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Background Glioblastoma (GBM) is a primary brain tumor with a 5-year survival rate of ≤5%. We have shown earlier that GBM-antibody-linked curcumin (CC) and also phytosomal curcumin (CCP) rescue 50–60% of GBM-bearing mice while repolarizing the tumor-associated microglia/macrophages (TAM) from the tumor-promoting M2-type to the tumoricidal M1-type. However, systemic application of CCP yields only sub-IC50 concentrations of CC in the plasma, which is unlikely to kill GBM cells directly. This study investigates the role of CC-evoked intra-GBM recruitment of activated natural killer (NK) cells in the elimination of GBM and GBM stem cells. Methods We have used an immune-competent syngeneic C57BL6 mouse model with the mouse-GBM GL261 cells orthotopically implanted in the brain. Using immunohistochemistry and flow cytometry, we have quantitatively analyzed the role of the intra-GBM-recruited NK cells by (i) injecting (i.p.) the NK1.1 antibody (NK1.1Ab) to temporarily eliminate the NK cells and (ii) blocking NK recruitment by injecting an IL12 antibody (IL12Ab). The treatment cohorts used randomly-chosen GL261-implanted mice and data sets were compared using two-tailed t-test or ANOVA. Results CCP treatment caused the GBM tumor to acquire M1-type macrophages (50–60% of the TAM) and activated NK cells. The treatment also elicited (a) suppression of the M2-linked tumor-promoting proteins STAT3, ARG1, and IL10, (b) induction of the M1-linked anti-tumor proteins STAT1 and inducible nitric oxide synthase in the TAM, (c) elimination of CD133(+) GBM stem cells, and (d) activation of caspase3 in the GBM cells. Eliminating intra-GBM NK cell recruitment caused a partial reversal of each of these effects. Concomitantly, we observed a CCP-evoked dramatic induction of the chemokine monocyte chemotactic protein-1 (MCP-1) in the TAM. Conclusions The recruited NK cells mediate a major part of the CCP-evoked elimination of GBM and GBM stem cells and stabilization of the TAM in the M1-like state. MCP-1 is known to activate peripheral M1-type macrophages to secrete IL12, an activator of NK cells. Based on such observations, we postulate that by binding to peripheral M1-type macrophages and IL12-activated NK cells, the brain-released chemokine MCP-1 causes recruitment of peripheral immune cells into the GBM, thereby causing destruction of the GBM cells and GBM stem cells.

Our earlier studies reported a unique potentiated combination (TriCurin) of curcumin (C) with two other polyphenols. The TriCurin-associated C displays an IC50 in the low micromolar range for cultured HPV+ TC-1 cells. In contrast, because of rapid degradation in vivo, the TriCurin-associated C reaches only low nano-molar concentrations in the plasma, which are sub-lethal to tumor cells. Yet, injected TriCurin causes a dramatic suppression of tumors in TC-1 cell-implanted mice (TC-1 mice) and xenografts of Head and Neck Squamous Cell Carcinoma (HNSCC) cells in nude/nude mice. Here, we use the TC-1 mice to test our hypothesis that a major part of the anti-tumor activity of TriCurin is evoked by innate and adaptive immune responses. TriCurin injection repolarized arginase1high (ARG1high), IL10high, inducible nitric oxide synthaselow (iNOSlow), IL12low M2-type tumor-associated macrophages (TAM) into ARG1low, IL10low, iNOShigh, and IL12high M1-type TAM in HPV+ tumors. The M1 TAM displayed sharply suppressed STAT3 and induced STAT1 and NF-kB(p65). STAT1 and NF-kB(p65) function synergistically to induce iNOS and IL12 transcription. Neutralizing IL12 signaling with an IL12 antibody abrogated TriCurin-induced intra-tumor entry of activated natural killer (NK) cells and Cytotoxic T lymphocytes (CTL), thereby confirming that IL12 triggers recruitment of NK cells and CTL. These activated NK cells and CTL join the M1 TAM to elicit apoptosis of the E6+ tumor cells. Corroboratively, neutralizing IL12 signaling partially reversed this TriCurin-mediated apoptosis. Thus, injected TriCurin elicits an M2→M1 switch in TAM, accompanied by IL12-dependent intra-tumor recruitment of NK cells and CTL and elimination of cancer cells.

