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Aim: Bile acids (BAs) are implicated in the pathogenesis of several metabolic syndrome‐related diseases, including insulin resistance (IR) and type 2 diabetes (T2D). It has been reported that IR and T2D are associated with an increased ratio of 12α/non‐12α‐hydroxylated BAs in the circulating BA pool. It is, however, unknown whether the improvement of insulin sensitivity inversely affects BA composition in humans. Therefore, we assessed whether lifestyle‐induced weight loss induces changes in BA metabolism in people with obesity, with or without T2D, and if these changes are associated with metabolic parameters. Materials and Methods: Individual BAs and C4 were quantified by ultra‐high‐performance liquid chromatography‐tandem mass spectrometry in plasma samples collected from two cohorts of people with obesity (OB) and with T2D and obesity (T2D), before and after a lifestyle intervention. Results: Lifestyle‐induced weight loss improved glycaemic control in both cohorts, with plasma BA concentrations not affected by the lifestyle interventions. The ratio of 12α/non‐12α‐hydroxylated BAs remained unchanged in OB (p =.178) and even slightly increased upon intervention in T2D (p =.0147). Plasma C4 levels were unaffected in OB participants (p =.20) but significantly reduced in T2D after intervention (p =.0003). There were no significant correlations between the ratio of 12α/non‐12α‐hydroxylated BAs and glucose, insulin, or homeostatic model assessment‐IR, nor in plasma triglycerides, low‐density lipoprotein cholesterol, lipoprotein (a) in the T2D cohort. Conclusions: Lifestyle‐induced weight loss did improve glycaemic control but did not affect BA concentrations. Improvements in insulin sensitivity were not associated with changes in BA parameters in people with obesity, with or without T2D. [ABSTRACT FROM AUTHOR]

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24‐dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti‐inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3‐Leiden. CETP mice, a well‐established translational model that develops diet‐induced human‐like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet‐induced hepatic steatosis and inflammation in a strictly LXRα‐dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH. Synopsis: Non‐alcoholic fatty liver disease (NAFLD) affects over 30% of the general population, yet there is currently no medication available for its treatment. This study reports a novel strategy to activate liver X receptors (LXR) via pharmacological Δ24‐dehydrocholesterol reductase (DHCR24) inhibition for the treatment of NAFLD and potentially other cardiometabolic diseases. SH42 inhibits DHCR24 to increase levels of the endogenous LXR agonist desmosterol in the circulation and liver.Inhibition of DHCR24 exerts metabolic and immune benefits in a strictly LXRα‐dependent manner without causing hyperlipidemia.Inhibition of DHCR24 decreases liver collagen content and plasma alanine transaminase levels in an established NAFLD model. [ABSTRACT FROM AUTHOR]

Lowering intraocular pressure (IOP) by placement of a glaucoma shunt is an effective treatment for glaucoma. However, fibrosis of the outflow site can hamper surgical outcome. In this study, the antifibrotic effect of adding an endplate (with or without microstructured surface topographies) to a microshunt made of poly(styrene‐block‐isobutylene‐block‐styrene) is investigated. New Zealand white rabbits are implanted with a control implant (without endplate) and modified implants. Afterward, bleb morphology and IOP is recorded for 30 days. After killing of the animals, eyes are collected for histology, Addition of an endplate extended bleb survival, Topography‐990 has the longest recorded bleb‐survival time. Histology reveals that the addition of an endplate increases the presence of myofibroblasts, macrophages, polymorphonuclear cells, and foreign body giant cells compared to the control. However, an increased capsule thickness and inflammatory response are observed in the groups with surface topographies, The addition of an endplate results in prolonged bleb survival, demonstrating that engineering of the shape of glaucoma implants could prolong bleb functionality. Future research should further elaborate the effect of surface topographies on long‐term bleb survival, since an increased presence of pro‐fibrotic cells and increased capsule thickness are observed compared to the control. [ABSTRACT FROM AUTHOR]

