Evaluation of treatment parameters for focused-extracorporeal shock wave therapy in knee osteoarthritis patients with bone marrow lesions: a pilot study.

OBJECTIVES: To evaluate the effect of different dosage parameters of focused-extracorporeal shock wave therapy on pain and physical function in knee osteoarthritis patients with bone marrow lesions. In addition, to investigate pathophysiological changes based on imaging and biomarker measures. METHODS: Using a single-case experimental design, a total of 12 participants were randomly allocated in 4 equal groups of 3 to receive different dosages of focused-extracorporeal shock wave therapy. Each group received either 4 or 6 sessions of 1500 or 3000 shocks over 4 or 6 weekly sessions. Participants underwent repeated measurements during the baseline, intervention, and post-intervention phases for Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, aggregated locomotor function score and pressure pain threshold. Imaging and inflammatory biomarker outcomes were measured at baseline and 3 months following the intervention. RESULTS: The group receiving the highest dosage of focused-extracorporeal shock wave therapy showed clinical improvements superior to those of participants in the other 3 groups. Statistically significant changes during the follow-up phase in contrast to baseline measurements for the WOMAC score (Tau-U= -0.88, p < 0.001), aggregated locomotor function score (Tau-U= -0.77, p = 0.002), and pressure pain threshold (Tau-U= 0.54, p = 0.03) were observed. Bone marrow lesion and inflammatory cytokines demonstrated no change. CONCLUSION: A dose-dependent effect for focused-extracorporeal shock wave therapy on osteoarthritis-related symptoms was suggested. However, these improvements were not associated with changes in the underlying pathophysiological mechanisms.

Population coding of strategic variables during foraging in freely moving macaques.

Until now, it has been difficult to examine the neural bases of foraging in naturalistic environments because previous approaches have relied on restrained animals performing trial-based foraging tasks. Here we allowed unrestrained monkeys to freely interact with concurrent reward options while we wirelessly recorded population activity in the dorsolateral prefrontal cortex. The animals decided when and where to forage based on whether their prediction of reward was fulfilled or violated. This prediction was not solely based on a history of reward delivery, but also on the understanding that waiting longer improves the chance of reward. The task variables were continuously represented in a subspace of the high-dimensional population activity, and this compressed representation predicted the animal's subsequent choices better than the true task variables and as well as the raw neural activity. Our results indicate that monkeys' foraging strategies are based on a cortical model of reward dynamics as animals freely explore their environment.

Visuo-frontal interactions during social learning in freely moving macaques.

Social interactions represent a ubiquitous aspect of our everyday life that we acquire by interpreting and responding to visual cues from conspecifics1. However, despite the general acceptance of this view, how visual information is used to guide the decision to cooperate is unknown. Here, we wirelessly recorded the spiking activity of populations of neurons in the visual and prefrontal cortex in conjunction with wireless recordings of oculomotor events while freely moving macaques engaged in social cooperation. As animals learned to cooperate, visual and executive areas refined the representation of social variables, such as the conspecific or reward, by distributing socially relevant information among neurons in each area. Decoding population activity showed that viewing social cues influences the decision to cooperate. Learning social events increased coordinated spiking between visual and prefrontal cortical neurons, which was associated with improved accuracy of neural populations to encode social cues and the decision to cooperate. These results indicate that the visual-frontal cortical network prioritizes relevant sensory information to facilitate learning social interactions while freely moving macaques interact in a naturalistic environment.

GSK-J4 Inhibition of KDM6B Histone Demethylase Blocks Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells by Modulating NF-κB Signaling.

Multiple signaling pathways facilitate the survival and drug resistance of malignant B-cells by regulating their migration and adhesion to microenvironmental niches. NF-κB pathways are commonly dysregulated in mantle cell lymphoma (MCL), but the exact underlying mechanisms are not well understood. Here, using a co-culture model system, we show that the adhesion of MCL cells to stromal cells is associated with elevated levels of KDM6B histone demethylase mRNA in adherent cells. The inhibition of KDM6B activity, using either a selective inhibitor (GSK-J4) or siRNA-mediated knockdown, reduces MCL adhesion to stromal cells. We showed that KDM6B is required both for the removal of repressive chromatin marks (H3K27me3) at the promoter region of NF-κB encoding genes and for inducing the expression of NF-κB genes in adherent MCL cells. GSK-J4 reduced protein levels of the RELA NF-κB subunit and impaired its nuclear localization. We further demonstrated that some adhesion-induced target genes require both induced NF-κB and KDM6B activity for their induction (e.g., IL-10 cytokine gene), while others require induction of NF-κB but not KDM6B (e.g., CCR7 chemokine gene). In conclusion, KDM6B induces the NF-κB pathway at different levels in MCL, thereby facilitating MCL cell adhesion, survival, and drug resistance. KDM6B represents a novel potential therapeutic target for MCL.

"Not Like This": Embodying Blackness and Childhood Cancer in the United States.

The embodiment of cancer is always shaped by multiple social identities and relations, including racial and developmental identities and relations. Here I explore how a 12-year-old, Black cancer patient, who I call Rashad, and his parents negotiated the entangled harms of cancer and anti-Black stereotypes in their everyday lives, inside and outside of healthcare settings. At the same time, I show that the embodiment of Blackness served as an affirmative and protective resource, as the family drew on cultures of hip-hop, Black kinship, and anti-racist activism in their attempts to ameliorate and heal the pain of life with cancer.

Properties of iconic and visuospatial working memory in pigeons and humans using a location change-detection procedure.

Tests of visuospatial memory following short (<1 s) and medium (1 to 30 s) delays have revealed characteristically different patterns of behavior in humans. These data have been interpreted as evidence for different memory systems operating during short (iconic memory) and long delays (working memory). Leising et al. (2019, Behavioural Processes, 169, Article 103957 ) found evidence for both systems in pigeons and humans completing a location change-detection task using a visual mask that disrupted accuracy following a short (100 ms), but not a long (1,000 ms) delay. Another common finding is that adding to-be-remembered items should disrupt accuracy after a long, but not short, delay. Experiments 1a and 1b reported this memory system crossover effect in pigeons and people, respectively, tested on location change detection with delays of 0, 100, and 1,000 ms and displays of two to 16 items. Experiments 2a and 2b reported that the color of the items had little (pigeons) or no (humans) effect on change-detection accuracy. Pigeons tested in Experiment 3 with longer delays (2,000, 4,000, and 8,000 ms) and large set sizes demonstrated the crossover effect with most displays but did not demonstrate an abrupt drop in accuracy characteristic of iconic memory. In Experiment 4, accuracy with novel types of change (color, shape, and size) was better after a 0-ms delay and above-chance levels on color and shape trials. These data demonstrate the memory system crossover effect in both humans and pigeons and expand our knowledge of the properties of memory systems across species.

Reliability of a standardized tool for evaluating severity of cellulite in the female posterior thigh.

Numerous products and minimally-invasive procedures are available to reduce cellulite. However, there are a limited number of tools to evaluate the effects of these interventions and some are relatively complex to implement. OBJECTIVE: This study evaluated the reliability of a standardized grading system for scoring the overall severity of cellulite on the posterior thigh. The study evaluated inter-rater and intra-rater (test/re-test) reliability of the method and engaged in an iterative process to develop a reliable method to evaluate changes in the appearance of cellulite. METHODS: There were two stages in the validation process. The first stage was an open process without evaluator training. The second stage was a more controlled process with training given and moderator involvement to review grade selections. In the first stage, inter-rater reliability was examined across five evaluators who were asked to evaluate 24 photographs (right thighs) based on a cellulite graded severity chart. During the second stage, the same photographs were examined by paired evaluators who had received additional training. Scores were independently moderated by a third person. The inter-rater reliability and intra-rater reliability over a 4-week interval were evaluated using intraclass correlation coefficients (ICCs). RESULTS: Twenty-four female participants (18-51 years, mean 31.68 ± 9.03 years) with a mean BMI of 29.04 ± 6.52 participated in the trial. Five female evaluators completed the initial evaluations. In stage 1, the inter-rater reliability (ICC2,5 ) was 0.838 (95%CI:0.700-0.922) and test/retest ICC3,1 values ranged from 0.360-0.990. In stage 2, the inter-rater reliability for 2 evaluators improved to 0.978 (95%CI:0.948-0.991), and the test/retest reliability of the moderated scoring method improved to 0.993 (95%CI:0.983-0.997). CONCLUSION: The iterative process developed a simple and reliable method of rating cellulite severity, with excellent inter-and intra-rater reliability, based on evaluating images of cellulite against a standard set of graded severity images. A reliable method of assessing cellulite severity is essential for undertaking future clinical trials to evaluate cellulite treatments.

