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J. Riess, M. Redman, P. Wheatley-Price, B. Faller, L. Villaruz, Larry R. Corum, A. Gowda, G. Srkalović et al.

9024 Background: While prior studies have shown robust efficacy leading to FDA approval of PARP inhibitors (PARPi) in BRCA-associated cancers, data in NSCLC are much less clear. S1900A, a LUNG-MAP substudy, evaluated the PARPi rucaparib in advanced stage NSCLC harboring BRCA1/2 mutations or genomic loss of heterozygosity (LOH) as a phenotypic marker of homologous recombination deficiency (HRD). Methods: Eligible patients (pts) were required to have a deleterious mutation in BRCA1/BRCA2 and/or high (≥21%) genomic LOH. Key eligibility criteria: advanced NSCLC patients (pts) with progression on or after platinum based chemotherapy and/or PD-(L)1 antibody and progressed on most recent line of systemic therapy, a Zubrod performance status of 0-1, adequate organ function, no ≥ grade 3 hypercholesterolemia, no previous PARPi exposure and no systemic therapy within 21 days of registration. Pts stratified by histology into two cohorts (squamous [sq] and non-squamous/mixed histology [nsq]). With 40 eligible pts per cohort, the design had 91% power to rule out an ORR of 15% if the true ORR was at least 35% at the 1-sided 5% level. A planned interim analysis on the first 20 pts evaluable for response per cohort required ≥ 3 responses to proceed to full enrollment. Results: 64 pts enrolled (27 sq cohort; 37 nsq cohort) of whom 59 are eligible. Median age 65.7 yrs; M/F 33/26 (56/44%); 98% of the pts received at least 1 prior line of treatment for stage IV disease. Biomarker selection included 36 pts (61%) LOH only, 4 pts (7%) BRCA1 only, 11 pts (19%) BRCA2 only, 4 pts (7%) BRCA1 + LOH high and 4 pts (7%) BRCA2 + LOH high. Both cohorts were closed for futility with insufficient responses in the interim analysis populations. In the full study, 4 responses (3 nsq/1 sq) were reported. ORR was 7% (95% CI: 0-13) (9% nsq/4% sq) and DCR was 62% (95% CI: 50-75) (62% nsq/64% sq); 3 of the 4 responders harbored BRCA1/2 mutations and 1 of 4 high LOH; ORR in BRCA1/2+ pts 3/23 (13%). Median PFS was 3.2 months (95% CI: 1.6-4.6) in nsq cohort and 2.9 months (95% CI 1.6-6.2) in sq cohort. Median OS was 7.8 months in nsq cohort and 7.9 months in sq cohort. The most frequent grade ≥3 adverse events were anemia (22%), lymphopenia (8%), fatigue (8%) and transaminitis (5%). Conclusions: S1900A failed to show the requisite level of efficacy for rucaparib in advanced NSCLC pts with high genomic LOH and/or a BRCA1/2 mutation. There were no new safety signals and hematologic toxicities were the most frequent adverse events. Genomic LOH as a phenotypic marker of HRD does not predict sufficient activity of rucaparib in NSCLC. These results stand in contrast to the high level of efficacy of PARPi in patients with BRCA-associated or high LOH cancers of other tumor types. Underlying biologic differences in the genomic characteristics of these cancers vs. NSCLC may be responsible. Studies examining this premise are ongoing. (NCT03845296). Clinical trial information: NCT03845296.

Željko Stević, I. Tanackov, Adis Puška, G. Jovanov, Jovica Vasiljević, D. Lojaničić

To run a business successfully, quality determination and customer relations are very important factors. Therefore, it is necessary to measure quality and identify critical points of business. In this paper, an original integrated model for measuring the service quality of reverse logistics (RL) was developed for the company Komunalac Teslić, which was used as an example. The Delphi and Full Consistency Method (FUCOM) was applied to determine the significance of the quality dimensions, while a modified SERVQUAL (SQ) model was used to measure the service quality of the logistics. An original SQ questionnaire was formed with a total of 21 statements that were arranged in five standard dimensions. Examining the reliability of the questionnaire for quality dimensions using the Cronbach Alpha coefficient, it was found that the measurement scales for dimensions are appropriate in terms of user expectations, while in terms of quality perception there is no measurement scale for the empathy dimension. An extensive statistical analysis was then performed to verify the results. A Signum test was applied to identify the relationship between the responses in terms of expectations and perceptions, i.e., to examine their differences. The findings obtained by this research show that the expectations were higher than the perceived quality of the services and that there was a significant statistical difference for 12 of the SQ statements. For two statements, there was a significant statistical difference in favor of perceived quality compared to expectations. Based on the results obtained, the company must improve its services in order for service quality to be at a satisfactory level.

When reconstructing existing or constructing completely new intersections, the main problem is determining the type of future intersection. Capacity is one of the key indicators that influence the choice of traffic control type. In this paper, using different scenarios of theoretical traffic flow distributions and traffic volume scenarios, the authors have determined the applicability area of two-lane roundabouts. The results obtained were used to improve the existing applicability diagrams of the various intersection types presented in several issues of US Highway Capacity Manuals (US HCM). Capacity in each scenario is determined using HCM 2010 and Hagring methods with practically obtained values of the time gap acceptance parameters.

