Transforming growth factor-β and oxidative stress in cancer: A crosstalk in driving tumor transformation.

SIMPLE SUMMARY: Metabolic changes in tumor microenvironment play a critical role in cancer, related to the accumulated alterations in signaling pathways that control cellular metabolism. Cancer metabolic deregulation is related to specific events such as the control of oxidative stress, and in particular the redox imbalance with aberrant oxidant production and/or a deregulation of the efficacy of the antioxidant systems. In cancer cells, different cytokines are involved in the development and/or progression of cancer; among these cytokines, the transforming growth factor β (TGF-β) is central to tumorigenesis and cancer progression. In tumor cells, it has been demonstrated that there is a close correlation between oxidative stress and TGF-β; this crosstalk strongly contributes to tumorigenesis, both in tumor development and in mediating its invasiveness. This review is addressed to better understanding this crosstalk between TGF-β and oxidative stress in cancer cell metabolism, in an attempt to improve the pharmacological and therapeutic approach against cancer. ABSTRACT: Cancer metabolism involves different changes at a cellular level, and altered metabolic pathways have been demonstrated to be heavily involved in tumorigenesis and invasiveness. A crucial role for oxidative stress in cancer initiation and progression has been demonstrated; redox imbalance, due to aberrant reactive oxygen species (ROS) production or deregulated efficacy of antioxidant systems (superoxide dismutase, catalase, GSH), contributes to tumor initiation and progression of several types of cancer. ROS may modulate cancer cell metabolism by acting as secondary messengers in the signaling pathways (NF-kB, HIF-1α) involved in cellular proliferation and metastasis. It is known that ROS mediate many of the effects of transforming growth factor β (TGF-β), a key cytokine central in tumorigenesis and cancer progression, which in turn can modulate ROS production and the related antioxidant system activity. Thus, ROS synergize with TGF-β in cancer cell metabolism by increasing the redox imbalance in cancer cells and by inducing the epithelial mesenchymal transition (EMT), a crucial event associated with tumor invasiveness and metastases. Taken as a whole, this review is addressed to better understanding this crosstalk between TGF-β and oxidative stress in cancer cell metabolism, in the attempt to improve the pharmacological and therapeutic approach against cancer

Identification of redox-sensitive transcription factors as markers of malignant pleural mesothelioma.

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer

Stochastic PCA-based bone models from inverse transform sampling: Proof of concept for mandibles and proximal femurs

Principal components analysis is a powerful technique which can be used to reduce data dimensionality. With reference to three-dimensional bone shape models, it can be used to generate an unlimited number of models, defined by thousands of nodes, from a limited (less than twenty) number of scalars. The full procedure has been here described in detail and tested. Two databases were used as input data: the first database comprised 40 mandibles, while the second one comprised 98 proximal femurs. The “average shape” and principal components that were required to cover at least 90% of the whole variance were identified for both bones, as well as the statistical distributions of the respective principal components weights. Fifteen principal components sufficed to describe the mandibular shape, while nine components sufficed to describe the proximal femur morphology. A routine has been set up to generate any number of mandible or proximal femur geometries, according to the actual statistical shape distributions. The set-up procedure can be generalized to any bone shape given a sufficiently large database of the respective 3D shapes

1601d Hazard determinants of carbon nanotubes (cnts) driving molecular initiating events (mies) in adverse outcome pathways (aops) of airways diseases

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Efficacy and safety of dalbavancin in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and other infections in a real-life setting: data from an Italian observational multicentric study (DALBITA study)

Objectives: We evaluated the efficacy and safety of dalbavancin in ABSSSI and ‘other sites’ infections’ (OTA). Methods: Observational study involving 11 Italian hospitals including patients that received ≥1 dose of dalbavancin in 2016–2019. The outcome was end-of-treatment efficacy and safety in ABSSSI and OTA in a real-life setting. Results: 206 patients enrolled (males 50%, median age 62 [IQR 50–76] years), 60.2% ABSSSI, 39.8% OTA. 69.7% ABSSSI vs 90.7% OTA (p = 0.003) and 46.3% ABSSSI vs 37.2% OTA (p = 0.786) received previous and concomitant antibiotics, respectively. 82.5% reached clinical cure. Eleven (5.4%) patients had non-serious adverse events (AE). OTA patients showed longer hospitalization (13.5 days, 5.5–22 vs 3, 0–11.7; p<0.0001) and received longer previous (18 days, 9–30 vs 11, 7–19; p = 0.007)/concomitant antibiotic treatments (21 days, 14–52 vs 11, 8–14; p < 0.0001), compared to ABSSSI. ABSSSI and OTA showed similar efficacy (85.5% vs 75%, p = 0.459) and safety (no AE: 81.5% vs 64.3%, p = 0.258); efficacy was independent of previous/concomitant therapies. Conclusions: Dalbavancin demonstrated a success rate of >80%, with similar efficacy/safety in ABSSSI and off-label indications. The preferential use of dalbavancin as second-line or combination therapy would seem to suggest the need for in-depth studies focused on its off-label use

Language Usage Conditions of Multilingual Nations - Sri Lanka“Sinhalese native speakers and Tamil native speakers\u27 scenes, their word usage conditions in Western Province and Uva Province .

Sri Lanka is a multilingual nation, where various languages, races, and religions exist. Sinhalese, Muslims and Tamils reside together with Burger, Marais and native people called ‘Veddah\u27. Sri Lankan people use three languages; Sinhala, English, and Tamil in their daily communication. To examine the language situation in Sri Lanka means to analyze the cultural and social circumstances within Sri Lanka.In particular the Code Switching (CS) is seen in various situations in Sri Lanka. It is expected that a person would switch the language code depending on the situation. This also differs according to various circumstances such as speaker\u27s life style and living conditions at home, academic background and the social hierarchy. Furthermore, it is estimated that differences in CS between Tamil minority and Sinhala majority would exist. It is important to consider these points in order to examine the situation of communication. English is also used quite often in Sri Lanka. The influence and the necessity of English would be examined through a survey of English usage spreading in the real world.The questionnaire style survey has been conducted and it was administered based on pilot research in Japan. It is necessary to investigate various circumstances that people face in order to examine the true language usage conditions. The investigation considered people in various places and situations throughout Sri Lanka.Sri Lanka consists of nine states. The research was done in eight states: Central Province, Eastern Province, Northern Province, Southern Province, Western Province North western Province, Uva Province and Sabaragamuwa province.The research was done as follows:The locations : at a house of a standard family, at a bank, at a school and at a postoffice in each locations.The subjects : 525 people including students, office workers, house-wives, farmers,and elderly people.The format of investigation: The questionnaire included four communication situations and questionsIn this paper, the language usage conditions of Sinhalese native speakers and the Tamil native speakers of both Western Province and Uva Province are analyzed in various situations. As the result, the Sinhalese native speakers in Western Province showed many examples of code switching between Sinhalese and English. Moreover, English code switching was seen frequently in the home.When considering the Uva Province, the Sinhalese native speakers use both Sinhala and English while a significant proportion of them are trilingual speakers there. They often change between the three main languages; Sinhala, English and Tamil are used quite often at schools, offices, hospitals, and so on.To examine a number of communication scenes in different language groups in Sri Lanka, it was clearly seen that there are more trilingual speakers among Tamil native speakers who more likely to switch between three languages in different situations, while Sinhalese speakers switch between two languages. The data of the survey also showed that the usage of languages varies according to the speakers\u27 social status, region where he or she lives, academic background, age, etc.Moreover, when the communication is taking place at home, the Sinhalese native speakers often use the code switching between Sinhalese and English. However, the elderly people in Sri Lanka, especially people living in Uva Province, rarely speak English due to their poor academic background.It has become clear that the language usage conditions differ from one another depending on the society, the region, and the educational level, and age of the person in Sri Lanka.However it is not well known yet when and how the code switching happens. As for code switching between English and Sinhalese, it is important to record their natural conversation in various scenes to analyze certain characteristics of the code switching. This would help clarify how Sri Lankans use these languages.千葉大学大学院人文社会科学研究科研究プロジェクト報告書第239集「ユーラシアの多言語社会と言語政策」中川裕 編Eurasian Multilingual Society and Language Policy Report on Research Project No.23

Toward a Regulatory Pathway for the Use of in Silico Trials in The Ce Marking of Medical Devices

In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing

Artemisinin Attenuates Lipopolysaccharide-Stimulated Proinflammatory Responses by Inhibiting NF-κB Pathway in Microglia Cells

Microglial activation plays an important role in neuroinflammation, which contributes to neuronal damage, and inhibition of microglial activation may have therapeutic benefits that could alleviate the progression of neurodegeneration. Recent studies have indicated that the antimalarial agent artemisinin has the ability to inhibit NF-κB activation. In this study, the inhibitory effects of artemisinin on the production of proinflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated primary microglia. Our results show that artemisinin significantly inhibited LPS-induced production of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO). Artemisinin significantly decreased both the mRNA and the protein levels of these pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) and increased the protein levels of IκB-α, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Artemisinin treatment significantly inhibited basal and LPS-induced migration of BV-2 microglia. Electrophoretic mobility shift assays revealed increased NF-κB binding activity in LPS-stimulated primary microglia, and this increase could be prevented by artemisinin. The inhibitory effects of artemisinin on LPS-stimulated microglia were blocked after IκB-α was silenced with IκB-α siRNA. Our results suggest that artemisinin is able to inhibit neuroinflammation by interfering with NF-κB signaling. The data provide direct evidence of the potential application of artemisinin for the treatment of neuroinflammatory diseases

Ventilatory associated barotrauma in COVID-19 patients: A multicenter observational case control study (COVI-MIX-study)

Background: The risk of barotrauma associated with different types of ventilatory support is unclear in COVID-19 patients. The primary aim of this study was to evaluate the effect of the different respiratory support strategies on barotrauma occurrence; we also sought to determine the frequency of barotrauma and the clinical characteristics of the patients who experienced this complication. Methods: This multicentre retrospective case-control study from 1 March 2020 to 28 February 2021 included COVID-19 patients who experienced barotrauma during hospital stay. They were matched with controls in a 1:1 ratio for the same admission period in the same ward of treatment. Univariable and multivariable logistic regression (OR) were performed to explore which factors were associated with barotrauma and in-hospital death. Results: We included 200 cases and 200 controls. Invasive mechanical ventilation was used in 39.3% of patients in the barotrauma group, and in 20.1% of controls (p<0.001). Receiving non-invasive ventilation (C-PAP/PSV) instead of conventional oxygen therapy (COT) increased the risk of barotrauma (OR 5.04, 95% CI 2.30 - 11.08, p<0.001), similarly for invasive mechanical ventilation (OR 6.24, 95% CI 2.86-13.60, p<0.001). High Flow Nasal Oxygen (HFNO), compared with COT, did not significantly increase the risk of barotrauma. Barotrauma frequency occurred in 1.00% [95% CI 0.88-1.16] of patients; these were older (p=0.022) and more frequently immunosuppressed (p=0.013). Barotrauma was shown to be an independent risk for death (OR 5.32, 95% CI 2.82-10.03, p<0.001). Conclusions: C-PAP/PSV compared with COT or HFNO increased the risk of barotrauma; otherwise HFNO did not. Barotrauma was recorded in 1.00% of patients, affecting mainly patients with more severe COVID-19 disease. Barotrauma was independently associated with mortality. Trial registration: this case-control study was prospectively registered in clinicaltrial.gov as NCT04897152 (on 21 May 2021)