Structural changes in the human stria vascularis induced by aminoglycosides and loop diuretics.

The human stria vascularis has been examined both by scanning and transmission electron microscopy in normal controls and from individuals who had received loop diuretics, aminoglycoside antibiotics or some combination of the two prior to their deaths. The tissues were preserved by perilymphatic perfusion of fixative within an hour of death and preservation was adequate. The normal ultrastructure is described and does not differ significantly from that found in experimental animals. The loop diuretics are associated with structural changes that cannot be distinguished from those found in animals treated with large doses of the same drugs. The aminoglycosides caused some changes, but the patients had been in renal failure and this probably contributed to the structural alterations. The combination of a loop diuretic and aminoglycoside was associated with a range of alterations from mild to severe. Overall, the three treatment groups had a series of ultrastructural changes resembling those found in animal models thereby justifying the use of experimental animals to predict human ototoxicity.

Tarsal coalition resections: a long-term retrospective analysis of 97 resections in 78 patients.

BACKGROUND: Resection of tarsal coalitions provides good patient satisfaction scores, reduced pain, and improved long-term function in both athletic and non-athletic populations. This study aimed to determine when athletic patients undergoing resection of a tarsal coalition were able to return to their desired activity, and whether they experienced a decreased desired activity level (DDA). METHODS: Data on a total of 78 patients who underwent 97 tarsal coalition resections (49 talocalcaneal coalitions, 47 calcaneo-navicular, 14 cuboid-navicular, and three cuneo-navicular; some patients had more than one coalition) operated between January 2001 and June 2020 were prospectively collected. To subjectively assess outcomes, the Roles and Maudsley score (RM) was utilized. RESULTS: At an average follow-up from the index procedure of 33.6 ± 41.5 months, return to activity for the entire cohort was 18.3 ± 9.6 weeks. Post-RM was 1.3 ± 0.6. CONCLUSION: Surgical excision of tarsal coalitions produced favorable results, with most patients able to return to their desired activity level. LEVEL OF EVIDENCE: IV.

Algal-Derived Halogenated Sesquiterpenes from Laurencia dendroidea as Lead Compounds in Schistosomiasis Environmental Control.

Schistosomiasis has been controlled for more than 40 years with a single drug, praziquantel, and only one molluscicide, niclosamide, raising concern of the possibility of the emergence of resistant strains. However, the molecular targets for both agents are thus far unknown. Consequently, the search for lead compounds from natural sources has been encouraged due to their diverse structure and function. Our search for natural compounds with potential use in schistosomiasis control led to the identification of an algal species, Laurencia dendroidea, whose extracts demonstrated significant activity toward both Schistosoma mansoni parasites and their intermediate host snails Biomphalaria glabrata. In the present study, three seaweed-derived halogenated sesquiterpenes, (-)-elatol, rogiolol, and obtusol are proposed as potential lead compounds for the development of anthelminthic drugs for the treatment of and pesticides for the environmental control of schistosomiasis. The three compounds were screened for their antischistosomal and molluscicidal activities. The screening revealed that rogiolol exhibits significant activity toward the survival of adult worms, and that all three compounds showed activity against S. mansoni cercariae and B. glabrata embryos. Biomonitored fractioning of L. dendroidea extracts indicated elatol as the most active compound toward cercariae larvae and snail embryos.

