 Cluster Are Synthetic Lethal in Non–Small Cell Lung Cancer due to Upregulation of Vitamin D Signaling
Authors: Borkowski Robert , Du Liqin , Zhao Zhenze , McMillan Elizabeth , Kosti Adam , Yang Chin-Rang , Suraokar Milind , Wistuba Ignacio I. , Gazdar Adi F. , Minna John D. , White Michael A. , Pertsemlidis Alexander
Published: December 2014

Lung cancer is the leading cause of cancer-related fatalities. Recent success developing genotypically targeted therapies, with potency only in well-defined subpopulations of tumors, suggests a path to improving patient survival. We used a library of oligonucleotide inhibitors of microRNAs, a class of posttranscriptional gene regulators, to identify novel synthetic lethal interactions between miRNA inhibition and molecular mechanisms in non–small cell lung cancer (NSCLC). Two inhibitors, those for miR-92a and miR-1226*, produced a toxicity distribution across a panel of 27 cell lines that correlated with loss of p53 protein expression. Notably, depletion of p53 was sufficient to confer sensitivity to otherwise resistant telomerase-immortalized bronchial epithelial cells. We found that both miR inhibitors cause sequence-specific downregulation of the miR-17∼92 polycistron, and this downregulation was toxic only in the context of p53 loss. Mechanistic studies indicated that the selective toxicity of miR-17∼92 polycistron inactivation was the consequence of derepression of vitamin D signaling via suppression of CYP24A1, a rate-limiting enzyme in the 1α,25-dihydroxyvitamin D3 metabolic pathway. Of note, high CYP24A1 expression significantly correlated with poor patient outcome in multiple lung cancer cohorts. Our results indicate that the screening approach used in this study can identify clinically relevant synthetic lethal interactions and that vitamin D receptor agonists may show enhanced efficacy in p53-negative lung cancer patients. Cancer Res; 75(4); 666–75. ©2014 AACR.
Longitudinal Noninvasive Imaging of Progesterone Receptor as a Predictive Biomarker of Tumor Responsiveness to Estrogen Deprivation Therapy
Authors: Chan Szeman Ruby , Fowler Amy M. , Allen Julie A. , Zhou Dong , Dence Carmen S. , Sharp Terry L. , Fettig Nicole M. , Dehdashti Farrokh , Katzenellenbogen John A.
Published: December 2014

Purpose: To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [18F]FDG (to measure glucose uptake), [18F]FES [to measure estrogen receptor (ER) levels], or [18F]FFNP [to measure progesterone receptor (PgR) levels] is predictive of response to estrogen-deprivation therapy.

Experimental Design: [18F]FDG, [18F]FES, and [18F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors was quantified serially by PET before ovariectomy or estrogen withdrawal in mice, and on days 3 and 4 after estrogen-deprivation therapy. Specificity of [18F]FFNP uptake in ERα+ mammary tumors was determined by competition assay using unlabeled ligands for PgR or glucocorticoid receptor (GR). PgR expression was also assayed by immunohistochemistry (IHC).

Results: The levels of [18F]FES and [18F]FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estrogen-deprivation therapy compared with those at pretreatment. In contrast, estrogen-deprivation therapy led to a reduction in PgR expression and [18F]FFNP uptake in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days after treatment; the changes in PgR levels were confirmed by IHC. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone blocked [18F]FFNP tumor uptake, indicating that [18F]FFNP bound specifically to PgR. Therefore, a reduction in FFNP tumor to muscle ratio in mammary tumors predicts sensitivity to estrogen-deprivation therapy.