Biomaterials can control cell and nuclear morphology. Since the shape of the nucleus influences chromatin architecture, gene expression and cell identity, surface topography can control cell phenotype. This study provides fundamental insights into how surface topography influences nuclear morphology, histone modifications, and expression of histone‐associated proteins through advanced histone mass spectrometry and microarray analysis. The authors find that nuclear confinement is associated with a loss of histone acetylation and nucleoli abundance, while pathway analysis reveals a substantial reduction in gene expression associated with chromosome organization. In light of previous observations where the authors found a decrease in proliferation and metabolism induced by micro‐topographies, they connect these findings with a quiescent phenotype in mesenchymal stem cells, as further shown by a reduction of ribosomal proteins and the maintenance of multipotency on micro‐topographies after long‐term culture conditions. Also, this influence of micro‐topographies on nuclear morphology and proliferation is reversible, as shown by a return of proliferation when re‐cultured on a flat surface. The findings provide novel insights into how biophysical signaling influences the epigenetic landscape and subsequent cellular phenotype. [ABSTRACT FROM AUTHOR]

Background: Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia. Aims: We evaluated the clinicopathological characteristics and risk factors for developing (advanced) neoplasia (AN) in HL survivors. Methods: In all, 101 HL survivors (median age 51 years, median age of HL diagnosis 25 years) underwent colonoscopy and 350 neoplasia and 44 AN (classified as advanced adenomas/serrated lesions or colorectal cancer), mostly right‐sided, were detected, as published previously. An average‐risk asymptomatic cohort who underwent screening colonoscopy were controls (median age 60 years). Clinicopathological characteristics of AN were evaluated in both groups. Mismatch repair (MMR) status was assessed using immunohistochemistry (MLH1/MSH2/MSH6/PMS2). Logistic regression analysis was performed to evaluate the risk factors for AN in HL survivors, including age at HL diagnosis and interval between HL and colonoscopy. Results: In 101 colonoscopies in HL survivors, AN was primarily classified based on polyp size ≥10 mm, whereas (high‐grade)dysplasia was more often seen in AN in controls. An interval between HL diagnosis and colonoscopy >26 years was associated with more AN compared with an interval of <26 years, with an odds ratio for AN of 3.8 (95% confidence interval 1.4–9.1) (p < 0.01). All 39 AN that were assessed were MMR proficient. Conclusions: Colorectal neoplasia in HL survivors differ from average‐risk controls; classification AN was primarily based on polyp size (≥10 mm) in HL survivors. Longer follow‐up between HL diagnosis and colonoscopy was associated with a higher prevalence of AN in HL survivors. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: To further improve the quality of head and neck cancer (HNC) care, we developed a composite measure defined as "textbook outcome" (TO). Methods: We analyzed a retrospective cohort of patients after curvative‐intent primary surgery, radiotherapy (RT), or chemoradiation (CRT) for HNC between 2015 and 2018 at the Netherlands Cancer Institute. TO was defined as 1) the start of treatment within 30 days, 2a) satisfactory pathologic outcomes, without 30‐day postoperative complications, for the surgically treated group, and 2b), for RT and CRT patients, no unexpected or prolonged hospitalization and toxicity after the completion of treatment as planned. Results: In total, 392 patients with HNC were included. An overall TO was achieved in 9.6% of patients after surgery, 20.6% after RT, and 2.2% after CRT. Two indicators (margins >5 mm and start treatment <30 days) reduced TO radically for both groups. Conclusion: TO can aid the evaluation of the quality of care for HNC patients and guide improvement processes. Level of Evidence: 3 Laryngoscope, 132:78–87, 2022 [ABSTRACT FROM AUTHOR]

