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Mechanisms of Resistance to Kinase Inhibitors and Strategies to Prevent the Development of Drug Resistance

Targeting mutant proteins and associated signaling pathways of driver oncogenes by small molecule kinase inhibitors (KIs) are a promising strategy of cancer therapy. However, despite the initial success of treatment, KIs often become ineffective as intrinsic and acquired resistance. This article reviews the English-language literature to explore the underlying mechanisms of drug resistance and to present a challenge for developing drugs to overcome resistance. Mechanisms of acquired resistance include 1) the selection of pre-existing subclones with other mutations, 2) the emergence of secondary mutations in the target kinase domain, 3) upregulation of kinases both within the same kinase family and their related kinase families, as well as activation of alternative bypass pathways, 4) epithelial-mesenchymal transition, 5) overexpression of pro-survival Bcl-2 family proteins and 6) drug efflux mechanisms. Currently available methods are to obtain tumor biopsy samples at recurrence or progression if the tumor lesion is accessible to a biopsy and to use the second- and third-generation KIs based on the individual need of each patient. Furthermore, recent computational challenges provide design principles to prevent the development of drug resistance. In conclusion, we provide an overview of the postulated resistance mechanisms and highlight the future direction of computational structure-based design of new potent KIs.
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Giemsa Staining and Antibody Characterization of Colpodella sp. (Apicomplexa)

Colpodella species are free-living alveolates that possess an apical complex used for attaching to eukaryotic prey protists for ingestion of the cytoplasmic contents of the prey. Colpodella sp. are the closest relatives of the Apicomplexa, a phylum that includes the important human pathogens Plasmodium falciparum, Toxoplasma gondii and Cryptosporidium parvum. In this study, we investigated morphological characteristics of Colpodella (ATCC 50594) in a diprotist culture containing Bodo caudatus as prey in order to identify features differentiating both protists. The level of apical complex protein conservation among free living alveolate relatives of apicomplexans and intracellular apicomplexan pathogens is unknown. Antibodies against proteins of the apical complex in Colpodella sp. are currently unavailable. We performed staining and immunological characterization of Colpodella in a diprotist culture containing B. caudatus to aid routine differentiation of predator and prey in culture. Staining revealed distinguishing morphological features of both protists. The kinetoplast in B.caudatus was identified using Giemsa staining and was used to differentiate B. caudatus from Colpodella sp. trophozoites.
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A Randomized Double-Blind Placebo Controlled Clinical Trial Evaluating the Effects of an Investigational Study Product on Exercise Induced Muscle Soreness, Markers of Inflammation, Muscle Damage and Exercise Performance in Healthy Males

Gherkin, a pure botanical extract from cucumber is a phytonutrient rich vegetable which may have been shown to have anti-inflammatory and pain relieving properties. The purpose of this randomized double-blind placebo study was to determine the effects of Gherkin (Cuvitus™, Actido®)on exercise performance, markers of inflammation and acute muscle soreness in healthy males.
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The Case of Fetal Maceration in Two Different Bitches

Prenatal development consists of three stages in dogs. These stages are called preimplantation, embryonic and fetal period respectively. Embryonic or fetal losses may occur as a result of any causes that damage embryo or fetus during prenatal development period. These losses are called resorption, abortion, mummification and maceration according to the stage of pregnancy. Fetal maceration is often observed in cattle, but also can occur in other domestic animals. The incidence is quite low in bitches. The materials of this case were two bitches in different breeds that are Pointer and Golden retriever. They were brought to Clinics of Obstetrics and Gynecology by their owners with the complaints of growth in their abdomen, increase in weight and decrease in movements at different times. Firstly, detailed anamnesis was taken from their owners. As the mating status of both bitches is unknown, the probabilities of pregnancy and pregnancy pathologies have been neglected in the clinics previously referred to with the same complaints and both bitches were diagnosed with obesity by considering breed predisposition. In this context, it was learned that there was no treatment except for the suggestion of on low energy content foods and exercises however no healthy improvements were observed in both bitches. Gynecological, ultrasonography and radiographic examinations, whole blood and serum biochemistry analysis were performed on both bitches after anamnesis was taken. When the findings of the analysis and examination were evaluated, it was concluded that the fetuses were autolyzed in the uterus without being aborted. It was concluded to perform ovariohysterectomy operation on both dogs for treatment. When the removed uterus tissues were examined, it was seen that both bitches had fetal maceration.
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Is Metal Leakage from Aluminum Foil without Adverse Effects? A Study on Ants as Models