Building Information Modelling (BIM) is a relatively new technology. The industry, especially when it comes to infrastructure projects, is just beginning to realize the potential benefits of it. Large capital projects are being done today using BIM technology and standards, while in Bosnia and Herzegovina today, we do not have a project implemented by it. BIM is still exhibiting varying states of maturity among its participants. The research was carried out in B&H to realize perceptions of BIM in the infrastructures projects from the perspective of different participants (investor, consultant, designer, supervising engineer, contractor, supplier). The following aims are to demonstrate perception about BIM, the willingness to apply it, and different varying states of maturity among its participants and the current degree of application in practice

I. Lovrić, B. Čutura, T. Campisi, A. Canale, Marko Renčelj

In the first phases of study and design documentation of rural roads, one of the key parameters to determine in the analyses is the Design Hourly Volume (DHV). The required level of service and the feasibility of the project depend to a large extent on a properly established DHV. Essentially, the problem is to determine the value of the K-factor for a certain nth highest hour of the year. This paper points to the need for additional analysis of existing databases of long-term automatic traffic counting, from which the necessary guidance for planners and designers can be derived, enabling them to understand and apply the K-factors in a clearer and more detailed way. Using specific data examples, characteristic sections of rural roads with different functions and types (seasonal variations) of traffic demand were selected to show significant differences in the values of the K-factors for the same selected nth highest hour of the year. Several guidelines (BiH, Slovenia, Croatia, Italy, Serbia) were analysed beforehand to get a better understanding of how the K-factor or DHV is explained and used in different countries. The main objective of the article is to show that, on the basis of the existing databases of continuous automatic counting in these countries, with additional analyses presented in this paper or in a similar form, significant regularities in determining the DHV can be achieved, eliminating difficulties of application in engineering practice. As all guidelines practically recommend the use of HCM in capacity analyses, specific examples are selected to show the difference between the definition of HCM for a route with dominant recreational traffic and our route with dominant tourist traffic (recreational versus tourist).

R. Lee, D. Rothwell, S. Chow, H. Shaw, S. Turajlic, N. Smith, A. Clipson, H. Clarke et al.

TPS9587 Background: Circulating tumor DNA (ctDNA; the tumour derived fraction of circulating free DNA in the blood) has been shown to be a biomarker of tumor burden/progression in many cancers. We recently accurately monitored treatment response and resistance in stage IV melanoma by ctDNA analysis in serial peripheral blood samples. Pre-clinical data has previously revealed that BRAF inhibition provokes a micro-environment with increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines that could enhance immune responses. We aimed to test the hypothesis that ctDNA could be implemented as a personalised, real-time liquid biopsy to identify when tumours are responding to targeted therapy in order optimise a switch to immunotherapy. Methods: We validated the ctDNA assays for BRAF mutation calling as a primary trial endpoint. We designed a phase II multicenter, parallel arm study across 6 UK sites, to assess primary objectives of i). Whether a ctDNA result can be turned around within 7 days and actioned in a clinically relevant timeframe ii). to assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% from baseline on targeted therapy is an appropriate ‘cut off’ to instruct switching to immunotherapy. Secondary endpoints include Overall Response Rate (ORR) to immunotherapy, radiological/clinical and ctDNA determined progression free survival (PFS) on each treatment. Forty patients are planned based on inclusion criteria of stage IV or stage III unresectable cutaneous BRAF mutant melanoma, baseline ctDNA BRAF variant allele frequency (VAF) ≥1.5%, ECOG 0/1/2, no symptomatic brain metastases, no prior adjuvant nivolumab plus ipilimumab (N+I). Prior adjuvant dabrafinib + trametinib (D+T) is allowed as long as recurrence is >6 months from completion. Patients are randomised 1:1 to either standard Arm A; investigator choice of either D+T (150mg BD +2mg OD respectively) or N+I (1 mg/kg N +3 mg/kg I q3 wkly, then N 480mg q4 wkly) first line, then switch on progression to the other treatment. In the experimental Arm B; all patients start on D+T and have BRAF ctDNA monitored q2 wkly for 4 wks then q4 wkly. When ≥80% decrease vs. baseline in ctDNA BRAF VAF occurs, patients switch to N+I. If patients subsequently progress on N+I, they will resume D+T. The study is open with 9 patients enrolled at time of submission. Clinical trial information: NCT03808441.

Chaolan Lin, S. Šabanović, L. Dombrowski, Andrew D. Miller, Erin L. Brady, K. Macdorman

Parent–child story time is an important ritual of contemporary parenting. Recently, robots with artificial intelligence (AI) have become common. Parental acceptance of children’s storytelling robots, however, has received scant attention. To address this, we conducted a qualitative study with 18 parents using the research technique design fiction. Overall, parents held mixed, though generally positive, attitudes toward children’s storytelling robots. In their estimation, these robots would outperform screen-based technologies for children’s story time. However, the robots’ potential to adapt and to express emotion caused some parents to feel ambivalent about the robots, which might hinder their adoption. We found three predictors of parental acceptance of these robots: context of use, perceived agency, and perceived intelligence. Parents’ speculation revealed an uncanny valley of AI: a nonlinear relation between the human likeness of the artificial agent’s mind and affinity for the agent. Finally, we consider the implications of children’s storytelling robots, including how they could enhance equity in children’s access to education, and propose directions for research on their design to benefit family well-being.

