Epimural bacterial community structure in the rumen of Holstein cows with different responses to a long-term subacute ruminal acidosis diet challenge

Publication date: March 2017
Source:Journal of Dairy Science, Volume 100, Issue 3
Author(s): S.U. Wetzels, E. Mann, P. Pourazad, M. Qumar, B. Pinior, B.U. Metzler-Zebeli, M. Wagner, S. Schmitz-Esser, Q. Zebeli
Subacute ruminal acidosis (SARA) is a prevalent metabolic disorder in cattle, characterized by intermittent drops in ruminal pH. This study investigated the effect of a gradual adaptation and continuously induced long-term SARA challenge diet on the epimural bacterial community structure in the rumen of cows. Eight rumen-cannulated nonlactating Holstein cows were transitioned over 1 wk from a forage-based baseline feeding diet (grass silage-hay mix) to a SARA challenge diet, which they were fed for 4 wk. The SARA challenge diet consisted of 60% concentrates (dry matter basis) and 40% grass silage-hay mix. Rumen papillae biopsies were taken at the baseline, on the last day of the 1-wk adaptation, and on the last day of the 4-wk SARA challenge period; ruminal pH was measured using wireless sensors. We isolated DNA from papillae samples for 16S rRNA gene amplicon sequencing using Illumina MiSeq. Sequencing results of most abundant key phylotypes were confirmed by quantitative PCR. Although they were fed similar amounts of concentrate, cows responded differently in terms of ruminal pH during the SARA feeding challenge. Cows were therefore classified as responders (n = 4) and nonresponders (n = 4): only responders met the SARA criterion of a ruminal pH drop below 5.8 for longer than 330 min/d. Data showed that Proteobacteria, Firmicutes, and Bacteroidetes were the most abundant phyla, and at genus level, Campylobacter and Kingella showed highest relative abundance, at 15.5 and 7.8%, respectively. Diversity analyses revealed a significant increase of diversity after the 1-wk adaptation but a decrease of diversity and species richness after the 4-wk SARA feeding challenge, although without distinction between responders and nonresponders. At the level of the operational taxonomic unit, we detected diet-specific shifts in epimural community structure, but in the overall epimural bacterial community structure, we found no differences between responders and nonresponders. Correlation analysis revealed significant associations between grain intake and operational taxonomic unit abundance. The study revealed major shifts in the 3 dominating phyla and, most importantly, a loss of diversity in the epimural bacterial communities during a long-term SARA diet challenge, in which 60% concentrate supply for 4 wk was instrumental rather than the magnitude of the drop of ruminal pH below 5.8.



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Muddy conditions reduce hygiene and lying time in dairy cattle and increase time spent on concrete

Publication date: March 2017
Source:Journal of Dairy Science, Volume 100, Issue 3
Author(s): Jennifer M. Chen, Carolyn L. Stull, David N. Ledgerwood, Cassandra B. Tucker
Dairy cattle spend less time lying and show signs of increased stress when housed in rainy and windy conditions, but no work has separated the effects of exposure to inclement weather from muddy conditions underfoot. Our objective was to evaluate the effects of muddy conditions alone on lying behavior, hygiene, and physiological responses. We housed pairs of pregnant, nonlactating dairy cattle (n = 12; 6 primigravid heifers, 6 multiparous cows) in enclosed pens with dirt floors and a concrete feed apron. Cattle were exposed to 3 levels of soil moisture: 90 (dry), 74 (muddy), or 67% (very muddy) dry matter for 5 d each in a replicated 3 × 3 Latin square design. Lying time was measured on all days with data loggers, and lying locations and postures were recorded on the final day of each treatment. Before and after each treatment, blood samples were collected, and the percentage of dirty surface area was measured on the udder, hind leg, and side of each animal. Cattle spent less time lying down in muddier conditions, especially in the first 24 h of exposure, when cows and heifers spent only 3.2 and 5.8 h, respectively, lying down in the muddiest treatment compared with 12.5 and 12.7 h on dry soil. When the soil was dry, cattle never chose to lie down on concrete, but in muddier conditions they spent a greater proportion of their lying time on concrete (mean ± SE: 56 ± 14 and 10 ± 8% in the very muddy and muddy treatments, respectively). The shift in lying location was more marked for heifers, and all 6 spent ≥87% of their lying time on concrete in the muddiest treatment. When cattle chose to lie down on wetter soil, they limited the surface area exposed to their surroundings by tucking their legs beneath their bodies (mean ± SE: 30 ± 11, 15 ± 4, and 5 ± 2% of lying observations in the very muddy, muddy, and dry treatments, respectively). Despite cattle spending less time on wetter soil, all 3 measured body parts became dirtier in muddier conditions (1.4-, 1.6-, and 1.8-fold more on the leg, udder, and side, respectively, in the muddiest compared with the driest treatment). In addition, higher soil moisture levels resulted in greater reductions in white blood cell counts relative to baseline levels (−0.95, −0.43, and 0.34 × 10⁹/L relative to baseline levels in the very muddy, muddy, and dry treatments). Muddy conditions, even in the absence of wind or rain, are aversive for cattle and have negative implications for their welfare.



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Associations between housing and management practices and the prevalence of lameness, hock lesions, and thin cows on US dairy operations

Publication date: March 2017
Source:Journal of Dairy Science, Volume 100, Issue 3
Author(s): A.E. Adams, J.E. Lombard, C.P. Fossler, I.N. Román-Muñiz, C.A. Kopral
The objective of this study was to determine the association among different housing and management practices on the prevalence of lameness, hock lesions, and thin cows on US dairy operations. This study was conducted as part of the National Animal Health Monitoring System's Dairy 2014 study, which included dairy operations in 17 states. Size categories were assigned as follows: small (30–99 cows), medium (100–499 cows), and large (≥500 cows). Trained assessors visited 191 dairy operations from March through July 2014 and recorded locomotion and hock scores (on a 3-point scale), and the number of thin cows (body condition score ≤2.25) from a total of 22,622 cows (average 118 cows per farm). The majority of cows (90.4%) were considered to be sound (locomotion score = 1), 6.9% were mild/moderately lame (locomotion score = 2), and 2.7% were severely lame (locomotion score = 3). Similarly, most cows (87.3%) had no hock lesions (hock score = 1), 10.1% had mild lesions (hock score = 2), and 2.6% had severe hock lesions (hock score = 3). A low percentage of cows (4.2%) were thin. Univariate comparisons were performed using PROC LOGLINK, which accounts for study design and weighting. Variables meeting the univariate screening criterion of P < 0.20 were eligible for entry into multivariable models. Statistical significance in the multivariable models was declared at P < 0.05. Large operations had a lower within-herd prevalence of cows with locomotion score ≥2 and locomotion score = 3 compared with small or medium-sized operations. Operations on which cows were kept primarily on pasture had a lower percentage of locomotion score = 3 than those housed in freestall or open/dry lot operations. The use of sand bedding was associated with a lower within-herd prevalence of locomotion score ≥2 than straw/hay or dry/composted manure as the primary bedding material. Sand bedding was also associated with a lower within-herd prevalence of locomotion score = 3 than other bedding types except for rubber mats or mattresses. Operations that housed cows in an open/dry lot had a lower percentage of hock score ≥2 and hock score = 3 than other housing types. Providing sprinklers for heat abatement and having a nutritionist balance rations for cows was associated with a lower percentage of thin cows. Results from this study highlight management practices that may reduce the prevalence of lameness, hock lesions, and thin cows on dairy operations in the United States.



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Short communication: Characterization of Salmonella phages from dairy calves on farms with history of diarrhea

Publication date: March 2017
Source:Journal of Dairy Science, Volume 100, Issue 3
Author(s): Fernando Dueñas, Dácil Rivera, Viviana Toledo, Rodolfo Tardone, Luis P. Hervé-Claude, Christopher Hamilton-West, Andrea I. Moreno Switt
Salmonella enterica can cause disease and mortality in calves. This pathogen is also a zoonosis that can be transmitted by animal contact or by food. The prevalence of Salmonella in dairy farms has been reported to range from 0 to 64%, and, due to the diversity of Salmonella serovars that can be circulating, Salmonella is an important concern for dairy production. Bacteriophages that infect Salmonella have been documented to be abundant and widely distributed in the dairy environment. The current study investigated the diversity of Salmonella serovars and Salmonella phages in 8 dairy farms with a history of diarrhea in southern Chile. A total of 160 samples from sick calves, healthy calves, and the environment were analyzed for Salmonella and phage. Isolated phages were characterized and classified by their host range using a panel of 26 Salmonella isolates representing 23 serovars. Host ranges were classified according to lysis profiles (LP) and their spatial distribution was mapped. Salmonella-infecting phages were identified, but none of the 160 samples were positive for Salmonella. A total of 45 phage isolates were obtained from sick calves (11), healthy calves (16), or the environment (18). According to their host range, 19 LP were identified, with LP1 being the most common on all 8 farms; LP1 represents phages that only lyse serogroup D Salmonella. The identification of Salmonella phages but not Salmonella in the same samples could suggest that these phages are controlling Salmonella in these farms.



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Brain Atrophy in Multiple Sclerosis

Publication date: Available online 20 February 2017
Source:Neuroimaging Clinics of North America
Author(s): Jaume Sastre-Garriga, Deborah Pareto, Àlex Rovira

Teaser

There is evidence of a neurodegenerative process running in parallel with or as a consequence of the inflammatory phenomenon in multiple sclerosis (MS). MR imaging has been central in the generation of such knowledge and has played a pivotal role in investigating the neurodegenerative process. However, there is insufficient evidence supporting MR imaging–measured brain atrophy as a biomarker of the neurodegenerative component of MS in the daily care of patients with MS. This article discusses the prognostic value of brain volume measurements and their potential role in monitoring treatment response in patients with MS.


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Worry-inducing stimuli in an aversive Go/NoGo task enhance reactive control in individuals with lower trait-anxiety

Publication date: Available online 17 February 2017
Source:Biological Psychology
Author(s): Anja Leue, Carmen Cano Rodilla, André Beauducel
This study relates predictions on reactive and proactive cognitive control to findings on anxious apprehension/worry and ERN/Ne. We investigated whether worry-inducing stimuli in an aversive performance setting lead to a more pronounced increase of the ERN/Ne in individuals with lower anxious apprehension/worry. We also explored the N2 amplitude in the context of worry-inducing stimuli. Fifty-eight participants performed an extended Go/NoGo task. A neutral or fearful face was presented at the beginning of each trial, with the fearful face as a worry-inducing, distracting stimulus. In an aversive feedback condition, aversive feedback was provided for false or too slow responses. We found a more pronounced decrease of the ERN/Ne after worry-inducing stimuli compared to neutral stimuli in participants with lower anxious apprehension/worry. Moreover, less pronounced N2 amplitudes were associated with shorter reaction times in the aversive feedback condition. Implications for future research on error monitoring and trait-anxiety are discussed.