Aluminum is a metal largely present in many products used by humans (in vaccines, cosmetics, baby milk and packages for food among others). Such a presence is nowadays debated. Using ants as models, we showed that the presence of aluminum foil in their sugar water has effectively several adverse effects. It increased the ants’ general activity, sugar water consumption, sinuosity of locomotion, and decreased their meat consumption, audacity, tactile perception, cognition, ability in escaping from an enclosure, and their ability in acquiring conditioning, affecting thus their short and middle term memory.
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Assessment of the Efficacy, Safety and Cost-Effectiveness of Micafungin Compared to Caspofungin and Low Dose Liposomal Amphotericin B for the Treatment of Candidaemia and Clinically Diagnosed Invasive Candidiasis: A Retrospective Audit

Despite several studies having highlighted that candidaemia and invasive fungal disease (IFD) are associated with high mortality and increased costs, there are currently few published studies which provide an insight into real-life practice of invasive candidal diseases. In a medium-sized district general hospital in the UK we sought to compare the efficacy, safety and treatment cost of micafungin versus caspofungin and low dose of liposomal amphotericin B (L-AmB) 1mg/kg/day for the treatment of confirmed candidaemia or clinically diagnosed invasive fungal disease (CDIFD). In the present retrospective audit, a total of 126 patients with candidaemia or CDIFD were reviewed from hospital records and 94 were included in our audit.
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Gastric Partitioning Bypass Procedure: A Novel Technique in Bariatric Surgery

The current standard of care offers surgery as the most favored treatment modality for morbidly obese patients to achieve weight loss. The currently available surgical techniques have some limitations and introduction of novel techniques is inevitable. The aim of this study is to introduce the novel gastric partitioning bypass technique and assess its effectiveness and adverse effects.Thirty individuals were randomly recruited from a population who were eligible for bariatric surgery. The subjects had a baseline visit and were followed-up after surgery assessing weight loss and adverse effects related to the surgery.The study population included 30 patients (Mean age 41±5 and 93% female). Mean BMI and excess body weight at the baseline were 49±7 kg/m² and 79±15 Kg, respectively. Median follow-up time was 36 months and 27 (90%) patients completed the study. Excess weight loss was 54.76 ± 13.76 % and 60.43 ± 14.49% after 12 and 48 months, respectively. In post-operative period Two patients (6.6%) developed surgical site infection, other complications such as bleeding or anastomotic leakage, or any complication requiring emergent surgery were not detected.
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Tracing Echinococcosis in Portugal - The Role of the Abattoirs in North Douro Region

The occurrence of cystic echinococcosis (CE) at a national level or in large regional areas is an issue difficult to determine in a cost-effective way, integrating both human and animal data, and thus leading to effective control measures. In Portugal, the abattoirs in north Douro region receive a large percentage of heads of cattle from the whole country which makes them ideal places for the implementation of a surveillance system for this zoonosis. Data was obtained for cattle slaughtered in 9 abattoirs in north region of Douro River, with visible CE-like cysts at meat inspection. An excel database was constructed with the records of condemned viscera due to hydatid cysts in cattle for 2008, 2009, 2010, and the first half of 2011. Most of the cysts were found in the lungs and livers (23.5%), only in livers (21.5%) or only in lungs (18.1%). Individual information concerning each animal contributed to the depiction of a distribution map by regions of the occurrence of positive cases in Portugal. From the 149 cases registered, it was possible to identify the place of infection in 93 cases (62.4%), in which the rate of distribution was 21 (22.6%) in the north, 14 (15.1%) in the center, 57 (61.3%) in Alentejo and 1 case (1.1%) in Algarve. This distribution of cases coincides with the location of human and animal cases reported before, with special focus on the Alentejo and in the northeast of the country.
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Infantile Acute Generalized Pustular Psoriasis: A Case Report

Generalized pustular psoriasis (GPP) is an acute and uncommon form of psoriasis, representing about 3% of all psoriasis cases. Triggers may include streptococcical infections, emotional stress, vaccinations and exposure to medications such as penicillin. Systemic therapy is often necessary for GPP, since it may rapidly evolve, leading to significant and potentially fatal complications. Here, we describe the case of a 5-year-old male presenting with diffuse erythema, confluent scaly plaques and painful pustules localized on the trunk and limbs. Systemic manifestations such as fever, general lymphadenopathy and arthritis were also observed. To date, no standardized treatment guideline exists for infantile acute generalized pustular psoriasis. Our patient responded successfully to cyclosporine treatment within 4 weeks without any side effects. Thus, cyclosporine could be considered a useful agent in cases of pediatric GPP, keeping in mind its side effect profile in child population.
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Protocol for Root Canals’ Irrigation in Endodontic Practice in Ivory Coast: A Survey of 100 Dentists

