Impact of ABC transporters in osteosarcoma and ewing’s sarcoma: Which are involved in chemoresistance and which are not?

The ATP-binding cassette (ABC) transporter superfamily consists of several proteins with a wide repertoire of functions. Under physiological conditions, ABC transporters are involved in cellular trafficking of hormones, lipids, ions, xenobiotics, and several other molecules, including a broad spectrum of chemical substrates and chemotherapeutic drugs. In cancers, ABC transporters have been intensely studied over the past decades, mostly for their involvement in the multidrug resistance (MDR) phenotype. This review provides an overview of ABC transporters, both related and unrelated to MDR, which have been studied in osteosarcoma and Ewing’s sarcoma. Since different backbone drugs used in first-line or rescue chemotherapy for these two rare bone sarcomas are substrates of ABC transporters, this review particularly focused on studies that have provided findings that have been either translated to clinical practice or have indicated new candidate therapeutic targets; however, findings obtained from ABC transporters that were not directly involved in drug resistance were also discussed, in order to provide a more complete overview of the biological impacts of these molecules in osteosarcoma and Ewing’s sarcoma. Finally, therapeutic strategies and agents aimed to circumvent ABC-mediated chemoresistance were discussed to provide future perspectives about possible treatment improvements of these neoplasms

Total Synthesis of Asparenydiol by Two Sonogashira Cross-Coupling Reactions Promoted by Supported Pd and Cu Catalysts

Asparenydiol, which is an important natural compound with potential pharmacological activities, was synthesized through two Sonogashira cross-coupling reactions catalyzed by supported Pd and Cu catalysts and by a Mitsunobu etherification. The optimization of the Sonogashira couplings allowed the use of catalysts supported on different matrices with good results in terms of catalytic efficiency and yields

Successful implementation of inquiry-based physiology laboratories in undergraduate major and nonmajor courses. Adv Physiol Educ 32

Casotti G, Rieser-Danner L, Knabb MT. Successful implementation of inquiry-based physiology laboratories in undergraduate major and nonmajor courses. Adv Physiol Educ 32: 286-296, 2008; doi:10.1152/advan.00100.2007.-Recent evidence has demonstrated that inquiry-based physiology laboratories improve students' criticaland analytical-thinking skills. We implemented inquiry-based learning into three physiology courses: Comparative Vertebrate Physiology (majors), Human Physiology (majors), and Human Anatomy and Physiology (nonmajors). The aims of our curricular modifications were to improve the teaching of physiological concepts, teach students the scientific approach, and promote creative and critical thinking. We assessed our modifications using formative (laboratory exams, oral presentations, and laboratory reports) and summative evaluations (surveys, laboratory notebook, and an end of semester project). Students appreciated the freedom offered by the new curriculum and the opportunity to engage in the inquiry process. Results from both forms of evaluation showed a marked improvement due to the curricular revisions. Our analyses indicate an increased confidence in students' ability to formulate questions and hypotheses, design experiments, collect and analyze data, and make conclusions. Thus, we have successfully incorporated inquiry-based laboratories in both major and nonmajor courses. pedagogy; curriculum; evaluation INQUIRY-BASED LEARNING is an alternative pedagogical method of classroom teaching that is characterized by a focus on learning through discovery. It incorporates four approaches to teaching: 1) a focus on ideas and concepts generated by students rather than by instructors, 2) an activity component where students actively participate in performing tasks (experiments) to test their ideas, 3) an emphasis on learning the methods of verifying and testing hypotheses, and 4) an emphasis on the importance of both content and process as components of learning Some individual studies of the effectiveness of an inquirybased approach have been reported. For example, DiPasquale et al. (2) modified the curriculum in an exercise physiology course at San Diego State University. The course was previously taught in a traditional style. Their new approach was to cover core exercise physiology topics in the first third of the course using the traditional teacher-centered style of learning while emphasizing the scientific process. In the last 9 wk of the course, students worked in small groups of three to four and completed independent research projects. In contrast, Myers and Burgess (11) redesigned an organismal physiology course centering on student-designed experiments throughout the course of the semester. Both studies reported an increase in student achievement of learning outcomes using student-designed experiments compared with a teacher-centered approach. Moreover, a recent review (10) published in Advances of Physiology Education summarized the evidence supporting the conclusion that forms of active learning, such as an inquirybased approach, are more effective in enhancing student learning than traditional modes of teaching. Problems With the Existing Curriculum The physiology curriculum using a teacher-centered approach resulted in several problems related to student learning. One of the problems was that students in our nonmajor course failed to connect physiological concepts taught in lecture with the laboratory activities. In addition, the laboratories did not emphasize the scientific approach to problem solving, and students were restricted in the types of experiments they were able to perform (13). Our old curriculum provided students with detailed step-bystep instructions for completing their experiments. As a result, students commented to the laboratory instructors that they lost sight of the educational purpose of the experiments. Furthermore, regimented instructions did not allow our students any flexibility to deviate from the experimental protocol, thereby impeding student creativity Students had no opportunity to develop their own understanding of physiology using the scientific approach. Even though our majors were required to write laboratory reports in prerequisite courses such as Cell Physiology and Organic Chemistry, they did not communicate their ideas effectively in a scientific report. For example, students did not refer to the neural control of respiration when discussing irregular respiratory patterns when solving a math problem. This resulted in low scores on laboratory reports. Clearly, this called for the need to offer students more opportunities using the scientific method, from researching background information to developing a testable hypothesis using appropriate written communication and reporting of scientific findings. Similar problems in understanding the scientific approach were also evident in our nonmajor course (see Precurricula Survey). Verbal comments from students in our physiology courses indicated a dissatisfaction with simply repeating experiments that had already been done by other researchers. Students could not see the purpose of performing some of the experiments, especially those involving animals, and often asked "Why ar

