Emphasizing customer satisfaction as a strategic lever for enhancing business performance is a widespread business practice. However, just over 25 years of empirical studies by academic researchers ...has produced evidence that is sometimes contradictory. Hence, greater academic clarity and improved managerial understanding could result from a meta-analysis of the customer satisfaction-business performance relationship. To that end, the authors analyzed 251 correlations from 96 studies published between 1991 and 2017. While the satisfaction-performance relationship is positive and statistically significant on average (
r
= .101), more meaningful insights emerge from the explication of moderating and mediating relationships. Illustrative of these insights is the finding that satisfaction is more appropriately depicted as mediating the effects of selected marketing strategy variables on firm performance outcomes. Moreover, when satisfaction is viewed in the right setting using the right satisfaction and performance measures, a most favorable contingencies (MFC) perspective, the estimated correlation is reasonably strong (
r
= .349).
Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in ...males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor‐treating fields, delivering low‐intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood‐brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker‐enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.
Genomic aberrations of the PTEN tumour suppressor gene are among the most common in prostate cancer. Inactivation of PTEN by deletion or mutation is identified in ∼20% of primary prostate tumour ...samples at radical prostatectomy and in as many as 50% of castration-resistant tumours. Loss of phosphatase and tensin homologue (PTEN) function leads to activation of the PI3K-AKT (phosphoinositide 3-kinase-RAC-alpha serine/threonine-protein kinase) pathway and is strongly associated with adverse oncological outcomes, making PTEN a potentially useful genomic marker to distinguish indolent from aggressive disease in patients with clinically localized tumours. At the other end of the disease spectrum, therapeutic compounds targeting nodes in the PI3K-AKT-mTOR (mechanistic target of rapamycin) signalling pathway are being tested in clinical trials for patients with metastatic castration-resistant prostate cancer. Knowledge of PTEN status might be helpful to identify patients who are more likely to benefit from these therapies. To enable the use of PTEN status as a prognostic and predictive biomarker, analytically validated assays have been developed for reliable and reproducible detection of PTEN loss in tumour tissue and in blood liquid biopsies. The use of clinical-grade assays in tumour tissue has shown a robust correlation between loss of PTEN and its protein as well as a strong association between PTEN loss and adverse pathological features and oncological outcomes. In advanced disease, assessing PTEN status in liquid biopsies shows promise in predicting response to targeted therapy. Finally, studies have shown that PTEN might have additional functions that are independent of the PI3K-AKT pathway, including those affecting tumour growth through modulation of the immune response and tumour microenvironment.
Gliomas, the most common malignant primary brain tumours, remain universally lethal. Yet, seminal discoveries in the past 5 years have clarified the anatomy, genetics and function of the immune ...system within the central nervous system (CNS) and altered the paradigm for successful immunotherapy. The impact of standard therapies on the response to immunotherapy is now better understood, as well. This new knowledge has implications for a broad range of tumours that develop within the CNS. Nevertheless, the requirements for successful therapy remain effective delivery and target specificity, while the dramatic heterogeneity of malignant gliomas at the genetic and immunological levels remains a profound challenge.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has necessitated changes in cancer care delivery as resources are reallocated. Clinical trials and other research activities ...are inevitably impacted. Start-up activities for new trials may be deferred and recruitment suspended. For patients already enrolled however, there are challenges in continuing treatment on trial. Regulatory bodies have issued guidance on managing clinical trials during the pandemic, including contingency measures for remote study visits, delivery of investigational product, and site monitoring visits. New cancer clinical trial practices during the SARS-CoV-2 pandemic include new risk assessment strategies, decentralized and remote trial coordination, data collection, and delegation of specific therapeutic activities. This experience could provide evidence of more feasible and cost-effective methods for future clinical trial conduct.
Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) ...dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.
The last several years have seen revolutionary advances in DNA sequencing technologies with the advent of next-generation sequencing (NGS) techniques. NGS methods now allow millions of bases to be ...sequenced in one round, at a fraction of the cost relative to traditional Sanger sequencing. As costs and capabilities of these technologies continue to improve, we are only beginning to see the possibilities of NGS platforms, which are developing in parallel with online availability of a wide range of biological data sets and scientific publications and allowing us to address a variety of questions not possible before. As techniques and data sets continue to improve and grow, we are rapidly moving to the point where every organism, not just select “model organisms”, is open to the power of NGS. This volume presents a brief synopsis of NGS technologies and the development of exemplary applications of such methods in the fields of molecular marker development, hybridization and introgression, transcriptome investigations, phylogenetic and ecological studies, polyploid genetics, and applications for large genebank collections.
The ability to quickly discover reliable hits from screening and rapidly convert them into lead compounds, which can be verified in functional assays, is central to drug discovery. The expedited ...validation of novel targets and the identification of modulators to advance to preclinical studies can significantly increase drug development success. Our SaXPy
("SAR by X-ray Poses Quickly") platform, which is applicable to any X-ray crystallography-enabled drug target, couples the established methods of protein X-ray crystallography and fragment-based drug discovery (FBDD) with advanced computational and medicinal chemistry to deliver small molecule modulators or targeted protein degradation ligands in a short timeframe. Our approach, especially for elusive or "undruggable" targets, allows for (i) hit generation; (ii) the mapping of protein-ligand interactions; (iii) the assessment of target ligandability; (iv) the discovery of novel and potential allosteric binding sites; and (v) hit-to-lead execution. These advances inform chemical tractability and downstream biology and generate novel intellectual property. We describe here the application of SaXPy in the discovery and development of DNA damage response inhibitors against DNA polymerase eta (Pol η or POLH) and apurinic/apyrimidinic endonuclease 1 (APE1 or APEX1). Notably, our SaXPy platform allowed us to solve the first crystal structures of these proteins bound to small molecules and to discover novel binding sites for each target.
Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric ...symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.
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