Capsaicin triggers autophagic cell survival which drives epithelial mesenchymal transition and chemoresistance in bladder cancer cells in an Hedgehog-dependent manner

Bladder cancer (BC) is a common urologic tumor characterized by high risk of recurrence and mortality. Capsaicin (CPS), used as an intravesical drug for overactive bladder, was demonstrated to induce cell death in different cancer cells including BC cells.Here we found that treatment of high-grade BC cells with high dose of CPS triggers autophagy. Infact, the CPS treatment alters the redox homeostasis by inducing production of radicals, mitochondrial depolarization, alterations of ADP/ATP ratio and activation of AMPK pathway stimulating the autophagic process in BC cells. The inhibition of autophagy, by using the specific inhibitor bafilomycin A or Beclin 1 knock-down, enhanced the CPS-induced cell death, demonstrating that CPS-induced autophagy acts as a pro-survival process in BC cells. By using PCR arrays and FACS analysis, we found that the CPS-treated BC cells displayed typical mesenchymal features of the epithelial mesenchymal transition (EMT) as elongated shape and over-expression of vimentin, α5 and β1 integrin subunits, integrin-like kinase and the anti-apoptotic Bcl-2 proteins. Moreover, we demonstrated that CPS treatment stimulates upregulation of Dhh/Ptch2/Zeb2 members of the Hedgehog signaling pathway, increases CD24, VEGFA and TIMP1 and decreases CD44 and ALCAM mRNA expression levels. By PTCH2 knock-down we found that the Hedgehog signaling pathway is involved in the CPS-induced autophagy and EMT phenotype.Finally, we also showed that the CPS-resistant EMT-positive BC cells displayed an increased drug-resistance to the cytotoxic effects of mitomycin C, gemcitabine and doxorubicine drugs commonly used in BC therapy

Lithium abundances in globular cluster giants: NGC 6218 (M12) and NGC 5904 (M5)

Convergent lines of evidence suggest that globular clusters host multiple stellar populations. It appears that they experience at least two episodes of star formation whereby a fraction of first-generation stars contribute astrated ejecta to form the second generation(s). To identify the polluting progenitors we require distinguishing chemical signatures such as that provided by lithium. Theoretical models predict that lithium can be synthesised in AGB stars, whereas no net Li production is expected from other candidates. It has been shown that in order to reproduce the abundance pattern found in M4, Li production must occur within the polluters, favouring the AGB scenario. Here we present Li and Al abundances for a large sample of RGB stars in M12 and M5. These clusters have a very similar metallicity, whilst demonstrating differences in several cluster properties. Our results indicate that the first-generation and second-generation stars share the same Li content in M12; we recover an abundance pattern similar to that observed in M4. In M5 we find a higher degree of complexity and a simple dilution model fails in reproducing the majority of the stellar population. In both clusters we require Li production across the different stellar generations, but production seems to have occurred to different extents. We suggest that such a difference might be related to the cluster mass with the Li production being more efficient in less-massive clusters. This is the first time a statistically significant correlation between the Li spread within a GC and its luminosity has been demonstrated. Finally, although Li-producing polluters are required to account for the observed pattern, other mechanisms, such as MS depletion, might have played a role in contributing to the Li internal variation, though at relatively low level.Comment: Accepted for publication in The Astrophysical Journal. 15 pages, 14 figure

Axitinib induces senescence-associated cell death and necrosis in glioma cell lines: The proteasome inhibitor, bortezomib, potentiates axitinib-induced cytotoxicity in a p21(Waf/Cip1) dependent manner.

Glioblastoma is associated with a poor overall survival despite new treatment advances. Antiangiogenic strategies targeting VEGF based on tyrosine kinase inhibitors (TKIs) are currently undergoing extensive research for the treatment of glioma. Herein we demonstrated that the TKI axitinib induces DNA damage response (DDR) characterized by γ-H2AX phosphorylation and Chk1 kinase activation leading to G2/M cell cycle arrest and mitotic catastrophe in U87, T98 and U251 glioma cell lines. Moreover, we found that p21(Waf1/Cip1) increased levels correlates with induction of ROS and senescence-associated cell death in U87 and T98 cell lines, which are reverted by N-acetyl cysteine pretreatment. Conversely, U251 cell line showed a resistant phenotype in response to axitinib treatment, as evidenced by cell cycle arrest but no sign of cell death. The combinatorial use of axitinib with other therapies, with the aim of inhibiting multiple signaling pathways involved in tumor growth, can increase the efficiency of this TKI. Thus, we addressed the combined effects of axitinib with no toxic doses of the proteasome inhibitor bortezomib on the growth of U87 and T98 axitinib- sensitive and axitinib-resistant U251 cell lines. Compared to single treatments, combined exposure was more effective in inhibiting cell viability of all glioma cell lines, although with different cell death modalities. The regulation of key DDR and cell cycle proteins, including Chk1, γ-H2AX and p21(Waf1/Cip1) was also studied in glioma cell lines. Collectively, these findings provide new perspectives for the use of axitinib in combination with Bortezomib to overcome the therapy resistance in gliomas