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Electro-clinical-etiological associations of epilepsia partialis continua in 57 Chinese children

Publication date: Available online 21 February 2017
Source:Brain and Development
Author(s): Hui Li, Jiao Xue, Ping Qian, Yuehua Zhang, Xinhua Bao, Xiaoyan Liu, Zhixian Yang
ObjectiveEpilepsia partialis continua (EPC) was one type of focal status epilepticus. The aim of this study was to analyze the clinical and electroencephalography (EEG) characteristics, and outcome of 57 child-onset patients with EPC according to different etiologies, and further explore the electro-clinical-etiological associations.MethodsWe retrospectively reviewed 57 children diagnosed with EPC in our department over last ten years. Etiology, clinical and EEG data, and outcome were categorized and analyzed.ResultsFor the 57 child-onset patients, EPC was caused by different etiologies, including immune-related disease (43.9%), focal lesions (17.5%), inborn errors of metabolism (24.6%), and unknown (14.0%). EEG background abnormalities showed generalized slowing in 45 patients (78.9%) and focal slowing in two patients (3.5%). Nineteen patients (33.3%) presented clear correlation of ictal EEG/EMG and the remaining 38 patients (66.7%) showed no clear correlation of ictal EEG/EMG. Both EEG background activity and ictal EEG/EMG correspondence among different etiologies had statistical significance (P<0.05). The ictal patterns without clear EEG/EMG correspondence in immune-related disease and the ictal patterns with clear EEG/EMG correspondence in focal lesions were more prominent (P<0.05).ConclusionThis is the first study of child-onset EPC with a large series in a pediatric epilepsy center in China. The most common cause for EPC was immune-related disease. The EEG background activity and the EEG/EMG correspondence might be influenced by the etiologies of EPC to some degree. These findings might guide the direction of EPC diagnosis in conjunction with other examinations.



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Prenatal and lactational bisphenol A exposure does not alter serotonergic neurons morphologically in the murine dorsal raphe nucleus

Publication date: Available online 21 February 2017
Source:Brain and Development
Author(s): Shoko Goto, Hiroshi Ogi, Shinji Fushiki, Kyoko Itoh
ObjectiveThere is concern that bisphenol A (BPA), an endocrine-disrupting chemical, affects brain development when exposed to a fetus and/or infant. We previously reported that increased serotonin (5-HT) and its metabolite (5-HIAA) in the dorsal raphe nucleus (DRN) in murine adult brains when they were prenatally exposed to low doses of BPA. This study investigates the morphological alteration of the dorsal raphe nucleus (DRN) in order to explain the disrupted serotonergic system after prenatal and lactational exposure to bisphenol A (BPA).MethodsThe murine dams were orally administrated with 500μg/kg/day of BPA from embryonic day 0 to postnatal 3weeks. The DRN, the main region of serotonin production, was morphometrically analyzed at 8weeks, using immunohistochemistry and image analysis combined with 3-dimensional reconstruction.ResultsNo significant differences were revealed in the number of tryptophan hydroxylase 2-immunoreactive neurons in any of the DRN sub-regions or the morphometric parameters, including the whole volume, ventrodorsal, longitudinal, and wing lengths of the DRN among the BPA treatment and sex groups.ConclusionsThe murine DRN was not morphologically affected by prenatal and lactational exposure to low doses of BPA. Further studies are necessary regarding the function of serotonergic neurons and the activity of different kinds of related receptors in the brain.



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Nonlinear Optical Properties of Colloids with Carbon Nanoparticles

Publication date: 2017
Source:Physics Procedia, Volume 86
Author(s): A.Yu. Mayor, D.Yu. Proschenko, S.S. Golik, I.V. Postnova, Yu.A. Shchipunov, A.A. Podlesnyh
Experimentally studied linear and nonlinear characteristics of colloid on the basis of a new class of carbon nanoparticles (CN) synthesized by hydrothermal synthesis. The spectral characteristics of supercontinuum of the colloids with CN in the range 420 - 700nm were investigated. The effectiveness of excitation of one- and two-photon fluorescence colloids with UN was determined. The anomalous dependence of the nonlinear refractive index of the wavelength of the radiation was revealed. It was installed that the efficiency of spectral transformation of the supercontinuum process in the case of colloid with carbon nanoparticles is less in the anti-stokes region than in case with water.



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Fabrication of fluorescent carbon dots-linked isophorone diisocyanate and β-cyclodextrin for detection of chromium ions

Publication date: Available online 20 February 2017
Source:Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy
Author(s): Jie Wang, Fengxian Qiu, Haiyan Wu, Xin Li, Tao Zhang, Xiangheng Niu, Dongya Yang, Jiangming Pan, Jicheng Xu
A water-soluble fluorescent carbon dots (FCDs) from cellulose was prepared using one-pot simple hydrothermal method. In this work, a novel fluorescent probe material, fluorescent carbon dots-linked isophorone diisocyanate and β-cyclodextrin (FCDs-IPDI-CD), was prepared with FCDs, isophorone diisocyanate (IPDI) and β-cyclodextrin (β-CD) as raw materials. The structure and morphology of FCDs-IPDI-CD were characterized using the Fourier transform infrared spectroscopy (FT-IR) and transmission electron microscopy (TEM). The as-prepared FCDs-IPDI-CD exhibits excellent emission property and high stability. The fluorescence of the FCDs-IPDI-CD could be quenched by Cr(VI) ions, and the results indicate that FCDs-IPDI-CD can be used as an effective fluorescent probe for the detection of Cr(VI) ions with good selectivity and sensitivity in an aqueous solution. The influences of environment factors (such as pH, reaction time) on relative fluorescence intensity were studied. According to the optimum conditions, a new sensitive method detecting Cr(VI) ions was established. The method has been successfully applied to detect Cr(VI) ions in water and soil samples with satisfactory results.



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Behavioral effects in adolescence and early adulthood in two length models of maternal separation in male rats

Publication date: 1 May 2017
Source:Behavioural Brain Research, Volume 324
Author(s): María Banqueri, Marta Méndez, Jorge L. Arias
Maternal separation (MS) is an extensively used early life stress model. There is some variability in the MS lengths used. Maternal separation leads to emotional and behavioral alterations such as anxiety, despair, or memory problems. We performed MS in Wistar rats with two length models from postnatal day 1 until day 10 and from postnatal day 1 until day 21 during 4h per day in both groups. We performed a test battery of a wide range of behaviors to measure anxiety, despair, prepulse inhibition, recognition memory, and associative memory both in adolescent and adult subjects. We found that the longer model leads to anxious behavior and impairs recognition in adolescence and adulthood whereas the shorter one deteriorates associative/emotional learning only in adolescence and protects against anhedonic-like behaviors. In our opinion, these results can be explained by the fact that different lengths lead to different profiles: the longer one is an anxious profile, whereas the shorter one is more impulsive.



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Activation of type 4 dopaminergic receptors in the prelimbic area of medial prefrontal cortex is necessary for the expression of innate fear behavior

Publication date: 1 May 2017
Source:Behavioural Brain Research, Volume 324
Author(s): Macarena D. Vergara, Victor N. Keller, José A. Fuentealba, Katia Gysling
The prelimbic area (PL) of the medial Prefrontal cortex (mPFC) is involved in the acquisition and expression of conditioned and innate fear. Both types of fear share several neuronal pathways. It has been documented that dopamine (DA) plays an important role in the regulation of aversive memories in the mPFC. The exposure to an aversive stimulus, such as the smell of a predator odor or the exposure to footshock stress is accompanied by an increase in mPFC DA release. Evidence suggests that the type 4 dopaminergic receptor (D4R) is the molecular target through which DA modulates fear expression. In fact, the mPFC is the brain region with the highest expression of D4R; however, the role of D4R in the expression of innate fear has not been fully elucidated. Therefore, the principal objective of this work was to evaluate the participation of mPFC D4R in the expression of innate fear. Rats were exposed to the elevated plus-maze (EPM) and to the cat odor paradigm after the intra PL injection of L-745,870, selective D4R antagonist, to measure the expression of fear-related behaviors. Intra PL injection of L-745,870 increased the time spent in the EPM open arms and decreased freezing behavior in the cat odor paradigm. Our results also showed that D4R is expressed in GABAergic and pyramidal neurons in the PL region of PFC. Thus, D4R antagonism in the PL decreases the expression of innate fear-behavior indicating that the activation of D4R in the PL is necessary for the expression of innate fear-behavior.



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Application of colon interposition among the esophageal cancer patients with partial gastrectomy

Qiuqiang Chen, Weimin Mao, Huanming Yu, Yixian Liang, Jiane Wang, Guoping Chen

Journal of Cancer Research and Therapeutics 2016 12(7):212-216

Background: Esophageal reconstruction with colon interposition is an alternative solution for the esophageal cancer patients who have partial gastrectomy. The aim of this study was to investigate the therapeutic effects of colon interposition among the esophageal carcinoma patients with partial gastrectomy. Materials and Methods: Under institutional review board approval, 32 esophageal carcinoma patients with a history of partial gastrectomy were included in this study. All the patients had been diagnosed and confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma by histopathological examination. Surgical approaches, complications and therapeutic results were analyzed in the current study. Results: Thirty-two esophageal carcinoma patients (29 men, 3 women, median age 63.2 years) were included in this study. Isoperistaltic colon interposition was carried out on 14 patients; their 1-year and 2-year survival rate was 92.9% and 78.6%, respectively. Antiperistaltic colon interposition was carried out on 18 patients; their 1-year and 2-year survival rate was 88.9% and 77.8%, respectively. In which, cervical anastomotic leakage was observed on six patients. Conclusion: Colon interposition is an ideal surgical approach for the esophageal carcinoma patients who had partial gastrectomy. Isoperistaltic colon interposition is preferred, but antiperistaltic colon interposition has the advantage that a longer colon can be used.

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Screening of gene mutations associated with bone metastasis in nonsmall cell lung cancer

Kun Zhang, Min Zhang, Jinlong Zhu, Wang Hong

Journal of Cancer Research and Therapeutics 2016 12(7):186-190

Objective: The objective of this study is to assess the gene mutation of advanced nonsmall cell lung cancer (NSCLC) patients with bone metastasis using next-generation sequencing (NGS), and screen for the driver genes which are associated with bone metastasis of lung cancer. Materials and Methods: Eight clinicopathologic samples from advanced NSCLC combined with bone metastasis patients were collected. Exome sequencing was conducted within 483 tumor-associated genes using Hiseq 2000_PE75 NGS platform. Results: Three thousand six hundred and twenty gene mutations were identified, including point mutation, insertion, and deletion. Among all genes associated with lung cancer signaling pathways, fibroblast growth factor receptor (FGFR), and cyclin-dependent kinase 12 (CDK12) were found to be mutated in all eight patients. The top three genes were FGFR, ataxia telangiectasia mutated, and CDK12, according to mutation frequency. In the meanwhile, hepatocyte nuclear factor 1 alpha, adenomatous polyposis coli, and CD22 were found to be mutated in all eight patients with an over 50% mutation frequency (75%, 62.5%, and 50%, respectively), which would be the most potential genes accounting for bone metastasis in lung cancer patients. Conclusion: Our findings shed light on several important signalling pathways involved in NSCLC, and suggest new potential molecular targets for treatment of NSCLC patients with bone metastasis.

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Evaluation of the safety and efficacy of percutaneous radiofrequency ablation for treating multiple breast fibroadenoma

Ping Li, Tang Xiao-yin, Dan Cui, Jia-chang Chi, Zhi Wang, Tao Wang, Xing-xing Qi, Bo Zhai

Journal of Cancer Research and Therapeutics 2016 12(7):138-142

Background: This study was conducted to evaluate the safety and efficacy of ultrasound (US)-guided percutaneous radiofrequency ablation (RFA) for multiple breast fibroadenoma as an alternative to surgical resection. Patients and Methods: Sixty-five patients with multiple breast fibroadenoma accepted general anesthesia and US-guided percutaneous RFA in our hospital from September 2014 to January 2016. Contrast-enhanced US (CEUS) was used immediately after operation to determine whether the tumor was ablated completely. The complete ablation rate (CAR) and the change of focal volume were evaluated by CEUS at the 1st month and the 3rd month after operation. Results: All the patients were diagnosed by needle biopsy. Among all the patients, 256 nodules were found. Forty-six nodules (17.96%) were located <5 mm from epidermis; 26 nodules (10.15%) were located below areola. Complete ablation was achieved for 251 nodules (98.04%) after the 1st month of operation. The volume reduce rate was 39.06% and 75.99% at the 1st and the 3rd month after operation, respectively, of which 45 nodules were completely absorbed (17.58%). There was a statistically significant difference of the volume reduction rate (VRR) after operation (P < 0.01) compared with preoperative breast nodules volume. There were no complications such as skin burn, hemorrhage, and hematoma, nipple discharge in the process during and after RFA. Conclusion: Given advantages of high CAR, mild injury, rapid recovery, and cosmetic outcome desired by the patients, RFA has the potential to become the preferred method in the treatment of breast fibroadenoma.