Background: Low skeletal muscle mass (SMM) is an adverse prognostic factor for chemotherapy dose‐limiting toxicity (CDLT). In patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy (CRT), low SMM is a predictor for CDLT. We aimed to validate these findings. Methods: Consecutive LA‐HNSCC patients treated with primary CRT with high‐dose cisplatin were retrospectively included. SMM was measured on pre‐treatment CT‐imaging. A cumulative cisplatin dose below 200 mg/m2 was defined as CDLT. Results: One hundred and fifty three patients were included; 37 (24.2%) experienced CDLT, and 84 had low SMM (54.9%). Patients with low SMM experienced more CDLT than patients with normal SMM (35.7% vs. 10.1%, p < 0.01). Low SMM (OR 3.99 [95% CI 1.56–10.23], p = 0.01) and an eGFR of 60–70 ml/min (OR 5.40 [95% CI 1.57–18.65], p < 0.01) were predictors for CDLT. Conclusion: Pre‐treatment low SMM is associated with CDLT in LA‐HNSCC patients treated with primary CRT. Routine SMM assessment may allow for CDLT risk assessment and treatment optimization. [ABSTRACT FROM AUTHOR]

Macrophages play a central role in orchestrating immune responses to foreign materials, which are often responsible for the failure of implanted medical devices. Material topography is known to influence macrophage attachment and phenotype, providing opportunities for the rational design of "immune‐instructive" topographies to modulate macrophage function and thus foreign body responses to biomaterials. However, no generalizable understanding of the inter‐relationship between topography and cell response exists. A high throughput screening approach is therefore utilized to investigate the relationship between topography and human monocyte–derived macrophage attachment and phenotype, using a diverse library of 2176 micropatterns generated by an algorithm. This reveals that micropillars 5–10 µm in diameter play a dominant role in driving macrophage attachment compared to the many other topographies screened, an observation that aligns with studies of the interaction of macrophages with particles. Combining the pillar size with the micropillar density is found to be key in modulation of cell phenotype from pro to anti‐inflammatory states. Machine learning is used to successfully build a model that correlates cell attachment and phenotype with a selection of descriptors, illustrating that materials can potentially be designed to modulate inflammatory responses for future applications in the fight against foreign body rejection of medical devices. [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors.Methods: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis.Results: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P < .001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P < .001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P = .08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P < .001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P < .001).Conclusions: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered. [ABSTRACT FROM AUTHOR]

Background: Human papillomavirus (HPV)‐positive oropharyngeal squamous cell carcinoma (OPSCC) is a highly immunogenic tumor and differences in tumor microenvironment might contribute to the improved survival of HPV‐positive OPSCC patient. Methods: A comprehensive multivariate analysis with clinical and immune variables (human leukocyte antigen [HLA] I/II, programmed death ligand 1 (PD‐L1), programmed death receptor 1 (PD1), T cells, and macrophages) was performed in 142 OPSCC patients. Results: We found an inverse correlation between the expression of HLA class II molecules on tumor cells and CD68+ CD163+ tumor‐associated macrophages (TAMs). High HLA‐DP/DQ/DR expression and low number of TAMs were associated with longer disease‐specific survival and disease‐free survival (DFS). Furthermore, a new population of CD8+ FoxP3+ T cells was correlated with shorter DFS in multivariate analysis. Conclusions: \We identified new prognostic markers for patients with oropharyngeal cancer, which can be used for selecting patients that can benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

Background: This study evaluated ototoxicity in locally advanced head and neck cancer patients treated in the CONDOR study with docetaxel/cisplatin/5‐fluorouracil (TPF) followed by conventional radiotherapy with concomitant cisplatin 100 mg/m2 on days 1, 22, and 43 (cis100+RT) versus accelerated radiotherapy with concomitant cisplatin weekly 40 mg/m2 (cis40+ART). Methods: Sixty‐two patients were treated in this study. Audiometry was performed at baseline, during TPF, before start of chemoradiotherapy, and 1, 4, 8, and 12 months after treatment. Results: A complete dataset of audiometric data was available of 12 patients treated with high‐dose cisplatin and of 11 patients treated with intermediate‐dose cisplatin. Patients in the high‐dose group showed significant more hearing loss than in the intermediate group at 4 kHz ([z = 1.98; P = .04] and 8 kHz [z = 2.07; P < .03]). Interindividual variation was high in both groups. Conclusion: After induction TPF, more ototoxicity was observed in chemoradiotherapy with cis100+RT than after chemoradiotherapy with cis40+ART. [ABSTRACT FROM AUTHOR]

Fibroblasts are abundantly present in the prostate tumor microenvironment (TME), including cancer‐associated fibroblasts (CAFs) which play a key role in cancer development. Androgen receptor (AR) signaling is the main driver of prostate cancer (PCa) progression, and stromal cells in the TME also express AR. High‐grade tumor and poor clinical outcome are associated with low AR expression in the TME, which suggests a protective role of AR signaling in the stroma against PCa development. However, the mechanism of this relation is not clear. In this study, we isolated AR‐expressing CAF‐like cells. Testosterone (R1881) exposure did not affect CAF‐like cell morphology, proliferation, or motility. PCa cell growth was not affected by culturing in medium from R1881‐exposed CAF‐like cells; however, migration of PCa cells was inhibited. AR chromatin immune precipitation sequencing (ChIP‐seq) was performed and motif search suggested that AR in CAF‐like cells bound the chromatin through AP‐1‐elements upon R1881 exposure, inducing enhancer‐mediated AR chromatin interactions. The vast majority of chromatin binding sites in CAF‐like cells were unique and not shared with AR sites observed in PCa cell lines or tumors. AR signaling in CAF‐like cells decreased expression of multiple cytokines; most notably CCL2 and CXCL8 and both cytokines increased migration of PCa cells. These results suggest direct paracrine regulation of PCa cell migration by CAFs through AR signaling. [ABSTRACT FROM AUTHOR]

ABSTRACT Background The radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) phase III trial compared intra-arterial (IA) to intravenous (IV) cisplatin-based chemoradiation for head and neck cancer. Long-term efficacy and toxicity are reported after a median follow-up of 7.5 years. Methods Patients with inoperable squamous cell carcinoma (SCC) of the oropharynx, oral cavity, or hypopharynx, were randomized between radiotherapy (RT) + IA cisplatin 150 mg/m2, followed by systemic rescue or RT + I.V. cisplatin 100 mg/m2. RT consisted of 46 Gy to the affected and elective areas, followed by a boost of 24 Gy. Results Among 237 patients, 57 recurred locally, 35 regionally, and 80 locoregionally. There were 32 second primary tumors, 65 distant metastases, and 154 deaths. Locoregional control and overall survival were not different between the treatment arms. Late dysphagia was worse in the I.V. arm (log-rank p = .014). Conclusion IA cisplatin did not improve tumor control compared to I.V. administered cisplatin, despite the higher dose in IA delivery of the drug. © 2015 Wiley Periodicals, Inc. Head Neck 38: E488-E493, 2016 [ABSTRACT FROM AUTHOR]

Im Zeitalter der Wissensarbeit steigt die Bedeutung mentaler und psychologischer Faktoren wie Konzentrationsfähigkeit, Stimmung und Motivation für eine hohe Leistungsfähigkeit. Die physikalischen Bedingungen an Büroarbeitsplätzen können einerseits einen Stressor darstellen, der die Konzentration erschöpft und den Nutzer ermüdet, oder eine räumliche Ressource, die Arbeitstätigkeiten erleichtert oder Nutzerbedürfnisse befriedigt und dadurch Engagement und Stimmung bei der Arbeit steigert. Inwiefern bestimmte räumliche Bedingungen am Arbeitsplatz eine Ressource oder einen Stressor darstellen, lässt sich anhand der drei Ebenen des Komforts abschätzen: physischer, funktionaler und psychischer Komfort. Ein solcher Ansatz soll helfen, 'psychisch nachhaltige' physikalische Raumbedingungen zu schaffen, die die psychischen Ressourcen der Nutzer schonen. Im vorliegenden Beitrag wird dieses neue Verständnis von Komfort mithilfe der zugrunde liegenden psychologischen Prozesse erklärt und am Beispiel der bauphysikalischen Variablen 'Beleuchtung' illustriert. Stressor or resourse? The significance of physical conditions and comfort exemplified by lighting conditions. In the era of knowledge work, high performance increasingly depends on mental and psychological factors like concentration, mood, and motivation. Physical conditions in offices can either constitute a stressor depleting concentration and fatiguing users, or an environmental resource facilitating work activities and satisfying user needs and, in turn, heightening engagement and mood at work. To what extent certain physical conditions at the workplace function as resources or as stressors can be estimated based on three levels of comfort: physical, functional, and psychological comfort. This approach aims at supporting the creation of 'psychologically sustainable' physical conditions, which conserve the users' psychological resources. In this article, this new understanding of comfort will be explained based on the underlying psychological processes and will be illustrated using the example of the physical variable of lighting. [ABSTRACT FROM AUTHOR]

Copyright of Bauphysik is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: Anti-oxidative properties of high density lipoproteins (HDL) are relevant for atheroprotection. HDL carry serum amyloid A (SAA), which may impair HDL functionality. We questioned whether HDL anti-oxidative capacity is determined by SAA. Design and Methods: Relationships of HDL anti-oxidative capacity (% inhibition of low density lipoprotein oxidation in vitro) with SAA were determined in 54 non-diabetic subjects without metabolic syndrome (MetS) and 68 subjects with MetS (including 51 subjects with Type 2 diabetes mellitus). Results: SAA levels were higher in MetS subjects, coinciding higher high sensitive C-reactive protein (hs-CRP) and lower HDL cholesterol and apolipoprotein (apo) A-I levels ( P<0.001 for all). HDL anti-oxidative capacity was not different between subjects with and without MetS ( P=0.76), but the HDL anti-oxidation index (HDL anti-oxidative capacity multiplied by individual HDL cholesterol concentrations), as a measure of global anti-oxidative functionality of HDL, was lower in Mets subjects ( P<0.001). HDL anti-oxidative capacity was correlated inversely with SAA levels in subjects without MetS (r=-0.286, P=0.036). Notably, this relationship was independent of HDL cholesterol or apoA-I ( P<0.05 for both). In contrast, no relation of HDL anti-oxidative capacity with SAA was observed in MetS subjects (r=0.032, P=0.80). The relationship of SAA with HDL anti-oxidative capacity was different in subjects with MetS compared to subjects without MetS ( P=0.039 for the interaction between the presence of MetS and SAA on HDL anti-oxidative capacity) taking age and diabetes status into account. Conclusion: Higher SAA levels may impair HDL anti-oxidative functionality. The relationship of this physiologically relevant HDL functionality measure with circulating SAA levels is apparently disturbed in metabolic syndrome. [ABSTRACT FROM AUTHOR]

Background The purpose of this investigation was to present 5-years of quality-of-life (QOL) results of a multicenter randomized phase III trial, assessing intra-arterial (IA) versus standard intravenous (IV) chemoradiation for inoperable stage IV head and neck cancer. Methods Evaluation of 71 patients through European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core Module (EORTC QLQ-C30) and Head and Neck Module (QLQ-H&N35), and trial-specific questionnaires. Treatment consisted of standard radiotherapy with 4 weekly IA or 3 weekly IV cisplatin infusions. Results No significant differences in treatment-related QOL problems between 1 and 5 years posttreatment were observed, except for 'dry mouth' (gradually improving; p = .004). Survivors have lower fatigue levels ( p = .04), better voice ( p = 0.3), and swallowing ( p = .03) than patients who could not complete all subsequent follow-up questionnaires. Conclusions Most treatment-related QOL issues deteriorate during treatment, improve in the first year, and then remain stable, except xerostomia, improving up to the 5-year assessment point. Survivors show more positive scores for fatigue, voice, and swallowing. QOL issues at 1 year, thus, for most already represent those after 5-year follow-up. © 2011 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Copyright of Bauphysik is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Eur J Clin Invest 2012; 42 (5): 487-495 Abstract Background Type 2 diabetes mellitus increases the risk of atherosclerotic cardiovascular disease. Antioxidative properties of high density lipoprotein (HDL) are important for atheroprotection. This study investigated whether the antioxidative functionality of HDL is altered in type 2 diabetes mellitus and aimed to identify potential determinants of this parameter. Materials and methods In a cross-sectional study, we investigated 74 patients with type 2 diabetes and 75 control subjects. Antioxidative properties of HDL were measured and expressed as either (i) HDL antioxidative capacity or (ii) HDL antioxidation index after multiplying HDL antioxidative capacity results with individual plasma HDL cholesterol concentrations. Lecithin:cholesterol acyltransferase (LCAT) and paraoxonase-1 (PON-1) activities were determined. Results HDL antioxidative capacity was similar in patients with diabetes and controls, while the HDL antioxidation index was decreased in patients with diabetes ( P = 0·005) owing to lower plasma HDL cholesterol ( P < 0·001). LCAT activity was higher and PON-1 activity lower in type 2 diabetes mellitus (each P < 0·001). In the combined subjects, HDL antioxidative capacity was inversely related to LCAT activity ( P < 0·01). The HDL antioxidation index correlated negatively with blood glucose ( P < 0·001), HbA1c and LCAT activity (each P < 0·01), and positively with PON-1 activity ( P < 0·01). Multiple linear regression analysis demonstrated that high LCAT activity was associated with both decreased HDL antioxidation capacity ( P < 0·05) and index ( P < 0·001) independent of diabetes status, glycaemic control and PON-1. Conclusions Overall, the antioxidative functionality of HDL is impaired in type 2 diabetes mellitus mostly because of lower HDL cholesterol. Hyperglycaemia, increased LCAT activity and lower PON-1 activity likely contribute to impaired antioxidative functionality of HDL. [ABSTRACT FROM AUTHOR]

Human mesenchymal stromal cells (hMSCs) represent an attractive cell source for clinic applications. Besides being multi-potent, recent clinical trials suggest that they secrete both trophic and immunomodulatory factors, allowing allogenic MSCs to be used in a wider variety of clinical situations. The yield of prospective isolation is however very low, making expansion a required step toward clinical applications. Unfortunately, this leads to a significant decrease in their stemness. To identify the mechanism behind loss of multi-potency, hMSCs were expanded until replicative senescence and the concomitant molecular changes were characterized at regular intervals. We observed that, with time of culture, loss of multi-potency was associated with both the accumulation of DNA damage and the respective activation of the DNA damage response pathway, suggesting a correlation between both phenomena. Indeed, exposing hMSCs to DNA damage agents led to a significant decrease in the differentiation potential. We also showed that hMSCs are susceptible to accumulate DNA damage upon in vitro expansion, and that although hMSCs maintained an effective nucleotide excision repair activity, there was a progressive accumulation of DNA damage. We propose a model in which DNA damage accumulation contributes to the loss of differentiation potential of hMSCs, which might not only compromise their potential for clinical applications but also contribute to the characteristics of tissue ageing. [ABSTRACT FROM AUTHOR]

The article presents a study which determined the effects of the introduction of the mutant activin receptor-like kinase 2 (ALK2)-R206H receptor (FOP-ALK2) to fibrodysplasia ossificans progressiva (FOP). The results of the study show that when taken together, constitutive activity in the mutant receptor is conferred by the R206H mutation in ALK2. Results further reveal that it sensitized mesenchymal cells to bone morphogenetic protein (BMP)-induced osteoblast differentiation and stimulated the formation of new bones.

The article presents a study that compares outcome of intra-arterial (IA) cisplatin chemoradiation and intravenous chemoradiations in unresectable head and neck cancer patients. The study performs different cisplatin level treatments, with additional 70 gray in 35 daily fractions and sodium thiosulfate for IA and intravenous chemoradiation, respectively. Result shows higher renal toxicity in intravenous compared with IA; however, overall survival (OS) and locoregional control is similar.

Background: In chronic liver injury, hepatic stellate cells (HSCs) proliferate and produce excessive amounts of connective tissue causing liver fibrosis and cirrhosis. Oxidative stress has been implicated as a driving force of HSC activation and proliferation, although contradictory results have been described. Aim: To determine the effects of oxidative stress on activated HSC proliferation, survival and signalling pathways. Methods: Serum-starved culture-activated rat HSCs were exposed to the superoxide anion donor menadione (5–25 μmol/L) or hydrogen peroxide (0.2–5 mmol/L). Haem oxygenase-1 mRNA expression, glutathione status, cell death, phosphorylation of mitogen-activated protein (MAP) kinases and proliferation were investigated. Results: Menadione induced apoptosis in a dose- and time-dependent, but caspase-independent manner. Hydrogen peroxide induced necrosis only at extremely high concentrations. Both menadione and hydrogen peroxide activated Jun N-terminal kinase (JNK) and p38. Hydrogen peroxide also activated extracellular signal-regulated protein. Menadione, but not hydrogen peroxide, reduced cellular glutathione levels. Inhibition of JNK or supplementation of glutathione reduced menadione-induced apoptosis. Non-toxic concentrations of menadione or hydrogen peroxide inhibited platelet-derived growth factor- or/and serum-induced proliferation. Conclusion: Reactive oxygen species (ROS) inhibit HSC proliferation and promote HSC cell death in vitro. Different ROS induce different modes of cell death. Superoxide anion-induced HSC apoptosis is dependent on JNK activation and glutathione status. [ABSTRACT FROM AUTHOR]

Background. We report the results of a multicenter randomized phase III study, assessing quality of life (QOL) in intra-arterial (IA) versus standard intravenous (IV) chemoradiation in advanced head and neck cancer. Methods. Two hundred seven patients with inoperable stage IV disease—152 men and 55 women; mean age, 55 years—were included in this study. The patients were treated with standard radiotherapy with 4 weekly IA or 3 weekly IV cisplatin infusions. The QOL assessments carried out were EORTC-C30, H&N35, and trial-specific questionnaires. Results. Overall QOL deteriorated in all patients during treatment, is gradually improving over 1 year. IA patients showed significantly less nausea and vomiting at week 7 (p <.001). IV patients were significantly more fatigued (p <.006). At 1 year, no significant difference in tube feeding was found. Voice quality slightly exceeded the pretreatment values at 1 year. Forty-two of 62 employed patients returned to work. Conclusion. During treatment, significantly fewer problems with nausea and vomiting occurred in IA than in IV patients. Both groups showed improved voicing and oral intake during follow-up, often exceeding pretreatment values at 1 year. © 2008 Wiley Periodicals, Inc. Head Neck, 2009 [ABSTRACT FROM AUTHOR]

The use of multipotent human mesenchymal stem cells (hMSCs) for tissue engineering has been a subject of extensive research. The donor variation in growth, differentiation and in vivo bone forming ability of hMSCs is a bottleneck for standardization of therapeutic protocols. In this study, we isolated and characterized hMSCs from 19 independent donors, aged between 27 and 85 years, and investigated the extent of heterogeneity of the cells and the extent to which hMSCs can be expanded without loosing multipotency. Dexamethasone-induced ALP expression varied between 1.2- and 3.7-fold, but no correlation was found with age, gender, or source of isolation. The cells from donors with a higher percentage of ALP-positive cells in control and dexamethasone-induced groups showed more calcium deposition than cells with lower percentage of ALP positive cells. Despite the variability in osteogenic gene expression among the donors tested, ALP, Collagen type 1, osteocalcin, and S100A4 showed similar trends during the course of osteogenic differentiation. In vitro expansion studies showed that hMSCs can be effectively expanded up to four passages (approximately 10-12 population doublings from a P0 culture) while retaining their multipotency. Our in vivo studies suggest a correlation between in vitro ALP expression and in vivo bone formation. In conclusion, irrespective of age, gender, and source of isolation, cells from all donors showed osteogenic potential. The variability in ALP expression appears to be a result of sampling method and cellular heterogeneity among the donor population. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:1029-1041, 2007 [ABSTRACT FROM AUTHOR]

Summary A microarray was printed containing cDNAs from a library made from cytoplasm microaspirated from the oesophageal gland cell region of parasitic stages of the soybean cyst nematode, Heterodera glycines . The array contained both previously described clones ( Wang et al . Mol. Plant-Microbe Interact. 2001 , 14 , 536–544) and uncharacterized cDNAs. Fluorescent probes for array hybridization were prepared using RNA polymerase amplification of nematode mRNA. Developmental expression profiles of the arrayed cDNAs were determined by hybridizing the microarray with probes from parasitic and non-parasitic H. glycines life stages. Distinct patterns of developmental expression were ascertained for the previously described gland expressed genes. In addition, four H. glycines cDNAs (SCN1018, SCN1020, SCN1028 and SCN1167) were identified that showed up-regulation in one or more parasitic life stages. Clone SCN1018 encodes a C-type lectin domain and is expressed in the hypodermis of females. Clone SCN1020 encodes a probable S-adenosylmethionine synthetase. Clone SCN1028 encodes a piwi protein with high similarity to the germ-line-specific protein R06C7.1 of Caenorhabditis elegans . The sequence of SCN1167 had no similarity to known genes. This paper describes the first use of cDNA microarrays to analyse genes of a plant-parasitic nematode and establishes a functional method to mine nematode cDNA libraries. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: The purpose of this study was to determine whether concomitant chemoradiation (CCRT)-induced hearing loss is progressive over time or not., Study Design: Long-term (LT) follow-up study., Methods: Between 1999 and 2004, 158 patients with head and neck cancer were treated with intravenous (IV) CCRT (n = 80) or intraarterial CCRT (n = 78). Audiometry was performed before, short-term (ST), and LT posttreatment. Differences in hearing were assessed with a multivariable linear regression analysis, incorporating the effect of aging., Results: Long-term audiometry (median 4.5 years) was available in 67 patients (42%). At ST follow-up, a deterioration of 21.6 decibel was seen compared to baseline at pure-tone averages (PTA) 8-10-12.5 kHz. At LT follow-up, this deterioration further increased with 5 decibel (P = 0.005). Only in CCRT-IV patients was a significant progressive treatment-induced hearing loss seen, at PTA 8-10-12.5 kHz (P = 0.005), PTA 1-2-4 kHz air conduction (P = 0.014), and PTA 0.5-1-2 kHz bone conduction (P = 0.045)., Conclusion: CCRT-induced hearing impairment was progressive over time, especially in higher frequencies and only in CCRT-IV patients, with a modest deterioration of 5 decibel 4.5 years post-treatment., Level of Evidence: 4., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

The surface marker profile of mesenchymal stromal cells (MSCs) suggests that they can escape detection by the immune system of an allogeneic host. This could be an optimal strategy for bone regeneration applications, where off-the-shelf cells could be implanted to heal bone defects. However, it is unknown how pre-differentiation of MSCs to an osteogenic lineage, a means of improving bone formation, affects their immunogenicity. Using immunohistological techniques in a rat ectopic implantation model, we demonstrate that allogeneic osteoprogenitors mount a T cell- and B cell-mediated immune response resulting in an absence of in vivo bone formation. Suppression of the host immune response with daily administration of an immunosuppressant, FK506, is effective in preventing the immune attack on the allogeneic osteoprogenitors. In the immunosuppressed environment, the allogeneic osteoprogenitors are capable of generating bone in amounts similar to those of syngeneic cells. However, using osteoprogenitors from one of the allogeneic donors led to newly deposited bone that was attacked by the host immune system, despite the continued administration of the immunosuppressant. This suggests that, although using an immunosuppressant can potentially suppress the immune attack on the allogeneic cells, optimizing the dose of the immunosuppressant may be crucial to ensure bone formation within the allogeneic environment. Overall, allografts comprising osteoprogenitors derived from allogeneic MSCs have the potential to be used in bone regeneration applications., (© 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)