Administration of long-acting injectable suspensions is an increasingly common approach to increasing patient compliance and improving therapeutic efficacy through less frequent dosing. While several long-acting suspensions have recently been marketed, parameters modulating drug absorption from suspension-based formulations are not well understood. Further, methods for predicting clinical pharmacokinetic data from preclinical studies are not well established. Together, these limitations hamper compound selection, formulation design and formulation selection through heavy reliance on iterative optimization in preclinical and clinical studies. This article identifies key parameters influencing absorption from suspension-based formulations through compilation and analysis of preclinical and clinical pharmacokinetic data of seven compounds marketed as suspensions; achievable margins for predicting the clinical dose and input rate from preclinical studies as a function of the preclinical species, the clinical injection location and the intended therapeutic duration were also established.

Background Primary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials. Method Communication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms: (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment. Discussion The CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA. Trial Registration ClinicalTrials.gov NCT03371706 . Registered prospectively on December 13, 2017.

Thrombospondin-1 Is an Adipokine Associated With Obesity, Adipose Inflammation, and Insulin Resistance Vijayalakshmi Varma 1 , Aiwei Yao-Borengasser 1 , Angela M. Bodles 1 , Neda Rasouli 1 , Bounleut Phanavanh 1 , Greg T. Nolen 2 , Emily M. Kern 1 , Radhakrishnan Nagarajan 3 , Horace J. Spencer III 3 , Mi-Jeong Lee 4 , Susan K. Fried 4 , Robert E. McGehee, Jr. 2 5 , Charlotte A. Peterson 6 and Philip A. Kern 1 1 Central Arkansas Veterans Healthcare System and the Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 2 Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 3 Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 4 Department of Medicine, University of Maryland, Baltimore, Maryland 5 Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 6 College of Health Sciences, University of Kentucky, Lexington, Kentucky Address correspondence and reprint requests to Philip A. Kern, MD, Central Arkansas Veterans Healthcare System, 598/151 LR, 4300 West 7th St., Little Rock, AR 72205. E-mail: kernphilipA{at}uams.edu Abstract OBJECTIVE— We examined the relationship between the expression of thrombospondin (TSP)1, an antiangiogenic factor and regulator of transforming growth factor-β activity, obesity, adipose inflammation, and insulin resistance. RESEARCH DESIGN AND METHODS— TSP1 gene expression was quantified in subcutaneous adipose tissue (SAT) of 86 nondiabetic subjects covering a wide range of BMI and insulin sensitivity, from visceral adipose (VAT) and SAT from 14 surgical patients and from 38 subjects with impaired glucose tolerance randomized to receive either pioglitazone or metformin for 10 weeks. An adipocyte culture system was also used to assess the effects of pioglitazone and coculture with macrophages on TSP1 gene expression. RESULTS— TSP1 mRNA was significantly associated with obesity (BMI) and insulin resistance (low insulin sensitivity index). Relatively strong positive associations were seen with markers of inflammation, including CD68, macrophage chemoattractant protein-1, and plasminogen activator inhibitor (PAI)-1 mRNA ( r ≥ 0.46, P = 0.001 for each), that remained significant after controlling for BMI and S i . However, TSP1 mRNA was preferentially expressed in adipocyte fraction, whereas inflammatory markers predominated in stromal vascular fraction. Coculture of adipocytes and macrophages augmented TSP1 gene expression and secretion from both cell types. Pioglitazone (not metformin) treatment resulted in a 54% decrease ( P < 0.04) in adipose TSP gene expression, as did in vitro pioglitazone treatment of adipocytes. CONCLUSIONS— TSP1 is a true adipokine that is highly expressed in obese, insulin-resistant subjects; is highly correlated with adipose inflammation; and is decreased by pioglitazone. TSP1 is an important link between adipocytes and macrophage-driven adipose tissue inflammation and may mediate the elevation of PAI-1 that promotes a prothrombotic state. ADHASC, adult-derived human adipocyte stem cell cDNA, complementary DNA Ct, cycle threshold IGT impaired glucose tolerant MCP, macrophage chemoattractant protein PAI, plasminogen activator inhibitor SAT, subcutaneous adipose tissue SGBS, Simpson-Golabi-Behmel syndrome SVF, stromal vascular fraction TGF, transforming growth factor TSP, thrombospondin TZD, thiazoladinediones VAT, visceral adipose tissue Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 5 December 2007. DOI: 10.2337/db07-0840. R.E.M., C.A.P., and P.A.K. are cosenior authors. N.R. has received investigator-initiated grant support from Takeda (2004–2005) and Abbott (2006–2007). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 16, 2007. Received June 20, 2007. DIABETES