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Current mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and updated therapy strategies in human nonsmall cell lung cancer

Kaixian Zhang, Qianqian Yuan

Journal of Cancer Research and Therapeutics 2016 12(7):131-137

Lung cancer continues to be a major health problem and the most common cancer-related mortality worldwide with about 80%–85% patients suffering from nonsmall cell lung cancer (NSCLC). More than 80% of NSCLC cases are often diagnosed as advanced stage and harbor epidermal growth factor receptor (EGFR) activating mutation. Although great success in initial response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are found in EGFR-mutant NSCLC patients, acquired resistance usually occurs on the continuous treatment. Here, we provide an overview on the mechanism of acquired resistance to EGFR-TKIs in NSCLC therapy as well as current preclinical and clinical evidence of new therapy strategies and inhibitors in the treatment of NSCLC. Many studies have shown that original or induced T790M mutation, human EGFR 2 amplification, and activated secondary signaling such as MET amplification or phosphatidylinositol 3-kinase mutation can lead to acquired resistance to EGFR-TKIs. In addition, transformation from NSCLC to SCLC or conferred epithelial to mesenchymal transition has also been identified as mechanisms of acquired resistance to EGFR-TKIs. Increasing evidence has proven that non-coding RNA including long noncoding RNAs and microRNAs or new EGFR mutation is involved in acquired resistance. Preclinical and clinical Phase 1–3 evidence on combination drug therapy or new generation inhibitors with different tumor-targeting approaches have made those strategies the promising options for EGFR-TKI-resistant NSCLC therapy. This review aims to get deep insight into providing a state-of-the-art overview of the recent advances in the mechanisms of acquired resistance and new strategies for targeted cancer therapy in EGFR-TKI-resistant NSCLC.

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Laparoscopic combined with percutaneous ablation for hepatocellular carcinoma under liver capsule: A single Chinese center experience of thirty patients

Zhe Tang, Yi Zhu, Kezhong Tang, Linping Dong, Bin Yang, Heqin Fang, Yulian Wu, Bo Zhang

Journal of Cancer Research and Therapeutics 2016 12(7):143-147

Aim of Study: For the tumor lesions close to capsule of the liver, traditional percutaneous radiofrequency ablation (PRFA) is limited due to high incidence of postoperative complications. The aim of the present study is to whether laparoscopic combined with PRFA (LCPR) could effectively ablate the tumor lesions close to capsule of the liver. Methods: A total of 119 patients with subcapsular hepatocellular carcinoma (HCC) were divided into two groups: PRFA group (89 patients) and LCPR group (30 patients). RFA was accomplished through cool-tip RFA system. For LCPR, PRFA was first carried out to destroy tumors deep inside the liver tissue. Then, laparoscopic RFA was performed under the guide of laparoscopic view and destroyed the superficial part of the tumor. Postoperative morbidity and technique effectiveness between two groups were evaluated. Results: In PRFA group, the rate of fever was 70.8% (63/89), and two patients had gallbladder damage. Five patients had ascites. Pain was found in 26 patients (29.2%). In LCPR group, the rate of fever was 22/30 (73.3%). Two patients had ascites and only two patients complained of pain. In PRFA group, 77.5% (69/89) of the tumors were totally ablated, and in LCPR, 93.3% (28/30) of the tumors were destroyed without any residuals. Conclusion: LCPR could significantly reduce the incidence of postoperative pain and the rate of regional tumor residuals compared to the PRFA, suggesting this method could potentially be useful for subcapsular HCC ablation treatment.

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Comparison of perioperative outcomes between laparoscopic and open surgery for mid-low rectal cancer with total mesorectal excision following neoadjuvant chemoradiotherapy

Weiping Chen, Qiken Li, Pengnian Qiu, Lai Jiang, Zhixuan Fu, Yongtian Fan, Dechuan Li, Peng Liu, Lilong Tang

Journal of Cancer Research and Therapeutics 2016 12(7):199-204

Objective: The objective of our study was to determine the feasibility and safety of laparoscopic total mesorectal excision (TME) for mid-low rectal cancer following neoadjuvant chemoradiotherapy (nCRT). Methods: We retrospectively reviewed the records of 172 patients with locally advanced rectal cancer who underwent laparoscopic (n = 75) or conventional open (n = 97) surgery with TME following nCRT from June 2009 to October 2015. Perioperative outcomes and related clinical variables were collected and statistically analyzed. Results: Our results showed that patients who underwent laparoscopic surgery had significantly less blood loss and shorter time to pass first flatus and to start a liquid diet compared to those on open surgery. However, other perioperative outcomes, including operative times, postoperative morbidity rates, number of lymph nodes harvested, and sphincter preservation rates, were not significantly different between the two groups. After controlling for surgical approaches, we found that age, gender, tumor stages, and tumor distance to anal verge were significantly correlated with operative times in both groups. Likewise, age, body mass index, tumor T stages, and tumor distance to anal verge were predictors for postoperative morbidity in both groups. Conclusions: We concluded that laparoscopic TME following nCRT is feasible and safe for patients with mid-low rectal cancer. Furthermore, tumor distance to anal verge and age are two important determinants of both operative times and postoperative morbidity, regardless of surgical option.

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Analysis of therapeutic effectiveness and prognostic factor on argon-helium cryoablation combined with transcatheter arterial chemoembolization for the treatment of advanced hepatocellular carcinoma

Chen Huang, Weizhao Zhuang, Huigang Feng, Huizhuang Guo, Yukuan Tang, Hanwei Chen, Yi Huang

Journal of Cancer Research and Therapeutics 2016 12(7):148-152

Objective: The objective of this study was to evaluate the effectiveness on argon-helium cryoablation combined with transcatheter arterial chemoembolization (TACE) in treating advanced hepatocellular carcinoma (HCC) and its influence factor. Materials and Methods: This trial was approved by the Guangzhou Panyu Central Hospital Ethics Committee. This was a prospective, single-center study conducted in Guangzhou Panyu Central Hospital. After informed consent was obtained, the prospective randomized clinical data of 120 patients with advanced HCC were collected. Based on the therapeutic scheme, the patients were divided into control group (TACE + argon-helium cryoablation) and observed group (TACE group). All the patients were followed up for 60 months. The pre- and post-operative cancer situation, hepatic function situation, complete remission (CR) rate, total effective rate, and survival time were evaluated. The short-term and long-term effectiveness were compared between the two groups. Results: Both the CR rate and total effective rate of the combination group were significantly higher than those of TACE group (P < 0.05). Liver function damage of the combination group was lower than those of TACE group. The survival rate of the combination group was significantly longer than that of TACE group P < 0.05). The Cox regression model revealed that ages, tumor diameter, tumor periportal location, and liver function (Child-Pugh) were significant variables influencing survival time P < 0.05). Conclusion: For the treatment of advanced HCC, argon-helium cryoablation combined with TACE is obviously effective and safe. The ages, tumor diameter, tumor periportal location, and grade of liver function (Child-Pugh) have obvious impacted the treatment effectiveness.

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Percutaneous intraductal radiofrequency ablation combined with biliary stent placement for malignant biliary obstruction: A case report and review of the literature

Lijun Guan, Jianfeng Wang, Kun Gao, Renyou Zhai

Journal of Cancer Research and Therapeutics 2016 12(7):221-224

Percutaneous management of unresectable malignant biliary obstruction remains challenging. Biliary radiofrequency ablation (RFA) using the Habib EndoHBP catheter is a new palliation therapy for malignant biliary obstruction. We report our initial experience of RFA for the management of malignant biliary obstruction. A 58-year-old male was diagnosed with gallbladder cancer. Intraductal bipolar RFA was delivered at power of 10 W for 120 s, followed by stent placement. The patient had immediate stricture improvements after RFA. No severe adverse event occurred. Percutaneous RFA seems to be safe and feasible for the treatment of malignant biliary obstruction. Further studies are warranted.

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Effect of heat sink on the recurrence of small malignant hepatic tumors after radiofrequency ablation

Zheng-Yu Lin, Guo-Lin Li, Jin Chen, Zhong-Wu Chen, Yi-Ping Chen, Sun-Zhi Lin

Journal of Cancer Research and Therapeutics 2016 12(7):153-158

Aims: The aim of this study was to investigate the effect of heat sink on the recurrence of hepatic malignant tumors <3 cm after percutaneous radiofrequency ablation (RFA). Subjects and Methods: This study included 564 hepatic malignant tumors <3 cm in 381 patients. Preoperative images were used to determine whether these tumors were adjacent to vessels, and the diameter of adjacent vessels was measured. RFA was performed computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US) guidance, and postoperative imaging follow-up was then conducted. Statistical Analysis Used: SPSS software version 17.0 was used for data processing, and the χ2 test was used for comparative analysis. Two-sided P < 0.05 indicated statistical significance. Results: A total of 33 recurrences were found: 15 in the MR group (15/468), 12 in the US group (12/53), and 6 in the CT group (6/43). Of the 101 lesions adjacent to blood vessels larger than 3 mm, 20 showed recurrence: 10 in the MR group (10/77), 7 in the US group (7/17), and 3 in the CT group (3/7). The recurrence rate of perivascular lesions was higher than that of nonperivascular lesions, and the rate in the MR group was lower those in the US and CT groups. Conclusions: The curative effect of MRI-guided RFA is better than those of US- and CT-guided ablation. The heat sink effect is an important factor affecting recurrence of hepatic malignant tumors after RFA.

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Nimotuzumab treatment and outcome analysis in patients with leptomeningeal metastasis from nonsmall cell lung cancer

Yanfang Ju, Jinliang Wang, Shengjie Sun, Shunchang Jiao

Journal of Cancer Research and Therapeutics 2016 12(7):181-185

Objective: Leptomeningeal metastasis (LM) leades a devastating consequence in patients with nonsmall cell lung cancer(NSCLC). Treatment is very limited for patients with LM. We introduced to use nimotuzumab (also known as h-R3) combined with methotrexate for treating LM in NSCLC patients. Patients and Methods: In the present report, twenty patients with LM of NSCLC were included, and the clinicopathology information and outcomes after treatment were analyzed. Results: All the twenty patients with LM were lung adenocarcinoma. Thirteen patients had poor Eastern Cooperative Oncology Group performance status (≥ 3) before treatment, fifteen patients received combined administration of h-R3 and methotrexate, and another five patients received h-R3 treatment alone. The median survival time after the diagnosis of LM was 5 months (range, 2.4–7.6 months) for these twenty patients. The mean cerebrospinal fluid opening pressure was 270mmH2O before treatment and decreased significantly after treatment (140 mmH2O) (P < 0.001). Associated symptoms were relieved quickly after one or two cycles of intrathecal therapy. Conclusion: These findings indicated that nimotuzumab might be a potential drug for treatment of LM in NSCLC patients.

