Melanoma is a lethal form of skin cancer triggered by genetic and environmental factors. Excision of early-stage, poorly aggressive melanoma often leads to a successful outcome; however, left ...undiagnosed these lesions can progress to metastatic disease. This research investigates whether the exposure of poorly aggressive melanoma to certain normal skin cells can explain how non-metastatic melanoma becomes more aggressive while still confined to the skin. To this end, we used a serial co-culture approach to sequentially expose cells from two different, poorly aggressive human melanoma cell lines against normal cells of the skin beginning with normal melanocytes, then epidermal keratinocytes, and finally dermal fibroblasts. Protein extraction of melanoma cells occurred at each step of the co-culture sequence for western blot (WB) analysis. In addition, morphological and functional changes were assessed to detect differences between the serially co-cultured melanoma cells and non-co-cultured cells. Results show that the co-cultured melanoma cells assumed a more mesenchymal morphology and displayed a significant increase in proliferation and invasiveness compared to control or reference cells. WB analysis of protein from the co-cultured melanoma cells showed increased expression of Snail and decreased levels of E-cadherin suggesting that epithelial-to-mesenchymal transition (EMT) is occurring in these co-cultured cells. Additional WB analysis showed increased levels of Nodal protein and signaling and signs of increased Wnt activity in the co-cultured melanoma cells compared to reference cells. These data suggest that interaction between poorly aggressive melanoma cells with normal cells of the skin may regulate the transition from localized, poorly aggressive melanoma to invasive, metastatic disease via Nodal and/or Wnt induced EMT.
Role of Presenilin-1 in Aggressive Human Melanoma Sidor, Julia; Gillette, Megan; Dezi, Lindsay Ann ...
International journal of molecular sciences,
04/2022, Letnik:
23, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer's disease (AD) and in tumorigenesis. Interestingly, AD risk is inversely related to ...melanoma, suggesting that AD-related factors, such as PS-1, may affect melanomagenesis. PS-1 has been shown to reduce Wnt activity by promoting degradation of beta-catenin (β-catenin), an important Wnt signaling partner. Since Wnt is known to enhance progression of different cancers, including melanoma, we hypothesized that PS-1 could affect Wnt-associated melanoma aggressiveness. Western blot results showed that aggressive melanoma cells expressed significantly lower levels of both PS-1 and phosphorylated-β-catenin (P-β-catenin) than nonaggressive melanoma cells. Immunohistochemistry of human melanoma samples showed significantly reduced staining for PS-1 in advanced stage melanoma compared with early stage melanoma. Furthermore, γ-secretase inhibitor (GSI) treatment of aggressive melanoma cells was followed by significant increases in PS-1 and P-β-catenin levels, suggesting impaired Wnt signaling activity as PS-1 expression increased. Finally, a significant reduction in cell migration was associated with the higher levels of PS-1 and P-β-catenin in the GSI-treated aggressive melanoma cells. We demonstrate for the first time that PS-1 levels can be used to assess melanoma aggressiveness and suggest that by enhancing PS-1 expression, Wnt-dependent melanoma progression may be reduced.
Summary
Background
Youth in rural areas are disproportionally affected by obesity. Given the unique barriers rural populations face, tailoring and increasing access to obesity interventions is ...necessary.
Objective
This paper evaluates the effectiveness of iAmHealthy, a family‐based paediatric obesity intervention delivered to rural children, compared to a Newsletter Control.
Methods
Participating schools (n = 18) were randomly assigned to iAmHealthy or Newsletter Control. iAmHealthy consists of individual health coaching and group sessions delivered via televideo to a participant's home. The child and parent's body mass index (BMI), child physical activity and child dietary intake were assessed at baseline, post‐treatment (8 months) and follow‐up (20 months). Multilevel modeling estimated the effect of treatment at both time points.
Results
Parent and child dyads were recruited (n = 148) and randomised to iAmHealthy (n = 64) or the Control group (n = 84). The Control group had significant increases in child BMIz from baseline to follow‐up. iAmHealthy youth had no significant changes in BMIz from baseline to post or follow‐up. Child dietary intake, physical activity and parent BMI results are also discussed.
Conclusions
This trial extends previous paediatric obesity work by simultaneously increasing convenience and dose of treatment. Results suggest iAmHealthy resulted in a change in BMIz trajectories and long‐term health behaviour for youth.
Histological evidence points to the presence of dopamine (DA) in the cephalic sensory organs of multiple gastropod molluscs, suggesting a possible sensory role for the neurotransmitter. We ...investigated the sensory function of DA in the nudipleuran Pleurobranchaea californica, in which the central neural correlates of sensation and foraging behavior have been well characterized. Tyrosine hydroxylase-like immunoreactivity (THli), a signature of the dopamine synthetic pathway, was similar to that found in two other opisthobranchs and two pulmonates previously studied: 1) relatively few (<100) THli neuronal somata were observed in the central ganglia, with those observed found in locations similar to those documented in the other snails but varying in number, and 2) the vast majority of THli somata were located in the peripheral nervous system, were associated with ciliated, putative primary sensory cells, and were highly concentrated in chemotactile sensory organs, giving rise to afferent axons projecting to the central nervous system. We extended these findings by observing that applying a selective D2/D3 receptor antagonist to the chemo- and mechanosensory oral veil-tentacle complex of behaving animals significantly delayed feeding behavior in response to an appetitive stimulus. A D1 blocker had no effect. Recordings of the two major cephalic sensory nerves, the tentacle and large oral veil nerves, in a deganglionated head preparation revealed a decrease of stimulus-evoked activity in the former nerve following application of the same D2/D3 antagonist. Broadly, our results implicate DA in sensation and engender speculation regarding the foraging-based decisions the neurotransmitter may serve in the nervous system of Pleurobranchaea and, by extension, other gastropods.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The treatment of chronic pain is poorly managed by current analgesics, and there is a need for new classes of drugs. We recently developed a series of bioactive lipids that inhibit the human glycine ...transporter GlyT2 (SLC6A5) and provide analgesia in animal models of pain. Here, we have used functional analysis of mutant transporters combined with molecular dynamics simulations of lipid-transporter interactions to understand how these bioactive lipids interact with GlyT2. This study identifies a novel extracellular allosteric modulator site formed by a crevice between transmembrane domains 5, 7, and 8, and extracellular loop 4 of GlyT2. Knowledge of this site could be exploited further in the development of drugs to treat pain, and to identify other allosteric modulators of the SLC6 family of transporters.
The purpose of this study is to evaluate two recruitment strategies on schools and participant participation rates and representativeness (reach) within a pediatric obesity treatment trial tailored ...for families who live in rural areas.
Recruitment of schools was evaluated based on their progress toward enrolling participants. Recruitment and reach of participants were evaluated using (1) participation rates and (2) representativeness of demographics and weight status of participants compared to eligible participants (who did not consent and enroll) and all students (regardless of eligibility). School recruitment, as well as participant recruitment and reach, were evaluated across recruitment methods comparing opt-in (i.e., caregivers agreed to allow their child to be screened for eligibility) vs. screen-first (i.e., all children screened for eligibility).
Of the 395 schools contacted, 34 schools (8.6%) expressed initial interest; of these, 27 (79%) proceeded to recruit participants, and 18 (53%) ultimately participated in the program. Of schools who initiated recruitment, 75% of schools using the opt-in method and 60% of schools using the screen-first method continued participation and were able to recruit a sufficient number of participants. The average participation rate (number of enrolled individuals divided by those who were eligible) from all 18 schools was 21.6%. This percentage was higher in schools using the screen-first method (average of 29.7%) compared to schools using the opt-in method (13.5%). Study participants were representative of the student population based on sex (female), race (White), and eligibility for free and reduced-price lunch. Study participants had higher body mass index (BMI) metrics (BMI, BMIz, and BMI%) than eligible non-participants.
