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The composite behaviour of fixings acting in shear between gypsum board and thin steel sections depends on the effective properties of the board material in compression at the base of the fixing and the contribution of the head of the fixing as it rotates. An elastic method is presented to determine the stiffness of the fixings, which uses the effective elastic modulus of the gypsum board determined from a ‘dowel’ test in bearing based on the BS EN 383:2007 test. The deformation of the board in front of the fixing was determined by finite-element (FE) modelling as acting over a constant strain zone of approximately 1·5 times the fixing diameter. A plastic method is also presented to determine the shear resistance of fixings into gypsum board based on the compression resistance obtained from a dowel test on the BS EN 383:2007 test. The theory is compared with the results of FE models using Abaqus for 3·5 mm dia. fixings into 12·5 mm thick gypsum board and with tests on fixings in shear and dowel tests; the correlation is shown to be good. A small-scale push test is proposed to determine fixing properties in shear.

Gonadotropin secretion, which is stimulated by gonadotropin-releasing hormone (GnRH), is a critical feature of reproductive control and maintenance of fertility. GnRH stimulation increases LH secretion 50-100-fold over baseline per pulse, whereas Lhb gene expression increases a modest 1.4-fold. This observation shows that significant post-transcriptional regulation of gonadotropin synthesis and secretion must occur. We have previously shown that GnRH-induced Dusp1 expression, a factor central for feedback control of GnRH signaling in gonadotropes, depends on interaction of the 3'UTR of its mRNA with the RNA binding protein (RBP) ELAVL1, which binds AU-rich elements (ARE) in target mRNAs (1). Recently, using RIP-Chip analysis, we have shown that GnRH receptor (Gnrhr) expression depends on interaction of its mRNA with ELAVL1. Gnrhr mRNA is among the most highly represented ELAVL1-associated mRNAs (2). Further, many mRNAs encoding proteins essential to gonadotropin gene expression, including the immediate-early transcription factor genes Egr1, 2, and 4, Fos, Fosb, Jun, and Junb, as well as Dusp1 and 2, show increased binding to ELAVL1 after GnRH treatment, although gonadotropin Lhb mRNA is not, due to the absence of ARE site to be bound. Typically, association with ELAVL1 stabilize expression of target mRNAs, promoting their translation. Also, of interest is the role of the RBP ZFP36, which competes with ELAVL1 for binding to ARE's but has the opposing effect of directing mRNA to the degradation pathway. Significantly, 5 minutes pulsatile GnRH stimulated ZFP36 protein production in 30-60 minutes in LbetaT2 cells. And, knockdown of ELAVL1 results in the deterioration of Gnrhr expression and of the immediate-early gene Egr1 a transcription factor central to Lhb expression. We have examined the direct role of ZFP36 protein in GnRH-induced gene expression. Interestingly, Gnrhr and Lhb mRNA expression levels were decreased by ZFP36 overexpression in LbetaT2 cells compared with control cells. Also, GnRH-stimulated EGR1 production by was decreased by ZFP36 overexpression. These observations are consistent with previous results with ELAVL1 knockdown showing decreased mRNA stability. We cloned Egr1, Gnrhr and Zfp36 3'UTRs which contain AREs bound by ELAVL1 into luciferase reporter genes in pmirGLO vector to evaluate whether the 3'UTR is directly affected by ZFP36. These Egr1, Gnrhr and Zfp36 3'UTR contained mirGLOs were transfected in both ZFP36 overexpression and control cells and luciferase activity was monitored. The results showed that luciferase expression from reporters bearing the target 3'UTR were significantly reduced in ZFP36 overexpressed cells. Collectively, our studies show that ELAVL1, ZFP36 and their target mRNAs are regulated by GnRH and this indirectly regulates Lhb gene expression in gonadotropes. ) Do MT, T Kim et al. Mol Cell Endocrinology 382 (1): 1346-1357, 2014 ) Terasaka T et al. Endocrinology 160(8): 1999-2014, 2019 Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

In light steel framing, the compression resistance of the walls may be improved by the stabilising effect of plasterboard attached to one or both sides of the wall. This paper presents the results of 28 load tests on 2·4 m high walls using 75, 100 and 150 mm deep C-sections in 1·2 to 1·6 mm thick steel with various types of board. The results were compared to the methodology in the standards BS EN 1993-1-3 and BS 5950-5, taking account of restraint to minor axis buckling. The test results showed that the lateral restraint provided by 12 or 15 mm thick fire-resistant or moisture-resistant plasterboard fixed to one flange is equivalent to an effective length reduction factor of 0·7 in the minor axis direction for a 100 mm × 1·6 mm C-section in a 2·4 m high wall. A theory is developed based on distortional buckling of the C-sections, which allows the test results to be extended to other wall heights and section sizes. The failure loads were predicted by finite-element modelling by considering initial imperfections in the C-sections and the torsional restraint due to the boards.

The performance of a newly developed back pass non-perforated unglazed solar air collector (BPSC) is investigated in this paper for its thermal efficiency. BPSC is a cost-effective solar panel for new commercial buildings and industrial facades, which can be used as a main building wall or for the retrofitting of old buildings. BPSC provides a preheated air source for heating and ventilation, leading to a reduction in energy consumption. This study investigates the potential energy saving of a large scale non-domestic building that uses the BPSC system to provide pre-heated air for heating and ventilation. For this purpose, two identical buildings were constructed and tested at Kingspan R&D facilities in Kingscourt, Ireland. From the test results, it was found that the back pass solar air collector was able to reduce the heating load of the test buildings by approximately 20%. The most critical factors affecting the collector efficiency are air flow rate, collector height, and solar radiation. To enhance the performance of the BPSC system, it was assisted with a pre-heated air to water heat pump (AWHP) system. Finally, the performance of the BPSC, assisted with AWHP system was also evaluated experimentally, and it was found that an electricity savings of 36%, can be achieved through thermal energy efficiency of BPSC.

This paper explores the concept of the optimum span to depth ratio of reusable composite beams with demountable bolted shear connectors so that the beams may be designed most efficiently in terms of their weight and the shear connector distribution along the span. Three patterns of shear connectors were evaluated by a simple pseudo-plastic model and calibrated by finite element modules in terms of their effect on the overall composite beam stiffness in the range of 9 to 15 m span. The optimum span to depth ratio of symmetrical and asymmetrical beams was determined and compared to equivalent beams with welded shear connectors. It was found that the optimum span to depth ratio of uniformly loaded unpropped composite beams with demountable bolted shear connectors may be taken as 22 which allows for a utilisation factor of 0.7 at the ultimate limit state to ensure that plasticity does not occur in the first use cycle. It was found that the effect of asymmetry on the optimum span to depth ratio is small. For propped beams with demountable shear connectors, the optimum span to depth ratio may be increased to 24.

A new form of light steel composite beam has been developed that uses C sections acting in tension with shear connectors in the form of screws or bolts or perforations in the web of the C section. The shear and bending resistance is also increased by using side C sections to the beams. Bending tests on point-loaded beams of 0.8, 1.1 and 1.7 m span showed that for the short span beams, the longitudinal shear bond strength of the base C sections is 1.4 N/mm2 for plain C sections and 2.3 N/mm2 for perforated C sections when expressed over the horizontal plane. Plain side C sections added 80% and perforated side Cs added 130% to the load-bearing capacity of the composite beams with base Cs. The theory is extended to cover elastic design taking account of partial shear connection in which the shear stiffness of the perforated web of the C section is approximately 10 N/mm3 (per unit web area) and that of the plain web is approximately 3 N/mm3.

The deflection of steel beams with circular openings is dependent on the loss of bending stiffness and shear area of the web, which adds to the deflection of the solid web beam. The additional deflection is a function of the ratio of opening diameter, ho, to section depth, h, and also of the spacing of the openings. This paper presents derived formulae for the additional deflection of beams with circular web openings that are expressed as a function of the pure bending deflection of the unperforated beam. The formulae are calibrated against finite element models and against short span beam tests with opening diameters, ho, of 0.6 h and 0.72 h, in which the additional defection is mainly due to the effects of shear. Further simplified design formulae for additional deflection are also presented which are shown to be accurate for C-section beams with a span: depth ratio exceeding 15. It is also shown that circular openings may be represented for analysis purposes as an equivalent rectangle of width x depth equal to 0.75 ho x ho.

Background: Predicting patient-specific clinical response to anticancer therapy is the holy grail of treatment-selection. It is now clear that response or resistance to therapy depends on the heterogeneous tumor microenvironment, which is comprised of malignant cells, normal stroma, soluble ligands, and tumor-immune contexture; attributes that are unique to each individual patient. This is particularly true for emerging anticancer drugs, such as immune checkpoint inhibitors, which recalibrate the body's own immune defense largely by modulating exhaustion of cytotoxic lymphocytes including T cells and natural killer (NK) cells. However, clinical response to therapy varies enormously. There is a critical gap in our understanding for the mechanisms that drive response or resistance to conventional drugs and immunotherapies at the individual patient level. Methods: Here, we used a fully patient-autologous, clinically-validated ex-vivo tumor model that recreates and preserves the native, patient tumor microenvironment (CANscriptTM), which incorporates an algorithm-driven method to predict clinical response to therapy (M-Score). Utilizing tissue from patients diagnosed with luminal, HER2 positive, and triple-negative (ER- PR- HER2-) breast cancers (N=10), we studied phenotypic alterations to the tumor-immune contexture under pressure of conventional standard-of-care regimens and immunotherapies including immune-checkpoint inhibitors, ex-vivo. To do this, we used a comprehensive panel of immunological assays to evaluate changes in cytotoxic lymphocytes by flow cytometry and multiplex immunohistochemistry (i.e. CD56, MHC class 1A/B, NKG2D/C, CD8, CD3, PD-1, CTLA-4, TIM-3, LAG-3, 4-1BB, granzyme A/B). In addition, we used multiplex cytokine analysis to study the soluble components of the tumor microenvironment. Results: We identified that tumor response, predicted by M-Score, correlates to increased infiltration of NK cells, which associated a pro-inflammatory cytokine signature from the tumor microenvironment. Interestingly, these evidences were concordant with induction of the tumor-expressing biomarker MICA/B, which is known to attract and recruit active NK cells. Furthermore, we determined that therapy-induced expression of protein biomarkers associated with NK cell exhaustion inversely correlated to the expression of cytotoxic granzyme B in the tumor microenvironment. Conclusions: Taken together, these data demonstrate an integral role that NK cells contribute to the antitumor effect of therapy including conventional and immuno-modulatory drugs. It further demonstrates how a novel ex-vivo platform can be harnessed to study the mechanisms of response and resistance, which couldn't otherwise be known in a drug naïve state. Such an advance in our preclinical methods to study anticancer drugs at the individual patient level can help guide treatment decisions for clinicians while simultaneously functioning as a platform to study clinical efficacy of novel and emerging agents. Citation Format: Smalley M, Shanthappa BU, Gertje H, Lawson M, Ulaganathan B, Thayakumar A, Maciejko L, Radhakrishnan P, Biswas M, Thiyagarajan S, Majumder B, Gopinath KS, K GB, Goldman A. Therapy-induced priming of natural killer cells predicts patient-specific tumor rejection in multiple breast cancer indications [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-11-04.

The study presents a proposed approach towards developing the core engine for a simplified Rapid Overheating ASSessment Tool (ROASST), which is intended to help assist early-stage analysis of the risks of indoor overheating for apartments located in Greater London. Using a discrete number of plan forms selected from case studies, a virtual risk database was populated with the results of a large number of parametric dynamic thermal simulations based on the EnergyPlus calculation engine and including aspects such as location within Greater London, orientation, fenestration size and natural ventilation, which are associated with known overheating risk factors. Alternative statistical meta-models were developed with both explanatory and predictive purposes, correlating the simulation input with the overheating risk predictions expressed according to multiple metrics. Results from multiple linear regression analysis show that while all factors considered are relevant towards determining the propensity to overheating, window opening and natural ventilation capacity are by far the strongest predictors among those considered. The implementation of machine learning algorithms is shown to improve the accuracy of the meta-model, producing very high coefficients of determination (R2) and lower prediction errors (RMSE). The development of a meta-model demonstrates the ability of returning accurate predictions with limited input, albeit with significant limitations. Possibilities of further improvements to the tool are briefly outlined, including the coupling with a User Interface for applicability in a design environment for early-stage design advice.

This paper presents the basis for the design of steel and composite beams with large web openings. The main design requirements are the transfer of shear by Vierendeel bending and the control of web buckling next to and between the openings. Cellular beams with regular circular openings are a common example of highly perforated beams and their flange areas are often highly asymmetric. For these beams, web-post moments may be generated to develop the full shear resistance of the cross-section. Tests on beams with circular, elongated circular and rectangular openings are presented which are used to verify the design methodology. In addition, the openings cause local displacements due to shear and bending, which add to the overall deflection of perforated beams. Simplified formulae are presented to determine the additional deflection relative to the equivalent solid-web beams.

Diversity-focused committees continue to play essential roles in the efforts of professional scientific societies to foster inclusion and facilitate the professional development of underrepresented minority (URM) young scientists in their respective scientific disciplines. Until recently, the efforts of these committees has remained independent and disconnected from one another. Funding from the National Science Foundation has allowed several of these committees to come together and form the Alliance to Catalyze Change for Equity in STEM Success, herein referred to as ACCESS. The overall goal of this meta-organization is to create a community in which diversity-focused committees can interact, synergize, share their collective experiences, and have a unified voice on behalf of URM trainees in STEM disciplines. In this article, we compare and contrast the broad approaches that scientific societies in ACCESS use to implement and assess their travel award programs for URM trainees. We also report a set of recommendations, including both short- and long-term outcomes assessment in populations of interest and specialized programmatic activities coupled to travel award programs.

Cold-formed steel studs and purlins with staggered slotted perforations in webs are used in building structures to produce a better thermal performance of the profiles and for the energy efficiency of structures. On the other hand, the slotted webs result in an unfavourable effect in terms of the structural performance of the element, prominently their shear, bending and combined bending and shear strengths. Relatively little research has been reported on this subject despite its importance. Many research studies have been undertaken to examine the behaviour of conventional cold-formed steel (CFS) channel sections subject to combined bending and shear. To date, however, no research has been carried out to investigate how CFS channels with staggered slotted perforations behave under combined bending and shear actions. An extensive study on this area is therefore essential. Finite element (FE) models of CFS channels with staggered slotted perforations were developed to investigate their combined bending and shear capacity. A parametric study was conducted in detail by developing FE models based on the validation process with available experimental data. This paper presents the FE analysis details of CFS channels with staggered slotted perforations subject to combined bending and shear actions and the FE results. New design equations were also proposed to predict the combined bending and shear capacity of steel channels with staggered slotted perforations.

Background: Outgrowth of new blood vessels (neovascularization) allows tumors to supply themselves with oxygen and nutrients, and to rapidly metastasize throughout the body. Triple negative breast cancer (TNBC) is particularly susceptible to neovascularization. However, success with anti-angiogenics is highly variable and often patient-specific. This is particularly true as anti-angiogenics are being combined with immunotherapies. Thus, there is a huge unmet need for clinicians to test and predict clinical efficacy of anti-angiogenics at the individual patient level, prior to treatment. Methods: Here, we characterize a patient-autologous, ex-vivo tumor model, termed CANscript, as a platform to study the intratumor microvascular density (iMVD) of breast cancer samples (N=15). To profile iMVD we used immunohistochemical (IHC) analysis of CD34, an early biomarker of neovascularization. We then introduced anticancer and anti-angiogenic agents (e.g. Avastin) for 72 hours, and subsequently quantified phenotypic response to drugs by testing viability, cell death, proliferation and morphology. These quantitative data were then fed into a machine learning algorithm that provides a clinical response prediction (M-Score). Results: We determined that ex-vivo culture reliably retains baseline heterogeneity of iMVD based on expression of CD34+ nodes per visual field by IHC. Furthermore, we show that anticancer and anti-angiogenic agents will dynamically alter iMVD, ex-vivo, in a patient-specific manner. Finally, we show that prediction of clinical response using the 'M-Score' algorithm associates with diminished expression of CD34 per visual field of IHC after drug pressure. Summary: Neovascularization and iMVD are features of aggressive cancers, such as TNBC. CANscript provides a rapid assessment of clinical response to anticancer drugs, many of which induce their antitumor effect by targeting the tumor vasculature. We show that pharmacodynamics of antiangiogenics can be captured during acute ex-vivo culture under drug pressure, which associate to clinical response prediction. Therefore, we highlight the ability of CANscript as a platform to predict clinical response to anti-angiogenic drugs, and may therefore be a logical 'testing ground' to predict clinical efficacy of antiangiogenic drugs combined with immunotherapies. Citation Format: Smalley M, Alam N, Murmu N, Somashekhar S, Ulaganathan B, Thayakumar A, Maciejko L, Ganesh J, Lawson M, Gertje H, Shanthappa BU, Goldman A. A live tissue platform allows dynamic measurement of neovascularization and prediction of clinical response in human breast cancer samples, ex vivo [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-07-03.

This paper describes a sequence of experiments on a long-span asymmetric composite cellular beam. This type of beam has become very popular, combining the composite action between the steel and concrete with the increased section depth, compared with more commonly used solid-web I sections. Openings in the steel web also reduce the self-weight and can accommodate the passage of service ducts. Eurocode 4 recommends a high degree of shear connection for asymmetric composite beams despite the practical difficulties in achieving this. Recent research suggests that the required degree of shear connection could be reduced, particularly for beams that are unpropped during construction. However, little test data exists to verify the behaviour of unpropped composite cellular beams. Therefore two series of tests were conducted on a 15.26 m long asymmetric composite cellular beam with regular circular openings and an elongated opening at the mid-span. The degree of shear connection was 36%, less than half of that recommended in Eurocode 4, and the beam was unpropped during construction. The beam was subjected to uniformly distributed loading and shear load during the tests. The end-slip, mid-span vertical deflection, shear connector capacity and strain distribution were examined. The beam failed at an applied uniform load of 17.2 kN/m 2 (3.4 × design working load 5.0 kN/m 2 ). The member withstood an applied shear load that was 45% higher than predicted, and exhibited a Vierendeel mechanism at the elongated opening. Overall, these tests demonstrated the potential of unpropped composite cellular beams with low degrees of shear connection.

The European Directive on the Energy Performance of Buildings (EPBD) obliges the member states to ensure that, by 31 December 2020, all new buildings are nearly zero-energy buildings (nZEB). This paper presents solutions for steel-intensive commercial buildings that achieve this requirement. Several key components such as facades, floor systems and steel piles for ground energy storage were investigated in detail using numerous numerical simulations and practical tests of selected options. Furthermore, options for a whole building which fulfil the zero-energy building approach were identified for different European climates by performing a parametric study using a thermal building simulation tool.

This article reviews the performance characteristics of and some recent developments in slim-floor and integrated beam construction. This form of construction provides a flat floor using precast concrete slabs or deep composite decking and offers advantages over other forms of construction in many sectors. Composite slim-floor beams have superior stiffness and can achieve longer spans.

Composite floors are often used in building construction where beams typically span from 6 to 18 m. They are commonly used together with decking of 50 to 80 mm depth that spans 3 to 4.5 m between the beams. Rules for the minimum degree of shear connection in composite beams are presented in Eurocode 4 and other international Codes, and were derived for beams in propped construction.Eurocode 4 defines a minimum limit for the degree of shear connection, primarily to ensure that slip at the steel-concrete interface does not exceed a limiting value. This limit is proportionate to the beam span and also depends on the steel strength and the asymmetry of the flange areas of the section. Currently, many designs cannot achieve the codified degree of shear connection demands, since it is not possible to accommodate a sufficient number of shear connectors on the span as dictated by the spacing of the deck ribs. However, there are special cases which are not explicitly accounted for in Codes. This paper aims to investigate the degree of shear connection requirements in such cases, including beams that are unpropped in construction, beams that are not fully utilised in bending because serviceability criteria govern their design and beams that are predominantly loaded by point loads rather than uniform loading.The results from parametric finite element analyses carried out using ANSYS for beams in the span range of 6 to 18 m are presented. The finite element models have been calibrated against composite beam tests. Comparisons are made with the current Eurocode 4 provisions and modifications are proposed where appropriate.

Transpired solar collectors (TSCs) are an elegantly simple, façade-integrated solar air-heating technology that is widely used to pre-heat the ventilation air supply of buildings. TSCs have historically been manufactured from long profiled pre-finished steel cladding sheets and used on industrial buildings, with which they are aesthetically compatible. Buildings such as offices and multi-storey residential buildings, however, often use flat building façade elements. In order to provide architects with the choice between a profiled or flat TSC absorber, which may be more suitable aesthetically in some circumstances, a novel, flat, cassette-panel TSC (CP-TSC) solar air-heating system has been developed and trialled in situ. Two prototype CP-TSC systems were installed onto an unoccupied 1960s multi-storey residential building at Oxford Brookes University and operated for 95 days during the winter of 2010/2011. The results show that under typical operating conditions, the CP-TSCs heated the ventilation air stream by 10–15°C on clear-skied, winter days, and that this air temperature rise can be predicted by a relatively simple energy balance model.

A design method for continuous profiled decking based on post-elastic moment re-distribution is presented. This method is based on that permitted in EN 1993-1-3: Eurocode 3, and in this paper, its application to highly stiffened composite deck profiles is explored. The new aspect is the way in which the residual negative bending moment is established at high rotations using a non-linear moment–rotation stiffness relationship. Tests on three modern deck profiles of 80 mm depths are presented. It was found that the degree of redistribution of negative moment can be high, and so the stiffness coefficient used for deflection calculations should also reflect the degree of redistribution of moment that occurs at the serviceability limit state.

This paper presents the results of 20 push-out tests on shear stud connectors, placed centrally in the ribs of 58 mm and 80 mm deep steel decking. The tests were designed to investigate the realistic load–slip behaviour of the shear connectors and the influence of transverse loading. The tests considered two different stud diameters and the effect of concentric and eccentric transverse loading. In addition, the influence of a second layer of reinforcement, the welding procedure and the number of shear connectors in each rib have been considered. The observed influence of these parameters on the load–slip behaviour is presented and explained with regard to material properties and load-bearing models. In addition, the test results are compared with the current analytical approaches, which are shown to be non-conservative in some cases, because the presented deck shapes were not well considered in the development and calibration of EN 1994-1-1.

Modular construction is widely used in Europe for multi-story residential buildings. A review of modular technologies is presented, which shows how the basic cellular approach in modular construction may be applied to a wide range of building forms and heights. Case studies on 12-, 17-, and 25-story modular buildings give design and constructional information for these relatively tall buildings. The case studies also show how the structural action of modular systems affects the architectural design concept of the building. The combination of modules with steel or concrete frames increases the range of design opportunities, particularly for mixed-use commercial and residential buildings. An overview of the sustainability benefits and economics of modular construction is presented based on these case studies. © 2012 American Society of Civil Engineers.

The elasto-plastic analysis of composite beams is important when considering the increase in bending resistance of the beam and the end slip between the steel and concrete at higher strains. This paper provides a simplified method of elasto-plastic analysis by considering equilibrium of the composite cross-section as a function of its strain profile. A parabolic–rectangular stress block for concrete is used in this model with a declining concrete strength at strains exceeding 0.0035. The bending resistance of the composite beam is expressed as a function of the bottom flange strain, and is compared to fully plastic design to EN 1994-1-1: Eurocode 4 and the AISC LRFD Code. The effect of various parameters on the development of the plastic bending resistance of composite beams is investigated, such as asymmetry of the section, the steel strength, the influence of propped or un-propped construction, strain hardening in the steel and reducing concrete strength at high strains, interface slip, and the effect of openings in the web of the beams. It was found that a moment of 95% of the plastic bending resistance of a composite beam (0.95 M pl ) is reached at a flange strain of 2 to 4 × yield strain for propped beams and 5 to 10 × yield strain for un-propped beams. When strain hardening in the steel is included in the analysis, bottom flange strains at a moment of 0.95 M pl are reduced by up to 30% relative to the case without strain hardening.

Modular construction is widely used for residential buildings of 4 to 8 storeys. In the context of open building systems, modular construction provides a systemised approach to design in which the benefits of prefabrication are maximised. There is demand to extend this form of construction to more than 12 storeys for residential buildings. This paper presents a review of modular technologies, and describes load tests and analysis on light steel modular walls that are used to justify the use of light steel technology to support higher loads. For taller modular buildings, the effect of installation and geometric inaccuracies must be taken into account and it is proposed that maximum out of verticality of a vertical group of modules is 50mm relative to ground datum. Using these geometric tolerances, the notional horizontal force used to evaluate stability of a group of modules should be taken as a minimum of 1% of the applied vertical load on the modules. Robustness to accidental load effects is important in all high-rise buildings and it is proposed that the tie force in the connections between modules should be taken as not less than 30% of the total vertical load applied to the module in both horizontal directions.

Background: Immunotherapy is a developing paradigm in the treatment of head and neck squamous cell carcinoma (HNSCC). Most notably, blocking programmed cell death protein 1 (PD-1) has shown early promise as a single-agent in second-line, platinum resistant HNSCC (see for example: KEYNOTE-055). In effort to improve the outcome of PD-1 blockade, clinical trials are testing combinations of immunotherapy and standard of care drugs. Indeed, an unreported clinical trial (KEYNOTE-048) is one example combining a PD-1 checkpoint inhibitor (pembrolizumab) + platinum (Pt) + 5-fluorouricil (5-FU) versus cetuximab + Pt + 5-FU (EXTREME regimen) as a frontline treatment for patients with recurrent or metastatic HNSCC. The lack of effective pre-clinical models to profile immunotherapy has widened the search for effective combinations. Methods: Here, with informed consent under IRB, fresh tumor biopsies were obtained from a randomly-selected cohort of HNSCC patients diagnosed with metastatic or locally advanced disease (N=39). We then employed CANscriptTM, a clinically-validated ex-vivo tumor platform that preserves the native, patient tumor and immune microenvironment. Using this platform we interrogated the following treatment schedules in every sample: (i) pembrolizumab as single agent, (ii) combination of pembro + Pt + 5-FU and (iii) EXTREME regimen. Indeed, these represent the same treatment arms from the yet unreported KEYNOTE-048. Next, using a strategy that integrates phenotypic reflex to drug, ex-vivo, with a proprietary algorithm-driven approach, we predicted clinical response to each treatment arm (M-Score). In addition to this, PDL-1 status was determined for every patient by immunohistochemistry, and RNA gene expression was performed to interrogate transcriptomic differences induced by each treatment. Results: We predicted, based on M-Score, that single agent pembrolizumab results in an overall response rate of 12.8% (5/39), which closely matched previous single agent results from KEYNOTE-040 (14.6%). In contrast, we determined the EXTREME regimen resulted in a response rate of 30.7% (12/39), a finding consistent with reported clinical data (NCT00122460; ORR 36%). Interestingly, we predicted no benefit is achieved with the combination pembro/Pt/5-FU compared to EXTREME (30.7% vs. 30.7%). However, when samples were interpreted based on the type of platinum used (Carboplatin vs. Cisplatin) we determined that greater clinical response is achieved with the combination of Pembro/Carbo/5-FU (43.7% or 7/16) vs. Pembro/Cis/5-FU (21.7% or 5/23). In contrast, we predicted EXTREME regimen alone results in similar response rates regardless of the addition of Carbo or Cis (31.3% vs. 30.4%, respectively). Conclusions: Here we prognosticate clinical trial results yet to be reported using an ex-vivo platform. Many of the retrospective clinical evidence closely matches our data. If prediction for response to the novel combination strategy in KEYNOTE-048 correlates, this would provide the first evidence that a human tumor model can be used to effectively profile immunotherapy response, while also providing translational insights into mechanisms of response and resistance. Citation Format: Saravanan Thyiagarajan, Biswanath Majumder, Abhisekh Basu, Padhma Radhakrishnan, Manjusha Biswas, Munisha Smalley, Hans Gertje, Parker Cassidy, Mark Lawson, KS Sabitha, Govind Babu, Aaron J. Goldman. An ex-vivo tumor platform used to predict clinical trial efficacy: Pembrolizumab+Pt+5-FU vs. EXTREME in recurrent head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-286.

Background: It is now clear that the tumor microenvironment drives response or resistance to therapy. More specifically, the stroma, vasculature and immune compartment shape tumor response to therapy. In addition, heterogeneity within a tumor and between metastatic sites will invariably affect the outcome of treatment. Due in large part to these biological complexities, predicting how treatment response varies among multiple metastatic sites may impact overall outcome remains poorly established. Methods: Here, we interrogated the genomic and transcriptomic profile of three metastatic lesions from a patient diagnosed with relapsed head and neck squamous cell carcinoma (HNSCC), refractory to second-line Pembrolizumab (PD-1 checkpoint blockade). In addition, we employed CANscript™, a patient-derived ex-vivo model, which uses live tissue to recapitulate the native 3D tumor microenvironment coupled with an algorithm-driven strategy to predict clinical response in the form of an S-Score (Majumder et al., Nat. Comm., 2015). Using this platform, we tested two combination therapies; carboplatin with gemcitabine, and adriamycin with cyclophosphamide. Moreover, we characterized the tumor microenvironment, following combination treatment, using a multiplexed immunohistochemistry (IHC) panel (Ki67, PanCK, CD3, CD4, CD8, DAPI). Results: We determined that the three metastatic sites displayed distinct transcription and whole exome signatures, prior to CANscriptTM. Based on CANscriptTM predicted responses (S-Score) for the two combinations tested, all three sites responded in a non-uniform manner. Interestingly, each site also displayed distinct patterns of proliferative immune subsets (Ki67 staining) and CD4:CD8 ratios, following treatment with each combination therapy. Conclusion: Together, these findings demonstrate that, due to the underlying genetic and tumor microenvironment heterogeneity, metastatic sites might each confer distinct clinical responses to the same drug regimen, even in immunotherapy-resistant disease. Moreover, we highlight the utility of ex-vivo profiling as a tool to predict therapeutic response - not only at the individual patient level, but also at the level of multiple metastatic sites from a single patient. These findings underscore the importance of characterizing the entire tumor-immune contexture under pressure anticancer drugs. Such information can revise our understanding of personalized cancer care, and may impact rational treatment options. Citation Format: Chukwuemeka Ikpeazu, Munisha Smalley, Baraneedharan Ulaganathan, Allen Thayakumar, Laura Majeiko, Jyothsana Ganesh, Basavaraja Shanthappa, Hans Gertje, Mark Lawson, Sara Lapomarda, Aaron Goldman. Case study: Non-uniform response to therapy in multiple metastatic is predicted using CANscriptTM, a live tissue, ex-vivo, platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-346.

e18021Background: Tumor heterogeneity drives response or resistance to therapy. This is particularly true in cases of metastatic disease, in which distant tumors are governed by their unique microe...

e18042Background: PD-1 inhibition has shown promise in second-line, platinum (Pt) resistant HNSCC (e.g. KEYNOTE-055). To improve the outcome of PD-1 blockade, clinical trials are testing immunother...

This paper addresses the design of stainless steel sections with large circular openings subject to shear and bending. A total of nine tests on pairs of C sections using 2 and 3 mm thick stainless steel in austenitic 1.4301 and lean duplex 1.4162 grades was performed. The tests showed that the shear resistance at an opening is controlled by local compression at a radial cross-section at approximately 25° to the vertical. For closely spaced openings, the angle of highest stress increases to about 65° to the vertical. The shear resistance of a Class 4 web is also affected by local buckling around the opening, which is a function of its diameter to steel thickness ratio. An equilibrium model is presented which predicts the normal stress on the radial planes around an opening. A simplified formula for the local buckling strength around circular web openings is also presented, which agrees well with the test results.