Damir Kapidžić, O. Komar

Abstract This article examines the role of ethnicity and ethnic parties as stabilizing factors in Southeast European party systems. It compares two ethnically divided countries in Southeast Europe: Bosnia and Herzegovina, where ethnic identities that form the political cleavage are firm, and Montenegro, where they are malleable. Theoretically, it addresses the debate between scholars who either find stability or instability in East European post-communist party systems. The article traces the role of ethnicity in the formation and development of electoral contests and compares the two cases by utilizing measures of block volatility, based on analysis of official electoral data. We argue that party systems in ethnically diverse countries are stable at the subsystems level, but unstable within them. In BiH, firm ethnic identity stabilizes the party system by limiting competition between blocks, leading to closure. Malleable ethnic identity in Montenegro opens competition to non-ethnic parties seeking to bridge ethnic divisions, leading to more instability. We find that party system dynamics in ethnically divided new democracies depend on identity rigidity and cleavage salience, in addition to levels of heterogeneity.

Anassuya Ramachandran, Merima Mehić, Laabiah Wasim, D. Malinova, Ilaria Gori, B. Blaszczyk, Diana M. Carvalho, E. Shore et al.

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are debilitating diseases that share causal mutations in ACVR1, a TGF‐β family type I receptor. ACVR1R206H is a frequent mutation in both diseases. Pathogenic signaling via the SMAD1/5 pathway is mediated by Activin A, but how the mutation triggers aberrant signaling is not known. We show that ACVR1 is essential for Activin A‐mediated SMAD1/5 phosphorylation and is activated by two distinct mechanisms. Wild‐type ACVR1 is activated by the Activin type I receptors, ACVR1B/C. In contrast, ACVR1R206H activation does not require upstream kinases, but is predominantly activated via Activin A‐dependent receptor clustering, which induces its auto‐activation. We use optogenetics and live‐imaging approaches to demonstrate Activin A‐induced receptor clustering and show it requires the type II receptors ACVR2A/B. Our data provide molecular mechanistic insight into the pathogenesis of FOP and DIPG by linking the causal activating genetic mutation to disrupted signaling.

E. Salkić, B. Salkić, Amela Hercegovac, A. Avdić, Azra Dorić, E. Imširović

Aims: The basic precondition for apple breeding is the genetic diversity of varieties, which implies a large number of different, positive genes that enable adaptation to different weather conditions, resistance to new diseases and pests. One of the reliable sources of genetic diversity are indigenous varieties of Bosnia and Herzegovina. Their genetic identification is the first step in a process that has as its ultimate goal the collection of genetic material. The main goal of this research is to analyze the genetic variability of five indigenous varieties of apple in Tuzla Canton, Bosnia and Herzegovina in terms of contributing to the management of conservation and expansion of existing genetic resources, spreading this material through registered nurseries. Study Design: The research included fiveautochthonous apple varieties: "Ovčji nos“ “Dobrić“, "Šarenika“, "Rančica“ and "Petrovača“. Place and Duration of Study: Samples of young leaves were collected at the site of Donji Moranjci, City of Srebrenik,Tuzla Canton, Bosnia and Herzegovina in the spring of 2019. Methodology: In order to determine the genetic diversity of five indigenous apple varieties were genotyped ten SSR(Simple Sequence Repeats) markers. Original Research Article Salkić et al.; BJI, 25(2): 37-43, 2021; Article no.BJI.67908 38 Results: No cases of synonyms or homonyms were found within the analyzed set.The results of the study indicate a pronounced differentiation, ie all five examined varieties represent unique genotypes. Conclusion: The examined sets of genotypes possess significant genetic variability, which is important especially when we consider that a relatively small number of samples have been analyzed.

Sasan Sadrizadeh, Amar Aganovic, A. Bogdan, Cong Wang, A. Afshari, A. Hartmann, C. Croitoru, Amirul Khan et al.

M. Versteegh, S. Steinhauer, J. Bajo, Thomas Lettner, Ariadna Soro, A. Romanova, S. Gyger, L. Schweickert et al.

Rydberg excitons are, with their ultrastrong mutual interactions, giant optical nonlinearities, and very high sensitivity to external fields, promising for applications in quantum sensing and nonlinear optics at the single-photon level. To design quantum applications it is necessary to know how Rydberg excitons and other excited states relax to lower-lying exciton states. Here, we present photoluminescence excitation spectroscopy as a method to probe transition probabilities from various excitonic states in cuprous oxide, and we show giant Rydberg excitons at $T=38$ mK with principal quantum numbers up to $n=30$, corresponding to a calculated diameter of 3 $\mu$m.

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