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This study investigated the setter's decision-making on setting direction based on interpersonal (interaction between players) and extra personal (interaction between players and some place or object) coordination. The sample consisted of 86 sequences of play involving settings performed by males (n = 43) and females (n = 43). Fifty-nine spatiotemporal measures of interpersonal and extra personal coordination were obtained from the x and y coordinates of volleyball players' displacements using the TACTO software. Settings to each court zone were compared in relation to each spatiotemporal measure. Results showed that when the final area between attacker in the zone 3 and block was greatest and emerged from highest velocity, setters decided to set to zone 2. On the other hand, when the foregoing area was smallest and emerged from lowest velocity, setters decided to set to zones 3 and 4. It was concluded that the final area between attacker in the zone 3 and block and its emerging velocity constrained the setters' decision-making on setting direction. This study provides useful insights into the design of practice tasks in volleyball, suggesting that setters should be advised to be attuned to the interpersonal coordination involving attacker in the zone 3 and block. [ABSTRACT FROM AUTHOR]

This study investigated how information emerging from interpersonal coordination affects the decision-making on tipping in different phases of the volleyball game. Eighty-six sequences of play involving tips performed by players of both sexes were selected from 20 games of a professional championship of volleyball (attack phase, n = 56; counterattack phase, n = 30). The following spatiotemporal measures of interpersonal coordination were calculated from the x and y coordinates of the player's positioning: area forming a gap between opponents, setter's displacement to the ball, setter's distances to the net and blockers, and passing velocity. A multivariate analyses of variance (MANOVAs) were run to compare the tips in the attack vs. counterattack phases, and traditional tips vs. non-traditional tips. The results revealed that the defending area and passing velocity were greater in attacking tips than in counterattacking tips. Setter's distance and velocity to reach the ball and the blockers were smaller in attacking tips than in the counterattacking ones. It was also revealed that the final distances between the setter and the net and him/her and the blockers were smaller in traditional tips than in non-traditional tips. It was concluded that the interpersonal coordination information based on which volleyball setter players make decisions on tipping differs between attacks and counterattacks, as well as traditional and non-traditional tipping. These findings provide a useful insight for practice tasks, since setters should be instructed to be perceptually attuned to their spatiotemporal relationship with defenders and ball in order to make decision on tipping. [ABSTRACT FROM AUTHOR]

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Purpose: Anti-EGFR antibodies show limited response in breast cancer, partly due to activation of compensatory pathways. Furthermore, despite the clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors in hormone receptor-positive tumors, aggressive triple-negative breast cancers (TNBC) are largely resistant due to CDK2/cyclin E expression, whereas free CDK2 inhibitors display normal tissue toxicity, limiting their therapeutic application. A cetuximab-based antibody drug conjugate (ADC) carrying a CDK inhibitor selected based on oncogene dysregulation, alongside patient subgroup stratification, may provide EGFR-targeted delivery., Experimental Design: Expressions of G1/S-phase cell cycle regulators were evaluated alongside EGFR in breast cancer. We conjugated cetuximab with CDK inhibitor SNS-032, for specific delivery to EGFR-expressing cells. We assessed ADC internalization and its antitumor functions in vitro and in orthotopically grown basal-like/TNBC xenografts., Results: Transcriptomic (6,173 primary, 27 baseline, and matched post-chemotherapy residual tumors), single-cell RNA sequencing (150,290 cells, 27 treatment-naïve tumors), and spatial transcriptomic (43 tumor sections, 22 TNBCs) analyses confirmed expression of CDK2 and its cyclin partners in basal-like/TNBCs, associated with EGFR. Spatiotemporal live-cell imaging and super-resolution confocal microscopy demonstrated ADC colocalization with late lysosomal clusters. The ADC inhibited cell cycle progression, induced cytotoxicity against high EGFR-expressing tumor cells, and bystander killing of neighboring EGFR-low tumor cells, but minimal effects on immune cells. Despite carrying a small molar fraction (1.65%) of the SNS-032 inhibitor, the ADC restricted EGFR-expressing spheroid and cell line/patient-derived xenograft tumor growth., Conclusions: Exploiting EGFR overexpression, and dysregulated cell cycle in aggressive and treatment-refractory tumors, a cetuximab-CDK inhibitor ADC may provide selective and efficacious delivery of cell cycle-targeted agents to basal-like/TNBCs, including chemotherapy-resistant residual disease., (©2024 The Authors; Published by the American Association for Cancer Research.)

Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumor mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, antitumor immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C -expressing tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer., Significance: This study develops a mouse model of immunogenic KRAS-mutant lung cancer to facilitate the investigation of optimal combinations of targeted therapies with immunotherapies., (©2022 American Association for Cancer Research.)

Recently developed KRAS G12C inhibitory drugs are beneficial to lung cancer patients harboring KRAS G12C mutations, but drug resistance frequently develops. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterized how KRAS G12C inhibition reverses immunosuppression driven by oncogenic KRAS in a number of preclinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRAS G12C inhibition up-regulates interferon signaling via Myc inhibition, leading to reduced tumor infiltration by immunosuppressive cells, enhanced infiltration and activation of cytotoxic T cells, and increased antigen presentation. However, the combination of KRAS G12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumor model. KRAS G12C inhibition fails to sensitize cold tumors to immunotherapy, with implications for the design of clinical trials combining KRAS G12C inhibitors with anti-PD1 drugs.