Factors associated with paradoxical immune response to antiretroviral therapy in HIV infected patients: a case control study

<p>Abstract</p> <p>Background</p> <p>A paradoxical immunologic response (PIR) to Highly Active Antiretroviral Therapy (HAART), defined as viral suppression without CD4 cell-count improvement, has been reported in the literature as 8 to 42%, around 15% in most instances. The present study aims to determine, in a cohort of HIV infected patients in Brazil, what factors were independently associated with such a discordant response to HAART.</p> <p>Methods</p> <p>A case-control study (1:4) matched by gender was conducted among 934 HIV infected patients on HAART in Brazil. Cases: patients with PIR, defined as CD4 < 350 cells/mm³(hazard ratio for AIDS or death of at least 8.5) and undetectable HIV viral load on HAART for at least one year. Controls: similar to cases, but with CD4 counts ≥ 350 cells/mm³. Eligibility criteria were applied. Data were collected from medical records using a standardized form. Variables were introduced in a hierarchical logistic regression model if a p-value < 0.1 was determined in a bivariate analysis.</p> <p>Results</p> <p>Among 934 patients, 39 cases and 160 controls were consecutively selected. Factors associated with PIR in the logistic regression model were: total time in use of HAART (OR 0.981; CI 95%: 0.96-0.99), nadir CD4-count (OR 0.985; CI 95%: 0.97-0.99), and time of undetectable HIV viral load (OR 0.969; CI 95%: 0.94-0.99).</p> <p>Conclusions</p> <p>PIR seems to be related to a delay in the management of immunodeficient patients, as shown by its negative association with nadir CD4-count. Strategies should be implemented to avoid such a delay and improve the adherence to HAART as a way to implement concordant responses.</p

Structural modifications induced by adsorption of pharmaceuticals from water on Y organophilic zeolite

Domestic and commercial wastewaters contain a variety of organic wastewater contaminants such as pharmaceuticals and personal care products. These compounds undergo incomplete removal in wastewater treatment plants and they are found in the surface waters receiving the effluents of these plants. In the present work the removal of several drugs (which differ in chemical properties and molecular dimensions) from water by Y organophilic zeolite (SiO2/Al2O3 ratio equal to 200) was investigated. All selected drugs (erythromycine, carbamazepine, levofloxacin, hydrochlorothiazide, ketoprofene, diclofenac) are ubiquitous contaminants in the sewage waters, nor effectively removed by conventional activated sludge treatment and membrane bioreactors (MBRs). This study has a dual purpose: i) to measure the sorption capacity of hydrophobic commercial zeolite material weighed against drugs dissolved in water and to quantify aspects of their removal efficiency for potential use in wastewater and groundwater remediation, and ii) to understand the zeolite structure features for adsorption of drugs in aqueous solutions. Kinetics and adsorption isotherm batch data were obtained via HPLC-DAD. Breakthrough curves were obtained by using 0.2x2 cm SS column and a standard HPLC equipment. Powder diffraction patterns were measured on a Bruker D8 Advance Diffractometer equipped with Sol-X detector. Thermogravimetric (TG) and differential thermal analyses (DTA) measurements were performed in air up to 900C using a STA 409 PC LUXX® - Netzch at 10C/min heating. After adsorption, the X-ray diffraction patterns of untreated and exhausted samples show relevant differences both in the intensity and position of the diffraction peaks, indicating that the zeolite crystal structure was markedly modified by the pharmaceuticals adsorption experiment. Rietveld refinement demonstrated that the adsorption of the tested pharmaceuticals in Y zeolite induces strong unit cell parameter variations as well as remarkable distortion of the framework, thus confirming the adsorption of the drugs inside the channel system. The results of this study indicate that Y zeolite is an efficient materials for the removal of selected contaminants in wastewater remediation rate

Drug resistance in osteosarcoma: Emerging biomarkers, therapeutic targets and treatment strategies

Simple Summary Despite the adoption of aggressive, multimodal treatment schedules, the cure rate of high-grade osteosarcoma (HGOS) has not significantly improved in the last 30 years. The most relevant problem preventing improvement in HGOS prognosis is drug resistance. Therefore, validated novel biomarkers that help to identify those patients who could benefit from innovative treatment options and the development of drugs enabling personalized therapeutic protocols are necessary. The aim of this review was to give an overview on the most relevant emerging drug resistance-related biomarkers, therapeutic targets and new agents or novel candidate treatment strategies, which have been highlighted and suggested for HGOS to improve the success rate of clinical trials. High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40-50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed