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Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcγR signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, FcεR-dependent immune mechanisms in human basophils and mast cell-dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib's unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of immune-mediated diseases.

BACKGROUND: Brutons tyrosine kinase (BTK) is important in B-cell signalling. Efficacy has been reported for BTK inhibitors (BTKi) in human autoimmune diseases. Canine pemphigus foliaceus (cPF) is one of the most common canine autoimmune skin diseases. OBJECTIVES: To determine the safety and efficacy of the BTKi PRN1008 in the treatment of cPF. ANIMALS: Four privately owned dogs. METHODS AND MATERIALS: Four dogs diagnosed with PF were administered BTKi PRN1008. Initial dosages approximated to 15 mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for 20 weeks, attempting to decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels and urinalyses, and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Serum anti-desmocollin-1 (DSC-1) and desmoglein-1 (DSG-1) immunoglobulin (Ig)G titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells (PBMC). RESULTS: All four dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. Three dogs continued to improve and sustained near complete remission by 20 weeks, at which point three responses were considered good and one fair. Final daily dosages were in the range 17-33 mg/kg. Anti-DSC-1 IgG titre decreased dramatically in one dog, was undetectable in two and was uninterpretable in one dog. No dogs had detectable IgG to DSG1. A possible adverse event occurred in one dog. CONCLUSIONS AND CLINICAL IMPORTANCE: BTKi PRN1008 monotherapy may have some beneficial effects in some cases of cPF.

We examine the interaction effect of country-level aggregate advertising spending and internet access on women's development. We explain why this interaction effect either enhances or discourages women's development. Our empirical analysis of aggregate advertising spending across forty-eight countries over five years uncovers a conditional effect. Advertising may have adverse consequences on women's development when internet access is low. However, in conjunction with high levels of internet access, advertising corresponds to advancing women's development. Through an experimental study, we show one possible mechanism for this development: on one hand, the growing trend of femvertising produces comments supportive of women's empowerment. On the other, stereotypically-sexist ads elicit psychological reactance to objectifying messages. Both the celebration of messaging that supports women and the criticism of sexist stereotyping are now being widely shared online. To explore this phenomenon globally, we conducted a qualitative analysis of social media responses to Dove ads aired within multiple countries. We find that consumers amplified empowering advertisements across a range of different cultural contexts. These findings have implications for advertisers, marketers, and policy makers: such constituencies should consider how advertising can facilitate women's development by providing marketplace conditions that promote personal evolution into unattained-but-attainable versions of the self., Author(s): Gautham Vadakkepatt [sup.1] , Andrew Bryant [sup.2] , Ronald Paul Hill [sup.3] , Joshua Nunziato [sup.4] Author Affiliations: (1) grid.22448.38, 0000 0004 1936 8032, Associate Professor of Marketing, School [...]

This research challenges the entrenched belief that financial vulnerability affects only low-income consumers. Instead, most consumers across the socioeconomic spectrum experience varying degrees of financial vulnerability at different points during their lives, whether sporadically or chronically; vulnerability is dynamic and heterogeneous. The authors propose a novel, theory-driven definition of consumer financial vulnerability (CFV) as the risk of incurring future harm, given the consumer's current access to various financial resources. A new conceptual framework decouples "vulnerability" from "harm" to distinguish the state of CFV, its determinants (access to various interdependent financial resources), and the constructs it foreshadows (multiple interconnected forms of realized harm). Five research propositions follow: (1) financial resource volatility plays a vital role in CFV, (2) recovering from harm requires more financial resources than preventing harm, (3) a multiperiod lens is needed to assess CFV accurately, (4) greater financial resource access can increase CFV, and (5) generalized financial literacy is not a panacea for mitigating CFV. The propositions and their implications for marketing strategy, public policy, and consumer well-being offer a rich research agenda. The authors propose a measure of CFV—the probability that financial resources are insufficient to meet or exceed a harm threshold—for future empirical investigations. [ABSTRACT FROM AUTHOR]

Background and purposeFollowing inflammatory stimuli, neutrophils are recruited to sites of inflammation and exert effector functions that often have deleterious effects on tissue integrity, which can lead to organ failure. Bruton's tyrosine kinase (Btk) is expressed in neutrophils and constitutes a promising pharmacological target for neutrophil-mediated tissue damage. Here, we evaluate a selective reversible inhibitor of Btk, PRN473, for its ability to dampen neutrophil influx via inhibition of adhesion receptor signalling pathways.Experimental approachIn vitro assays were used to assess fMLP receptor 1 (Fpr-1)-mediated binding of ligands to the adhesion receptors macrophage antigen-1 (Mac-1) and lymphocyte function antigen-1. Intravital microscopy of the murine cremaster was used to evaluate post-adhesion strengthening and endoluminal crawling. Finally, neutrophil influx was visualized in a clinically relevant model of sterile liver injury in vivo. Btk knockout animals were used as points of reference for Btk functions.Key resultsPharmacological inhibition of Btk by PRN473 reduced fMLP-induced phosphorylation of Btk and Mac-1 activation. Biochemical experiments demonstrated the specificity of the inhibitor. PRN473 (20 mg·kg-1 ) significantly reduced intravascular crawling and neutrophil recruitment into inflamed tissue in a model of sterile liver injury, down to levels seen in Btk-deficient animals. A higher dose did not provide additional reduction of intravascular crawling and neutrophil recruitment.Conclusions and implicationsPRN473, a highly selective inhibitor of Btk, potently attenuates sterile liver injury by inhibiting the activation of the β2 -integrin Mac-1 and subsequently neutrophil recruitment into inflamed tissue.

Skin color affects women's self-image, a fact that has long been a consequence of racial discrimination and dominance as well as the prevalence of light-skinned models in modern advertisements and other forms of communication. Although not all women aspire to greater whiteness of complexion, this standard has influenced many countries that were once dominated by white invaders. As multiculturalism infuses developed and developing nations, however, these standards may be shifting away from generic and hegemonic visions toward more realistic and varied standards, requiring international marketers to be proactive rather than reactive in their customer engagement practices under the ethical frame of "perfectionism." To examine this perspective, the authors completed a cross-national qualitative study (in-depth interviews) in India, Egypt, and Ghana, where lightness of skin tone has been a culturally imposed prerequisite for women to be considered (and consider themselves) beautiful. Using customer engagement literature and the ethical perfectionism framework, this study investigates women in these countries who embrace or reject this standard, further contextualizing customer engagement research across international markets. Implications are offered as a way to advance multinational corporations' development of customer engagement along a mutually beneficial path. [ABSTRACT FROM AUTHOR]

Children are more likely to be poor than their adult counterparts, and they are also more likely to suffer from poverty's adverse consequences. While constituting about one-third of the world's population, they make up half of those persons suffering from multidimensional impoverished conditions such as lack of access to nutritious foods or clean water. The consumer behavior field has little to say about these environments and their impacts on the development and lived experiences of these youths. To partially fill this gap and set the stage for future research, we examine research done to date on poor children chronicled in the consumer behavior literature, followed by a broader look at extant research in this intellectual domain and empirical findings. Together, they set the stage for a new orientation for research that moves the field's aperture toward vulnerable children, emphasizing consumption adequacy for all youths. Recommendations for marketers are offered that recognize what they have and have not done to serve such youths. [ABSTRACT FROM AUTHOR]

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo.

Melanoma and nonmelanoma skin cancers are among the most prevalent and most lethal forms of skin cancers. To identify new lead compounds with potential anticancer properties for further optimization, in vitro assays combined with in‐silico target fishing and docking have been used to identify and further map out the antiproliferative and potential mode of action of molecules from a small library of compounds previously prepared in our laboratory. From screening these compounds in vitro against A375, SK‐MEL‐28, A431, and SCC‐12 skin cancer cell lines, 35 displayed antiproliferative activities at the micromolar level, with the majority being primarily potent against the A431 and SCC‐12 squamous carcinoma cell lines. The most active compounds 11 (A431: IC50 = 5.0 μM, SCC‐12: IC50 = 2.9 μM, SKMEL‐28: IC50 = 4.9 μM, A375: IC50 = 6.7 μM) and 13 (A431: IC50 = 5.0 μM, SCC‐12: IC50 = 3.3 μM, SKMEL‐28: IC50 = 13.8 μM, A375: IC50 = 17.1 μM), significantly and dose‐dependently induced apoptosis of SCC‐12 and SK‐MEL‐28 cells, as evidenced by the suppression of Bcl‐2 and upregulation of Bax, cleaved caspase‐3, caspase‐9, and PARP protein expression levels. Both agents significantly reduced scratch wound healing, colony formation, and expression levels of deregulated cancer molecular targets including RSK/Akt/ERK1/2 and S6K1. In silico target prediction and docking studies using the SwissTargetPrediction web‐based tool suggested that CDK8, CLK4, nuclear receptor ROR, tyrosine protein‐kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, might be prospective targets for the two most active compounds. Further validation of these targets by western blot analyses, revealed that ROCK/Fyn and its associated Hedgehog (Hh) pathways were downregulated or modulated by the two lead compounds. In aggregate, these results provide a strong framework for further validation of the observed activities and the development of a more comprehensive structure–activity relationship through the preparation and biological evaluation of analogs. [ABSTRACT FROM AUTHOR]