Novel Experimental In-Office Bleaching Gels Containing Co-Doped Titanium Dioxide Nanoparticles.

The present study reports on the development and testing of novel bleaching agents containing co-doped metaloxide nanoparticles (NP; 0%, 5%, 10% v/w) and hydrogen peroxide (HP, 0%, 6%, 15%, and 35%). Bovine blocks (n = 200, A = 36 mm2) were obtained and randomly distributed into experimental groups (n = 10/group). NPs were incorporated into gels before bleaching (3 sessions, 7 days apart, 30 min/session, irradiated with violet light-LT). Color changes (ΔE00, ΔWID), mineral content (CO32−, PO43−), and topography were assessed (spectrophotometer, ATR-FTIR, and AFM) before and after bleaching procedures (14 days). Metabolic status and three-dimensional components of non-disrupted Streptococcus mutans biofilms were investigated using a multimode reader and confocal microscopy. The results indicate that ΔE00 and ΔWID significantly increased with NPs' concentrations and LT. The enamel's mineral ratio was adversely impacted by HP, but alterations were less pronounced when using NP-containing gels. The enamel's topography was not damaged by the bleaching protocols tested. The bioluminescence results show that bleaching protocols do not render latent antibacterial properties to enamel, and the confocal microscopy results demonstrate that the 3-dimensional distribution of the components was affected by the protocols. The proposed nanotechnology improved the bleaching efficacy of experimental materials independent of hydrogen peroxide or irradiation and did not adversely impact the enamel's surface properties or its chemical content.

Process Models to Understand Resident-to-Resident Aggression Among Residents With Dementia in Long-Term Care.

BACKGROUND/OBJECTIVES: Resident-to-resident aggression (RRA) is a prevalent form of interpersonal violence in long-term care (LTC) settings. Research to guide preventive interventions is limited. Using social-ecological and need-driven dementia-compromised behavior perspectives, we sought to generate process models representing common RRA pathways in dementia-specific LTC units. RESEARCH METHODS: We used qualitative focus group methodology involving staff (n = 36) exposed to everyday resident interactions at two urban LTC facilities in Toronto, Canada. Semistructured interviews were audio-recorded and transcribed. Two independent raters coded the transcripts using iterative, constant comparison analytic processes. RESULTS: Two distinct RRA process models in dementia-specific LTC units were developed. Models reflect sequential pathways driven by residents' benign or responsive behaviors and cognitive processing limitations, with escalation points within resident dyads or groups. IMPLICATIONS: This study furthers RRA conceptualization as a process rather than an aggressive event. Models capture unique RRA manifestations in dementia-specific LTC units and entrypoints for prevention or management.

YAP-mediated mechanotransduction tunes the macrophage inflammatory response.

Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.

More Than Just a Room: A Scoping Review of the Impact of Homesharing for Older Adults.

BACKGROUND AND OBJECTIVES: "Aging in place" is commonly defined as the ability to remain living safely and independently for as long as possible either in the home or community of one's choosing. Yet, the literature indicates that older adults prefer to remain specifically in their own homes. Homesharing, an innovative exchange-based housing approach, is a means by which older adults can obtain additional income, companionship, and assistance by renting out a room to a home seeker, potentially increasing capacity to remain living independently in their homes. But what is known about their experiences of homesharing? RESEARCH DESIGN AND METHODS: A scoping review was conducted to map and consolidate the literature related to the experience of homeshare participation for adults aged 55 and older published from 1989 to 2018. Fifteen databases were searched, including 3 medical, 5 social science, and 7 gray literature databases. Following abstract and full-text review, 6 sources were retained for study inclusion. Thematic content analysis was used to identify major themes. RESULTS: Within included studies, 4 major themes were identified: (i) benefits of homeshare participation for older adults; (ii) challenges of participating in homeshare for older adults; (iii) intergenerational engagement as social exchange; and (iv) the key role of agency facilitation. DISCUSSION AND IMPLICATIONS: Findings were used to derive practice, policy, and research implications. By focusing on older adults and the ways homesharing impacts their lives, we can better determine the viability of homeshare as a means for improving and prolonging experiences of living at home.

Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1.

Matrix crosslinking enhances macrophage adhesion, migration, and inflammatory activation.

Macrophages are versatile cells of the innate immune system that can adopt a variety of functional phenotypes depending on signals in their environment. In previous work, we found that culture of macrophages on fibrin, the provisional extracellular matrix protein, inhibits their inflammatory activation when compared to cells cultured on polystyrene surfaces. Here, we sought to investigate the role of matrix stiffness in the regulation of macrophage activity by manipulating the mechanical properties of fibrin. We utilize a photo-initiated crosslinking method to introduce dityrosine crosslinks to a fibrin gel and confirm an increase in gel stiffness through active microrheology. We observe that matrix crosslinking elicits distinct changes in macrophage morphology, integrin expression, migration, and inflammatory activation. Macrophages cultured on a stiffer substrate exhibit greater cell spreading and expression of αM integrin. Furthermore, macrophages cultured on crosslinked fibrin exhibit increased motility. Finally, culture of macrophages on photo-crosslinked fibrin enhances their inflammatory activation compared to unmodified fibrin, suggesting that matrix crosslinking regulates the functional activation of macrophages. These findings provide insight into how the physical properties of the extracellular matrix might control macrophage behavior during inflammation and wound healing.

A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti-PD-(L)1 and Anti-CTLA-4 in Preclinical Models.