INTRODUCTION Primary progressive aphasia (PPA), a language‐based neurodegenerative dementia, negatively impacts communication and quality of life. Previous non‐pharmacologic interventions show promise but lack efficacy trials. Here, outcomes are provided from Communication Bridge‐2 (CB2), a speech‐language randomized controlled trial (RCT) for PPA. METHODS CB2 is the first Phase 2, Stage II, parallel‐group RCT delivered via video chat with global enrollment. Ninety‐five dyads were randomized into one of two speech‐language intervention arms. Primary outcomes included communication confidence and participation measures. Marginal linear models assessed efficacy across ≈12 months. RESULTS Ninety‐five dyads were randomized from four countries. Experimental arm superiority in communication‐participation measurement of goal attainment was demonstrated (66.7% vs 49.1%, respectively, p = 0.006), and corroborated by post‐study interviews. DISCUSSION Outcomes demonstrate the feasibility and initial efficacy of a person‐centered telemedicine intervention for maximizing communication participation for mild‐to‐moderate PPA, providing a pathway for developing and implementing clinically meaningful interventions for Alzheimer's disease and related dementias. Highlights Primary progressive aphasia (PPA) negatively impacts communication participation. Communication Bridge‐2 (CB2) is a telemedicine‐delivered randomized controlled trial (RCT). Global recruitment of 95 PPA participant dyads into an RCT with low dropout. First international superiority trial for PPA using video chat shows efficacy. The study provides a model for rigorous non‐pharmacologic trials for Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD).

INTRODUCTION Non‐pharmacological interventions may offer significant benefits to the quality of life for persons with primary progressive aphasia (PPA) and their care partners but have lacked efficacy trials. To help fill the efficacy gap, we provide the feasibility of recruitment, enrollment, randomization, and baseline data for the Communication Bridge‐2 (CB2) randomized controlled trial (RCT). METHODS CB2 is the first international, single enrollment site, Phase 2, Stage 2, parallel‐group, active control, RCT delivered via video chat to individuals with PPA and their care partners. Participants were recruited, screened, and randomized into one of two speech–language intervention arms. RESULTS Ninety‐five participant dyads (PPA mean baseline age: 67.1; 48% female) from four countries were enrolled and randomized. DISCUSSION Global recruitment, enrollment, and randomization of individuals with PPA into a video chat–delivered non‐pharmacologic RCT is feasible. This trial provides a potential model for conducting rigorous non‐pharmacologic efficacy trials for Alzheimer's disease and related dementias. Highlights Primary progressive aphasia (PPA) negatively impacts communication participation. Communication Bridge‐2 (CB2) is a telemedicine‐delivered randomized controlled trial. CB2 included global recruitment and randomization of 95 PPA participant dyads. CB2, the first international superiority trial for PPA using video chat shows feasibility. The study provides a model for rigorous non‐pharmacologic trials for Alzheimer's disease and related dementias.

