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Purpose:The activating mutation AKT1E17K occurs in approximately 7% of estrogen receptor–positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1E17K-mutant ER+ MBC.Patients and Methods:Patients with an AKT1E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort.Results:From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].Conclusions:Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.

Copyright: © 2022 by the authors. This paper is concerned with the behaviour of stainless steel reinforcing bar following exposure to elevated temperatures from a fire, followed by subsequent cooling. Stainless steel-reinforced concrete is an increasingly popular solution for structural applications which require corrosion resistance, excellent mechanical properties, and long life cycles with little maintenance. In addition, although stainless steel reinforcement has a higher initial cost compared with traditional carbon steel bars, the overall life cycle costs are likely to be quite similar, owing to the lack of maintenance required for stainless steel materials. There is no information available in the literature on the post-fire properties of austenitic stainless steel reinforcement, although these data are essential for any engineer who wishes to study the structural integrity of a reinforced concrete component or system following a fire. Accordingly, this paper presents a detailed discussion and analysis from the results of a series of laboratory experiments on three grades of austenitic stainless steel reinforcement following various levels of temperature exposure and also different cooling rates. Both the mechanical and metallurgical properties are examined, and the behaviour is compared to that of B500B carbon steel reinforcement. It is shown that the stainless steel bars retained their mechanical properties under the majority of the scenarios examined and to a greater degree than traditional materials. This is important for the rehabilitation and salvage of existing reinforced concrete structures following a fire and also to avoid unnecessary demolition and replacement.

Parent-of-origin effects arise when a phenotype depends on whether it is inherited maternally or paternally. Parent-of-origin effects can exert a strong influence on F1 seed size in flowering plants, an important agronomic and life-history trait that can contribute to biomass heterosis. Here we investigate the natural variation in the relative contributions of the maternal and paternal genomes to F1 seed size across 71 reciprocal pairs of F1 hybrid diploids and the parental effect on F1 seed size heterosis. We demonstrate that the paternally derived genome influences F1 seed size more significantly than previously appreciated. We further demonstrate (by disruption of parental genome dosage balance in F1 triploid seeds) that hybridity acts as an enhancer of genome dosage effects on F1 seed size, beyond that observed from hybridity or genome dosage effects on their own. Our findings indicate that interactions between genetic hybridity and parental genome dosage can enhance heterosis effects in plants, opening new avenues for boosting heterosis breeding in crop plants.

Shear walls are structural members in buildings that are used extensively in reinforced concrete frame buildings, and almost exclusively in the UK, regardless of whether or not they are actually required. In recent years, the UK construction industry, led by the Concrete Centre, has questioned the need for such structural elements in low to mid-rise reinforced concrete frame buildings. In this context, a typical modern, 5-storey residential building is studied, and its existing shear walls are replaced with columns as used elsewhere in the building. The aim is to investigate the impact of several design variables, including concrete grade, column size, column shape and slab thickness, on the building’s structural performance, considering two punching shear limits (VEd/VRd,c), lateral drift and accelerations, to evaluate its maximum possible height under wind actions without the inclusion of shear walls. To facilitate this study, a numerical model has been developed using the ETABS software. The results demonstrate that the building examined does not require shear walls in the design and has no lateral displacement or acceleration issues. In fact, with further analysis, it is shown that a similar building could be constructed up to 13 and 16 storeys high for 2 and 2.5 punching shear ratios (VEd/VRd,c), respectively, with adequate serviceability and strength, without the need for shear walls, albeit with thicker columns.\ud Keywords: High-rise RC buildings; wind actions; Concrete grade; Concrete section size; Column shape; Slab thickness; Shear wall

Copyright © 2021 The Authors. This paper describes an investigation into the cross-sectional behaviour of elliptical hollow section (EHS) columns made from ferritic and duplex stainless steel. The EHS is a relatively new structural shape with a number of favourable attributes including aesthetic appeal, high strength-to-weight ratio, good torsional resistance and excellent flexural strength. In recent years there have been significant developments in the analysis and understanding of these shapes, although most studies have focused on carbon steel EHS. The work so far is taken a step further here by considering some of the newer grades of stainless steel that are used in structural applications. A numerical model is developed and validated against test data from the literature and is then employed to generate structural performance data. Subsequently, parametric studies are performed to investigate the influence of individual parameters such as the material properties, aspect ratio and local slenderness of cross-sectional elements. The accuracy of existing design procedures is assessed by comparing the numerical data with the resistances obtained using Eurocode 3. It is shown that the cross-sectional slenderness limits given in Eurocode 3 for EHS members made from carbon steel can also be safely used for sections made from ferritic and duplex stainless steel.

Copyright: © 2021 by the authors. The probability of extreme events such as an earthquake, fire or blast occurring during the lifetime of a structure is relatively low but these events can cause serious damage to the structure as well as to human life. Due to the significant consequences for occupant and structural safety, an accurate analysis of the response of structures exposed to these events is required for their design. Some extreme events may occur as a consequence of another hazard, for example, a fire may occur due to the failure of the electrical system of a structure following an earthquake. In such circumstances, the structure is subjected to a multi-hazard loading scenario. A post-earthquake fire (PEF) is one of the major multi-hazard events that is reasonably likely to occur but has been the subject of relatively little research in the available literature. In most international design codes, structures exposed to multi-hazards scenarios such as earthquakes, which are then followed by fires are only analysed and designed for as separate events, even though structures subjected to an earthquake may experience partial damage resulting in a more severe response to a subsequent fire. Most available analysis procedures and design codes do not address the association of the two hazards. Thus, the design of structures based on existing standards may contribute to a significant risk of structural failure. Indeed, a suitable method of analysis is required to investigate the behaviour of structures when exposed to sequential hazards. In this paper, a multi-hazard analysis approach is developed, which considers the damage caused to structures during and after an earthquake through a subsequent thermal analysis. A methodology is developed and employed to study the nonlinear behaviour of a steel framed structure under post-earthquake fire conditions. A three-dimensional nonlinear finite element model of an unprotected steel frame is developed and outlined. View Full-Text

Stainless steel reinforcement has become a very attractive option for reinforced concrete structures owing to its distinctive properties including outstanding corrosion resistance, excellent fire behaviour, long life cycle as well as low maintenance requirements. Additionally, stainless steel reinforcement offers exceptional ductility and strain hardening characteristics compared with other common materials, which are very desirable in design to avoid sudden collapse. However, most global design standards do not incorporate an appropriate design approach for reinforced concrete members with stainless steel. The substantial strain hardening characteristics of stainless steel are typically not represented in standardised material models and therefore this attractive characteristic is not exploited in design resulting in structural and economic inefficiencies. Hence, the aim of this paper is to propose and validate a new deformation-based design approach for stainless steel reinforced concrete beams based on the continuous strength method, with reference to the current design rules provided in Eurocode 2. This approach is shown to be an effective design tool that exploits the distinctive characteristics of stainless steel reinforcement in an efficient and reliable manner. It is shown to provide a more efficient design with less over-conservatism and greater accuracy, compared with other methods. A comprehensive parametric study is conducted using Abaqus software to study the influence that various geometric and material properties have on the capacity of the members. Moreover, the serviceability limit state is also explored through a detailed analysis of the deflection behaviour.

Cardiovascular diseases remain the leading cause of mortality and a major contributor to preventable deaths worldwide. The dominant modifiable risk factors and the social and environmental determinants that increase cardiovascular risk are known, and collectively, are as important in racial and ethnic minority populations as they are in majority populations. Their prevention and treatment remain the foundation for cardiovascular health promotion and disease prevention. Genetic and epigenetic factors are increasingly recognized as important contributors to cardiovascular risk and provide an opportunity for advancing precision cardiovascular medicine. In this review, we explore emerging concepts at the interface of precision medicine and cardiovascular disease in racial and ethnic minority populations. Important among these are the lack of racial and ethnic diversity in genomics studies and biorepositories; the resulting misclassification of benign variants as pathogenic in minorities; and the importance of ensuring ancestry-matched controls in variant interpretation. We address the relevance of epigenetics, pharmacogenomics, genetic testing and counseling, and their social and cultural implications. We also examine the potential impact of precision medicine on racial and ethnic disparities. The National Institutes of Health’s All of Us Research Program and the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine Initiative are presented as examples of research programs at the forefront of precision medicine and diversity to explore research implications in minorities. We conclude with an overview of implementation research challenges in precision medicine and the ethical implications in minority populations. Successful implementation of precision medicine in cardiovascular disease in minority populations will benefit from strategies that directly address diversity and inclusion in genomics research and go beyond race and ethnicity to explore ancestry-matched controls, as well as geographic, cultural, social, and environmental determinants of health.

Copyright © The Author(s) 2021. Despite substantial progress in recent years to improve the design guidance for high strength steel (HSS) structural elements, this has mainly been for ambient conditions with their fire response still in need of further research. Accordingly, this paper reports on an investigation into the structural performance of unprotected HSS hollow section columns in fire. Finite element models of columns made from square, circular and rectangular hollow sections are developed and are validated against test data at ambient and elevated temperature. The validated models are employed to perform parametric studies to assess the influence of a range of variables such as the grades of HSS, levels of temperature exposure and cross-sectional geometry. The structural fire design resistance method for a column given in the Eurocode is assessed based on the FE results. Consequently, new buckling curves are proposed, which provide a more accurate prediction of the real capacity and reliability analysis is also performed on the new proposed design formulations.

What does ordinary language philosophy contribute to the solution of the problems it diagnoses as violations of linguistic use? One of its biggest challenges has been to account for the epistemic asymmetry of mental states experienced by the subject of those states and the application of psychological properties to others. The epistemology of other minds appears far from resolved with reference to how sensation words are used in everyday language. In this paper, I revisit the Wittgensteinian arguments and show how they engage the ordinary language method (in the modified form of grammatical investigation) to ‘dissolve’ the problem. Several important results are generated by way of this reconstruction. An expressive view of the vocabulary of sensation is defended which facilitates a discussion of sensation discourse emphasising the normative grammatical conditions for the communication of psychological states. This motivates a reassessment of criterial justification for the ascription of psychological concepts in the third person. In the final sections, I mobilise a normative approach to expose the moral relevance of the epistemology of other minds. Even if it is conceded that belief in other minds lacks warrant from an epistemological standpoint, this does not justify adopting the skeptical attitude from an ethical standpoint. In light of this, a normative justification for the a priori belief that others are subjects of consciousness is defended., a, Bd. 6 Nr. 2 (2011)

Summary Despite the remarkable success of chimeric antigen receptor (CAR)-T cells against hematologic malignancies, severe off-tumor effects have constrained their use against solid tumors. Recently, CAR-engineered natural killer (NK) cells have emerged as an effective and safe alternative. Here, we demonstrate that HER2 CAR-expression in NK cells from healthy donors and patients with breast cancer potently enhances their anti-tumor functions against various HER2-expressing cancer cells, regardless of MHC class I expression. Moreover, HER2 CAR-NK cells exert higher cytotoxicity than donor-matched HER2 CAR-T cells against tumor targets. Importantly, unlike CAR-T cells, HER2 CAR-NK cells do not elicit enhanced cytotoxicity or inflammatory cytokine production against non-malignant human lung epithelial cells with basal HER2 expression. Further, HER2 CAR-NK cells maintain high cytotoxic function in the presence of immunosuppressive factors enriched in solid tumors. These results show that CAR-NK cells may be a highly potent and safe source of immunotherapy in the context of solid tumors., Graphical abstract, Highlights • Primary HER2 CAR-NK cells from patients with cancer have potent anti-tumor functions • HER2 CAR-NK cells have a higher tumor killing capacity than HER2 CAR-T cells • HER2 CAR-NK cells are not overly activated against HER2+ lung epithelial cells • CAR-NK cells can overcome inhibition by the immunosuppressive factors TGF-β and PGE2, Immunology; Cancer