Molecular determinants of sensitivity to poly(ADP-ribose) polymerase inhibitors in epithelial ovarian cancer

Less than half of patients with epithelial ovarian cancer (EOC) survive five years following diagnosis, underscoring the imperative need for improved treatment. Many patients, including those with advanced disease, initially respond to platinum agents, which constitute the backbone of therapy. However, tumors ultimately become resistant, rendering further treatment ineffective. Additionally, the poor tolerability of these agents warrants the exploration of more targeted treatments – one such strategy is exploiting synthetic lethal genetic relationships. Recent genomic sequencing efforts have revealed that as many of half of EOCs have homologous recombination (HR) alterations. HR is a critical pathway for the repair of platinum-induced ICLs, thus compromised HR is hypothesized to explain the initial response to chemotherapy in many patients. Accordingly, women whose tumors harbor mutations in the critical HR genes, BRCA1 or BRCA2 (BRCA1/2), demonstrate improved prognosis. BRCA1/2 mutations also confer exquisite sensitivity to inhibitors of the enzyme, poly(ADP-ribose) polymerase 1 (PARPis), hence loss of BRCA1/2 and PARP1 is synthetic lethal. A number of models have been proposed to explain this synthetic lethality, yet a consensus model that accounts for the diverse cellular roles of BRCA1/2 and PARP1 has yet to be established. Delineating the precise molecular underpinnings of PARPi action in BRCA1/2-deficient cells will aid clinicians in identifying the appropriate population of women with EOC likely to benefit from PARPi treatment and provide insight into resistance mechanisms that arise in these patients. Combining this approach with retrospective analysis of PARPi clinical trials will best define the proper indication for PARPi in EOC and other human cancers

Alexithymia, meaning, and well-being: how emotional processes relate to meaning in life and calling in career

2018 Summer.Includes bibliographical references.Emotional factors such as positive affect and empathy have been proposed as key factors influencing the constructs of meaning in life and calling in career. Alexithymia, or difficulty identifying and describing one's emotional experience, represents an emotional factor that has not been examined in relationship to either meaning in life or calling. This study used self-report measures to examine relationships between meaning in life, alexithymia, and psychological well- being along with relationships between calling, alexithymia, and career development well-being. Results revealed a significant, negative relationship between alexithymia and meaning in life. Furthermore, analyses provided evidence that meaning in life partially mediated the relationship between alexithymia and psychological well-being variables. The relationship between calling and alexithymia was non-significant. Results suggest that the ability to identify and describe one's emotions and discernment of meaning in one's life are linked and jointly influence psychological well-being. Limitations of the current study and implications for theory, practice, and future research are discussed

Gantry crane control of a double-pendulum, distributed-mass load, using mechanical wave concepts

© Author(s) 2013. This work is distributed under the Creative Commons Attribution 3.0 License.The overhead trolley of a gantry crane can be moved in two directions in the plane. The trolley is attempting to control the motion of a suspended, rigid-body, distributed mass load, supported by a hook, modelled as a lumped mass, in turn connected to the trolley by a light flexible cable. This flexible system has six degrees of freedom, four variables describing the flexible, hanging load dynamics and two (directly controlled) input variables for the trolley position. The equations of motion are developed and the crane model is verified. Then a form of wave-based control (WBC) is applied to determine what trolley motion should be used to achieve a reference motion of the load, with minimum swing during complex manoeuvres. Despite the trolley's limited control authority over the complex, flexible 3-D dynamics, WBC enables the trolley to achieve very good motion control of the load, in a simple, robust and rapid way, using little sensor information, with all measurements taken at or close to the trolley

Guide to Geographical Indications: Linking Products and Their Origins (Summary)

Geographical Indications present significant opportunities for differentiating products or services that are uniquely related to their geographic origin. While they can offer many positive economic, social, cultural, and even environmental benefits, they can also be problematic and therefore caution is warranted when pursuing them. The publication distills the relevant lessons that could apply, particularly to developing countries, from a review of more than 200 documents and a number of original Case Studies. It presents a groundwork to better understand the costs and the benefits of undertaking Geographical Indications by outlining the basic processes, covering the pros and cons of different legal instruments, and offering insights into the important factors of success. It reviews and presents current data on the key issues of global GIs such as: economic results, public and private benefits; and market relevance.Geographical Indications, developing country, marketing, local, traditional, culture, appellation, legal protection, Denomination of Origin