Conclusions: Monitoring the acute changes in ERα activity by measuring [18F]FFNP uptake in mammary tumors predicts tumor response to estrogen-deprivation therapy. Longitudinal noninvasive PET imaging using [18F]FFNP is a robust and effective approach to predict tumor responsiveness to endocrine treatment. Clin Cancer Res; 21(5); 1063–70. ©2014 AACR.
The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy
Authors: Di Venosa Gabriela , Vallecorsa Pablo , Giuntini Francesca , Mamone Leandro , Batlle Alcira , Vanzuli Silvia , Juarranz Angeles , MacRobert Alexander J. , Eggleston Ian M. , Casas Adriana
Published: December 2014

The use of endogenous protoporphyrin IX generated after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However, the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature. The aim of this work was to evaluate the potential of two ALA dipeptide derivatives, N-acetyl terminated leucinyl-ALA methyl ester (Ac-Leu-ALA-Me) and phenylalanyl-ALA methyl ester (Ac-Phe-ALA-Me), for their use in PDT of cancer, by investigating the generation of protoporphyrin IX in an oncogenic cell line (PAM212-Ras), and in a subcutaneous tumor model. In our in vitro studies, both derivatives were more effective than ALA in PDT treatment, at inducing the same protoporphyrin IX levels but at 50- to 100-fold lower concentrations, with the phenylalanyl derivative being the most effective. The efficient release of ALA from Ac-Phe-ALA-Me appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase. In vivo studies revealed that topical application of the peptide prodrug Ac-Phe-ALA-Me gave greater selectivity than with ALA itself, and induced tumor photodamage, whereas systemic administration improved ALA-induced porphyrin generation in terms of equivalent doses administered, without induction of toxic effects. Our data support the possibility of using particularly Ac-Phe-ALA-Me both for topical treatment of basal cell carcinomas and for systemic administration. Further chemical fine-tuning of this prodrug template should yield additional compounds for enhanced ALA-PDT with potential for translation to the clinic. Mol Cancer Ther; 14(2); 440–51. ©2014 AACR.
Sunitinib Dose Escalation Overcomes Transient Resistance in Clear Cell Renal Cell Carcinoma and Is Associated with Epigenetic Modifications
Authors: Adelaiye Remi , Ciamporcero Eric , Miles Kiersten Marie , Sotomayor Paula , Bard Jonathan , Tsompana Maria , Conroy Dylan , Shen Li , Ramakrishnan Swathi , Ku Sheng-Yu , Orillion Ashley , Prey Joshua , Fetterly Gerald , Buck Michael , Chintala Sreenivasulu , Bjarnason Georg A. , Pili Roberto
Published: December 2014

Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib's clinical efficacy, patients eventually develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDX) were treated 5 days per week with a dose-escalation schema (40–60–80 mg/kg sunitinib). Tumor tissues were collected before dose increments for immunohistochemistry analyses and drug levels. Selected intrapatient sunitinib dose escalation was safe and several patients had added progression-free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro antitumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention. Mol Cancer Ther; 14(2); 513–22. ©2014 AACR.
MLN0128, an ATP-Competitive mTOR Kinase Inhibitor with Potent In Vitro and In Vivo Antitumor Activity, as Potential Therapy for Bone and Soft-Tissue Sarcoma
Authors: Slotkin Emily K. , Patwardhan Parag P. , Vasudeva Shyamprasad D. , de Stanchina Elisa , Tap William D. , Schwartz Gary K.
Published: December 2014

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists in two complexes (mTORC1 and mTORC2) and integrates extracellular and intracellular signals to act as a master regulator of cell growth, survival, and metabolism. The PI3K/AKT/mTOR prosurvival pathway is often dysregulated in multiple sarcoma subtypes. First-generation allosteric inhibitors of mTORC1 (rapalogues) have been extensively tested with great preclinical promise, but have had limited clinical utility. Here, we report that MLN0128, a second-generation, ATP-competitive, pan-mTOR kinase inhibitor, acts on both mTORC1 and mTORC2 and has potent in vitro and in vivo antitumor activity in multiple sarcoma subtypes. In vitro, MLN0128 inhibits mTORC1/2 targets in a concentration-dependent fashion and shows striking antiproliferative effect in rhabdomyosarcoma (RMS), Ewing sarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, osteosarcoma, and liposarcoma. Unlike rapamycin, MLN0128 inhibits phosphorylation of 4EBP1 and NDRG1 as well as prevents the reactivation of pAKT that occurs via negative feedback release with mTORC1 inhibition alone. In xenograft models, MLN0128 treatment results in suppression of tumor growth with two dosing schedules (1 mg/kg daily and 3 mg/kg b.i.d. t.i.w.). At the 3 mg/kg dosing schedule, MLN0128 treatment results in significantly better tumor growth suppression than rapamycin in RMS and Ewing sarcoma models. In addition, MLN0128 induces apoptosis in models of RMS both in vitro and in vivo. Results from our study strongly suggest that MLN0128 treatment should be explored further as potential therapy for sarcoma. Mol Cancer Ther; 14(2); 395–406. ©2014 AACR.
Early Childhood Caries Is Associated with Genetic Variants in Enamel Formation and Immune Response Genes
Authors: Abbasoğlu Zerrin , Tanboğa İlknur , Calvano Küchler Erika , Deeley Kathleen , Weber Megan , Kaspar Cigdem , Korachi May , Vieira Alexandre R.
Published: December 2014