Adenosine signaling through A2A receptors (A2AR) expressed on immune cells suppresses antitumor immunity. CPI-444 is a potent, selective, oral A2AR antagonist. Blockade of A2AR with CPI-444 restored T-cell signaling, IL2, and IFNγ production that were suppressed by adenosine analogues in vitro CPI-444 treatment led to dose-dependent inhibition of tumor growth in multiple syngeneic mouse tumor models. Concentrations of extracellular adenosine in the tumor microenvironment, measured using microdialysis, were approximately 100-150 nmol/L and were higher than corresponding subcutaneous tissue. Combining CPI-444 with anti-PD-L1 or anti-CTLA-4 treatment eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that incompletely responded to anti-PD-L1 or anti-CTLA-4 monotherapy. Tumor growth was fully inhibited when mice with cleared tumors were later rechallenged, indicating that CPI-444 induced systemic antitumor immune memory. CD8+ T-cell depletion abrogated the efficacy of CPI-444 with and without anti-PD-L1 treatment, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. The antitumor efficacy of CPI-444 with and without anti-PD-L1 was associated with increased T-cell activation, a compensatory increase in CD73 expression, and induction of a Th1 gene expression signature consistent with immune activation. These results suggest a broad role for adenosine-mediated immunosuppression in tumors and justify the further evaluation of CPI-444 as a therapeutic agent in patients with solid tumors. Cancer Immunol Res; 6(10); 1136-49. ©2018 AACR.

Incorporation of a Ligand Peptide for Immune Inhibitory Receptor LAIR-1 on Biomaterial Surfaces Inhibits Macrophage Inflammatory Responses.

Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is an inhibitory receptor broadly expressed on immune cells, with its ligands residing within the extracellular matrix protein collagen. In this study, surfaces are modified with a LAIR-1 ligand peptide (LP), and it is observed that macrophages cultured on LAIR-1 LP-conjugated surfaces exhibit significantly reduced secretion of inflammatory cytokines in response to proinflammatory stimuli that reflect an injured environment. These downregulated mediators include TNF-α, MIP-1α, MIP-1ß, MIP-2, RANTES, and MIG. Knockdown of LAIR-1 using siRNA abrogates this inhibition of cytokine secretion, supporting the specificity of the inhibitory effect to this receptor. These results are the first to demonstrate that integration of LAIR-1 ligands with biomaterials could suppress inflammatory responses.

Differential regulation of macrophage inflammatory activation by fibrin and fibrinogen.

Fibrin is a major component of the provisional extracellular matrix formed during tissue repair following injury, and enables cell infiltration and anchoring at the wound site. Macrophages are dynamic regulators of this process, advancing and resolving inflammation in response to cues in their microenvironment. Although much is known about how soluble factors such as cytokines and chemokines regulate macrophage polarization, less is understood about how insoluble and adhesive cues, specifically the blood coagulation matrix fibrin, influence macrophage behavior. In this study, we observed that fibrin and its precursor fibrinogen elicit distinct macrophage functions. Culturing macrophages on fibrin gels fabricated by combining fibrinogen with thrombin stimulated secretion of the anti-inflammatory cytokine, interleukin-10 (IL-10). In contrast, exposure of macrophages to soluble fibrinogen stimulated high levels of inflammatory cytokine tumor necrosis factor alpha (TNF-α). Macrophages maintained their anti-inflammatory behavior when cultured on fibrin gels in the presence of soluble fibrinogen. In addition, adhesion to fibrin matrices inhibited TNF-α production in response to stimulation with LPS and IFN-γ, cytokines known to promote inflammatory macrophage polarization. Our data demonstrate that fibrin exerts a protective effect on macrophages, preventing inflammatory activation by stimuli including fibrinogen, LPS, and IFN-γ. Together, our study suggests that the presentation of fibrin(ogen) may be a key switch in regulating macrophage phenotype behavior, and this feature may provide a valuable immunomodulatory strategy for tissue healing and regeneration. STATEMENT OF SIGNIFICANCE: Fibrin is a fibrous protein resulting from blood clotting and provides a provisional matrix into which cells migrate and to which they adhere during wound healing. Macrophages play an important role in this process, and are needed for both advancing and resolving inflammation. We demonstrate that culture of macrophages on fibrin matrices exerts an anti-inflammatory effect, whereas the soluble precursor fibrinogen stimulates inflammatory activation. Moreover, culture on fibrin completely abrogates inflammatory signaling caused by fibrinogen or known inflammatory stimuli including LPS and IFN-γ. Together, these studies show that the presentation of fibrin(ogen) is important for regulating a switch between macrophage pro- and anti-inflammatory behavior.

Periurethral smooth muscle tumor of undetermined malignant potential.

Smooth muscle tumors of undermined malignant potential (STUMP) are atypical smooth muscle tumors. The majority of these tumors are of uterine origin. We report the first known periurethral STUMP. Complete surgical resection is recommended for all cases of STUMP. They can recur in the form of STUMP or leiomyosarcoma.

Gastrointestinal stromal tumor of the pelvic soft tissue presenting with symptomatic hypoglycemia: A case report and brief review of current literature of non-islet cell tumor-induced hypoglycemia.

► Presentation of a rare case of pelvic gastrointestinal stromal tumor. ► Non-islet cell induced hypoglycemia causing severe hypoglycemia. ► The pathogenesis of non-islet cell induced hypoglycemia due to over-production of precursors of insulin-like growth factor-II. ► Complete resolution of hypoglycemia following resection of the tumor.