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Dosimetry study of three-dimensional print template-guided precision 125I seed implantation

Zhang Hongtao, Di Xuemin, Yu Huimin, Wang Zeyang, Zhang Lijuan, Zhao Jinxin, Liu Zezhou, Sui Aixia, Wang Juan

Journal of Cancer Research and Therapeutics 2016 12(7):159-165

Objective: This study aimed to compare the dose difference in 125 I seed implantation between three-dimensional (3D) print template-guided operation and traditional implantation. Materials and Methods: This study retrospectively analyzed 27 patients who underwent 125I seed implantation from August 2015 to December 2015 in Hebei General Hospital. Of these, 13 underwent seed implantation guided by a 3D print template, named the template group, and 14 underwent traditional implantation, named the traditional group. All patients underwent computed tomography (CT) scan. Then, 3D templates were printed in the template group. The implantation was guided by CT and 3D templates. The patients in the traditional group underwent implantation with free hands guided by CT scan. Postplan was performed after the operation. The dose-volume histogram, D90, and V90 were calculated. The D90 values pre- and post-operation were compared in each group. The postoperation V90 values of the two groups were also compared. Results: The mean D90 values pre- and post-operation in the template group were (87.09 ± 33.63) Gy and (85.31 ± 34.40) Gy, respectively, with no statistically significant difference. The mean D90 values pre- and post-operation in the traditional group were (86.04 ± 29.93) Gy and (74.96 ± 46.10) Gy, respectively, with a statistically significant difference. The mean V90 values postoperation in the template and traditional groups were (92.76% ± 1.89%) and (84.59% ± 7.56%), respectively, with a statistically significant difference. Conclusions: The postplan and preplan dose parameters of 3D print template-guided seed implantation were nearly consistent. The dose parameters of template group superior to the traditional group. The seeds can be implanted accurately with 3D print template.

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Evaluation and identification of factors related to KRAS and BRAF gene mutations in colorectal cancer: A meta-analysis

Li Lin, Guang-yong Chen, Chun-wei Xu, Hai-yan Wang, Yong-fang Wu, Mei-yu Fang

Journal of Cancer Research and Therapeutics 2016 12(7):191-198

Objective: The aim of this meta-analysis is to evaluate the distribution pattern of KRAS and BRAF mutations in colorectal cancer. Materials and Methods: The database was searched without language restrictions. Meta-analyses were conducted using the STATA software. We calculated the odds ratio (OR) and its 95% confidence interval (95% CI) to estimate the distribution of and correlation between KRAS and BRAF mutations, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) in left- and right-sided colorectal cancer. Results: The studies were divided into five groups: (1) distribution of KRAS/BRAF mutations in distal and proximal colorectal cancer, the summary OR value was 1.24 versus 4.03, (2) distribution of KRAS/BRAF mutations in CIMP-low/Neg and CIMP-high (CIMP-H) tumors, the summary OR value was 0.77 versus 10.49, (3) distribution of KRAS/BRAF mutations in MSI-low (MSI-L)/microsatellite stable (MSS) and MSI-high (MSI-H) tumors, the summary OR value was 0.51 versus 9.60, (4) proportion of CIMP-H/MSI-H tumors among distal and proximal colorectal tumors, the summary OR value was 3.66 versus 6.54, and (5) proportion of CIMP-H tumors among MSI-L/MSS and MSI-H tumors, the summary OR value was 5.87. Conclusion: The meta-analysis reveals that KRAS has a slightly higher mutation rate in MSI-L/MSS tumors. Moreover, BRAF mutations have higher detection rates in right-sided colorectal cancer, which suggests that BRAF mutations are likely in CIMP-H tumors. Therefore, based on these findings, the molecular diagnostic tests to be conducted in colorectal cancer patients can be determined according to the location/clinical features of the tumor.

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Changes of CD4+ T-cell subsets after radiofrequency ablation in lung cancer and its significance

Wang Shaobin, Xiong Yu, Lin Jiatian, Chen Zaizhong, Dai Luping, Chen Junhui

Journal of Cancer Research and Therapeutics 2016 12(7):166-170

Aims: To analyze the changes of CD4+ T-cell subsets following radiofrequency ablation (RFA) in lung cancer and the impact of RFA on the antitumor immunity. Subjects and Methods: Flow cytometry was employed to detect CD4+ T-cell subsets in the peripheral blood from 45 healthy controls and 45 lung cancer patients before and after RFA. The correlation between CD4+ T-cell subsets and the clinical characteristics was discussed by comparing the results between different groups. Results: Compared with the healthy controls, the lung cancer patients showed a decline in Th1 cells, but higher Th2, Th17, and Treg cells (P < 0.05). Th1 cell level and Th1/Th2 cell ratio were significantly lower for stage III/IV than Stage I/II and also lower for patients with Karnofsky Performance Status (KPS) score <60 than ≥ 60 (P < 0.05). The levels of Th2, Th17, and Treg cells were much higher for patients with Stage III/IV and KPS score <60 (P < 0.05). After 2 weeks of RFA, the level of Th1 cells and Th1/Th2 cell ratio increased, while the levels of Th2, Th17, and Treg cells declined (P < 0.05). For lesions with ablation volume ≥ 70%, the level of Th1 cells and Th1/Th2 cell ratio increased, whereas the levels of Th2, Th17, and Treg cells declined dramatically (P < 0.05). Conclusions: The level of Th1 cells declined in lung cancer patients, especially for patients with Stage III/IV and KPS score <60. After RFA, the level of Th1 cells and Th1/Th2 increased, whereas the levels of Th2, Th17, and Treg cells declined, indicating an improvement of antitumor immunity. The changes were more prominent for lesions with ablation volume ≥ 70%.

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The significance of transarterial chemoembolization combined with systemic chemotherapy for patients with KRAS wild-type unresectable metachronous colorectal carcinoma with liver metastases

Qiming Yu, Lusha Zhang, Sunfu Fan, Ling Huang, Xinbao Wang, Cai Xindun

Journal of Cancer Research and Therapeutics 2016 12(7):205-211

Purpose: The purpose of this study was to assess the survival benefits of transarterial chemoembolization (TACE) combined with systemic chemotherapy as the first-line treatment for metachronous unresectable colorectal carcinoma with liver metastases (CLMs) and to identify prognostic determinants. Patients and Methods: One hundred and fifty-four patients with KRAS wild-type metachronous unresectable CLMs were retrospectively collected from January 2006 to December 2014. Patients were divided into four groups according to treatment modality: 43 patients with chemotherapy alone (Group A), 39 patients with chemotherapy plus TACE (Group B), 38 patients with chemotherapy plus cetuximab (Group C), and 34 patients with chemotherapy plus TACE and cetuximab (Group D). We compared the rate of patients converted to resection for liver metastases (LMs), overall survival among these groups, and assessed prognostic factors. Results: The median interval time from resection of primary tumor to the diagnosis of CMLs was 12.0 months. The 1-, 3-, and 5-year survival rates and median survival time (MST) for all patients were 83.1%, 24.7%, 5.8%, and 22.9 months, respectively. Survival rates were significantly different in four groups at 1 year, 3 years, and 5 years with the MST of 17.5, 28.4, 18.9, and 30.3 months, respectively (P < 0.0001). The R0 resection rates for LMs were 7.0% in Group A, 30.8% in Group B, 10.5% in Group C, and 32.4% in Group D, which were statistically significantly different (P = 0.004). Univariate analysis revealed that posttreatment carcinoembryonic antigen serum level, tumor node (TN) stage, resection of LMs, tumor response, and treatment group were the significant prognostic factors. After adjusting the covariates in multivariate analysis, TN stage (hazard ratio [HR] = 1.394, 95% confidence interval [CI] = 1.027–1.893,P = 0.033), tumor response (HR = 2.901, 95% CI = 2.105–3.999,P < 0.0001), and treatment group (HR = 0.726, 95% CI = 0.594–0.887,P= 0.002) remained independent prognostic determinants. Conclusion: For patients with initially unresectable KRAS wild-type CLMs, chemotherapy plus TACE improved the resectability of LMs and survival compared with chemotherapy alone or chemotherapy plus cetuximab.

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Safety and feasibility within 24 h of discharge in patents with inoperable malignant lung nodules after percutaneous microwave ablation

Bin Li, Zhiwei Wang, Kang Zhou, Qinzong Gao, Xiaoguang Li

Journal of Cancer Research and Therapeutics 2016 12(7):171-175

Context: Minimally invasive interventional therapy is now the more effective treatment strategy for organ-confined malignancy in patients who are poor candidates for surgery. Microwave ablation (MWA) in lung malignancy has been receiving much attention as an effective minimally invasive approach. Aims: The aim of this study is to evaluate the safety and feasibility within 24 h of discharge of patients treated with percutaneous MWA for inoperable malignant lung nodules, and elucidate the factors predisposing to hospital readmission. Subjects and Methods: From September 2014 to April 2016, a total of eighty patients with inoperable malignant lung nodules who underwent 24 h of discharge following percutaneous MWA were consecutively enrolled in this retrospective study. Primary endpoints included the rate of short-term admission and procedure-related complications within 30 days of hospital discharge. The secondary outcomes included the rate of technical success and hospital readmission. Statistical Analysis Used: Student's t- test and Fisher exact test were used to analysis parametric and categorical variables accordingly. Results: The technical success was achieved in 94% of ablation sessions. Within 24 h of discharge was feasible in 73 cases (91.3%), and 7 (8.7%) required short-term admission. The complication rate was 27.5% (22/80), included the major 40.9% (9/22) and minor 59.1% (13/22) complications. Postoperative adverse event was 17.5% (14/80), these was managed conservatively. The lesion location and puncture technique were associated with an increased need for readmission. Conclusions: Routine 24 h discharge following percutaneous MWA for malignant lung nodules is safe and feasible, with relatively low complications and few requirements for short-term readmission.

http://ift.tt/2lhPlm1

Clinical study of transcatheter arterial chemoembolization combined with microwave ablation in the treatment of advanced hepatocellular carcinoma

Wei Li, Wenling Man, Huanqing Guo, Po Yang

Journal of Cancer Research and Therapeutics 2016 12(7):217-220

Objective: To evaluate the safety and efficacy of transcatheter arterial chemoembolization (TACE) combined with percutaneous microwave ablation (MWA) in the treatment of advanced hepatocellular carcinoma (HCC). Materials and Methods: Three thousand cases of advanced HCC patients were randomly divided into two groups: 1500 cases in the treatment group were treated with TACE combined with MWA and 1500 cases in the control group were treated with TACE. Results: The effective rate of the treatment group and control group was 71.4% and 42.8%, respectively, and the difference between the two groups was statistically significant (P < 0.05). During the follow-up period at 6, 12, 18, and 24 months postoperatively, the survival rates of the treatment group were 88.1%, 73.8%, 52.3%, and 33.3%, and the survival rates of the control group were 76.2%, 57.1%, 30.9%, and 9.5%, respectively. There was no significant difference in postoperative complications between the two groups. Conclusion: It is safe and effective to use TACE combined with MWA in the treatment of advanced HCC, and the effect of combined treatment is better than that of TACE alone.

