From bedside to bench: Use of patient-derived xenograft models to develop novel therapeutic strategies for triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a clinically aggressive disease that is associated with bleak outcomes due to its metastatic propensity, frequent failure to respond to chemotherapy, and lack of alternative treatment options. Despite decades of major translational research efforts, there has been very little success thus far in the development of effective targeted therapies for this disease. It is imperative to develop novel therapeutic strategies to improve patient outcomes, as well as minimize the toxicity associated with standard-of-care chemotherapeutics. Given that metastatic disease accounts for the vast majority of TNBC-related deaths, a better understanding of therapeutic responses within common sites of metastasis is crucial for developing effective treatment strategies. Given the molecular heterogeneity of TNBC, the clinical success of new therapies additionally depends on the identification of reliable drug targets within each TNBC subtype for more effective patient stratification. The studies presented herein sought to address these matters, using clinically relevant patient-derived xenograft (PDX) models to characterize chemotherapeutic efficacy in distinct metastatic sites, to identify promising targeted therapeutic candidates and combination strategies, and to assess the translational potential of these therapeutic strategies, with a focus on both the basal-like and luminal androgen receptor (LAR) subtypes of TNBC. We hypothesized that therapeutic efficacy in the primary tumor setting would be maintained in the metastatic setting, and that PDXs of distinct TNBC subtypes would respond to particular targeted therapies based on the distinct molecular pathways that drive their progression. We therefore expected that therapies targeting the epidermal growth factor receptor (EGFR) and the androgen receptor (AR) would have efficacy in basal-like TNBC and LAR TNBC, respectively, and would be ideal for incorporation into novel combination regimens for these specific disease subtypes. Using a combination of in vitro and in vivo drug response studies, we identified a drug combination, co-targeting EGFR and survivin, that was synergistic across multiple PDX models of basal-like TNBC, despite some of these models responding differently to standard chemotherapies, thus revealing potential pathways that may serve as reliable drug targets in this subset of patients. Furthermore, we identified several potential drug targets and therapeutic candidates for combination with AR-targeted therapies in LAR TNBC. In addition to identifying novel therapeutic strategies that have potential to provide clinical benefit for these subsets of TNBC patients, these studies highlight the utility of PDX models for in vitro and in vivo drug development studies, and demonstrate that the molecular and drug response profiles of primary tumors are maintained in the metastatic setting, indicating that studies employing PDX mammary tumor models can be applicable in advanced disease. Collectively, the data generated in these studies have the potential not only to directly provide clinical benefit for TNBC patients, but also to inspire and inform countless future research endeavors seeking to improve the therapeutic landscape in breast cancer

Homeless shelter food production: positive implications for clients and volunteers

Within the context of a longstanding project (Behavioral Activation Project in Homeless Shelters), the Shelter Farm was developed on the grounds of a homeless shelter located in a food desert. The Behavioral Activation Project, which represents a decade-long collaboration between a Professor of Psychology at the University of Dayton (Roger N. Reeb, Ph.D.) and St. Vincent de Paul (Dayton, Ohio), fosters self-sufficiency in shelter residents as they strive to overcome personal challenges and obstacles associated with homelessness. Past research shows that the Behavioral Activation Project enhances the psychological (and adaptive) functioning of shelter residents as well as the civic-related development of service-learning students who assist in implementing the Project. In 2017, Dr. Reeb (University of Dayton) established a collaboration with Ms. Mills-Wasniak (Extension Educator, The Ohio State University Extension Montgomery County) to develop the Shelter Farm at the St. Vincent de Paul Gettysburg Gateway Shelter for Men. A Memorandum of Understanding among the three collaborative entities was developed and approved. Shelter residents volunteered to work alongside service-learning students and community partners on the farm. In the first season, we harvested nearly a ton of produce – all of which was delivered to the shelter kitchen to enhance the nutrition of shelter residents. The Shelter Farm also enhanced St. Vincent de Paul’s budget for food, as we estimated wholesale value of the produce at almost $4,000. This same level of success was replicated in Shelter Farm’s second season. As we faced COVID-19 obstacles in the third season, safety protocols were approved by all three aforementioned collaborative entities, and we sustained the Shelter Farm, harvesting approximately 1500 pounds of produce for the shelters. In the first season, a graduate student in clinical psychology at the University of Dayton completed an M.A. Thesis providing preliminary evidence that, as shelter residents volunteer to work alongside students and community partners on the farm, they show decreases in state anxiety and improvements in wellness over time. This manuscript provides the following: (a) a description of the long-standing Project that provided the infrastructure for developing the Shelter Farm, (b) a description of the collaborative process underlying the initiative, the Shelter Farm itself, and the success in sustaining the Shelter Farm, even in the face of COVID-19; (c) an overview of the benefits (nutritional and psychological) of the Shelter Farm for shelter residents; and (d) plans for sustaining and expanding the Shelter Farm (and associated research)

