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Fibrosis has been considered as a hallmark of dysfunctional adipose tissue (AT), however the role and mechanisms of fibrosis in the age related AT dysfunction are not yet well characterized. The aim of the study was to investigate the mechanisms of extracellular matrix (ECM) alterations and the role of caveolins, using an in vitro model of adipocyte aging and hypoxia. Hypoxic adipocytes, but also aged adipocytes, were characterized by a significant increase in gene expression of pro-inflammatory cytokines and ECM components. Immunofluorescence analysis confirmed an increase in collagen VI-A3 in hypoxic and also in aged adipocytes. However aged adipocytes were characterized by only a slight increase in HIF1α immunofluorescence and by a more relevant increase in senescence compared to hypoxic and mature adipocytes, with an increase in p-53 protein and a decrease in SIRT 1 protein. Immunofluorescence and western blot analysis revealed a significant decrease in caveolin-1 expression in hypoxic adipocytes and even more in aged adipocytes. In conclusions, aging adipocytes are associated to alteration of ECM and fibrosis, by modulation of the caveolins through complex mechanisms where inflammation, hypoxia and cellular senescence are coexisting.

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The Dallol volcano and its associated hydrothermal field are located in a remote area of the northern Danakil Depression in Ethiopia, a region only recently appraised after decades of inaccessibility due to severe political instability and the absence of infrastructure. The region is notable for hosting environments at the very edge of natural physical-chemical extremities. It is surrounded by a wide, hyperarid salt plain and is one of the hottest (average annual temperatureDallol: 36-38°C) and most acidic natural systems (pHDallol ≈0) on Earth. Spectacular geomorphologies and mineral deposits produced by supersaturated hydrothermal waters and brines are the result of complex interactions between active and inactive hydrothermal alteration of the bedrock, sulfuric hot springs and pools, fumaroles and geysers, and recrystallization processes driven by hydrothermal waters, degassing, and rapid evaporation. The study of planetary field analog environments plays a crucial role in characterizing the physical and chemical boundaries within which life can exist on Earth and other planets. It is essential for the definition and assessment of the conditions of habitability on other planets, including the possibility for biosignature preservation and in situ testing of technologies for life detection. The Dallol area represents an excellent Mars analog environment given that the active volcanic environment, the associated diffuse hydrothermalism and hydrothermal alteration, and the vast acidic sulfate deposits are reminiscent of past hydrothermal activity on Mars. The work presented in this paper is an overview of the Dallol volcanic area and its hydrothermal field that integrates previous literature with observations and results obtained from field surveys and monitoring coupled with sample characterization. In so doing, we highlight its exceptional potential as a planetary field analog as well as a site for future astrobiological and exploration programs.

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BACKGROUND & AIMS: Little is known about the reduction of lean body mass (LBM) in obesity, or how to identify it in standard clinical settings. We therefore aimed to assess the prevalence of low LBM in adult females with obesity, and to identify the reliability of simple tools for its screening in this population. METHODS AND RESULTS: Dual-energy X-ray absorptiometry (DXA) body composition assessment was used to categorise 147 female participants with obesity as with or without low LBM, according to the new definition that takes into account both appendicular lean mass (ALM) and body mass index (BMI)-ALM/BMI <0.512. Participants were also administered the six-minute walking test, handgrip-strength test and 4-metre gait-speed test. Of the sample of 147 participants, 93 (63.3%) met the criteria for reduced LBM. Stepwise multivariate logistic regression analysis showed that the six-minute walking test was the only independent test associated with low LBM (OR = 0.992, 95%CI 0.987-0.998). Receiver operating characteristic (ROC) curve analysis found that the discriminating cut-off points of the tests considered were 470 m, 3.30 s (gait speed = 1.2 m/sec) and 23.5 kg respectively; the 4-metre gait-speed test seems to provide the best balance of sensitivity and specificity, and the greatest discriminatory power at 90% sensitivity. CONCLUSIONS: Treatment-seeking adult females with obesity display a great prevalence of reduced LBM. The six-minute walking test was the only independent test associated with low LBM, but the 4-metre gait-speed test seems to be the most accurate functional test for screening for this condition in that population.