On the serendipitous discovery of a Li-rich giant in the globular cluster NGC 362

We have serendipitously identified the first lithium-rich giant star located close to the red giant branch bump in a globular cluster. Through intermediate-resolution FLAMES spectra we derived a lithium abundance of A(Li)=2.55 (assuming local thermodynamical equilibrium), which is extremely high considering the star's evolutionary stage. Kinematic and photometric analysis confirm the object as a member of the globular cluster NGC 362. This is the fourth Li-rich giant discovered in a globular cluster but the only one known to exist at a luminosity close to the bump magnitude. The three previous detections are clearly more evolved, located close to, or beyond the tip of their red giant branch. Our observations are able to discard the accretion of planets/brown dwarfs, as well as an enhanced mass-loss mechanism as a formation channel for this rare object. Whilst the star sits just above the cluster bump luminosity, its temperature places it towards the blue side of the giant branch in the colour-magnitude diagram. We require further dedicated observations to unambiguously identify the star as a red giant: we are currently unable to confirm whether Li production has occurred at the bump of the luminosity function or if the star is on the pre zero-age horizontal branch. The latter scenario provides the opportunity for the star to have synthesised Li rapidly during the core helium flash or gradually during its red giant branch ascent via some extra mixing process.Comment: Accepted for publication in The Astrophysical Journal Letter

Pain From Bluebottle Jellyfish Stings

An 11‐year‐old girl presented to the emergency department with severe pain after a jellyfish sting at a New South Wales beach. Bluebottle (Physalia) jellyfish was deemed the most likely cause considering her geographical location. The Australian Resuscitation Council Guideline (2010) suggests immersing in water as hot as can be tolerated for 20 min for treating pain from jellyfish stings. This guideline was written based on past case reports, books and randomised controlled trials (RCTs). We performed a search to assess the most current evidence for relief of pain from Bluebottle jellyfish stings, which yielded two systematic reviews and seven RCT s. Both systematic reviews had similar conclusions, with one of the RCT s used in both reviews showing the most relevance to our presenting patient in terms of demographics, location and jellyfish type. This journal club article is an appraisal of this RCT by Loten et al . and the validity of its conclusion that hot water immersion is most effective for the relief of pain from Bluebottle stings

A time-varying shared frailty model with application to infectious diseases

We propose a new parametric time-varying shared frailty model to represent changes over time in population heterogeneity, for use with bivariate current status data. The model uses a power transformation of a time-invariant frailty U, and is particularly convenient when U is a member of the generalized gamma family. This model avoids some shortcomings of a previously suggested time-varying frailty model, notably time-dependent support. We describe some key properties of the model, including its relative frailty variance function in different settings and how the model can be fitted to data. We describe several applications to shared frailty modeling of bivariate current status data on infectious diseases, in which the frailty represents age-dependent heterogeneity in contact rates or susceptibility to infection

Therapy-based exercise from the perspective of adult patients: a qualitative systematic review conducted using an ethnographic approach