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Iodine-125 radioactive seed tissue implantation as a remedy treatment for recurrent cervical cancer

Lei Han, Changlun Li, Junye Wang, Xueqi He, Xiao Zhang, Jundong Yang, Guofeng Liu

Journal of Cancer Research and Therapeutics 2016 12(7):176-180

Purpose: This study was designed to discuss feasibility, short-term efficacy, and complications of iodine-125 radioactive seed tissue implantation for remedying recurrent cervical cancer. Materials and Methods: From June 2009 to December 2010, 17 patients with recurrent cervical cancer received radioactive seed implantation under computed tomography (CT) guidance. Matched peripheral dose was 145 Gy, while the number of implanted seeds was from 6 to 68 with a median of 20. Efficacy was determined based on the results of CT and 18 F-fluorodeoxyglucose positron emission tomography/CT. Results: Postoperative follow-ups were from 4 to 18 months with a median follow-up time of 9.5 months. Nine patients died during follow-up while remaining patients survived during the follow-up period. Evaluation of efficacy: six patients had a complete response, four patients had a partial response, and seven patients had progressive disease, clinical efficacy rate as 58% (10/17). No patients had complications of radiation injury. Rate of 6 months and 1-year survival period was 74.8% and 18.3%, respectively. Comparing to patients who responded ineffectively to radioactive seed implantation, patients who responded effectively to radioactive seed implantation had a longer survival period (median 7.2 vs. median 10.4), in which the difference was statistically significant (P = 0.038). Conclusion: Iodine-125 radioactive seed tissue implantation is a feasible, effective, and safe treatment method for remedying or palliative treatment of recurrent cervical cancer. Patients who have recurrent cervical cancer and responded effectively to radioactive seed implantation will have a longer survival period.

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Postesophagectomy airway–gastric fistula successfully treated with subcutaneous fascia flap, tracheal reconstruction, and gastric fistula drainage: A case report and literature review

Changchun Wang, Xun Yang, Jianqiang Zhao, Qixun Chen

Journal of Cancer Research and Therapeutics 2016 12(7):225-227

Airway–gastric fistula (AGF) is a dreaded complication of esophagectomy for esophageal cancer. Its presentations and treatment approaches differ from individual to individual. Herein, we report the case of a patient with postesophagectomy AGF that was successfully treated with a subcutaneous fascia flap twisting trachea, and gastric fistula drainage. On reviewing the related literature, we consider that protecting the airway with living soft tissues and draining the mediastinum are the key steps for the surgical treatment of AGF. Airway stenting may be used as a temporary solution, and conservative therapy can be successful in some carefully selected cases.

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Immunostaining for High-Risk Human Papillomavirus in Condyloma Lesions in Immunocompromised Patients

Abstract

Background

Human papillomavirus (HPV) is the underlying infectious cause of condyloma acuminata (CA) and high-risk types of HPV can cause cancer. Condyloma may undergo malignant degeneration, particularly in immunosuppressed patients. The presence of high-risk HPV in CA is a risk factor for developing malignancy; however, determining which patients with condyloma are clinically at risk can be difficult. High-risk HPV can now be localized within CA using routine immunohistochemical stains.

Methods

We examined HPV (cocktail, 16, 18) immunohistochemical staining of CA and the relevant clinical history from immunocompromised patients and compared them with age- and sex- matched immunocompetent patients with biopsied CA.

Results

HPV was detected in 9 of the 12 specimens from immunocompromised patients (75%), and 6 of the 12 specimens from the age- and sex-matched comparison patients (50%). HPV-16 was detected in 7 of the 12 specimens from immunocompromised patients (58%), and 4 of the 12 specimens from comparison patients (33%). HPV-18 was not detected in any of the 21 specimens from immunocompromised or comparison patients for which the stain was available.

Conclusion

High-risk HPV is found within CA lesions, more often in immunocompromised patients, and confirming the presence of these HPV types with stains in high-risk patient populations may help guide the clinician in treatment and surveillance in certain cases.

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Pyoderma Gangrenosum: An Update on Pathophysiology, Diagnosis and Treatment

Abstract

Pyoderma gangrenosum (PG) is a rare inflammatory neutrophilic disorder with prototypical clinical presentations. Its pathophysiology is complex and not fully explained. Recent information regarding the genetic basis of PG and the role of auto-inflammation provides a better understanding of the disease and new therapeutic targets. PG equally affects patients of both sexes and of any age. Uncontrolled cutaneous neutrophilic inflammation is the cornerstone in a genetically predisposed individual. Multimodality management is often required to reduce inflammation, optimize wound healing, and treat underlying disease. A gold standard for the management of PG does not exist and high-level evidence is limited. Multiple factors must be taken into account when deciding on the optimum treatment for individual patients: location, number and size of lesion/ulceration(s), extracutaneous involvement, presence of associated disease, cost, and side effects of treatment, as well as patient comorbidities and preferences. Refractory and rapidly progressive cases require early initiation of systemic therapy. Newer targeted therapies represent a promising pathway for the management of PG, and the main focus of this review is the management and evidence supporting the role of new targeted therapies in PG.

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Analysis of Facial Expressions in Parkinson's Disease Through Video-Based Automatic Methods

Publication date: Available online 20 February 2017
Source:Journal of Neuroscience Methods
Author(s): Andrea Bandini, Silvia Orlandi, Hugo Jair Escalante, Fabio Giovannelli, Massimo Cincotta, Carlos A. Reyes-Garcia, Paola Vanni, Gaetano Zaccara, Claudia Manfredi
BackgroundThe automatic analysis of facial expressions is an evolving field that finds several clinical applications. One of these applications is the study of facial bradykinesia in Parkinson's disease (PD), which is a major motor sign of this neurodegenerative illness. Facial bradykinesia consists in the reduction/loss of facial movements and emotional facial expressions called hypomimia.New MethodIn this work we propose an automatic method for studying facial expressions in PD patients relying on video-basedmethods17 Parkinsonian patients and 17 healthy control subjects were asked to show basic facial expressions, upon request of the clinician and after the imitation of a visual cue on a screen. Through an existing face tracker, the Euclidean distance of the facial model from a neutral baseline was computed in order to quantify the changes in facial expressivity during the tasks. Moreover, an automatic facial expressions recognition algorithm was trained in order to study how PD expressions differed from the standard expressions.ResultsResults show that control subjects reported on average higher distances than PD patients along the tasks.Comparison with Existing MethodsThis confirms that control subjects show larger movements during both posed and imitated facial expressions. Moreover, our results demonstrate that anger and disgust are the two most impaired expressions in PD patients.ConclusionsContactless video-based systems can be important techniques for analyzing facial expressions also in rehabilitation, in particular speech therapy, where patients could get a definite advantage from a real-time feedback about the proper facial expressions/movements to perform.



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Planar Implantable Sensor for In Vivo Measurement of Cellular Oxygen Metabolism in Brain Tissue

Publication date: Available online 20 February 2017
Source:Journal of Neuroscience Methods
Author(s): Vassiliy Tsytsarev, Fatih Akkenti, Elena Pumbo, Qinggong Tang, Yu Chen, Reha S. Erzurumlu, Dmitri B. Papkovsky
BackgroundBrain imaging methods are continually improving. Imaging of the cerebral cortex is widely used in both animal experiments and charting human brain function in health and disease. Among the animal models, the rodent cerebral cortex has been widely used because of patterned neural representation of the whiskers on the snout and relative ease of activating cortical tissue with whisker stimulation.New MethodWe tested a new planar solid-state oxygen sensor comprising a polymeric film with a phosphorescent oxygen-sensitive coating on the working side, to monitor dynamics of oxygen metabolism in the cerebral cortex following sensory stimulation.ResultsSensory stimulation led to changes in oxygenation and deoxygenation processes of activated areas in the barrel cortex. We demonstrate the possibility of dynamic mapping of relative changes in oxygenation in live mouse brain tissue with such a sensor.Comparison with Existing MethodOxygenation-based functional magnetic resonance imaging (fMRI) is very effective method for functional brain mapping but have high costs and limited spatial resolution. Optical imaging of intrinsic signal (IOS) does not provide the required sensitivity, and voltage-sensitive dye optical imaging (VSDi) has limited applicability due to significant toxicity of the voltage-sensitive dye. Our planar solid-state oxygen sensor imaging approach circumvents these limitations, providing a simple optical contrast agent with low toxicity and rapid application.ConclusionsThe planar solid-state oxygen sensor described here can be used as a tool in visualization and real-time analysis of sensory-evoked neural activity in vivo. Further, this approach allows visualization of local neural activity with high temporal and spatial resolution.



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Diagnostic value of sleep stage dissociation as visualized on a 2-Dimensional sleep state space in human narcolepsy

Publication date: Available online 20 February 2017
Source:Journal of Neuroscience Methods
Author(s): Anders Vinther Olsen, Jens Stephansen, Eileen Leary, Paul E Peppard, Hong Sheungshul, Poul Jenum, Helge Sorensen, Emmanuel Mignot
BackgroundType 1 narcolepsy (NT1) is characterized by symptoms believed to represent Rapid Eye Movement (REM) sleep stage dissociations, occurrences where features of wake and REM sleep are intermingled, resulting in a mixed state. We hypothesized that sleep stage dissociations can be objectively detected through the analysis of nocturnal Polysomnography (PSG) data, and that those affecting REM sleep can be used as a diagnostic feature for narcolepsy.New MethodA Linear Discriminant Analysis (LDA) model using 38 features extracted from EOG, EMG and EEG was used in control subjects to select features differentiating wake, stage N1, N2, N3 and REM sleep. Sleep stage differentiation was next represented in a 2D projection. Features characteristic of sleep stage differences were estimated from the residual sleep stage probability in the 2D space. Using this model we evaluated PSG data from NT1 and non-narcoleptic subjects. An LDA classifier was used to determine the best separation plane.Comparison with existing methods:This method replicates the specificity/sensitivity from the training set to the validation set better than many other methods.ResultsEight prominent features could differentiate narcolepsy and controls in the validation dataset. Using a composite measure and a specificity cut off 95% in the training dataset, sensitivity was 43%. Specificity/sensitivity was 94%/38% in the validation set. Using hypersomnia subjects, Specificity/sensitivity was 84%/15%. Analyzing treated narcoleptics the Specificity/sensitivity was 94%/10%.ConclusionSleep stage dissociation can be used for the diagnosis of narcolepsy. However the use of some medications and presence of undiagnosed hypersomnolence patients impacts the result.



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Erratum to ‘Exploring and exploiting the systemic effects of deregulated replication licensing’ [Seminars in Cancer Biology 37–38C, (2016) 3–15]

Publication date: Available online 21 February 2017
Source:Seminars in Cancer Biology
Author(s): Theodoros G. Petrakis, Eirini-Stavroula Komseli, Marilena Papaioannou, Kostas Vougas, Alexandros Polyzos, Vassilios Myrianthopoulos, Emmanuel Mikros, Ioannis P. Trougakos, Dimitris Thanos, Dana Branzei, Paul Townsend, Vassilis G. Gorgoulis




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Roles of G protein-coupled estrogen receptor GPER in metabolic regulation

Publication date: Available online 20 February 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Geetanjali Sharma, Franck Mauvais-Jarvis, Eric R. Prossnitz
Metabolic homeostasis is differentially regulated in males and females. The lower incidence of obesity and associated diseases in pre-menopausal females points towards the beneficial role of the predominant estrogen, 17β‐estradiol (E2). The actions of E2 are elicited by nuclear and extra-nuclear estrogen receptor (ER) α and ERβ, as well as the G protein-coupled estrogen receptor (GPER, previously termed GPR30). The roles of GPER in the regulation of metabolism are only beginning to emerge and much remains unclear. The present review highlights recent advances implicating the importance of GPER in metabolic regulation. Assessment of the specific metabolic roles of GPER employing GPER-deficient mice and highly selective GPER-targeted pharmacological agents, agonist G-1 and antagonists G-15 and G36, is also presented. Evidence from in vitro and in vivo studies involving either GPER deficiency or selective activation suggests that GPER is involved in body weight regulation, glucose and lipid homeostasis as well as inflammation. The therapeutic potential of activating GPER signaling through selective ligands for the treatment of obesity and diabetes is also discussed.