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BACKGROUND: An epidemiological association between excess weight and increased risk of cancer has been described in melanoma, for which the physiopathological mechanisms are still unknown. The study of tumor microenvironment and of the role of adipocytes in cancer development, progression and metastasis has recently received great interest. However, the role of peritumoral adipocytes has been characterized only in a few types of cancer, and in melanoma it still remains to be defined. METHODS: We investigated the interactions between adipocytes and melanoma cells using an in vitro co-culture system. We studied the morphological and functional properties of 3T3-L1 adipocytes before and after co-culture with A375 melanoma cells, in order to assess the role of adipocytes on melanoma migration. RESULTS: Morphological analysis showed that after 6 days of co-culture 3T3-L1 adipocytes were reduced in number and size. Moreover, we observed the appearance of dedifferentiated cells with a fibroblast-like phenotype that were not present in controls and that had lost the expression of some adipocyte-specific genes, and increased the expression of collagen, metalloproteinases and genes typical of dedifferentiation processes. Through the Matrigel Invasion Test, as well the Scratch Test, it was possible to observe that co-culture with adipocytes induced in melanoma cells increased migratory capacity, as compared with controls. In particular, the increase in migration observed in co-culture was suppressed after adding the protein SFRP-5 in the medium, supporting the involvement of the Wnt5a pathway. The activation of this pathway was further characterized by immunofluorescence and western blot analysis, showing in melanocytes in co-culture the activation of ß-catenin and LEF-1, two transcription factors involved in migration processes, neo-angiogenesis and metastasis. CONCLUSIONS: These data allow us to hypothesize a dedifferentiation process of adipocytes toward fibroblast-like cells, which can promote migration of melanoma cells through activation of Wnt5a and the intracellular pathways of ß-catenin and LEF-1.

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OBJECTIVES: Investigate the presence of a correlation between systemic inflammatory profile of community-dwelling individuals and the loss of muscular mass and performance in old age over a 4.5y follow-up, focusing on the role of anti-inflammatory cytokines in muscular changes in elderly. DESIGN: Longitudinal clinical study. SETTING: Subjects were randomly selected from lists of 11 general practitioners in the city of Verona, Italy. PARTICIPANTS: The study included 120 subjects, 92 women and 28 men aged 72.27±2.06 years and with BMI of 26.52±4.07 kg/m2 at baseline. MEASUREMENTS: Six minutes walking test (6MWT), appendicular and leg fat free mass (FFM) as measured with Dual Energy X-ray absorptiometry, were obtained at baseline and after 4.5 years (4.5y) of mean follow-up. Height, weight, body mass index (BMI), and circulating levels of TNFα, IL-4, IL-10, and IL-13 were evaluated at baseline. RESULTS: A significant reduction of appendicular FFM, leg FFM and 6MWT performance (all p<0.001) was observed after 4.5 y follow-up. In a stepwise regression model, considering appendicular FFM decline as dependent variable, lnIL-4, BMI, baseline appendicular FFM, lnTNFα and lnIL-13 were significant predictors of appendicular FFM decline explaining 30.8% of the variance. While building a stepwise multiple regression considering leg FFM as a dependent variable, lnIL-4, BMI and leg FFM were significant predictors of leg FFM decline and explained 27.4% of variance. When considering 6MWT decline as a dependent variable, baseline 6MWT, lnIL-13 and lnTNFα were significant predictors of 6MWT decline to explain 22.9% of variance. CONCLUSIONS: Our study suggest that higher serum levels of anti-inflammatory markers, and in particular IL-4 and IL-13, may play a protective role on FFM and performance maintenance in elderly subjects.

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OBJECTIVES: to validate the MSRA questionnaire proposed as prescreening tool for sarcopenia, in a population of community-dwelling elderly subjects. DESIGN: observational study. SETTING: community dwelling elderly subjects. PARTICIPANTS: 274 community dwelling elderly subjects, 177 women and 97 men, aged 66-78 years. MEASUREMENTS: Based on EWGSOP diagnostic criteria subjects were classified as sarcopenic and non-sarcopenic. The Mini Sarcopenia Risk Assessment (MSRA) questionnaire, is composed of seven questions and investigates anamnestic and nutritional characteristics related to risk of sarcopenia onset (age, protein and dairy products consumption, number of meals per day, physical activity level, number of hospitalizations and weight loss in the last year). RESULTS: 33.5% of the study population, were classified as sarcopenic. With the 7-item MSRA score, subjects with a score of 30 or less, had a 4-fold greater risk of being sarcopenic than subjects with a score higher than 30 (OR:4.20;95% CI:2.26-8.06); area under the ROC curve was 0.786 (95% CI:0.725-0.847). In a logistic regression, considering as dependent variable the probability of being sarcopenic, and as independent variables the 7 items of the questionnaire, two items (number of meals and milk and dairy products consumption) showed non-significant diagnostic power. A 5-item score was then derived and the area under the ROC curve was 0.789 (95% IC:0.728-0.851). Taking into account the cost of false positive and false negative costs and the prevalence of sarcopenia, the "optimal" threshold of the original MSRA score (based on 7 items) is 30, with a sensitivity of 0.804 and a specificity of 0.505, while the "optimal" threshold of the MSRA score based on 5 items, is 45, with a sensitivity of 0.804 and a specificity of 0.604. CONCLUSION: this preliminary study shows that the MSRA questionnaire is predictive of sarcopenia and can be suggested as prescreening instrument to detect this condition. The use of a short form of the MSRA questionnaire improves the capacity to identify sarcopenic subjects.

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OBJECTIVES: The aim of this study was to examine changes in physical performance and handgrip strength during hospitalization as well as to evaluate their interrelationship with inflammatory and nutritional status. DESIGN: Data were available on 302 elderly patients with a mean age of 80.83±7.14 years. Handgrip strength, gait speed and chair-stand test were assessed at admission and before discharge. In all subjects, serum CRP values and Mini Nutritional Assessment scores were also evaluated. RESULTS: The risk of worsening in chair-stand test performance was 4.2 (95% confidence interval (CI): 1.574-11.310) for subjects with simultaneous presence of malnutrition and CRP⩾50 and 3.3 mg/dl (95% CI: 1.127-9.423) for subjects with CRP⩾50 mg/l not malnourished in comparison with subjects with Mini Nutritional Assessment (MNA)⩾24 and CRP⩽10 mg/l. The risk of handgrip strength loss was 8.8 (95% CI: 3.545-21.662) in subjects with simultaneous presence of malnutrition and CRP⩾50 and 2.9 mg/dl (95% CI: 1.223-6.783) in subjects with CRP⩾50 mg/l not malnourished in comparison with subjects with MNA⩾24 and CRP⩽10 mg/l. CONCLUSIONS: Simultaneous presence of high CRP values and malnutrition determines an additive effect on muscle strength loss and physical performance.

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Graft-versus-host disease (GVHD) after solid organ transplantation is rare and usually fatal. We present, to our knowledge, the second successfully treated case in a simultaneous pancreas-kidney (SPK) transplant recipient. A 29-year-old female with end-stage renal disease from type 1 diabetes mellitus received an SPK transplant from a male donor, with rabbit-antithymocyte globulin induction. Twelve days posttransplant, she was readmitted with abdominal pain, nausea and vomiting. She developed leukopenia, abnormal liver enzymes, fever and a skin rash. Skin biopsy showed interface dermatitis consistent with allergic reaction versus GVHD. Fluorescence in situ hybridization of the skin biopsy showed 28% of cells had a Y chromosome confirming GVHD. Short tandem repeats (STR) enriched for CD3+ cells from peripheral blood showed a mixed chimerism. She was successfully treated with a single plasmapheresis to remove antithymocyte globulin, high-dose steroids, photopheresis and high tacrolimus levels (12-15 ng/mL). Five months after transplantation, she has normal renal function and white blood cell count, normal hemoglobin A1C and no evidence of peripheral blood donor chimerism. In conclusion, early diagnosis of GVHD after SPK transplantation may allow successful treatment. STR enriched for CD3+ may be useful to evaluate the response to therapy.

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BACKGROUNDS AND AIMS: We assessed the associations between pancreatic fat accumulation and other fat compartments, including liver fat and visceral adipose tissue as well as insulin resistance and other metabolic abnormalities in obese individuals. SUBJECTS AND METHODS: We studied 42 Caucasian adults with obesity [20 men and 22 women; mean body mass index (BMI) 35.2±4 kg/m(2)], who had no history of liver diseases or excessive alcohol consumption, in which subcutaneous, visceral, liver, and pancreatic fat contents were quantified by an in-opposed-phase magnetic resonance imaging (MRI) technique. RESULTS: Compared with patients in the lower tertile (<5.6%, no.=15), those in the upper tertile of liver fat content had more visceral adipose tissue, greater insulin resistance and had higher values of BMI, blood pressure, triglycerides and lower HDL-cholesterol and adiponectin. Notably, pancreatic fat accumulation also significantly increased across tertiles of liver fat content. In univariate analysis, the strongest correlates of pancreatic fat were visceral and liver fat contents (r=0.80 and r=0.54, p<0.001- 0.0001, respectively). Pancreatic fat accumulation was also moderately associated with insulin resistance and other metabolic syndrome features. However, when adjusted for age, gender and visceral adipose tissue, the associations of pancreatic fat accumulation with liver fat and other metabolic abnormalities were no longer significant. CONCLUSIONS: There are significant associations between pancreatic fat accumulation and liver fat content as well as insulin resistance and other metabolic abnormalities in obese, but otherwise healthy, individuals. However, these associations are largely mediated by the amount of visceral adipose tissue.

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OBJECTIVE: To compare the effects of weight loss on visceral and subcutaneous abdominal fat, liver and pancreas lipid content and to test the effects of these changes on metabolic improvement observed after weight loss. DESIGN: Weight-loss program designed to achieve a loss of 7-10% of the initial weight. SUBJECTS: 24 obese subjects (13 males and 11 females) with age ranging from 26 to 69 years and body mass index (BMI) 30.2-50.5 kg m(-2). MEASUREMENTS: weight, BMI, waist circumference, body composition as assessed by dual-energy X-ray absorptiometry, metabolic variables, leptin, adiponectin, visceral and subcutaneous abdominal fat, liver and pancreas lipid content as assessed by magnetic resonance were evaluated before and after weight loss achieved by hypocaloric diet. RESULTS: After a mean body weight decrease of 8.9%, BMI, waist circumference, fat mass, all metabolic variables, homeostasis model assessment of insulin resistance (HOMA), alanine amino transferase, gamma glutamyl transpeptidase, high-sensitivity C-reactive protein (hs-CRP) and leptin, but not adiponectin and high-density lipoprotein-cholesterol, significantly decreased (all P<0.01). Visceral and subcutaneos abdominal fat, liver and pancreas lipid content significantly decreased (all P<0.01). Percent changes in liver lipid content were greater (84.1±3%) than those in lipid pancreas content (42.3±29%) and visceral abdominal fat (31.9±15.6%). After weight loss, percentage of subjects with liver steatosis decreased from 75 to 12.5%. Insulin resistance improvement was predicted by changes in liver lipid content independently of changes in visceral fat, pancreas lipid content, systemic inflammation, leptin and gender. CONCLUSION: Moderate weight loss determines significant decline in visceral abdominal fat, lipid content in liver and pancreas. Reduction of liver lipid content was greater than that of pancreas lipid content and visceral fat loss. Liver lipid content is the strongest predictor of insulin resistance improvement after weight loss.

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In this phase II study, 41 patients with locally advanced urothelial bladder cancer (T2-4, N0, M0) were treated with primary chemotherapy (cisplatin, epirubicin, methotrexate: PEM-3). All the patients were assessable for response and toxicity. Clinical monitoring was performed with computerized tomography and cystoscopy. Nineteen clinical complete remissions (46%) and 10 partial remissions (24.5%) were obtained (CR + PR, 70.5%; 95% confidence interval, 57%-85%). Ten patients were considered to have clinically stable disease (24.5%), and 2 patients progressed (5%). Surgery after chemotherapy was performed in 22 cases: in 6 patients (27%) a pathologic complete response was achieved. The pathologic stage was lower than the initial clinical stage in 13 patients (59%). After a median follow-up of 3 years (range, 1-4), the median time to progression was 104 weeks. At this writing, 20 patients, 12 of which were submitted to surgery and 8 were not operated, are disease-free. The 3-year survival rate is 52%. No one had to interrupt the treatment because of toxicity. In conclusion, the PEM-3 regimen is a very active and well-tolerated regimen in locally advanced bladder cancer.

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Forty patients with advanced transitional cell cancer (TCC) of the bladder were treated with cisplatin, epirubicin, methotrexate (PEM, every 3-4 weeks). If creatinine clearance was reduced to 40 ml/min, the usual full doses of cisplatin and methotrexate, 50 mg/m2, were proportionally reduced. 23 patients had full-dose (FD) therapy, 17 had reduced dose (RD) (40-20 mg/m2). Two patients achieved complete response and 17 partial response. The overall response rate was 19/40 (47.5%), 11/23 (48%) for FD and 8/17 (47%) for RD (p = 1.000). 17/40 pts (42.5%) had no-change and 4/40 (10%) had disease progression. The median duration of CR and PR was 32 weeks, range 4-82 (22 weeks, range 12-52 for FD; 32 weeks, range 4-82 for RD, cisplatin p = .7362). The main side effect was vomiting (35/40 pts, 87.5%, 20/23 = 87% for FD, 15/17 = 90% for RD, p = 1.000). Leukopenia was observed in 12 patients (30%, nadir 3,240 range 900-3,800, 6/23 = 26% for FD, 6/17 = 35% for RD, p = .7285), alopecia in 18 patients (45%, 15/23 = 65% for FD, 3/17 = 18% for RD, p = .004). The results of this study show that a dose escalation to 50 mg/m2 for cisplatin, epirubicin and methotrexate in the PEM regimen results in an increase in overall response (OR) (19/40 = 47.5%) with respect to a historical control using the same drugs at doses of 40 mg/m2 (12/35 = 34%). In patients with normal renal function the escalated dose was tolerated without a corresponding increase in toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

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Thirty-seven patients with advanced head and neck tumors were treated with a polychemotherapy regimen (PEV-B: platinum 30 mg/m2 i.v., epirubicin 30 mg/m2 i.v., etoposide 75 mg/m2 i.v. on days 1 and 2 every 28 days, and bleomycin 15 mg i.m. weekly up to the total dose of 300 mg). All but 7 patients were pretreated with surgery and/or radiotherapy. Thirty-six patients were evaluable for response. Partial response (PR) was observed in 19 cases (53%), no change (NC) in 13 cases (36%) and progression (P) in 4 cases (11%). The median duration of PR was 5 months. The most frequent side-effects were leukopenia (78%), vomiting (57%) and alopecia (46%). The median duration of survival was 8 months for the responders and 5 months for the non-responders.

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Epirubicin (epiDX) pharmacokinetics was followed in 10 advanced cancer patients with hepatic metastases from colorectal carcinoma or primary liver tumor after single bolus administration (20-40 mg) in the hepatic artery, through a surgically implanted catheter and subcutaneous access port. EpiDX plasma and whole blood concentrations follow a triphasic decay qualitatively similar to that observed after IV administration. Blood levels are consistently higher than plasma levels. Plasma clearance (nine patients, mean: 93.4 l/hr; range: 69.3-129.5 l/hr) is higher than the corresponding parameter determined in patients with hepatic metastases after intravenous therapy. The remaining patient is characterised by an abnormally low plasma clearance (13.6 l/hr), due to a hepato-pulmonary shunt. The subjects in this study were exposed to very low drug concentrations, and therefore experienced no relevant adverse side-effects.

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The high hepatic clearance of the new doxorubicin analogue epirubicin (4'-epidoxorubicin, epiDX) suggests a possible use of this drug in local and regional therapy where a first pass through the liver is required before the drug can reach systemic circulation. EpiDX pharmacokinetics was followed in advanced cancer patients with liver metastases or a primary tumour after single bolus administration in the hepatic artery, through a surgically implanted catheter and subcutaneous access port. The first-pass effect through the liver was appreciable and only a relatively low fraction of the drug reached systemic circulation. Mild leucopenia and alopecia were observed only in a patient with a hepatopulmonary shunt; this subject was actually exposed to higher epiDX plasma levels. Low intraperitoneal doses of epiDX were administered in a weekly schedule to advanced cancer patients with peritoneal metastases and ascites. Drug concentrations were monitored in the ascitic effusion and in plasma. A high concentration gradient was present between the peritoneal cavity and peripheral circulation. No relevant local or systemic toxicity was observed.

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The authors report data concerning their study on the incidence of pain in advanced neoplastic patients and on the natural history of this symptom. They also report their experience in the treatment of solid tumours with non steroidal antiinflammatory drugs (Zomepirac, acetylsalicylic acid, Diflunisal, Ketoprofen) with a synthetic progestin (Medroxyprogesterone Acetate employed by authors at high or at very high doses for the first time) and with morphine hydrochloride used by oral, rectal, sublingual and nasal route. The authors also indicate the correct strategy of employing these drugs and criteria of evaluating their effectiveness.

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Thirty-six patients suffering from severe pain due to bone involvement from cancer participated in an analgesic study that compared single doses of ketoprofen 100 or 400 mg iv or injectable acetylsalicylic acid 1 g. A double-blind, balanced incomplete block design was adopted, in which each patient received two of the three test treatments, with an interval of 24 hours. Ketoprofen 400 mg proved significantly superior to 100 mg of the same drug, and was superior to 1 g of the acetylsalicylic acid derivative in the patients' assessment of the overall response. This was expressed by a visual analog scale and preferences. No adverse reaction was observed with any treatment.

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