© The Author(s) 2019.Objectives: Many patients do not meet recommended levels of therapy-based exercise. This review aims to explore how adult patients view being prescribed therapy-based exercise, the information/education they are given and receive and if/how they independently practise and adhere. Design: A qualitative systematic review conducted using an ethnographic approach and in accordance with the PRISMA statement. Sources: PubMed, CINAHL, SCOPUS and EMBASE databases (01 January 2000–31 December 2018). Methods: Qualitative studies with a focus on engagement/adherence with therapy-based exercise were included. Data extraction and quality appraisal were undertaken by two reviewers. Results were discussed and data synthesized. Results: A total of 20,294 titles were screened, with data extracted from 39 full texts and data from 18 papers used to construct three themes. ‘The Guidance received’ suggests that the type of delivery desired to support and sustain engagement was context-dependent and individually situated. ‘The Therapist as teacher’ advocates that patients see independent therapy-based exercise as a shared activity and value caring, kind and professional qualities in their therapist. ‘The Person as learner’ proposes that when having to engage with and practise therapy-based exercise because of ill-health, patients often see themselves as new learners who experience fear and uncertainty about what to do. Patients may have unacknowledged ambivalences about learning that impact on engagement and persistence. Conclusion: The quality of the interaction between therapists and patients appears integral to patients engaging with, and sustaining practice of, rehabilitation programmes. Programmes need to be individualized, and health care professionals need to take patients’ previous experiences and ambivalences in motivation and empowerment into account.Peer reviewe

Purification and characterization of an intracellular aminopeptidase from a wild strain of Lactobacillus plantarum isolated from traditional Serra da Estrela cheese

An intracellular hydrolase able to cleave Image -lysine-p-nitroanilide was purified from Lactobacillus plantarum strain ESB5004 via two steps of precipitation with ammonium sulfate (at 30 and 50% (w/v)), followed by hydrophobic interaction and ion-exchange chromatographies. The aminopeptidase was purified up to 11-fold, with a final yield of ca. 1%. Its native molecular weight is ca. 70 kDa, and it is apparently composed of two subunits, the molecular weight of which is 34 kDa. The enzyme was assayed using a wide variety of p-nitroanilide (pNA) derivatives as substrates: it hydrolyzed preferentially pNA adducts of hydrophobic and basic amino acid residues; no hydrolysis was in particular observed of Glu-pNA, Gly-pNA or Pro-pNA. The enzyme activity was removed by the metal-chelating agent EDTA, thus suggesting that it is a metallo-enzyme; however, the EDTA-inhibited enzyme was reactivated in the presence of Co2+. Optimal aminopeptidase activity was obtained at 28 °C (pH 7.0) and pH 6.5 (37 °C). The enzyme was inhibited by 10 mM CaCl2 or MgCl2

Influence of native lactic acid bacteria on the microbiological, biochemical and sensory profiles of Serra da Estrela cheese

Cheesemaking from batches of raw ewe’s milk was carried out via inoculation with wild strains of Lactococcus lactis subsp. lactis ESB110019 and Lactobacillus plantarum ESB5004 independently, or combined with each other. Those two strains had been isolated from the native microflora of typical Serra da Estrela cheese. One control batch was processed in parallel without addition of any starter. The evolution in viable counts of the main micro-organisms (viz. lactic acid bacteria, Enterobacteriaceae, staphylococci and yeasts), as well as in secondary proteolysis (WSN, 2% TCASN, 12% TCASN and 5% PTASN), was monitored throughout ripening time (over a 63-day period) in cheeses from each batch. The sensory features of the fully ripened cheeses were also assessed. Cheeses manufactured with starter showed significantly lower levels of viable Enterobacteriaceae than those manufactured without starter; viable counts of enterococci and staphylococci did significantly increase after addition of L. lactis or Lb. plantarum, respectively. Proteolysis in terms of WSN and 5% PTASN was not significantly affected by the lactic acid bacteria tested when compared to the control, but L. lactis played a significant role toward increasing the 2% TCASN content of cheeses; both strains led to a statistically significant increase of the 12% TCASN. The scores for flavor and texture of the control cheeses were somewhat above those for the experimental cheeses manufactured with starter

Integrated management strategies for chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) remains the fourth leading cause of death, is associated with significant morbidity and places a substantial time and cost burden on the health care system. Unfortunately, treatment for COPD remains underutilized and continues to focus on the acute care of complications. The chronic care model (CCM) shifts this focus from the acute management of symptoms and complications to the prevention and optimal management of the chronic disease. This model utilizes resources from the community and the health care system and emphasizes self-management, provides comprehensive clinic support, and implements evidence-based guidelines and technology into clinical practice to ensure delivery of the highest quality of care. The goal of this review is to use a case-based approach to provide practical information about how integrated care using the CCM can be applied to the clinical care of a complex patient with COPD, shifting the management goals for COPD from reactive to proactive and ultimately improving outcomes