Phenomenology and measurement of circumscribed interests in autism spectrum disorders

Circumscribed interests (CI) are important and understudied symptoms that affect individuals with autism spectrum disorders (ASD). The present study sought to develop quantitative measures of the content, intensity and functional impairment of CI in 50 children with high-functioning ASD compared to an age-, IQ-, and gender-matched sample of 50 typically developing (TD) peers. The Interests Scale, a parent-rating questionnaire, and the Interview for Repetitive Behaviors, a semi-structured interview, were used to assess CI. Groups did not differ on the number of interests children held, but they did differ on types of interests and impairment associated with them. The interests of ASD participants were more likely to be nonsocial in nature (e.g. mechanical systems) than TD participants. Parents of children with ASD endorsed higher degrees of functional impairment on metrics including frequency, interference, resistance when interrupted, flexibility, and accommodation required, as well as less involvement of other people, than parents of children with TD. These findings suggest that interests of individuals with ASD differ qualitatively and in intensity from individuals with TD. The present study offers further support for the notion that CI reflect a clinically significant feature of ASD that warrants intervention in some children

Children with autism demonstrate circumscribed attention during passive viewing of complex social and nonsocial picture arrays

Although circumscribed interests are a hallmark characteristic of autism spectrum disorders, providing a means for quantifying their functional impairment has proven difficult. We developed a passive viewing task to measure aspects of visual attention in children with autism spectrum disorders and typically developing controls. Task stimuli included picture arrays that were matched for social and nonsocial content. Nonsocial content was balanced to include items related to circumscribed interests (e.g., trains) as well as more commonplace items (e.g., furniture). Discrete aspects of gaze behavior were quantified using eye-tracking technology. Results indicate that visual attention in the autism group was more circumscribed (as indicated by the exploration of fewer images), more perseverative (as indicated by longer fixation times per image explored), and more detail oriented (as indicated by a greater number of discrete fixations on explored images). This pattern of results was similar for both social and object arrays. Within the autism group, overall severity of repetitive behavior symptoms correlated positively with exploration of object pictures and negatively with perseveration on social pictures. Results suggest that children with autism have a domain-general pattern of atypical visual attention that may represent an exaggeration of a typical attentional process and is related to a tendency to perseverate on images of interest and explore them in a more detail-oriented manner. Discrete measures of visual attention may therefore provide a reasonable means of quantifying aspects of the repetitive behavior phenotype in autism

Generativity Abilities Predict Communication Deficits but not Repetitive Behaviors in Autism Spectrum Disorders

Individuals with Autism Spectrum Disorders (ASD) often demonstrate impaired generativity that is thought to mediate repetitive behaviors in autism (Turner in J Child Psychol Psychiatry, 40(6):839–849, 1999a). The present study evaluated generativity in children with and without ASD via the use-of-objects task (Turner in J Child Psychol Psychiatry, 40(2):189–201, 1999b) and an Animals Fluency Task (Lezak in Neuropsychological assessment. Oxford University Press, Oxford, 1995). Groups differed significantly on two of four metrics from the Animals Fluency Task and two of seven metrics from the Use of Objects task. In the ASD sample, no significant relations were found between generativity and repetitive behaviors. Significant relations were found, however, between performance on the Animals Fluency Task and communication symptoms. Results replicate reports of generativity deficits in ASD and suggest that impaired generativity may reflect communication deficits that are characteristic of the disorder

Performance of Children with Autism Spectrum Disorders on the Dimension-Change Card Sort Task

Restricted and repetitive behaviors in autism spectrum disorders have been conceptualized to reflect impaired executive functions. In the present study, we investigated the performance of 6–17-year-old children with and without an autism spectrum disorder on a dimension-change card sort task that explicitly indicated sorting rules on every trial. Diagnostic groups did not differ in speed of responses after the first rule switch or in speed or accuracy on blocks with mixed versus single sort rules. However, performance of the ASD group was significantly slower and less accurate overall than the typically-developing group. Furthermore, within the ASD group, poorer DCCS task performance did not predict more severe autism symptoms. Implications for the executive dysfunction theory of autism are discussed

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass