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This study has employed mammalian transient expression systems to generate afucosylated antibodies and antibody Fc mutants for rapid candidate screening in discovery and early development. While chemical treatment with the fucose analogue 2-fluoro-peracetyl-fucose during transient expression only partially produced antibodies with afucosylated N-glycans, the genetic inactivation of the FUT8 gene in ExpiCHO-S™ by CRISPR/Cas9 enabled the transient production of fully afucosylated antibodies. Human IgG

Numerosity effects have been investigated in the psychology and marketing literatures. While the effects are documented in outcomes including money and temperature judgments, the potential application and effects of numerosity for nutrition labeling remain unexplored. In this work, we propose that vigilance offers one circumstance when individuals might succumb to numerosity effects. Within the context of nutrition labeling, we propose that the increased vigilance that people with diet-sensitive illnesses have for specific nutrients on nutrition labels, counter-intuitively, exacerbates the numerosity effect. We demonstrate that those with diabetes and those with hypertension, for example, are more vigilant for information on nutrition labels relevant to their condition, sugar, and salt, and this greater vigilance counterintuitively leads them to exhibit greater numerosity effects for those nutrients, influencing their food perceptions. As an illustration, we find that a person with hypertension would consider a food product with, say, 3 g of sodium to have less sodium content and be more healthful than one with 3000 mg, although the quantities are equivalent. Our research highlights to policymakers that a "one-size-fits-all" solution for nutrition labeling is not appropriate. Refereed/Peer-reviewed

Facioscapulohumeral muscular dystrophy (FSHD) is among the most common of the muscular dystrophies, affecting nearly 1 in 8000 individuals, and is a cause of profound disability. Genetically, FSHD is linked to the contraction and/or epigenetic de-repression of the D4Z4 repeat array on chromosome 4, thereby allowing expression of the DUX4 gene in skeletal muscle. If the DUX4 transcript incorporates a stabilizing polyadenylation site the myotoxic DUX4 protein will be synthesized, resulting in muscle wasting. The mechanism of toxicity remains unclear, as many DUX4-induced cytopathologies have been described, however cell death does primarily occur through caspase 3/7-dependent apoptosis. To date, most FSHD therapeutic development has focused on molecular methods targeting DUX4 expression or the DUX4 transcript, while therapies targeting processes downstream of DUX4 activity have received less attention. Several studies have demonstrated that inhibition of multiple signal transduction pathways can ameliorate DUX4-induced toxicity, and thus compounds targeting these pathways have the potential to be developed into FSHD therapeutics. To this end, we have screened a group of small molecules curated based on their reported activity in relevant pathways and/or structural relationships with known toxicity-modulating molecules. We have identified a panel of five compounds that function downstream of DUX4 activity to inhibit DUX4-induced toxicity. Unexpectedly, this effect was mediated through an mTor-independent mechanism that preserved expression of ULK1 and correlated with an increase in a marker of active cellular autophagy. This identifies these flavones as compounds of interest for therapeutic development, and potentially identifies the autophagy pathway as a target for therapeutics.

PURPOSE OF REVIEW Although a standard of care in the treatment of organ-confined prostate cancer, use of radiation for treatment in the high-risk, metastatic and salvage settings is evolving rapidly. RECENT FINDINGS Recent clinical trials have explored the role of increased treatment for high-risk disease with the addition of adjuvant chemotherapy and expanded the role of radiation in settings previously reserved for systemic therapy. Addition of adjuvant chemotherapy for high-risk prostate cancer is controversial and recent evidence is discussed that continues to refine the patient population for further evaluation. Evidence recently published demonstrates that for patients with low burden metastatic disease and those with oligometastatic disease may have a survival benefit with radiation treatment to all sites of known disease. Finally, reirradiation after prior radiotherapy-based treatment offers a potential salvage option for patients with locally recurrent prostate cancer. SUMMARY As treatment paradigms evolve for prostate cancer, recent evidence continues to demonstrate benefit for the use of local therapy, both in patients with organ-confined disease and, more increasingly, in those with limited metastatic or locally recurrent disease. Further work is needed to identify subgroups of patients who may benefit from available treatment escalation approaches.

P-cadherin-LP-DART is a bispecific antibody targeting P-cadherin expressed on the tumor cells and CD3 on the T-cells. Previously we demonstrated the development and efficacy of P-cadherin-LP-DART in in vitro and in vivo models. Here, we evaluated the three pillars: exposure, targeting specificity and pharmacodynamic modulation for P-cadherin-LP-DART using fluorescence molecular tomography (FMT). Bispecific antibodies and T-cells were conjugated with a near-infrared fluorophores: VivoTag®680XL (VT680) and CellVue®NIR815 (CV815), respectively. In vitro binding and cytotoxic T-lymphocyte assay demonstrated that P-cadherin-LP-DART significantly retained its properties after VT680 conjugation. In vivo FMT imaging was performed to determine the bispecific biodistribution and T-cell trafficking in HCT-116 xenograft model. Peak tumor exposure (2.71%ID) was observed at 96 hr post-injection with measurable quantity even at 240 hr (1.46%ID) (Pillar 1). P-cadherin-LP-DART accumulation in tumor was 20-25 fold higher compared to Control-LP-DART demonstrating the targeting specificity (Pillar 2). Imaging after engraftment of CV815 labeled T-cells showed P-cadherin-LP-DART mediated T-cell trafficking in tumors (Pillar 3). This study harnessed the multichannel capability of FMT and demonstrated the targeting of drug and trafficking of T cells to tumors, simultaneously. Our results show the impact of molecular imaging in demonstrating three pillars of pharmacology, longitudinally and non-invasively.

Unit pricing (i.e., displaying prices per unit of volume or weight) is deemed helpful for grocery shoppers. Many countries mandate that supermarkets provide unit prices. However, consumers only make limited use of unit pricing. Consumer advocates attribute this to the poor and inconsistent presentation of the unit price information. Using eye-tracking, the present research tests how unit price label design factors (position, font size, signposting and color highlighting on the price label) affect consumers' eye-movements during the product decision process. Additionally, the study assesses how the effects of the design factors depend on the consumer's price consciousness. The research also tests how the consistency of the label presentation affects eye-movements and choice. Findings from an experimentally designed shopping task using natural stimuli reveal that an enhanced label design leads to an increase in the number of eye fixations, in particular when the unit price is color highlighted and especially for consumers who are less price conscious. These increased fixations, however, do not result in changes in product choice. Refereed/Peer-reviewed

This research provides nuanced insights from a consumer-centric behavioural psychology perspective, by developing a theoretically grounded motivational process model of product evaluation, viewed through a country-of-origin (COO) lens, incorporating the focal constructs of product involvement, product knowledge, consumer ethnocentrism (CET) and antecedents related to wine buying in China. An online survey of 934 consumers across China in a range of 12 tier-1 and tier-2 cities investigates the effects of several independent variables on COO product category evaluation. The findings provide valuable contrasting insights between evaluations of products originating from developed economies (France and Australia) and a transitional economy (China), the home country. We validate a 10-item version of the CETSCALE and apply multiple linear regression (MLR) modelling to test the hypothesised relationships. We further contribute by examining both main and interaction effects of the empirically enhanced model. We conclude that CET, product involvement, product purchase experience and, travel exposure significantly impact COO product evaluations, through actual product purchase experience, while product purchase frequency does not. CET also has a significant mediating effect on product evaluation through both involvement and actual product purchasing experience. Gender has direct effects on CET and product evaluation, as does household income on product evaluation. Refereed/Peer-reviewed

Background: Same-day discharge after mastectomy has been demonstrated to be safe in appropriately selected candidates. However, the association between same-day discharge after mastectomy and quality of life (QOL) is unclear. Patient-reported outcome (PRO) measures represent important indicators of QOL among patients undergoing treatment for breast cancer. In this study, we aimed to evaluate the effect of same-day discharge after mastectomy on PROs. Methods: We performed a retrospective review of a prospectively collected, longitudinal PRO registry of female breast cancer patients treated at an academic breast center between June 2019 and June 2022. Patients were invited to complete the BREAST-Q module, a validated PRO questionnaire measuring QOL domains such as psychosocial wellbeing, physical wellbeing, satisfaction with their surgeon, and satisfaction with their medical team. Preoperative and 2-week postoperative questionnaire responses were analyzed in this study. Patients who had a mastectomy with or without reconstruction were included in this analysis. Those who underwent immediate reconstruction with autologous tissue were excluded as these operations are not conducive to same-day discharge. Patients were divided into two groups: the first was discharged on the date of surgery while the second was admitted to the hospital for a minimum of one night. Clinical and demographic factors were collected from a review of the electronic medical record. The primary endpoints were mean satisfaction scores as well as differences between postoperative and preoperative scores for the psychosocial and physical wellbeing domains. T-tests were used to evaluate differences between groups. A multiple regression model was fit to adjust for the effects of relevant clinical and demographic factors. Results: A total of 104 patients within the registry underwent mastectomy during the study period and were offered questionnaires. Of these, 58 completed both the preoperative and 2-week postoperative questionnaire (56% response rate); 20 (34%) in the same-day discharge group and 38 (66%) in the inpatient admission group. The groups were similar in age, stage, American Society of Anesthesiologists’ classification group, body mass index, frequency of unplanned readmission or reoperation, and receipt of bilateral mastectomy, axillary lymph node dissection, post-mastectomy reconstruction, and neoadjuvant chemotherapy. Mean patient satisfaction scores and mean changes in psychosocial and physical wellbeing scores were similar between the groups 2 weeks after surgery (Table 1). After controlling for age, type of reconstructive operation, receipt of unplanned reoperation, and preoperative score, same-day discharge did not have a significant effect on satisfaction with the surgeon (Beta=-4.3, p=0.37), satisfaction with the medical team (Beta=0.2, p=0.97), physical wellbeing score (Beta=-0.1, p=0.99), or psychosocial wellbeing score (Beta=8.0, p=0.15). Conclusions: Patients who are discharged from the hospital on the same day of a mastectomy display similar levels of satisfaction with their care team and similar short-term trends in physical and psychosocial wellbeing compared to those who are admitted to the hospital. While further data are being accrued, these early results suggest patients tolerate same-day discharge after mastectomy well. Table 1 Patient-reported outcomes at 2 weeks after mastectomy for patients discharged on the date of surgery compared to those admitted inpatient Citation Format: Sudheer Vemuru, Kathryn Colborn, Laura Leonard, Victoria Huynh, Christodoulos Kaoutzanis, Justin Cohen, David Mathes, Nicole Christian, Gretchen M. Ahrendt, Christine M. Fisher, Simon Kim, Sarah Tevis. Comparing Patient-Reported Outcomes for Same-day Discharge and Inpatient Admission After Mastectomy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-58.

Contains fulltext : 248601.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To examine how global health institutions are reducing the greenhouse gas emissions from their own operations and analyse the facilitators and barriers to achieving decarbonisation goals. METHODS: We reviewed the sustainability goals and implementation plans of 10 global health universities from the 'TropEd' network. We systematically collected information from institutional websites and annual reports. Through online interviews, 11 key informants validated the information from 9 of the institutions and shared their opinions regarding what factors are helping their institutions decarbonise and what factors are hindering progress. RESULTS: 4/10 institutions sampled have a sustainability strategy and implementation plan, only 3/10 have specific decarbonisation goals, and 3/10 are reporting on progress. 5/10 institutions reported that they are in the process of determining emission reduction targets. CONCLUSION: This paper identifies common success factors that facilitate decarbonisation as well as common challenges and how they are being tackled, and makes recommendations on sustainability efforts in academic institutions.

Breast-conserving therapy (BCT) offers oncologic outcomes similar to those of mastectomy, yet many patients, when provided the option, choose mastectomy. This study aimed to evaluate the relationship between patient-reported distress and surgical decisions and to determine factors predictive of choosing BCT versus mastectomy. Patients with newly diagnosed breast cancer deemed candidates for BCT who completed a distress screen at their initial visit to an academic institution between 2016 and 2019 were retrospectively reviewed. This screening tool captures distress in emotional, social, health, and practical domains on a scale of 0 to 10. The distress scores were compared against surgical decisions using nonparametric Wilcoxon rank-sum tests. Patient factors associated with surgical choice were analyzed using chi-square, Fisher’s exact, and Student’s t tests. A two-sided p value lower than 0.05 was considered significant. Of 506 patients deemed eligible for BCT, 430 (85%) chose BCT and 76 (15%) pursued mastectomy. The distress levels did not differ significantly between the surgical options. The patients who underwent mastectomy were on the average younger (50.7 vs 60.4 years; p

This article describes Dr. M. Michael Cohen, Jr.'s passion for art and music. His two sons share family memories and photos. Dr. Cohen developed a keen interest in the visual arts, collecting lithographs, enjoying many art exhibits, and conducting original research on Picasso's art. His interest in faces formed a central connection between his professional life and his artistic interest. His love of music began as a young boy. Classical music and opera were the soundtrack to his creative pursuits. He enjoyed sharing music with his family immensely, especially opera performances.

This study examines how wine by-the-glass (WBG) consumption by diners in USA restaurants is affected by their risk perception, product involvement, information seeking and dissemination-related behaviours and, how these constructs interact in this situation. We model their motivational process by developing a structural equation model (SEM) to examine these effects using a sample of 532 diners representing all restaurant categories in the USA. In the process we develop and validate a 17-item scale to measure the risk perception specific to WBG consumption. This empirical study supports all hypotheses tested in the motivational process model, which explicates the processes by which consumer WBG risk perception and product involvement are caused and influence one another, as well as the subsequent information processing behaviour-related responses of restaurant diners. Refereed/Peer-reviewed

Hylauronic acid (HA) is used as a viscoelastic in Ophthalmology during cataract surgery based on its high viscosity at rest, its ability to shear thin and dissipate energy during phacoemulsification. However, these properties of HA solutions would make them susceptible to migration when used as dermal filler materials. In this study, we apply a new technique termed vibrational optical coherence tomography (VOCT) to compare the physical properties of different HA solutions and fillers used in facial aesthetics. Results presented in this study suggest that HA solutions and HA dermal fillers have markedly different physical properties. HA solutions are highly viscoelastic with high % viscous losses while fillers tend to have lower viscous energy dissipation properties. Clinical observations suggest that the high loss fillers are injected more superficially in the face where tension and internal and external forces are more likely minimized giving tissue of the hands and lips more volume and allowing more natural movement. In contrast, the lower loss gels that are used to lift tissue, generally have a higher G’, and are injected deeper into the face where injection and internal forces are likely to be higher. It is concluded that HA filler gel design can be optimized by use of VOCT to evaluate the % viscous energy loss both in vitro and in vivo.

Background Previous studies have demonstrated that the A1A2A3 domains of von Willebrand factor (VWF) play a key role in regulating macrophage-mediated clearance in vivo. In particular, the A1-domain has been shown to modulate interaction with macrophage low-density lipoprotein receptor-related protein-1 (LRP1) clearance receptor. Furthermore, N-linked glycans within the A2-domain have been shown to protect VWF against premature LRP1-mediated clearance. Importantly, however, the specific regions within A1A2A3 that enable macrophage binding have not been defined. Objective and methods To address this, we utilized site-directed PEGylation and introduced novel targeted N-linked glycosylation within A1A2A3-VWF and subsequently examined VWF clearance. Results Conjugation with a 40-kDa polyethylene glycol (PEG) moiety significantly extended the half-life of A1A2A3-VWF in VWF-/- mice in a site-specific manner. For example, PEGylation at specific sites within the A1-domain (S1286) and A3-domain (V1803, S1807) attenuated VWF clearance in vivo, compared to wild-type A1A2A3-VWF. Furthermore, PEGylation at these specific sites ablated binding to differentiated THP-1 macrophages and LRP1 cluster II and cluster IV in-vitro. Conversely, PEGylation at other positions (Q1353-A1-domain and M1545-A2-domain) had limited effects on VWF clearance or binding to LRP1.Novel N-linked glycan chains were introduced at N1803 and N1807 in the A3-domain. In contrast to PEGylation at these sites, no significant extension in half-life was observed with these N-glycan variants. Conclusions These novel data demonstrate that site specific PEGylation but not site specific N-glycosylation modifies LRP1-dependent uptake of the A1A2A3-VWF by macrophages. This suggests that PEGylation, within the A1- and A3-domains in particular, may be used to attenuate LRP1-mediated clearance of VWF.

This paper compares the sales effectiveness of front versus back located end-of-aisle promotional displays (endcaps) in a supermarket, through measuring sales from the endcaps alone, as well as total brand sales, across three experiments. This paper reveals that rear endcaps generate a higher total brand sales uplift than front endcaps, acting like "billboards" to draw shoppers into the main aisle. On average, rear endcaps generated 416% sales uplift, while front endcaps generated 346% sales uplift. However, front endcaps deliver higher endcap-only sales uplift. These findings challenge industry assumptions about one of the most commonly used promotional tools. Refereed/Peer-reviewed

Manufacturers pay premiums for endcap real estate because shoppers navigate the perimeter of stores, avoiding the aisles. Research has not established how the physical and visual reach of endcaps-product displays strategically placed at the end of a shopping aisle-might vary across locations in a store. This study explores how foot traffic and visual reach of endcaps differ by location. The most prominent endcaps, in terms of both foot traffic and visual reach, were at the back of the store. These had 24 percent more foot traffic and 30 percent more visual reach than front endcaps. Evidence from this study will help marketers reach more shoppers in different endcap locations in the supermarket. Refereed/Peer-reviewed

Cellular senescence is a central component of the aging process. This cellular response has been found to be induced by multiple forms of molecular damage and senescent cells increase in number with age in all tissues examined to date. We have examined the correlation with age of two key proteins involved in the senescence program, p16INK4a and HMGB2. These proteins are involved in cell cycle arrest and chromatin remodeling during senescence. Circulating levels of these markers increases with age and correlates with functional status. The levels of HMGB2 appear to be significantly correlated with functional status, whereas p16INK4a levels are more weakly associated. Interestingly, there is a strong correlation between the two proteins independent of age. In particular, a single high-functioning individual over 90 years of age displays a disproportionately low level of HGMB2. The results suggest that with improved testing methodology, it may be possible to monitor circulating protein markers of senescence in human populations.

A well-established empirical generalization is that brand users are more likely than non-users to recall advertising for the brand they use. The pairing of a corporate and charity brand in advertising should create an expanded brand-user base, which should, in turn, lead to higher ad-memorability than either brand advertising alone. This study tests this hypothesis for consumer-packaged good sand charity brands in the United Kingdom and Australia. We find evidence that extends the generalization that ad-memorability is higher among brand users to charity supporters in non- profit contexts. We also find that when two brands are present, ad-memorability is highest among those who use the brand and support the partner charity. However, the uplift in ad-memorability among these dual-brand users is dampened by the lower ad-memorability experienced by those who use only one brand, due to a suspected information overload. The findings challenge accepted wisdom on the benefits of co-branded advertising and have implications for partner-selection for co-branded activities. Refereed/Peer-reviewed

Co-branded advertising, where advertisements feature two partnered brands from different categories, should ideally benefit both brands. We test this assertion by studying the effect of featuring a second brand in advertisements on ad and brand name memorability, and the role of category context on which brand is recalled. Our test covers online display advertisements for consumer-packaged brands paired with charity and retailer brands in three markets (USA, UK, and Australia). Independent sample comparisons across 54 brand pairs show that advertising two brands has a neutral effect on ad memorability and negative effect on brand memorability. Furthermore, the advertisement’s category context determines which of the brands is recalled. Our findings support a competitive interference theory of dual-brand processing, whereby the two brands compete for attention resources. The results have implications for the return on investment from advertising expenditure, which will vary substantively depending on whether the costs of advertising are shared or borne by one brand in the pair.

China has become the second biggest economy in the world and growth in wine consumption has been part of the overall economic trend. This chapter provides an overview of wine consumption trends in China starting with an overview of alcohol consumption. The Chinese have always been alcohol consumers; what has changed is the move away from spirits into wine made from grapes. The reasons for this change over the last 50 years are provided as an introduction to the current market for wine in China. Very little consumption data is available from the Chinese government or from reliable data firms; so, much of this chapter is based on the two authors’ research in China over the last 6 years. Overall, there has been a move from high-priced prestige wines to lower-priced wines for informal consumption. Even with all the news about online shopping in China, just over 29% is purchased through these channels. The chapter also provides information on the key countries selling wine to China, Chinese consumers’ awareness of different countries of origin and recommendations for growing wine sales and doing market research in China.

The fortuitously discovered antiaging membrane protein αKlotho (Klotho) is highly expressed in the kidney, and deletion of the Klotho gene in mice causes a phenotype strikingly similar to that of chronic kidney disease (CKD). Klotho functions as a co-receptor for fibroblast growth factor 23 (FGF23) signaling, whereas its shed extracellular domain, soluble Klotho (sKlotho), carrying glycosidase activity, is a humoral factor that regulates renal health. Low sKlotho in CKD is associated with disease progression, and sKlotho supplementation has emerged as a potential therapeutic strategy for managing CKD. Here, we explored the structure-function relationship and post-translational modifications of sKlotho variants to guide the future design of sKlotho-based therapeutics. Chinese hamster ovary (CHO)- and human embryonic kidney (HEK)-derived WT sKlotho proteins had varied activities in FGF23 co-receptor and β-glucuronidase assays in vitro and distinct properties in vivo. Sialidase treatment of heavily sialylated CHO-sKlotho increased its co-receptor activity 3-fold, yet it remained less active than hyposialylated HEK-sKlotho. MS and glycopeptide-mapping analyses revealed that HEK-sKlotho is uniquely modified with an unusual N-glycan structure consisting of N,N′-di-N-acetyllactose diamine at multiple N-linked sites, one of which at Asn-126 was adjacent to a putative GalNAc transfer motif. Site-directed mutagenesis and structural modeling analyses directly implicated N-glycans in Klotho's protein folding and function. Moreover, the introduction of two catalytic glutamate residues conserved across glycosidases into sKlotho enhanced its glucuronidase activity but decreased its FGF23 co-receptor activity, suggesting that these two functions might be structurally divergent. These findings open up opportunities for rational engineering of pharmacologically enhanced sKlotho therapeutics for managing kidney disease.

Purpose Regional nodal irradiation improves disease-free and distant disease–free survival in patients with high-risk breast cancer (BC). Trials demonstrating this used 2- or 3-dimensional conformal radiation therapy (2-dimensional or 3-dimensional [3D] conformal radiotherapy [CRT]) fields based on bony anatomy. Modern volumetric-modulated arc therapy (VMAT) and pencil beam scanning proton therapy (PBSPT) may underdose regional nodes (RNs) not contoured but covered by 3D CRT. Multiple atlases guide modern treatment planning. This study addresses the risk of underdosing when relying on published atlases and treating with 3D CRT, VMAT, and PBSPT. Methods and Materials Targets per the Radiation Therapy Oncology Group (RTOG), European Society for Radiotherapy and Oncology (ESTRO), and Radiotherapy Comparative Effectiveness Consortium (RADCOMP) atlases were contoured on a representative patient CT scan. 3D CRT plans based on anatomic borders and VMAT and PBSPT plans for each set of target volumes were generated. Positron emission tomography/computed tomography (PET/CT) scans were reviewed. CT-positive and 18F-fluorodeoxyglucose (18F-FDG)–avid RNs (n = 389) were mapped from 102 patients with locally advanced (n = 51; median 2; range, 1-8 nodes) and metastatic (n = 51; median 4; range, 1-19 nodes) BC: axillary (AX; n=284), supraclavicular (SCV; n = 60), and internal mammary nodal (IMN; n=45). 18F-FDG-avid RNs falling within the 95% isodose line were considered adequately covered. Results 3D CRT plans provided excellent RN coverage. Low AX nodes were covered (≥99%) in all plans. Underdosing of 18F-FDG–avid RNs falling in the high AX (78%-92%), SCV (52%-75%), and IMN (84%-89%) volumes was observed following the RTOG and ESTRO atlases for VMAT and PBSPT plans. Use of the RADCOMP atlas provided coverage of these areas (89%-100%) with slightly increased heart and lung doses. Atlas guided VMAT/PBSPT plans provided cumulative nodal coverage as follows: ESTRO (89%/88%), RTOG (93%/91%), and RADCOMP (98%/96%). Conclusions VMAT and PBSPT for regional nodal irradiation in patients with high-risk BC risks underdosage in the high AX, SCV, and IMN nodal regions unless comprehensive target delineation is performed.

This paper investigates the relationship between the choice drivers for wine among Chinese consumers with their personal values, using two sets of Best-Worst Scaling data.We first provide a ranking of the personal values and wine choice drivers of the population at hand. We then classify the respondents in terms of their choice drivers by means of a Latent Class Clustering. Lastly, we analyse the personal values and socio-demographic variables in each class. The sample (n=1,141) is sociodemographically representative in terms of age, gender, and income of the Chinese upper-middle class urban population.The results reveal the presence of three clusters, which are clearly identifiable in relation to their choice drivers, personal values and, partially, to their sociodemographic characteristics. The linking of value statements to the clusters strengthens the types of activities on-premise venues can use to attract different groups of customers. If on-premise operators know more about the personality of their clients and their choice drivers, they can engage their customers more appropriately throughout the choice process.The approach proposed in this paper can be extended to any research that aims to analyse the relationship between the elements driving the choice of a product and attitudinal variables. Refereed/Peer-reviewed

Retailers often feature manufacturer brands in their advertising with the aim to drive sales for those brands and, at the same time, increase in-store traffic. The adoption of such co-operative advertising strategies should reach an expanded audience base comprising of store and brand buyers. Based on empirical evidence in non-retail settings, these buyers are more likely to remember the advertising than non-buyers. This usage-bias effect implies that co-operative advertisements achieve greater cut through than would be the case if either brand advertised alone. Our paper tests this hypothesis in the context of retailer advertisements that feature manufacturer brands in the US, UK and Australia. Our results confirm that a retail brand's shoppers are more likely to recall its advertisements than non-shoppers, extending the usage-bias generalisation to a retailing context. However, while co-operative advertising does expand the buyer-base reach, any uplift in ad-memorability is negated by a reduced ability for buyers of only one of the two brands to recall the advertisement. Information overload on cognitive processing is a possible explanation for this finding, and has implications for extracting value from any investment in co-operative advertising. Refereed/Peer-reviewed

This paper uses a sample of approximately 60,000 US households to document fundamental basket size patterns across a range of retailer types (e.g. grocery stores, convenience stores, and warehouse clubs), and studies them in relation to retailer performance metrics (unit sales and dollar revenue). This research examines 1) how patterns in basket size (distribution, means, and medians) differ by retailer type, and 2) how the Pareto principle extends to shopping baskets across different retail types. The results show that basket size patterns in retailers are predictable. Shoppers purchase more items on average in retailers that offer a greater variety of items, and the distribution of basket sizes follows the Poisson lognormal model. The results also show that the largest 20% of shopping baskets on average generate 50% of unit sales, and 40% of dollar revenue. These patterns provide marketing academics with more knowledge about how people behave when they go shopping, and set additional benchmarks of what patterns can be expected on a basket-level. This research also offers support to marketing practitioners by showing the importance of different shopping basket characteristics (e.g. frequency of light buyers), which can guide more informed decision making to better manage their brands

Astrocytes participate in numerous aspects of central nervous system (CNS) physiology ranging from ion balance to metabolism, and disruption of their physiological roles can therefore be a contributor to CNS dysfunction and pathology. Cellular senescence, one of the mechanisms of aging, has been proposed as a central component of the age dependency of neurodegenerative disorders. Cumulative evidence supports an integral role of astrocytes in the initiation and progression of neurodegenerative disease and cognitive decline with aging. The loss of astrocyte function or the gain of neuroinflammatory function as a result of cellular senescence could have profound implications for the aging brain and neurodegenerative disorders, and we propose the term “astrosenescence” to describe this phenotype. This review summarizes the current evidence pertaining to astrocyte senescence from early evidence, in vitro characterization and relationship to age‐related neurodegenerative disease. We discuss the significance of targeting senescent astrocytes as a novel approach toward therapies for age‐associated neurodegenerative disease.

Developments in medicine have led to a significant increase in the average human lifespan. This increase in aging is most readily apparent in the case of HIV where antiretroviral therapy has shifted infection from a terminal to a chronic but manageable disease. Despite this advance, patients suffer from co-morbidities best described as an accelerated aging phenotype. A potential contributor is cellular senescence, an aging-associated growth arrest, which has already been linked to other HIV co-morbidities such as lipodystrophies and osteoporosis in response to antiretroviral drugs. We have previously demonstrated that astrocytes senescence in response to antiretroviral drugs. As endothelial cells play a critical role regulating the blood brain barrier (BBB) and senescence could severely impact barrier permeability, we investigate the role of a commonly used combination of HIV reverse transcriptase inhibitors on the senescence program of human umbilical vein endothelial cells (HUVECs). Our studies indicate that HUVECs underwent premature senescence associated with inflammation, oxidative stress and altered eNOS activation. Treated cells had detrimental paracrine effects on astrocytes including paracrine senescence, suggesting that senescent HUVECs could influence astrocytes, which line the other side of the BBB. These results may have implications for HIV-associated neurocognitive disorders (HAND), a set of neurological deficits.

The article Are two brands better than one? Investigating the effects of co-branding in advertising on audience memory, written by Cathy Nguyen, Jenni Romaniuk, Margaret Faulkner and Justin Cohen, was originally published electronically on the publisher’s internet portal (currently SpringerLink).

Research on the experiential aspects of wine tourism has been advocated but the evolution of this approach in this field is still in its infancy. This exploratory study proposes a behavioral model to simultaneously examine the role of hedonic and utilitarian shopping value as well as monetary value perceptions in predicting cellar door visitors' overall satisfaction and loyalty intentions. The application of partial least squares path modeling indicates that cellar door visitors are oriented toward the experiential aspects of the visit itself as much as to pragmatic considerations in purchasing wine. The insights are, therefore, directed toward the creation of a total cellar door experience. These findings contribute to the understanding of a cellar door visitors' decision-making process, providing managers and researchers with insights into how to effectively accommodate cellar door visitors' needs. Refereed/Peer-reviewed

Background In 2017, there will be an estimated 12,820 women diagnosed with cervical cancer in the United States, causing an estimation of 4,210 deaths. Among U.S. women, there is a 33% greater incidence and 71% higher cervical cancer mortality in high-poverty counties when compared to low-income counties [1]. In those dispositioned to chemoradiation, treatment time of less than eight weeks is associated with compromised pelvic control. We sought to identify patient or disease characteristics and socioeconomic or psychosocial barriers that contribute to delays in treatment completion in order to formulate new policies to address these needs. ​​​​​​Methods Cervical cancer patients treated with primary chemoradiation through the University of Maryland from 2011-2016 were identified retrospectively. Patients were placed in one of two groups: those who completed radiation treatment within 56 days, and those who failed to complete treatment within 56 days. Time to completion of radiation therapy was evaluated in relation to patient and disease variables. ​​​​Results Forty-three patients with sufficient information for inclusion were identified. The median age was 51 years. Ten patients were stage I at diagnosis (23.3%), 16 were stage II (37.2%), 11 were stage III (25.5%) and six were stage IV (14%). Histopathology revealed squamous cell carcinoma in 37 patients (86%), adenocarcinoma in three patients (7%), mixed histology in two patients (4.7%), and neuroendocrine histology in one patient (2.3%). Twenty patients (46.5%) completed treatment within the recommended timeframe of 56 days while 23 patients (53.5%) did not. The most common reasons for a protracted treatment, or failure to complete the prescribed treatment were non-compliance/psychosocial factors (10 patients, 43.5%). Age, race, primary language, marital status, insurance, employment status, HIV status, mental health, substance abuse, tobacco use, stage at diagnosis, performance status at diagnosis, BMI (body mass index, kg/m2) at diagnosis, and income by zip code were not significantly associated with protracted treatment. The distance to treatment center was a significant factor (p=0.07); patients who lived closest to the treatment center were least likely to complete RT in the designated time frame. This is most likely due to the location of the treatment center, which is in the heart of an urban, low socioeconomic area. Conclusions More than half of all cervical cancer patients presenting to an urban tertiary care center do not complete chemoradiation therapy in the recommended timeframe. Underlying psychosocial factors are prominent. The role for patient navigation in this vulnerable population must be investigated.

For this Speaker9s Box, we9ve asked three researchers and thought leaders for their views on the need for a more standardized typology for Internet advertising: Dr. Colin Campbell is a researcher who examines consumer-generated advertising, social media, and consumer engagement. In particular, he has a research and teaching interest in how the Internet affects consumer response to online advertising. Dr. Justin Cohen9s background with the Ehrenberg-Bass Institute brings a strong industry focus. Dr. Junzhao Ma completes the trio with his experience as—and insight into—big-data marketing analysis and research. In the words that follow, Drs. Campbell, Cohen, and Ma pool their intellectual-capital resources to explain the rationale for standardizing Internet advertising terminology and provide a number of useful best-practice examples. Douglas West Professor of Marketing, King9s College London Executive Editor, Journal of Advertising Research

By disentangling the static and dynamic components of a latent growth model, this study demonstrates how tourists' mere presence may influence the evaluation of the destination's products because of the halo effect of their perceived destination image. The results show that destination image positively influenced product evaluations. However, while visitors had more favourable initial product evaluations and purchase intentions, these enhanced evaluations decayed over time once the visitors returned home. Further, the effects were less pronounced for high-involvement visitors, who were more knowledgeable about the product. These findings imply that cross-sectional studies may yield an incomplete picture regarding the effects of destination image. This study also demonstrated how to apply latent growth modelling to longitudinal tourism research. Refereed/Peer-reviewed

OBJECTIVE: Non-ablative or mild hyperthermia (HT) has been shown in preclinical (and clinical) studies as a localized radiosensitizer that enhances the tumoricidal effects of radiation. Most preclinical in vivo HT studies use subcutaneous tumor models which do not adequately represent clinical conditions (e.g. proximity of normal/critical organs) or replicate the tumor microenvironment—both of which are important factors for eventual clinical translation. The purpose of this work is to demonstrate proof-of-concept of locoregional radiosensitization with superficially applied, radiofrequency (RF)-induced HT in an orthotopic mouse model of prostate cancer. METHODS: In a 4-arm study, 40 athymic male nude mice were inoculated in the prostate with luciferase-transfected human prostate cancer cells (PC3). Tumor volumes were allowed to reach 150–250 mm(3) (as measured by ultrasound) following which, mice were randomized into (i) control (no intervention); (ii) HT alone; (iii) RT alone; and (iv) HT + RT. RF-induced HT was administered (Groups ii and iv) using the Oncotherm LAB EHY-100 device to achieve a target temperature of 41 °C in the prostate. RT was administered ~30 min following HT, using an image-guided small animal radiotherapy research platform. In each case, a dual arc plan was used to deliver 12 Gy to the target in a single fraction. One animal from each cohort was euthanized on Day 10 or 11 after treatment for caspase-9 and caspase-3 Western blot analysis. RESULTS: The inoculation success rate was 89%. Mean tumor size at randomization (~16 days post-inoculation) was ~189 mm(3) . Following the administration of RT and HT, mean tumor doubling times in days were: control = 4.2; HT = 4.5; RT = 30.4; and HT + RT = 33.4. A significant difference (p = 0.036) was noted between normalized nadir volumes for the RT alone (0.76) and the HT + RT (0.40) groups. Increased caspase-3 expression was seen in the combination treatment group compared to the other treatment groups. CONCLUSION: These early results demonstrate the successful use of external mild HT as a localized radiosensitizer for deep-seated tumors. ADVANCES IN KNOWLEDGE: We successfully demonstrated the feasibility of administering external mild HT in an orthotopic tumor model and demonstrated preclinical proof-of-concept of HT-based localized radiosensitization in prostate cancer radiotherapy.

Background. Low-quality housing may confer risk of malaria infection, but evidence in low transmission settings is limited. Methods. To examine the relationship between individual level housing quality and locally acquired infection in children and adults, a population-based cross-sectional analysis was performed using existing surveillance data from the low transmission setting of Swaziland. From 2012 to 2015, cases were identified through standard diagnostics in health facilities and by loop-mediated isothermal amplification in active surveillance, with uninfected subjects being household members and neighbors. Housing was visually assessed in a home visit and then classified as low, high, or medium quality, based on housing components being traditional, modern, or both, respectively. Results. Overall, 11426 individuals were included in the study: 10960 uninfected and 466 infected (301 symptomatic and 165 asymptomatic). Six percent resided in low-quality houses, 26% in medium-quality houses, and 68% in high-quality houses. In adjusted models, low- and medium-quality construction was associated with increased risk of malaria compared with high-quality construction (adjusted odds ratio [AOR], 2.11 and 95% confidence interval [CI], 1.26–3.53 for low vs high; AOR, 1.56 and 95% CI, 1.15–2.11 for medium vs high). The relationship was independent of vector control, which also conferred a protective effect (AOR, 0.67; 95% CI, .50–.90) for sleeping under an insecticide-treated bed net or a sprayed structure compared with neither. Conclusions. Our study adds to the limited literature on housing quality and malaria risk from low transmission settings. Housing improvements may offer an attractive and sustainable additional strategy to support countries in malaria elimination.

Protein modifications by intricate cellular machineries often redesign the structure and function of existing proteins to impact biological networks. Disulfide bond formation between cysteine (Cys) pairs is one of the most common modifications found in extracellularly-destined proteins, key to maintaining protein structure. Unpaired surface cysteines on secreted mammalian proteins are also frequently found disulfide-bonded with free Cys or glutathione (GSH) in circulation or culture, the mechanism for which remains unknown. Here we report that these so-called Cys-capping modifications take place outside mammalian cells, not in the endoplasmic reticulum (ER) where oxidoreductase-mediated protein disulfide formation occurs. Unpaired surface cysteines of extracellularly-arrived proteins such as antibodies are uncapped upon secretion before undergoing disulfide exchange with cystine or oxidized GSH in culture medium. This observation has led to a feasible way to selectively modify the nucleophilic thiol side-chain of cell-surface or extracellular proteins in live mammalian cells, by applying electrophiles with a chemical handle directly into culture medium. These findings provide potentially an effective approach for improving therapeutic conjugates and probing biological systems.

Sortase mediated ligation is a highly specific platform for conjugation that relies on the specificity of the transpeptidase Sortase A (SrtA) for short peptide sequences (LPXTG and GGG). SrtA retains its specificity while accepting a wide range of potential substrates, but its broad use is limited by the wild-type enzyme’s poor kinetics, which require large amounts of SrtA and extended reaction times for efficient conjugation. Prior explorations have aimed to improve the kinetics of SrtA with limited success. Herein we describe the discovery of further improved SrtA variants with increased efficiency for the conjugation reaction, and demonstrate their robustness in labelling proteins and antibodies in a site-specific manner. Our variants require significantly lower amounts of enzyme than WT SrtA and can be used to attach small molecules to the N or C-terminus of the heavy or light chain in antibodies with excellent yields. These improved variants can also be used for highly efficient site-specific PEGylation.

Due to the advent of antiretroviral therapy HIV is no longer a terminal disease and the HIV infected patients are becoming increasingly older. While this is a major success, with increasing age comes an increased risk for disease. The age-related comorbidities that HIV infected patients experience suggest that they suffer from accelerated aging. One possible contributor to this accelerated aging is cellular senescence, an age-associated response that can occur prematurely in response to stress, and that is emerging as a contributor to disease and aging. HIV patients experience several stressors such as the virus itself, antiretroviral drugs and to a lesser extent, substance abuse that can induce cellular senescence. This review summarizes the current knowledge of senescence induction in response to these stressors and their relation to the comorbidities in HIV patients. Cellular senescence may be a possible therapeutic target for these comorbidities.

Antibody-drug conjugates (ADC) are currently an active area of research, focused primarily on oncology therapeutics, but also to a limited extent on other areas such as infectious disease. The success of this type of targeted drug delivery is dependent upon many factors, one of which is the performance of the linker in releasing an active drug moiety under the appropriate conditions. As a tool in the development of linker/payload chemistry, we have developed an in vitro method for the identification of payload species released from ADCs in the presence of lysosomal enzymes. This method utilizes commercially available human liver S9 fraction as the source of these enzymes, and this has certain advantages over lysosomal fractions or purified enzymes. This article describes the characterization and performance of this assay with multiple ADCs composed of known and novel linkers and payloads. Additionally, we report the observation of incomplete degradation of mAb protein chains by lysosomal enzymes in vitro, believed to be the first report of this phenomenon involving an ADC therapeutic.

Introduction Deficiencies of both von Willebrand Factor (VWF) and FVIII are associated with significant bleeding phenotypes. Consequently, patients with VWD or hemophilia A commonly require replacement therapy with coagulation factor concentrates. However, as infused VWF and FVIII have relatively short plasma half-lives, patient therapy generally necessitates frequent re-dosing. Development of a long-acting rVWF therapy thus represents an important unmet clinical need. We and others have previously demonstrated that the A1A2A3 domains of VWF play a critical role in regulating macrophage-mediated clearance of VWF in vivo. Importantly, crystal structures of the A-domains have also well characterized. In this study, we sought to utilize this data to investigate the hypothesis that site-specific PEGylation within the A1A2A3 domains could be used as a novel strategy to inhibit macrophage-mediated clearance, and thereby inform development of a rVWF molecule with extended plasma half-life. Methodology Site-directed mutagenesis was used to engineer novel surface cysteine residues at selected sites within A1A2A3-VWF. Following purification and characterization, individual A1A2A3 cysteine variants were PEGylated using 40kDa PEG maleimide. Clearance of unPEGylated and PEGylated A1A2A3 variants were assessed in VWF-/- mice. VWF-macrophage interactions were quantified in vitro using differentiated THP-1 macrophages. VWF binding to LRP1 clearance receptor was assessed using both immunosorbant assays and Surface Plasmon Resonance. Results Novel single cysteine residues were introduced at stringently selected sites within A1A2A3-VWF. These sites spanned all 3 A-domains and included; S1286C, Q1353C, M1545C, L1591C, V1636C, Q1652C, V1803C and S1807C. Interestingly, the introduction of these novel cysteine residues in both the A1 and A3 domains of VWF did not alter the rate of VWF clearance compared to WT A1A2A3-VWF. Conversely however, the A2 domain was less tolerant for the insertion of cysteines, with L1591C and V1636C variants demonstrating a significantly reduced VWF plasma half-life of approx. 1.5 fold versus WT-A1A2A3 (p Subsequently, the engineered cysteine residues were modified by covalent attachment of a 40kDa branched PEG molecule. All variants achieved greater than 80% PEG conjugation efficiency, except V1636C which was eliminated from further study. Remarkably, PEG conjugation displayed site-specific effects on the in vivo half-life of A1A2A3-VWF. For example, PEGylation at S1286C within the A1 domain resulted in a marked increased in VWF half-life compared to WT-A1A2A3 VWF (92.4±6 vs 18.3±0.9 mins, respectively, p Macrophage LDL receptor related protein 1 (LRP1) has been implicated as key cellular mediator of VWF clearance in vivo. Interestingly, in keeping with the reduced clearance observed for PEGylated VWF variants S1286C, V1803C and S1807C, binding of these variants to clearance receptor LRP1 cluster II and IV was ablated. Conversely, PEGylated variants which failed to extend VWF half-life (Q1353C and M1545C) displayed LRP1 binding that was comparable to WT-A1A2A3 VWF. Interestingly, PEGylation at specific sites in A2 (L1591C and Q1652C) which served to increased VWF half-life displayed normal binding to LRP1 cluster IV. However, binding of these variants to LRP1 cluster II was reduced by 90% compared to WT-A1A2A3. Conclusion Collectively, our novel data demonstrate that cysteine-directed PEGylation at specific sites within the A1 (S1286C), A2 (L1591C, Q1652C) and A3 (V1803C and S1807C) domains of A1A2A3-VWF inhibits binding to macrophage clearance receptor LRP1 in vitro. Consequently, these PEGylated A1A2A3-VWF variants demonstrate an extended circulatory half-life in vivo compared to wild type A1A2A3-VWF. Taken together, these results support the use of site-specific PEGylation as a potential approach to develop long-acting full length rVWF molecules. Disclosures Cooke: Pfizer: Employment. Terraube:Pfizer: Employment. Cohen:Pfizer: Employment. Pittman:Pfizer: Employment. Cunningham:Pfizer: Employment. Lambert:Pfizer: Employment. O'Donnell:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; CSL Behring: Consultancy; Octapharma: Speakers Bureau; Leo Pharma: Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Baxter: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau.

Senescence is an irreversible mitotic arrest of the cell that can result from replicative aging or stressors. It can be beneficial by conferring resistance to apoptosis, or detrimental by inducing pro-inflammatory signaling in the microenvironment. Senescent cells have been observed in both aged and diseased tissue, including the brain. The aging brain undergoes changes such as cortical atrophy and increases in inflammatory and oxidative factors, with decreases in synaptic plasticity and mitochondrial function. Significant neuronal loss is observed and thought to drive the atrophy in the corresponding areas of the brain in neurodegenerative diseases (ND). Despite being terminally differentiated, a senescence-like phenotype is observed in neurons upon stress in vitro and also in neurocognitive disorders like HIV-associated dementia and Alzheimer’s disease in vivo. Aging is also associated with lower regenerative capacity of neural stem and progenitor cells (NSPC). In vivo, their neurogenerative capacity is modulated by a variety of external factors, including growth factors, diet, and inflammation. NSPC have been observed to undergo stress-induced senescence in vitro. Deregulation of other CNS cell types, including oligodendrocytes and microglia occur in aging and ND. Microglia, which are not post-mitotic, senesce in culture in response to replicative or inflammatory stress. Astrocytes, which make up half of all cells in the CNS, maintain and protect neurons. In response to insult or injury however, astrocytes undergo phenotypic changes collectively termed reactive astrogliosis. This response can be both detrimental and beneficial to the neurons, and its downregulation improves disease parameters in a mouse model of AD. We have observed astrocyte senescence in vitro in response to replicative and oxidative stress and Aβ peptides, along with accumulation of senescent astrocytes in aged and AD brain. Given that astrocytes perform a myriad of complex functions in the CNS in order to maintain homeostasis, the loss of astrocyte function or the gain of neuroinflammatory function as a result of senescence could have profound implications for aging brain and neurodegenerative disorders.