Schools using the opt-in recruitment were more likely to enroll at least 5 families and administer the intervention. However, the participation rate was higher in screen-first schools. The overall study sample was representative of the school demographics.
Background: Youth in rural areas are disproportionally affected by pediatric obesity. Given the unique barriers rural populations face, tailoring and increasing access to obesity interventions is ...necessary. This study evaluated the effectiveness of a family-based pediatric obesity intervention delivered to rural children via televideo to a participant's home (iAmHealthy). Methods: Participating schools (n = 18) were randomly assigned to iAmHealthy or a newsletter control group. iAmHealthy is a family-based obesity intervention consisting of biweekly individual health coaching and 8 weekly group sessions followed by six monthly group sessions. Child height/weight and physical activity (MVPA) were assessed at baseline, post-treatment (8 months) and follow-up (20 months). Multi-level modeling accounting for the study's nested design estimated the effect of treatment on outcomes at both timepoints. Results: 148 youth (Mage = 8.9; 56.8% female; 87.1% White) were randomized to iAmHealthy (n = 64) or the control group (n = 84). For child BMIz change, the control group had a marginally significant increase, F (1,130) = 3.82, p = 0.053, from baseline to post and a significant increase, F(1,121) = 12.88, p < 0.001, from baseline to follow-up. The iAmHealthy group had no significant changes in BMIz from baseline to post or follow-up. For average daily MVPA, no differences were observed from baseline to post in either group; however, from baseline to follow-up a significant decrease was observed in the control group (F (1,97) = 20.59, p < 0.001), while iAmHealthy had no significant changes. Conclusions: This trial extends previous pediatric obesity work in an innovative direction by increasing convenience (moving the mHealth intervention into rural family homes) and dose of treatment. Results at follow-up suggest improved BMIz trajectories and long-term health behaviors for youth in the iAmHealthy group compared to the control group.
To examine the early impact of the COVID-19 pandemic on rural parental stress and family behaviors, parents who participated in a 2
nd
-4
th
grade pediatric obesity intervention completed a survey in ...May 2020. Parents (N = 77) experienced 7.8 ± 2.7 events on the COVID-19 Exposure and Family Impact Scales (CEFIS) with an average impact of 2.5 ± 0.5, with many parents reporting moderate stress (73%). Parental stress was predictive of personal well-being getting "worse" while loss of income events were predictive of family routines getting "better." Professionals working with rural families may want to assess for these factors when promoting positive changes in family health behaviors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Abstract
The prostate tumor microenvironment (TME) is strongly immunosuppressive; it is largely driven by alteration in cell phenotypes (i.e. tumor-associated macrophages and exhausted cytotoxic T ...cells) that result in pro-tumorigenic conditions and tumor growth. A greater understanding into how these altered immune cell phenotypes are developed and could potentially be reversed would provide important insights into improved treatment efficacy for prostate cancer. Here, we report a microfluidic model of the prostate TME that mimics prostate ducts across various stages of prostate cancer progression, with associated stroma and immune cells. Using this platform, we exposed immune cells to a benign prostate TME or a metastatic prostate TME and investigated their metabolism, gene and cytokine expression. Immune cells exposed to the metastatic TME showed metabolic differences with a higher redox ratio indicating a switch to a more glycolytic metabolic profile. These cells also increased expression of pro-tumor response cytokines that have been shown to increase cell migration and angiogenesis such as Interleukin-1 (IL-1) a and Granulocyte-macrophage colony-stimulating factor (GM-CSF). Lastly, we observed decreased TLR, STAT signaling and TRAIL expression, suggesting that phenotypes derived from exposure to the metastatic TME could have an impaired anti-tumor response. This platform could provide a valuable tool for studying immune cell phenotypes in in vitro tumor microenvironments.
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