Algal-derived halogenated Sesquiterpenes from Laurencia dendroidea as lead compounds in Schistosomiasis environmental control

Schistosomiasis has been controlled for more than 40 years with a single drug, praziquantel, and only one molluscicide, niclosamide, raising concern of the possibility of the emergence of resistant strains. However, the molecular targets for both agents are thus far unknown. Consequently, the search for lead compounds from natural sources has been encouraged due to their diverse structure and function. Our search for natural compounds with potential use in schistosomiasis control led to the identification of an algal species, Laurencia dendroidea, whose extracts demonstrated significant activity toward both Schistosoma mansoni parasites and their intermediate host snails Biomphalaria glabrata. In the present study, three seaweed-derived halogenated sesquiterpenes, (−)-elatol, rogiolol, and obtusol are proposed as potential lead compounds for the development of anthelminthic drugs for the treatment of and pesticides for the environmental control of schistosomiasis. The three compounds were screened for their antischistosomal and molluscicidal activities. The screening revealed that rogiolol exhibits significant activity toward the survival of adult worms, and that all three compounds showed activity against S. mansoni cercariae and B. glabrata embryos. Biomonitored fractioning of L. dendroidea extracts indicated elatol as the most active compound toward cercariae larvae and snail embryos.

Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype.

The MYC transcription factor regulates a vast number of genes and is implicated in many human malignancies. In some hematological malignancies, MYC is frequently subject to missense mutations that enhance its transformation activity. Here, we use a novel murine cell system to (i) characterize the transcriptional effects of progressively increasing MYC levels as normal primary B-cells transform to lymphoma cells and (ii) determine how this gene regulation program is modified by lymphoma-associated MYC mutations (T58A and T58I) that enhance its transformation activity. Unlike many previous studies, the cell system exploits primary B-cells that are transduced to allow regulated MYC expression under circumstances where apoptosis and senescence pathways are abrogated by the over-expression of the Bcl-xL and BMI1 proteins. In such cells, transition from a normal to a lymphoma phenotype is directly dependent on the MYC expression level, without a requirement for secondary events that are normally required during MYC-driven oncogenic transformation. A generalized linear model approach allowed an integrated analysis of RNA sequencing data to identify regulated genes in relation to both progressively increasing MYC level and wild type or mutant status. Using this design, a total of 7569 regulated genes were identified, of which the majority (n = 7263) were regulated in response to progressively increased levels of wild type MYC, while a smaller number of genes (n = 917) were differentially regulated, compared to wild type MYC, in T58A MYC- and/or T58I MYC-expressing cells. Unlike most genes that are similarly regulated by both wild type and mutant MYC genes, the set of 917 genes did not significantly overlap with known lipopolysaccharide regulated genes, which represent genes regulated by MYC in normal B cells. The genes that were differently regulated in cells expressing mutant MYC proteins were significantly enriched in DNA replication and G2 phase to mitosis transition genes. Thus, mutants affecting MYC proteins may augment quantitative oncogenic effects on the expression of normal MYC-target genes with qualitative oncogenic effects, by which sets of cell cycle genes are abnormally targeted by MYC as B cells transition into lymphoma cells. The T58A and T58I mutations augment MYC-driven transformation by distinct mechanisms.

Migration and Adhesion of B-Lymphocytes to Specific Microenvironments in Mantle Cell Lymphoma: Interplay between Signaling Pathways and the Epigenetic Landscape.

Lymphocyte migration to and sequestration in specific microenvironments plays a crucial role in their differentiation and survival. Lymphocyte trafficking and homing are tightly regulated by signaling pathways and is mediated by cytokines, chemokines, cytokine/chemokine receptors and adhesion molecules. The production of cytokines and chemokines is largely controlled by transcription factors in the context of a specific epigenetic landscape. These regulatory factors are strongly interconnected, and they influence the gene expression pattern in lymphocytes, promoting processes such as cell survival. The epigenetic status of the genome plays a key role in regulating gene expression during many key biological processes, and it is becoming more evident that dysregulation of epigenetic mechanisms contributes to cancer initiation, progression and drug resistance. Here, we review the signaling pathways that regulate lymphoma cell migration and adhesion with a focus on Mantle cell lymphoma and highlight the fundamental role of epigenetic mechanisms in integrating signals at the level of gene expression throughout the genome.

Association between Predicted Effects of TP53 Missense Variants on Protein Conformation and Their Phenotypic Presentation as Li-Fraumeni Syndrome or Hereditary Breast Cancer.

Rare germline pathogenic TP53 missense variants often predispose to a wide spectrum of tumors characterized by Li-Fraumeni syndrome (LFS) but a subset of variants is also seen in families with exclusively hereditary breast cancer (HBC) outcomes. We have developed a logistic regression model with the aim of predicting LFS and HBC outcomes, based on the predicted effects of individual TP53 variants on aspects of protein conformation. A total of 48 missense variants either unique for LFS (n = 24) or exclusively reported in HBC (n = 24) were included. LFS-variants were over-represented in residues tending to be buried in the core of the tertiary structure of TP53 (p = 0.0014). The favored logistic regression model describes disease outcome in terms of explanatory variables related to the surface or buried status of residues as well as their propensity to contribute to protein compactness or protein-protein interactions. Reduced, internally validated models discriminated well between LFS and HBC (C-statistic = 0.78-0.84; equivalent to the area under the ROC (receiver operating characteristic) curve), had a low risk for over-fitting and were well calibrated in relation to the known outcome risk. In conclusion, this study presents a phenotypic prediction model of LFS and HBC risk for germline TP53 missense variants, in an attempt to provide a complementary tool for future decision making and clinical handling.

Structural Variation and Chemical Performance-A Study of the Effects of Chemical Structure upon Epoxy Network Chemical Performance.

Epoxy resins are used widely as protective coatings, in a wide range of harsh chemical environments. This work explores the influence of subtle structural variation in both epoxy and amine monomers upon chemical performance of cured networks, whether changing molecular geometry, the nature of the chemistry, or the mass between cross-linking reactive groups. To achieve this, four industrially relevant epoxy resins (two based on bisphenol A-Epikote 828 (E828) and Dow Epoxy Resin 332 (DER 332)-and two based on bisphenol F-Dow Epoxy Resin 354 (DER 354) and Araldite PY306 (PY306)) and the isomerically pure para-para-diglycidyl ether of bisphenol F (ppDGEBF) were used to explore variation caused by epoxy monomer variation. Four similar amines (meta-xylylenediamine (MXDA), para-xylylenediamine (PXDA), 1,3-bis(aminomethyl)cyclohexane (1,3-BAC), 1,4-bis(aminomethyl)cyclohexane (1,4-BAC)) were used to explore any variations caused by regioisomerism and aromaticity. Bisphenol F-based resins were found to outperform bisphenol A-based analogues, and chain extension within the epoxy component was found to be detrimental to performance. For amines, 1,3-substitution (vs 1,4) and aromaticity were both found to be beneficial to chemical performance.

Intrinsic 5-lipoxygenase activity regulates migration and adherence of mantle cell lymphoma cells.

Human B-lymphocytes express 5-lipoxygenase (5-LOX) and 5-LOX activating protein (FLAP) and can convert arachidonic acid to leukotriene B4. Mantle cell lymphoma (MCL) cells contain similar amounts of 5-LOX as human neutrophils but the function and mechanism of activation of 5-LOX in MCL cells, and in normal B-lymphocytes, are unclear. Here we show that the intrinsic 5-LOX pathway in the MCL cell line JeKo-1 has an essential role in migration and adherence of the cells, which are important pathophysiological characteristics of B-cell lymphoma. Incubation of JeKo-1 with the FLAP inhibitor GSK2190915 or the 5-LOX inhibitor zileuton, at a concentration below 1 µM, prior to stimulation with the chemotactic agent CXCL12, led to a significant reduction of migration. CRISPR/Cas9 mediated deletion of ALOX5 gene in JeKo-1 cells also led to a significantly decreased migration of the cells. Furthermore, 5-LOX and FLAP inhibitors markedly decreased the adherence of JeKo-1 cells to stromal cells. In comparison, these drugs had a similar effect on adherence of JeKo-1 cells as the Bruton tyrosine kinase inhibitor ibrutinib, which has a proven anti-tumour effect. These results indicate that inhibition of 5-LOX may be a novel treatment for MCL and certain other B-cell lymphomas.

Novel Self-Nano-Emulsifying Drug Delivery Systems Containing Astaxanthin for Topical Skin Delivery.