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Testosterone rapidly increases Ca2+-activated K+ currents causing hyperpolarization in human coronary artery endothelial cells

Publication date: Available online 20 February 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Katesirin Ruamyod, Wattana B. Watanapa, Chairat Shayakul
Testosterone has endothelium-dependent vasodilatory effects on the coronary artery, with some reports suggesting endothelial ion channel involvement. This study employed the whole-cell patch clamp technique to investigate the effect of testosterone on ion channels in human coronary artery endothelial cells (HCAECs) and the mechanisms involved. We found that 0.03–3μM testosterone significantly induced a rapid, concentration-dependent increase in total HCAEC current (EC50, 71.96±1.66nM; maximum increase, 59.13±8.37%; mean±SEM). The testosterone-enhanced currents consisted of small- and large-conductance Ca²⁺-activated K⁺ currents (SKCa and BKCa currents), but not Cl⁻ and nonselective cation currents. Either a non-permeant testosterone conjugate or the non-aromatizable androgen dihydrotestosterone (DHT) could increase HCAEC currents as well. The androgen receptor antagonist flutamide prevented this testosterone, testosterone conjugate, and DHT effect, while the estrogen receptor antagonist fulvestrant did not. Incubating HCAECs with pertussis toxin or protein kinase A inhibitor H-89 largely inhibited the testosterone effect, while pre-incubation with phospholipase C inhibitor U-73122, prostacyclin inhibitor indomethacin, nitric oxide synthase inhibitor L-NAME or cytochrome P450 inhibitor MS-PPOH, did not. Finally, testosterone application induced HCAEC hyperpolarization within minutes; this effect was prevented by SKCa and BKCa current inhibitors apamin and iberiotoxin. This is the first electrophysiological demonstration of androgen-induced KCa current increase, leading to hyperpolarization, in any endothelial cell, and the first report of SKCa as a testosterone target. Our data show that testosterone rapidly increased whole-cell HCAEC SKCa and BKCa currents via a surface androgen receptor, Gi/o protein, and protein kinase A. This mechanism may explain rapid testosterone-induced coronary vasodilation seen in vivo.



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16-Dehydropregnenolone lowers serum cholesterol by up-regulation of CYP7A1 in hyperlipidemic male hamsters

Publication date: Available online 20 February 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Rachumallu Ramakrishna, Durgesh Kumar, Manisha Bhateria, Anil Nilkanth Gaikwad, Rabi Sankar Bhatta
16-dehydropregnenolone (DHP) has been developed and patented as a promising antihyperlipidemic agent by CSIR-Central Drug Research Institute (CSIR-CDRI), India. Although DHP is implicated in controlling cholesterol homeostasis, the mechanism underlying its pharmacological effect in hyperlipidemic disease models is poorly understood. In the present study, we postulated that DHP lowers serum lipids through regulating the key hepatic genes accountable for cholesterol metabolism. The hypothesis was tested on golden Syrian hamsters fed with high-fat diet (HFD) following oral administration of DHP at a dose of 72mg/kg body weight for a period of one week. The serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and total bile acids (TBA) in feces were measured. Real time comparative gene expression studies were performed for CYP7A1, LXRα and PPARα level in liver tissue of hamsters. The results revealed that the DHP profoundly decreased the levels of serum TC, TG, LDL-C and atherogenic index (AI), whilst elevated the HDL-C/TC ratio. Besides, DHP exhibited an anti-hyperlipidemic effect in the HFD induced hyperlipidemic hamsters by means of: (1) up-regulating the gene expression of CYP7A1 encoded cholesterol 7α-hydroxylase, that promotes the catabolism of cholesterol to bile acid; (2) inducing the gene expression of transcription factors LXRα and PPARα; (3) increasing the TBA excretion through feces. Collectively, the findings presented confer the hypolipidemic activity of DHP via up-regulation of hepatic CYP7A1 pathway that promotes cholesterol-to-bile acid conversion and bile acid excretion.

Graphical abstract

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STAR and AKR1B10 are down-regulated in high-grade endometrial cancer

Publication date: Available online 21 February 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Maša Sinreih, Saša Štupar, Luka Čemažar, Ivan Verdenik, Snježana Grazio-Frković, Špela Smrkolj, Tea Lanišnik Rižner
Endometrial cancer is the most frequent gynecological malignancy in the developed world. The majority of cases are estrogen dependent, and are associated with diminished protective effects of progesterone. Endometrial cancer is also related to enhanced inflammation and decreased differentiation. In our previous studies, we examined the expression of genes involved in estrogen and progesterone actions, in inflammation and tumor differentiation, in tissue samples from endometrial cancer and adjacent control endometrium. The aims of the current study were to examine correlations between gene expression and several demographic characteristics, and to evaluate changes in gene expression with regard to histopathological and clinical characteristics of 51 patients. We studied correlations and differences in expression of 38 genes involved in five pathophysiological processes: (i) estrogen-stimulated proliferation; (ii) estrogen-dependent carcinogenesis; (iii) diminished biosynthesis of progesterone: (iv) enhanced formation of progesterone metabolites; and (v) increased inflammation and decreased differentiation. Spearman correlation coefficient analysis shows that expression of PAQR7 correlates with age, expression of SRD5A1, AKR1B1 and AKR1B10 correlate with body mass, while expression of SRD5A1 and AKR1B10 correlate with body mass index. When patients with endometrial cancer were stratified based on menopausal status, histological grade, myometrial invasion, lymphovascular invasion, and FIGO stage, Mann-Whitney U tests revealed significantly decreased expression of STAR (4.4-fold; adjusted p=0.009) and AKR1B10 (9-fold; adjusted p=0.003) in high grade versus low grade tumors. Lower levels of STAR might lead to decreased de-novo steroid hormone synthesis and tumor differentiation, and lower levels of AKR1B10 to diminished elimination of toxic electrophilic carbonyl compounds in high-grade endometrial cancer. These data thus reveal the potential STAR and AKR1B10 as prognostic biomarkers, which calls for further validation at the protein level.

Graphical abstract

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TH1 and TH2 cytokines dataset in insulin users with diabetes mellitus and newly diagnosed breast cancer

Publication date: Available online 20 February 2017
Source:Data in Brief
Author(s): Zachary A.P. Wintrob, Jeffrey P. Hammel, George K. Nimako, Dan P. Gaile, Alan Forrest, Alice C. Ceacareanu
Exogenous insulin use may interfere with the T helper cells' cytokine production. This dataset presents the relationship between pre-existing use of injectable insulin in women diagnosed with breast cancer and type 2 diabetes mellitus, the T-helper 1 and 2 produced cytokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between T-helper cytokines stratified by of insulin use and controls is also provided.



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Dataset on granulopoiesis- and lymphopoiesis-stimulating cytokine levels in insulin secretagogue users with incident breast cancer

Publication date: Available online 20 February 2017
Source:Data in Brief
Author(s): Zachary A.P. Wintrob, Jeffrey P. Hammel, George K. Nimako, Dan P. Gaile, Alan Forrest, Alice C. Ceacareanu
GM-CSF and G-CSF are widely used for their benefit in reducing chemotherapy-associated neutropenia. However, whether GM- or G-CSF administration could have tumorigenic or pro-metastatic effects or whether insulin resistance could negatively impact such effects is not known. Their ability to stimulate monocyte production at the same time with the highly sought after neutrophils' production, enables an enhanced potential for activation of tumor-associated macrophages. At the same time, IL-7 remains the main driver of B and T cell differentiation and maturation, a process linked to the development of insulin resistance and response to diabetes pharmacotherapy.Insulin secretagogues have the potential to interfere with the hematopoiesis process, respectively with the formation of lineages that may lead to a tumorigenic or pro-metastatic phenotype, but this relationship has not been yet investigated. The data presented here shows the relationship between pre-existing use of insulin secretagogues in women diagnosed with breast cancer and type 2 diabetes mellitus, the GM-CSF, G-CSF and IL-7 cytokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between investigated cytokines stratified by secretagogue use and controls, and interferon is also provided.



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A novel arc heat treatment technique for producing graded microstructures through controlled temperature gradients

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): Vahid A Hosseini, Leif Karlsson, Kjell Hurtig, Isabelle Choquet, Dirk Engelberg, Matthew J. Roy, Chamara Kumara
This paper introduces a novel arc heat treatment technique to produce samples with graded microstructures through the application of controlled temperature gradients. Steady state temperature distributions within the sample can be achieved and maintained, for times ranging from a few seconds to several hours. The technique reduces the number of samples needed to characterize the response of a material to thermal treatments, and can consequently be used as a physical simulator for materials processing. The technique is suitable for conventional heat treatment analogues, welding simulations, multi-step heat treatments, and heat treatments with controlled heating and cooling rates. To demonstrate this technique, a super duplex stainless steel was treated with a stationary TIG arc, to confirm the relationship between generated steady-state temperature fields, microstructure development, hardness, and sensitization to corrosion. Metallographic imaging and hardness mapping provided information about graded microstructures, confirming the formation of secondary phases and microstructure sensitization in the temperature range 850–950°C. Modelling of temperature distributions and thermodynamic calculations of phase stabilities were used to simulate microstructure development and associated welding cycles.

Graphical abstract

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Structural effects in a composite nonwoven fabric on EMI shielding

Publication date: 15 April 2017
Source:Materials & Design, Volume 120
Author(s): Longsheng Lu, Di Xing, Kwok Siong Teh, Huilong Liu, Yingxi Xie, Xiaokang Liu, Yong Tang
A composite nonwoven fabric named CEF-NF in previous work was fabricated with carbon fibers (CFs) and polypropylene/polyethylene (PP/PE) core/sheath bicomponent fibers (denoted as ESFs). It holds great promise as an electromagnetic interference (EMI) shielding material, due to its good mechanical strength, excellent flexibility, ultra-thin thickness and remarkable electrical properties. This paper demonstrates a composite CEF-NF fabricated via two-step wet-papermaking/thermal-bonding processes. A flange coaxial test system was established to investigate the influences of material structure on EMI shielding effectiveness (EMI-SE) of CEF-NF fabrics in 30–1500MHz frequency range. Results indicate that the structure of a CEF-NF is highly correlated to its EMI-SE property, which increases with increasing areal density, fiber length and CF concentration. Under a set of optimal process parameters, the EMI-SE of CEF-NF with merely 40wt% of CF and 50g/m² areal density can achieve a specific overall EMI-SE as high as 30.29dB, or 110dB·cm³/g—meeting commercial EMI requirements. Lastly, the ideal and actual EMI shielding mechanism were fully investigated and analyzed. It was found that the electrical percolation threshold of CEF-NF had a great influence on the actual absorption and reflection performance. At the conductivity threshold, CEF-NF showed high absorption performance.