Early childhood caries (ECC) is a chronic, infectious disease that affects the primary dentition of young children. It is the result of an imbalance of risk factors and protective factors that influence the disease. The aim of this study was to assess genetic and environmental factors that may contribute to ECC. Two hundred and fifty-nine unrelated children were evaluated using a cross-sectional design. Data on oral habits were obtained through a questionnaire, and caries experience data were collected by clinical examination. Twenty-three markers in 10 genes were studied. Genotyping of the selected polymorphisms was carried out by real-time PCR. Regression analyses were performed comparing individuals with and without caries experience. Of 259 subjects, 123 were caries free. The genotype TT in ALOX15 (rs7217186) was a risk factor for ECC, whereas the genotypes GG in ENAM (rs1264848), AG and GG in KLK4 (rs198968), CT in LTF (rs4547741), and GG in TUFT1 (rs3790506) were protective for EEC. In conclusion, environmental factors and gene interactions can act as protective or risk factors for ECC. These factors together contribute to the presence and severity of the disease.
How Can Screening Colonoscopy Be Optimized?
Authors: Waldmann Elisabeth , Regula Jaroslaw , Ferlitsch Monika
Published: December 2014

Since the implementation of screening programmes, both the incidence and mortality of colorectal cancer have been decreasing. The choice of the preferred screening tool, however, is divergent and the adherence to screening programmes in most countries is still low. Cancer detection tests such as the guaiac faecal occult blood test (gFOBT) and the immunohistochemical FOBT (iFOBT) achieve higher acceptance than endoscopy. The sensitivity and specificity of iFOBT are higher than those of gFOBT, but gFOBT is cheaper and easier to perform. Endoscopic screening, which represents cancer prevention tests, has higher sensitivity for premalignant lesions than gFOBT and iFOBT and enables diagnosis and therapy in one single procedure. Since screening colonoscopy and sigmoidoscopy are invasive procedures with potentially severe adverse events, the highest possible quality must be provided. High-tech equipment, experience, training, quality control programmes, excellent bowel preparation and low adverse event rates are pivotal. Alternative screening tools such as CT colonography, barium enema CT and multitarget stool DNA tests have not been established as routine screening tools to date.
Small Bowel Crohn's Disease: An Emerging Disease Phenotype?
Authors: Hall Barry , Holleran Grainne , McNamara Deirdre
Published: December 2014

An increasing understanding of the pathogenesis of Crohn's disease (CD), coupled with improvements in therapeutic options, has promoted the concept of stratifying patients with CD into distinct disease phenotypes according to risk. Small bowel CD, due to the numerous non-specific potential symptoms and the anatomical location of the disease, is a particularly difficult phenotype to identify. The fact that the majority of de novo strictures occur in the ileum/ileo-colonic region ensures that recognition of small bowel involvement is essential. Certainly, it is becoming increasingly recognised due to improvements in imaging and endoscopic techniques. Both CT and MR enterography appear capable of accurately diagnosing small bowel CD. Furthermore, the development of capsule endoscopy and balloon-assisted enteroscopy allow direct visualisation of the small bowel. Limited data to date would suggest that small bowel CD is a difficult entity to treat even in the current era of the ever-expanding field of biological therapies. Further long-term follow-up studies are necessary using both small bowel capsule endoscopy and cross-sectional imaging to truly assess, firstly, whether small bowel CD is more resistant to treatment and, secondly, whether it has an effect over time in terms of complications. In the future, serological and genetic tests, coupled with the aforementioned investigations, will permit early diagnosis and early treatment of small bowel CD.
New Therapeutic Avenues for Treatment of Fibrosis: Can We Learn from Other Diseases?
Authors: Rogler Gerhard
Published: December 2014

Crohn's disease (CD) is characterized by the frequent occurrence of complications, such as fibrotic strictures and subsequently the need for CD-related surgery. Chronic or recurrent inflammation is generally regarded to be a necessary precondition for the initiation of intestinal fibrosis. In this view, fibrosis is a pathologically augmented healing response to inflammation-induced mucosal tissue destruction and injury. At present, there are no approved or effective medical therapies aimed specifically at fibrosis or stricture in IBD. Indirect benefits may occur from anti-inflammatory therapies, although there is no consensus on this. Therapy for fibrosis is complicated by the fact that a wound-healing response is essential in CD and ulcerative colitis. Several pharmaceutical companies are now working on the therapy of fibrosis in other diseases. Strategies interfering with TGF-β expression and activation are promising. Pirfenidone has been studied in several clinical trials. Further therapeutic options are second-generation and wide-spectrum tyrosine kinase inhibitors. These inhibit growth factor receptor signaling, thus reducing fibrosis in animal models and some patients with tumor-associated fibrosis. At present, the development of antifibrotic therapies takes place in other diseases such as lung and liver fibrosis. This is partially due to a lack of experimental models for gut fibrosis and the fact that reliable readouts (MRI, serum markers) in patients are lacking. It will be important to test the above-mentioned newly available treatment strategies in IBD to profit from progress in other fibrotic diseases.
Mesenchymal Stromal Cell Therapy for Crohn's Disease
Authors: Liew Aaron , O'Brien Timothy , Egan Laurence
Published: December 2014

Current treatment approaches fail to address the underlying factors responsible for the pathogenesis of Crohn's disease (CD). Mesenchymal stromal cells (MSCs) are fibroblastic plastic adherent cells with specific surface markers, and may demonstrate trilineage differentiation ability. MSCs can be isolated from either the adipose tissue, bone marrow or umbilical cord. In refractory fistulizing CD, both autologous and allogeneic MSC therapy with repeated administrations is a feasible and safe therapeutic option with suggestion of efficacy, and several phase 3 trials are currently underway to determine its efficacy. In this review, we discuss the potential therapeutic role of MSC therapy for CD, which is predominantly related to its immunomodulatory role. The characteristics of MSCs derived from patients with CD and its pharmacological interaction are outlined. Preclinical studies using experimental models of colitis and clinical studies using MSCs for the treatment of fistulizing CD are highlighted. Finally, the current perspective and potential limitations of this novel therapy with recommendations for future studies are discussed.
Immune Cell Therapy in IBD
Authors: Dunkin David , Mehandru Saurabh , Colombel Jean-Frédéric
Published: December 2014

The therapeutic landscape of IBD has undergone a dramatic transformation since the advent of biologic therapies, especially TNF inhibitors. However, 30% of patients are primary nonresponders to biologic therapy and secondary failures are frequent. Due to substantial progress in our understanding of the biology of regulatory T cells (Tregs) and in the pathways of homing to the gastrointestinal tract, novel cell-based therapies for IBD have become possible. For example, although a reductionist view, one could envisage IBD as an imbalance between the proinflammatory effectors (such as Th17 cells) and the anti-inflammatory regulators (like Tregs). Here we focus on the development of ex vivo and in vivo approaches to enhance Tregs in the gastrointestinal tract. Specifically, herein we highlight a recently concluded phase 1/2a clinical trial that investigated the safety and efficacy of a single injection of escalating doses of autologous ovalbumin-specific Tregs in patients with active Crohn's disease refractory to conventional therapy. This therapy was well tolerated and demonstrated dose-related efficacy. We also discuss the potential of directing Tregs derived through intranasal as well as epicutaneous immunization to the gastrointestinal tract by enhancing their gut homing signature and their potential to decrease gastrointestinal inflammation. Finally, the strengths and pitfalls of these new therapeutic approaches are discussed as we move forward in this largely uncharted territory.