Astaxanthin (ASX) is a potent lipophilic antioxidant derived from the natural pigment that gives marine animals their distinctive red-orange colour and confers protection from ultraviolet radiation. Self nano-emulsifying drug delivery systems (SNEDDS) have been successfully developed and evaluated to increase the skin penetration of ASX and target its antioxidant and anti-inflammatory potential to the epidermis and dermis. SNEDDS were prepared using a low-temperature spontaneous emulsification method, and their physical characteristics, stability, antioxidant activity, and skin penetration were characterized. Terpenes (D-limonene, geraniol, and farnesol) were included in the SNEDDS formulations to evaluate their potential skin penetration enhancement. An HPLC assay was developed that allowed ASX recovery from skin tissues and quantification. All SNEDDS formulations had droplets in the 20 nm range, with low polydispersity. ASX stability over 28 days storage in light and dark conditions was improved and antioxidant activity was high. SNEDDS-L1 (no terpene) gave significantly increased ASX penetration to the stratum corneum (SC) and the epidermis-dermis-follicle region (E + D + F) compared to an ASX in oil solution and a commercial ASX facial serum product. The SNEDDS-containing D-limonene gave the highest ASX permeation enhancement, with 3.34- and 3.79-fold the amount in the SC and E + D + F, respectively, compared to a similar applied dose of ASX in oil. We concluded that SNEDDS provide an effective formulation strategy for enhanced skin penetration of a highly lipophilic molecule, and when applied to ASX, have the potential to provide topical formulations for UV protection, anti-aging, and inflammatory conditions of the skin.

Abstract-concept learning in two species of new world corvids, pinyon jays (Gymnorhinus Cyanocephalus) and California scrub jays (Aphelocoma Californica).

concepts require individuals to identify relationships between novel stimuli. Previous studies have reported that the ability to learn abstract concepts is found in a wide range of species. In regard to a same/different concept, Clark's nutcrackers (Nucifraga columbiana) and black-billed magpies (Pica hudsonia), two corvid species, were shown to outperform other avian and primate species (Wright et al., 2017). Two additional corvid species, pinyon jays (Gymnorhinus cyanocephalus) and California scrub jays (Aphelocoma californica) chosen as they belong to a different clade than nutcrackers and magpies, were examined using the same set-size expansion procedure of the same/different task (the task used with nutcrackers and magpies) to evaluate whether this trait is common across the Corvidae lineage. During this task, concept learning is assessed with novel images after training. Results from the current study showed that when presented with novel stimuli after training with an 8-image set, discrimination accuracy did not differ significantly from chance for pinyon jays and California scrub jays, unlike the magpies and nutcrackers from previous studies that showed partial transfer at that stage. However, concept learning improved with each set-size expansion, and the jays reached full concept learning with a 128-image set. This performance is similar to the other corvids and monkeys tested, all of which outperform pigeons. Results from the current study show a qualitative similarity in full abstract-concept learning in all species tested with a quantitative difference in the set-size functions, highlighting the shared survival importance of mechanisms supporting abstract-concept learning for corvids and primates. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

3D heterospecies spheroids of pancreatic stroma and cancer cells demonstrate key phenotypes of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, partly due to the dense desmoplasia and a lack of suitable model systems to study. In the present work, we developed a 3D heterospecies spheroid model to study the microenvironmental interactions between tumor cells and stellate cells which can also be employed to test therapeutic regimens. We set up monospheroids and heterospheroids made up from murine pancreatic stellate cells (mPSCs) and human PDAC cells (Panc1), which allowed for direct isolation of mRNA from a mixed cell population followed by an in silico separation of the RNA-seq reads. Global transcript level changes for cells in heterospheroids versus monospheroids were calculated, followed by gene set enrichment analysis and molecular subtype analysis. We observed an apparent shift of Panc1 from the classical to the squamous/basal-like phenotype upon co-culture with mPSCs. Moreover, mPSCs acquired a different cancer-associated fibroblast-related phenotype upon co-culture with Panc1. We analyzed the tumor cell-specific chemosensitivities towards gemcitabine, paclitaxel and SN38 and compared these to published pharmacotranscriptomic signatures. In conclusion, our heterospecies spheroid model reflected key aspects of PDAC and facilitated the study of intercellular interactions between tumor and stroma while additionally proving to be a good model for studying therapeutic responses.