Graphical abstract

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Correlation between alpha phase morphology and tensile properties of a new beta titanium alloy

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): S. Sadeghpour, S.M. Abbasi, M. Morakabati, S. Bruschi
A novel beta titanium alloy Ti-4Al-7Mo-3Cr-3V (Ti-4733) was developed and the effect of its microstructure on the tensile properties was investigated and compared with the one of the commercial titanium alloy Ti-5553. Various alpha phase morphologies, namely globular, lamellar, acicular and a combination of them, were obtained as a result of the various heat treatments to which both the alloys were subjected. Although the alpha phase morphology for a given heat treatment was similar in both the alloys, the obtained microstructure was generally finer in the Ti-4733 alloy than in the Ti-5553 alloy, leading to enhanced tensile properties. The results showed that the microstructures with solely fine acicular alpha precipitates exhibited the highest tensile strength. While the highest reduction of area was derived in case of globular-acicular morphology, the maximum elongation was observed in microstructures containing lamellar-acicular alpha phase. Furthermore, for both the alloys the best balance between strength and ductility occurred in microstructures with a combination of globular and acicular alpha phase. The fractography analysis carried out on the tensile tested specimens showed a completely ductile fracture in case of globular-acicular morphology, ductile-transgranular brittle for lamellar-acicular morphology, and ductile-intergranular brittle for fully acicular α phase morphology.

Graphical abstract

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Effect of replacement of silica fume with calcined clay on the hydration and microstructural development of eco-UHPFRC

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): Wei Huang, Hadi Kazemi-Kamyab, Wei Sun, Karen Scrivener
In this paper, the replacement of high cost silica fume with calcined clay was investigated in UHPFRC mixes. The impact of two grades of calcined clay on the hydration and microstructural development of UHPFRC matrices was investigated, where 54% of the cement by volume has already been replaced by a limestone with similar PSD. It was seen that comparable mixes were obtained when silica fume was replaced with calcined clay by volume. The experimental results revealed a competition for water between the cement hydration and pozzolanic reaction of kaolinite to form more AFt and AFm phases, which affected the compressive strength development of the UHPFRC matrices. This competition is more pronounced in mixes where the kaolinite content increases in the calcined clay.

Graphical abstract

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Facile synthesis of Fe3O4@PPy core-shell magnetic nanoparticles and their enhanced dispersity and acid stability

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): Shun Tang, Qian Lan, Jiyuan Liang, Shengrui Chen, Chang Liu, Jinxing Zhao, Qi Cheng, Yuan-Cheng Cao, Jiyan Liu
We report a facile method to synthesize polypyrrole-coated Fe3O4 core-shell magnetic nanoparticles (Fe3O4@PPy). First, crude Fe3O4 nanoparticles were synthesized by co-precipitation approach. PPy layers were generated and deposited on the surface of Fe3O4via in-situ electropolymerization and electrodeposition, to construct core-shell structure nanoparticles. TEM observations showed the Fe3O4 nanoparticles changed from 15nm to 120nm in diameter after the PPy coating. The composition and morphology of Fe3O4@PPy nanoparticles were characterized by advanced spectroscopic and imaging techniques. The Fe3O4@PPy nanoparticles possess good dispersion property and acid stability in strong acid aqueous. The magnetic measurement at room temperature indicates that the Fe3O4@PPy nanoparticles exhibit superparamagnetic behavior, holding the saturation magnetization of 43.5emu/g. All the results show great potentials of the Fe3O4@PPy nanoparticles in wide range of applications.

Graphical abstract

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In situ analysis of the crystallization process of Sb2S3 thin films by Raman scattering and X-ray diffraction

Publication date: 5 May 2017
Source:Materials & Design, Volume 121
Author(s): Romain Parize, Thomas Cossuet, Odette Chaix-Pluchery, Hervé Roussel, Estelle Appert, Vincent Consonni
Sb2S3 thin films grown by chemical bath deposition have received increasing interest for its integration into solar cells. However, its crystallization by post-deposition annealing represents a major difficulty owing to its instability at relatively low temperature. We combine in situ Raman scattering at very low laser power with in situ X-ray diffraction over a broad range of annealing temperatures and durations under N2 atmosphere to elucidate its crystallization process on anatase-TiO2 layers. The thermally activated crystallization is found to systematically involve the intermediate formation of a metallic Sb phase and very often of a senarmontite cubic Sb2O3 phase, both of them vanishing prior to the formation of the stibnite Sb2S3 phase. Compact and continuous 150nm-thick Sb2S3 thin films with no pyramid-shaped clusters on their top surface are crystallized in the range of 240 to 270°C, namely below the commonly used annealing temperature of 300°C. Their texture is tunable from (420) and (520) to (020) and (200) planes parallel to the surface by raising the annealing temperature owing to a process of abnormal grain growth. The Sb2S3 thin films crystallized at the optimal annealing temperature of 270°C are composed of dense crystallites with a typical size of several tens of nanometers, which is of high interest for their integration into solar cells.

Graphical abstract

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Structure and electrical properties of pure and yttrium-doped HfO2 films by chemical solution deposition through layer by layer crystallization process

Publication date: 15 April 2017
Source:Materials & Design, Volume 120
Author(s): Hailong Liang, Jin Xu, Dayu Zhou, Xuexia Wang, Xiaohua Liu, Shichao Chu, Xiaoying Liu
Pure and yttrium doped HfO2 thin films were fabricated on Si (100) substrates by chemical solution deposition through a layer by layer crystallization process. We systematically investigated the effects of thickness and Y doped concentration on structure and electrical properties of the HfO2 films. Results revealed that 4nm thick undoped HfO2 was crystallized into a t/c-phase due to the surface energy effect, and this higher symmetry phase could be retained up to a film thickness of 16nm through the layer by layer crystallization process. This layer by layer crystallization process also required less Y doping to stabilize t/c-HfO2 in thick films. The films showed a high dielectric constant about 42, low leakage current density of about 10⁻⁷A/cm² (at 1MV/cm) and a breakdown field up to 5MV/cm. Considering the cost-effective deposition technique and good electrical properties, these films would be suitable for insulator applications in microelectronic devices.

Graphical abstract

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The interplay between morphology and photocatalytic activity in ZnO and N-doped ZnO crystals

Publication date: 15 April 2017
Source:Materials & Design, Volume 120
Author(s): Gabriela Byzynski, Camila Melo, Diogo P. Volanti, Mateus M. Ferrer, Amanda F. Gouveia, Cauê Ribeiro, Juan Andrés, Elson Longo
Intrinsic characteristics of the material such as superficial area, morphological structure, and crystalline phase exposition play a fundamental role in the corresponding reaction paths. However, especially in doped semiconductors, as ZnO:N, less is known about how the synthesis parameters affect the morphologies and the photocatalytic activity simultaneously. To solve this issue, ZnO and ZnO:N samples were obtained using microwave-assisted hydrothermal and modified polymeric precursor methods of synthesis. Samples morphologies were characterized by TEM and FE-SEM. Crystallographic phases were observed by XRD and optical characteristics by DRS. XPS results confirmed the doping process. Degradation of Rhodamine-B and Cr(VI) reduction were employed as probe reactions to investigate their photocatalytic activity. Although the crystallographic structure of these powders maintains the ZnO hexagonal wurtzite structure, the optical properties, morphologies, and photocatalytic activities present different behaviors. Also, density functional theory calculations were employed to determine the specific features related to electronic structure, morphology, and photocatalytic activity. Different synthesis methods produce a singular behavior in the physicochemical properties of materials, and the doping effect produces various modifications in RhB degradation and Cr(VI) reduction for each synthesis method. Crystal face exposition and morphologies are related to the improvement in the photocatalytic activity of the materials.

Graphical abstract

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Tyrosine kinase inhibition is an important factor for gene expression of CRTH2 in human eosinophils and lymphocytes: A novel mechanism for explaining eosinophils recruitment by the neuro-immune axis in allergic rhinitis

Publication date: April 2017
Source:International Immunopharmacology, Volume 45
Author(s): AE El-Shazly, P Roncarati, M Lejeune, PP Lefebvre, P Delvenne
We recently shown a novel neuro-immune competition between vasoactive intestinal peptide (VIP) and PGD2 for CRTH2 receptor, and that genistein augmented VIP and PGD2-induced eosinophil chemotaxis. However, there are neither studies on the CRTH2 gene expression in allergic rhinitis (AR) nor in the effect of tyrosine kinase inhibitors in CRTH2 gene regulation.Our Objectives were to study the gene expression modulation of CRTH2 receptor in AR patients and the effect of tyrosine kinase inhibitors (TKIs) on CRTH2 gene modulation. Nasal provocation tests, ELISA, qRT-PCR, western blot, flow cytometry and chemotaxis assays in modified micro-Boyden chambers, were all used, to achieve our objectives. Herein we show that AR patients increased the amounts of VIP and PGD2 in their nasal secretions in the early phase reaction, however CRTH2 gene expression from leukocytes recovered in their nasal secretions was upregulated only during the late phase reaction. The TKIs; Genistein, Erbstatin and Herbimycin A, induced the gene expression of CRTH2 and increased the protein content of CRTH2 in both human lymphocytes and eosinophils. This was functional as PGD2/VIP-induced eosinophil chemotaxis was augmented by the TKIs and inhibited by pervanadate, the tyrosine phosphatase inhibitor. These results open channels for therapeutic modalities targeting CRTH2 molecules in AR.



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Antioxidant activity and protective effect of suramin against oxidative stress in collagen induced arthritis

Publication date: 1 April 2017
Source:European Journal of Pharmaceutical Sciences, Volume 101
Author(s): Debasis Sahu, Shikha Sharma, Rajeev K. Singla, Amulya Kumar Panda
It is imperative to interrupt the link between arthritis and regulation of oxidative stress with the administration of antioxidants. Suramin is known for its anti-inflammatory, antineoplastic and antiangiogenic activities implying its possible antioxidant property. In this study, the antioxidant activity of suramin in cell free system was found to be higher than l-ascorbic acid (l-AA) with respect to its scavenging effect on nitric oxide (NO), hypochlorous acid and hydrogen peroxide radicals. Besides, suramin was found to be nontoxic to cultured RAW cells even at high concentrations along with marked inhibition of NO production. Suramin was found to curb the inflammation associated with the collagen induced arthritis (CIA) model. Administration of suramin significantly reduced the malondialdehyde and protein carbonyl content in joints, liver, kidney and spleen of rats as studied ex vivo. Furthermore, the increased antioxidant enzymes such as SOD, catalase, GST, GPx and GR activities in the tissues were restored significantly after suramin treatment. In silico experiments using Vlife MDS4.4-GRIP docking method showed strong affinity of suramin towards erythrocyte catalase followed by glutathione peroxidase thus corroborating with the findings of antioxidant enzyme assays. Our studies clearly indicate that suramin has remarkable antioxidant potential and can ameliorate arthritis via modulation of oxidative stress.

Graphical abstract

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Multifunctional LUV liposomes decorated for BBB and amyloid targeting. A. In vitro proof-of-concept

Publication date: 1 April 2017
Source:European Journal of Pharmaceutical Sciences, Volume 101
Author(s): Konstantina Papadia, Eleni Markoutsa, Spyridon Mourtas, Anastassios D. Giannou, Barabara La Ferla, Fransesco Nicotra, Mario Salmona, Pavlos Klepetsanis, Georgios T. Stathopoulos, Sophia G. Antimisiaris
Multifunctional LUV liposomes (mf-LIPs) were developed, having a curcumin-lipid ligand (TREG) with affinity towards amyloid species, together with ligands to target the transferrin and the LDL receptors of the blood-brain-barrier (BBB), on their surface. mf-LIPs were evaluated for their brain targeting, on hCMEC/D3 monolayers, and for their ability to inhibit Aβ-peptide aggregation. The transport of mf-LIP across hCMEC/D3 monolayers was similar to that of BBB-LIPs, indicating that the presence of TREG on their surface does not reduce their brain targeting potential. Likewise, mf-LIP inhibitory effect on Aβ aggregation was similar to that of LIPs functionalized only with TREG, proving that the presence of brain targeting ligands does not reduce the functionality of the amyloid-specific ligand. Addition of the curcumin-lipid in some liposome types was found to enhance their integrity and reduce the effect of serum proteins on their interaction with brain endothelial cells. Finally, preliminary in vivo results confirm the in vitro findings. Concluding, the current results reveal the potential of the specific curcumin-lipid derivative as a component of multifunctional LIPs with efficient brain targeting capability, intended to act as a theragnostic system for AD.

Graphical abstract

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Potential of amphiphilic graft copolymer α-tocopherol succinate-g-carboxymethyl chitosan in modulating the permeability and anticancer efficacy of tamoxifen

Publication date: 1 April 2017
Source:European Journal of Pharmaceutical Sciences, Volume 101
Author(s): Sunil K. Jena, Sanjaya K. Samal, Shamandeep Kaur, Mahesh Chand, Abhay T. Sangamwar
Recent studies showed an enhanced oral bioavailability of tamoxifen (TMX) by hydrophobically modified α-tocopherol succinate-g-carboxymethyl chitosan (Cmc-TS) micelles. As a continued effort, here we evaluated TMX-loaded polymeric micelles (TMX-PMs) for its enhanced permeability with increased anticancer efficacy and decreased hepatotoxicity. We employed co-solvent evaporation technique to encapsulate TMX into Cmc-TS. Apparent permeability assay of TMX-PMs was performed on Caco-2 cell line. The absorptive transport of TMX increased significantly about 3.8-fold when incorporated into Cmc-TS PMs. Cytotoxicity of Cmc-TS PMs was studied on MCF-7 cell line by MTT and; confocal microscopy was used for cellular uptake. Confocal microscopy revealed that Cmc-TS PMs could effectively accumulate in the cytosol of MCF-7 cell lines. In vitro data was further validated using N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model in Sprague-Dawley rats. Hepatotoxicity profiles of TMX-PMs at three different doses were also evaluated against the free drug TMX. TMX-PMs were more effective in suppressing breast tumor in MNU-induced mammary carcinoma model than free TMX with better safety profile. In addition, histological data shows that tumors are "benign" in TMX-PMs treated group compared with "malignant" tumors in free TMX treated and control groups. Overall, the results implicate that our Cmc-TS PMs may serve as a promising carrier for the intracellular delivery of anticancer drug molecules via oral route.

Graphical abstract

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Formulation and characterization of nanofibers and films with carvedilol prepared by electrospinning and solution casting method

Publication date: 1 April 2017
Source:European Journal of Pharmaceutical Sciences, Volume 101
Author(s): Marko Krstić, Marija Radojević, Dušica Stojanović, Vesna Radojević, Petar Uskoković, Svetlana Ibrić
The preparation and characterization of films and nanofibers with carvedilol as a poorly water-soluble drug in poly (ethylene oxide) (PEO) polymer were investigated. Films are prepared by solution casting method, and nanofibers by electrospinning from a polymer solution. Water and mixture of ethanol and water were used as solvents. FT-IR analysis of the samples showed that there was no interaction between the polymer and the drug substance. DSC analysis revealed that carvedilol was dissolved in the polymer and influenced the degree of crystallinity of PEO. Carvedilol release rate for all of the formulations was increased in comparison with pure carvedilol. Significant differences in the rate of release of carvedilol from the films and nanofibers were observed. Field Emission Scanning Electron Microscope (FESEM) images of the obtained fiber was revealed the dependence of the fiber diameter of formulation and electrospinning process parameters, and consequently influence the amount and distribution of carvedilol in the encapsulated fibers.

Graphical abstract

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Preparation, characterization and in vivo evaluation of a combination delivery system based on hyaluronic acid/jeffamine hydrogel loaded with PHBV/PLGA blend nanoparticles for prolonged delivery of Teriparatide

Publication date: 1 April 2017
Source:European Journal of Pharmaceutical Sciences, Volume 101
Author(s): Nika Bahari Javan, Hamed Montazeri, Leila Rezaie Shirmard, Nersi Jafary Omid, Ghullam Reza Barbari, Mohsen Amini, Mohammad Hossein Ghahremani, Morteza Rafiee-Tehrani, Farid Abedin Dorkoosh
In the current study, biodegradable PHBV/PLGA blend nanoparticles (NPs) containing Teriparatide were loaded in hyaluronic acid/jeffamine (HA-JEF ED-600) hydrogel to prepare a combination delivery system (CDS) for prolonged delivery of Teriparatide. The principal purpose of the present study was to formulate an effective and prolonged Teriparatide delivery system in order to reduce the frequency of injection and thus enhance patient's compliance. Morphological properties, swelling behaviour, crosslinking efficiency and rheological characterization of HA-JEF ED-600 hydrogel were evaluated. The CDS was acquired by adding PHBV/PLGA NPs to HA-JEF ED-600 hydrogel simultaneously with crosslinking reaction. The percentage of NPs incorporation within the hydrogel as well as the loading capacity and morphology of Teriparatide loaded CDS were examined. Intrinsic fluorescence and circular dichroism spectroscopy proved that Teriparatide remains stable after processing. The release profile represented 63% Teriparatide release from CDS within 50days with lower burst release compared to NPs and hydrogel. MTT assay was conducted by using NIH3T3 cell line and no sign of reduction in cell viability was observed. Based on Miller and Tainter method, LD50 of Teriparatide loaded CDS was 131.8mg/kg. In vivo studies demonstrated that Teriparatide loaded CDS could effectively increase serum calcium level after subcutaneous injection in mice. Favourable results in the current study introduced CDS as a promising candidate for controlled delivery of Teriparatide and pave the way for future investigations in the field of designing prolonged delivery systems for other peptides and proteins.

Graphical abstract

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Screening of inhibitors of angiotensin-converting enzyme (ACE) employing high performance liquid chromatography-electrospray ionization triple quadrupole mass spectrometry (HPLC-ESI-QqQ-MS)

Publication date: 1 April 2017
Source:European Journal of Pharmaceutical Sciences, Volume 101
Author(s): Syed Ghulam Musharraf, Muhammad Salman Bhatti, Muhammad Iqbal Choudhary, Atta-ur Rahman
Angiotensin-converting enzyme (ACE) plays a key role in regulating blood pressure in the body by converting the angiotensin I (AI) into angiotensin II (AII). Angiotensin II is a potent vaso-active peptide that causes arterioles to constrict, resulting in increased blood pressure. A rapid and sensitive method for the identification of inhibitors of ACE was developed, and optimized employing HPLC-ESI-QqQ-MS. In this assay, angiotensin I substrate was converted into the product angiotensin II with the catalytic action of ACE. A calibration curve for depleting concentration of angiotensin I was developed and linearity of R²=0.999 with a remarkably low concentration of substrate range 20–200nM. The limit of detection and quantification of angiotensin I was found to be 1.93 and 5.84nM, respectively. The enzymatic reaction was optimized for incubation time, concentration, and volume of enzyme and substrate. All reactions were performed at 37°C at pH7.5 with standard incubation time of 20min. Two standard inhibitors, Captopril and Lisinopril, were checked through the newly developed method for their inhibitory potential, and their IC50 values were found to be 3.969 and 0.852μM, respectively. Reproducibility and precision analysis of different experiments showed <9.9% RSD. The developed method can be used for the identification of new ACE inhibitors.

Graphical abstract

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Optimization of paeonol-loaded poly(butyl-2-cyanoacrylate) nanocapsules by central composite design with response surface methodology together with the antibacterial properties

Publication date: 1 April 2017
Source:European Journal of Pharmaceutical Sciences, Volume 101
Author(s): Jingjing Yao, Yangxin Zhang, Qiming Hu, Decheng Zeng, Fang Hua, Wei Meng, Weiyun Wang, Guan-Hu Bao
With the aim to enhance dissolution rate and bioavailability of paeonol, paeonol-loaded poly(butyl-2-cyanoacrylate) nanocapsules (Pae@PNCs) were prepared by interfacial spontaneous polymerization for the first time. Herein, a rotatable central composite design (RCCD) with three-factor five-level was applied to evaluate the optimization experiments. To the maximum percentage encapsulation efficiency (EE%) and minimum particle size (nm) of the Pae@PNCs, a quadratic polynomial model was generated to predict and evaluate the independent variables with respect to the dependent variables. RSM model goodness fitting were confirmed by the ANOVA Table (P<0.05) through variance analysis, which predicted values of EE (%) and particle size (R² and adjusted R² were close to 1, respectively) in good agreement with experimental values. By solving the regression equation and analyzing the response surface, three-dimensional model graphs and plots, the optimal result for the preparation of Pae@PNCs were found to be: pH (2.34), Poloxamer F-68 (0.80% m/v) and ethyl acetate/α-BCA ratio (16.67 v/v) for the highest EE% (73.58±2.76%) and the smallest particle size (42.06±1.20nm). The release profiles and antibacterial activity in vitro from the optimal Pae@PNCs were performed. The results indicated that it has slow and well-controlled release, and has strong antibacterial activity in vitro than paeonol. This understanding can help to predict the conditions of optimization of poly(butyl-2-cyanoacrylate) nanoparticles formation and to improve paeonol bioavailability and pharmacological properties.

Graphical abstract

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Identification of responsive proteins in Panonychus citri exposed to abamectin by a proteomic approach

Publication date: Available online 20 February 2017
Source:Journal of Proteomics
Author(s): Xiao-Min Shen, Rui Zhong, Wen-Kai Xia, Dong Wei, Tian-Bo Ding, Chong-Yu Liao, Jin-Zhi Niu, Wei Dou, Jin-Jun Wang
Abamectin is a microbial-derived pesticide widely used for control of agricultural pests. However, sustained use of abamectin has led to the development of resistance in some target species. Previous studies on arthropod resistance to abamectin have mainly used traditional biochemical and molecular approaches. To understand the responses of citrus red mite, Panonychus citri, exposed to abamectin, comparative proteomic analysis was conducted using two-dimensional electrophoresis (2-DE). A total of 26 distinct protein spots were present in response to abamectin exposure. Tandem mass spectrometry (MS/MS) identified 16 proteins that were mainly involved in energy metabolism and detoxification. Some remaining proteins were not identifiable, suggesting that they may be novel. The expression levels of transcripts associated with proteins were analyzed by quantitative reverse transcription PCR (qRT-PCR). Furthermore, to validate the proteomic data obtained in the present study, Western-blot experiment was performed and the expression of sHsp and PcE1 proteins were confirmed, respectively.Biological significanceThe citrus red mite has developed resistance to many acaricides, including abamectin. In the current study, we used the proteomic approaches involving 2-DE, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), and MS/MS to document changes in adult P. citri during 24h of abamectin exposure. Abamectin stress induced a total of 16 differentially regulated proteins. The proteomic results were validated in mRNA expression patterns using qRT-PCR. This is the first analysis of differentially expressed proteins in P. citri exposed to abamectin. The results help clarify the physiological mechanisms of P. citri responses to abamectin exposure.

Graphical abstract

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Is a “gut full” of bad bugs driving metabolic disease in shift workers?

Shift workers make up a significant proportion of the total workforce in industrialised countries, with about one in five employees working during night time hours.1 There is strong epidemiological evidence that these workers are at increased risk for developing obesity, type II diabetes, coronary heart disease, stroke and cancer.2 Furthermore, obesity can contribute to worsening of other conditions that are commonly suffered by shift workers such as sleep apnoea. The mechanisms that promote obesity and metabolic disease amongst shift workers are thought to arise from an imposed chronic disruption and misalignment between circadian rhythms, sleep cycles and eating patterns.

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