Weather conditions at the time of wildfire front arrival strongly influence fire behavior and effects, yet few methods exist for estimating weather conditions more spatio-temporally resolved than coarse-grain (e.g., 4 km) daily averages. When a fire front advances rapidly and weather conditions are heterogeneous over space and time, greater spatio-temporal precision is required to accurately link fire weather to observed fire effects. To identify the influence of fire weather on fire effects observed across a sample of existing forest inventory plots during a wind-driven megafire event in the US Pacific Northwest, we explored and compared three methods for estimating time of fire arrival and the wind speed at that arrival time for each plot location. Two methods were based on widely used, remotely sensed active fire data products with dissimilar spatial and temporal resolutions. The third and preferred method, Modeled-Weather Interpolated Perimeters (MoWIP), is a new approach that leveraged fine-grained (1.3 km, hourly) wind speed and direction from modeled fire weather to guide interpolation of aerial infrared-detected (IR) operational perimeters, subdividing the time intervals defined by sequential IR perimeters into quartile intervals to enhance temporal resolution of predicted fire arrival times. Our description of these fire arrival “time stamp” methods and discussion of their utility and shortcomings should prove useful to fire scientists, ecologists, land managers, and future analyses seeking to link estimated fire weather and observed fire effects.

BackgroundPatients’ motivations for undergoing direct-acting antiviral (DAA) therapy for chronic hepatitis C may include anticipation of treatment benefits not well described in the literature.AimsEvaluate patients’ anticipated and actualized improvements in several domains of functioning before and after viral cure.MethodsPre–post-study utilizing in-depth interviews with 28 patients prior to, and several months after, DAA therapy. Interviews were audio-recorded, transcribed, coded, and analyzed by two qualitative experts.ResultsPatients had a median age of 54 years, 43% were male, 57% white, 25% had cirrhosis, and 71% were treated with sofosbuvir/ledipasvir. Pre-treatment, patients hoped for improvements in several domains including psychological, emotional, physical, social, and occupational functioning. After viral cure, increased energy and less fear of transmission were pathways to better quality of life. Psychological and emotional improvements positively affected physical, social, and occupational functioning. Social improvements were due to better mood and motivation, fewer symptoms, and reduced fear of stigma and transmission. Occupational benefits were linked to increased stamina, self-confidence, and less pain, anxiety, and stigma. Reduced fear of stigma had a pervasive impact on all life improvements after cure. Patient characteristics such as the presence of cirrhosis or psychiatric issues influence treatment motivations. Qualitative data correspond with change in pre–post-survey scores.ConclusionsTremendous hope is placed on the ability of DAA therapy to bring about substantial improvements in life functioning after viral cure. Highly interconnected effects on quality of life worked synergistically through improved physical and psychological well-being. Stakeholders should appreciate the multi-dimensional benefits that viral eradication bestows upon individuals and society.

Background Six synchronous, wind-driven, high severity megafires burned over 300,000 hectares of mesic temperate forest in the western Cascades of NW Oregon and SW Washington states in early September 2020. While remote sensing data has been utilized to estimate fire severity across the fires, assessments of fire impacts informed by field observations are missing. We compiled field measurement data, pre- and post-fire, from a statistically representative sample of existing forest inventory analysis (FIA) plots, to estimate stand-level fire effects indices that describe (1) tree survival and its implications for carbon emissions, (2) effects on tree crowns, and (3) effects on soils. Field observations were analyzed in relation to fire weather when plots burned and to evaluate accuracy of remotely sensed burn severity classifications. Results Wind speed strongly interacted with tree size and stand age to influence tree survival. Under high fuel aridity but light winds, young stands composed of small trees, found primarily on private lands, exhibited a much lower survival rate than older stands composed of medium to large trees, found primarily on federal lands. Under moderate to high winds, poor tree survival was characteristic of all forest structures and ownerships. Fire impacts on tree crowns were strongly related to wind speed, while fire impacts on soils were not. These fires transferred nearly 70 MMT CO 2 e from wood in live and growing trees to a combination of immediate smoke and carbon emissions, plus delayed emissions from dead wood, that will release most of the embodied carbon over the next few decades. These emissions will exceed all 2020 anthropogenic emissions in Oregon (64 MMT CO 2 e). Substantial discrepancies were observed between two remotely sensed burn severity products, BAER-SBS and MTBS-TC, and field observed soil organic matter cover and tree mortality, respectively. Conclusions Post-fire FIA plot remeasurements are valuable for understanding fire’s impact on forest ecosystems and as an empirical basis for model validation and hypothesis testing. This continuous forest inventory system will compound the value of these post-fire remeasurements, enabling analysis of post-fire forest ecosystem trajectories in relation to both immediate fire impacts and pre-fire conditions.