In endodontics, a chemo-mechanical preparation is used to disinfect the root canal system. However, due to limitations of endodontic devices, which shape the main canal, this preparation is supplemented by irrigation solutions. In Ivory Coast, late consultations and advanced stages of pathologies characterized the endodontics.
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Scardovia Wiggsiae and the Other Microorganisms in Severe Early Childhood Caries

Severe early childhood caries (S-ECC) is an aggressive form of tooth caries in preschool children. New different bacteria were defined as associated with S-ECC. The aim of this study was to analysis the role of Scardovia wiggsiae and the other cariogenic microorganisms in S-ECC in Turkish children. Two same-sized groups of children were enrolled in the study: the first group consisted of 40 children with S-ECC (mean-age:52.93±11.5months), and the second group consisted of 40 caries-free children (mean-age:49.43±12.47months). The numbers of mutans streptococci, lactobacilli and yeasts were examined by culturing techniques, while the presences of S. wiggsiae, Streptococcus mutans, Streptococcus sobrinus, Actinomyces gerencseriae, Veillonella parvula, Fusobacterium nucleatum were examined by using 16S rRNA-based PCR technique in plaque samples. The prevalence of S. wiggsiae, S. mutans, A. gerencseriae, V. parvula and the numbers of mutans streptococci, lactobacilli, yeasts were found significantly high (P<0.05) in SECC. Also, the presence of S. wiggsiae with either S. mutans, A. gerencseriae, V. parvula or F. nucleatum were associated (P<0.01) with S-ECC. Understanding the effects of bacteria on initiation and progression of S-ECC will also help to improve protective and preventive treatments.
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Interrelation between Fluoride Content in Drinking Water and Dental Caries Prevalence Measured with DMF and ICDAS in Senegal

This study aimed to establish a correlation between the dental caries prevalence measured with the DMFT and ICDAS indexes and the rate of fluorine content in drinking water. A national dental caries prevalence data measured with ICDAS and DMFT indexes at several thresholds were correlated with the fluoride content of drinking water in several regions of Senegal. The dental caries prevalence was calculated based, distinctively, on the DMFT and ICDAS criteria. The variation of the rate of fluorine content in the drinking water of different regions was calculated according to the WHO reference rate. When the DMFT index is used, the dental caries prevalence correlates with the rate of fluor content in drinking water. But, when dental caries prevalence is measured with ICDAS, our results show that the rate of fluorine contained in drinking water does not affect the decayed teeth prevalence.
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Investigation on Silver Ion Release from Wound Dressings In Vitro and In Vivo

Introduction: In recent years, silver ion based dressings have been widely developed and approved in the market. Meanwhile, methods for selecting appropriate standard models to investigate the silver ion release in vitro and in vivo remains unknown with regard to the safety assessment.Methods and Results: In this study, we have identified that silver ion release in eagle minimum essential mediums(MEM) with 10% fetal calf serum had shown better release kinetics in comparison to other vehicles including simulated body fluid (SBF), 0.9% physiological saline, and 5% glucose.
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Gingival Stimulation: An Important Metabolic Regulator?

This study aimed to determine whether a relationship exists between gingival stimulation and the levels of leptin, ghrelin, insulin and glucose, which are important regulators of energy homeostasis. Blood samples for ghrelin, leptin, glucose and insulin were taken from 15 male volunteers (mean age 25.5±2.3 years; mean body mass index 24.4±2.79 kg/m2), who did not brush their teeth for one day, after a 12 h-long overnight fasting and before standard breakfast (0 min) and thereafter at 30, 60, 120 and 180 min after breakfast. After toothbrushing after dinner and after a 12 h-long overnight fasting, blood samples were taken again before standard breakfast (0 min) and then after at the same time points following tooth brushing.A significant reduction was found in the leptin levels measured at 0, 30, 60, 120 and 180 min after tooth brushing (p < 0.005). The ghrelin levels also declined at these time points but were significant at 0, 30 and 120 min (p < 0.05). Despite the reduced insulin levels at 120 and 180 min after tooth brushing (p < 0.05), no significant change was observed in the glucose levels.
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Biological Effect Tetra-Branched Anti-TNF-Peptide and Coating Ratio-Dependent Penetration of the Peptide-Conjugated Cerium3/4+ Cation-Stabilized Gamma-Maghemite Nanoparticles into Rat Inner Ear after Transtympanic Injection Visualized By MRI
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Ordered Growth of Anodic Aluminum Oxide in Galvanostatic and Galvanostatic-Potentiostatic Modes