Such an appointment would seem perverse and fanciful but, if the job were on the television pages rather than the sports pages, the above conversation would be fairly standard recruitment policy. There are at least two reported cases of national newspaper TV critics having to be bought a set at the time they signed up and, really late into the night at industry festivals, rumours circulate that one reviewer in the past refused to have a set in the house and relied on what he heard through his neighbour’s walls. The last anecdote is almost certainly apocryphal but the legends that develop around a profession are often revealing: it’s impossible to imagine, for instance, the myth growing up of a film critic who refused to watch movies or a theatre reviewer who always remained on the pavement outside in case his work affected his standing in society. And, even if such a figure existed, it’s impossible to think of them being employed by a major title. But while the weakness of theatre and dance critics as a breed is a tendency to over-praise from a sense of professional solidarity, the flaw of TV reviewers as a group is that they have often operated on the very opposite side of even-handedness, writing with fury-clenched fists. There are three reasons why British television attracts more hostile criticism than any other art form. The first is that newspapers instinctively resent TV. As the visual medium grew to maturity (of technology, if not content) in the 1950s and Why Newspapers Should Stop Publishing TV Reviews

Introduction: There is an urgent unmet need to improve the predictive value of animal and in vitro systems for drug development. The purpose of this study was to develop an in vitro vascular system that reflects the in vivo biology of the cynomolgus macaque (cyno). Methods: We co-cultured endothelial (EC) and smooth muscle cells (SMC) from cyno arteries and exposed them to physiologically relevant hemodynamics. Cyno velocity profiles were obtained from arterial regions prone to atherosclerosis (atheroprone) or healthy regions. Velocity waveforms were applied to the co-culture along with oxidized LDL from cyno or humans, and TNFα, which are pathogenic in humans and mimic advanced inflammatory conditions (AIC). Using RNA sequencing, we quantified the response of the system to 4 different statin treatments (atorvastatin, simvastatin, cerivastatin, rosuvastatin) under AIC. Using computational analyses of differentially expressed genes (DEGs), we characterized the response of our system by identifying functional biological themes that were associated with each statin treatment. Results: We found that AIC in the cyno system dramatically increased inflammatory DEGs and decreased vascular health DEGs. Cerivastatin elicited the most DEGs in both the cyno and human vascular system while the response to rosuvastatin did not reach statistical significance for any genes. Statin treatment decreased inflammatory cytokine gene expression, but not adhesion molecule expression under AIC. Except for rosuvastatin, all statins tested significantly increased the expression of genes that promote vascular health, while suppressing the expression of inflammatory genes. Biological themes were regulated by statin treatment in both the human and cyno vascular systems including: cholesterol biosynthesis, thrombosis, ethanol degradation, cell cycle regulation and notch signaling. Finally, we discovered functional themes related to glycogen metabolism, which may be relevant as a potential mechanism driving the risk of hyperglycemia with statin treatment. Conclusions: The cyno vascular system described here mirrors many of the well-known phenotypes of the human vascular system, and should provide a valuable predictive tool for in vivo studies.

Maize (Zea mays ssp. mays L.) is highly susceptible to drought stress. This work focused on whole-plant physiological mechanisms by which a biotechnology-derived maize event expressing bacterial cold shock protein B (CspB), MON 87460, increased grain yield under drought. Plants of MON 87460 and a conventional control (hereafter ‘control’) were tested in the field under well-watered (WW) and water-limited (WL) treatments imposed during mid-vegetative to mid-reproductive stages during 2009–2011. Across years, average grain yield increased by 6% in MON 87460 compared with control under WL conditions. This was associated with higher soil water content at 0.5 m depth during the treatment phase, increased ear growth, decreased leaf area, leaf dry weight and sap flow rate during silking, increased kernel number and harvest index in MON 87460 than the control. No consistent differences were observed under WW conditions. This indicates that MON 87460 acclimated better under WL conditions than the control by lowering leaf growth which decreased water use during silking, thereby eliciting lower stress under WL conditions. These physiological responses in MON 87460 under WL conditions resulted in increased ear growth during silking, which subsequently increased the kernel number, harvest index and grain yield compared to the control.

Modular construction can dramatically improve efficiency in construction, through factory production of pre-engineered building units and their delivery to the site either as entire buildings or as substantial elements. The required technology and application are developing rapidly, but design is still in its infancy. Good design requires a knowled