The results are presented of obtaining anodic aluminum oxide with an ordered pore arrangement by employing two anodizing modes - galvanostatic mode and combined (galvanostatic + potentiostatic) mode, at high values of the current density and voltage. Use has been made of an oxalate electrolyte and a complex electrolyte comprising oxalic acid and phosphoric acid. Scanning electron microscopy has been used to investigate the surface morphology of the barrier and porous layers and to determine pore sizes and inter-pore distance.
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Electronic-nose Applications in Forensic Science and for Analysis of Volatile Biomarkers in the Human Breath

The application of electronic-nose (E-nose) technologies in forensic science is a recent new development following a long history of progress in the development of diverse applications in the related biomedical and pharmaceutical fields. Data from forensic analyses must satisfy the needs and requirements of both the scientific and legal communities. The type of data collected from electronic-nose devices provides a means of identifying specific types of information about the chemical nature of evidentiary objects and samples under investigation using aroma signature profiles of complex gaseous mixtures containing volatile organic compounds (VOCs) released from manufactured products and parts of the human body. E-nose analyses also provide useful qualitative information about the physicochemical characteristics and metabolic conditions of human subjects without the need for time-consuming analyses to identify all chemical components in human-derived volatile mixtures.
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Analysis of Sweat Simulant Mixtures using Multiplexed Arrays of DNA-Carbon Nanotube Vapor Sensors

Carbon nanotube (NT) based electronic vapor sensors were tested against synthetic sweat solutions, consisting of 13 volatile organic compounds (VOCs) in saline, in order to probe the device ability to analyze and differentiate vapors derived from complex biological samples.
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Characteristic Human Scent Compounds Trapped on Natural and Synthetic Fabrics as analyzed by SPME-GC/MS

The collection of human odor volatiles is of interest to forensic applications as a path to investigate canine scent discriminations in legal investigations. A study using a selected array of previously identified human odor compounds has been conducted to determine the retention and release capabilities of five (5) natural and synthetic fabric types, cotton (mercerized fabric and gauze matrix), polyester, rayon and wool.
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Preparation of Large Area Anodic Alumina Membranes and their Application to Thin Film Fuel Cell

The design of an electrochemical reactor for the preparation of self-supported comparatively thin (up to 10 μm) and large area (up to 50 cm2) anodic alumina membranes is described allowing growth of porous alumina at high applied potential (up to 150 V) without burning.
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Fabrication of Vertical Cu2ZnSnS4 Nanowire Arrays by Two-Step Electroplating Method into Anodic Aluminum Oxide Template

Vertical Cu2ZnSnS4 (CZTS) nanowire arrays have been synthesized via two-step electroplating method into anodized aluminum oxide template. For deposition of CZTS nanowires, anodized aluminum oxide (AAO) was used as the growth mask for the growth of the nanowires. AAO templates with hole sizes of 70 nm in diameter were used in the experiments.
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Fabrication and Luminescence of Anodic Alumina with Incorporated Vanadyl Citrate Chelate Anions

Anodic aluminum oxide doped with vanadyl citrate chelate complex anions was formed by a two-step self-organized anodization in 2 wt. % sulfuric acid containing 0.04 M V2O5 and 0.08 M citric acid at voltage range 13-23 V, and at 0 and 15 oC. The combination of two temperatures and at least four voltages (depending on the applied temperature) was applied as the operating conditions of anodization.
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Editorial Board Members Related to GA

Adolfo Antonio Gutiérrez

National University of Tucumán
School of Natural Sciences and IML

Chandan Saha

Associate Professor
Department of Biostatistics
School of Medicine
Indiana University
United states

J. Philip Boudreaux

Department of Surgery
Louisiana State University Health Sciences Center
United States

Guey-Jen Lee-Chen

Department of Life Science
National Taiwan Normal University

R. C. Gupta

Pro vice chancellor
Nagaland University

Shin-ichi Yusa

Associate Professor
Department of Materials Science and Chemistry
University of Hyogo


Associate Professor
Department of Pediatrics
The Icahn School of Medicine at Mount Sinai
United States

Vivek Tanavde

Principal Investigator
Bioinformatics Institute

Antonina Argo

Associate Professor
Department of Medical Biotechnology and Forensic Medicine
University of Palermo

Sobhy Mohamed Gomaa

Professor of Organic Chemistry
Faculty of Science
Cairo University
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