Ablations of Ghrelin and Ghrelin Receptor Exhibit Differential Metabolic Phenotypes and Thermogenic Capacity during Aging

mice are adaptive. mice.Our data therefore suggest that GHS-R ablation activates adaptive thermogenic function(s) in BAT and increases EE, thereby enabling the retention of a lean phenotype. This is the first direct evidence that the ghrelin signaling pathway regulates fat-burning BAT to affect energy balance during aging. This regulation is likely mediated through an as-yet-unidentified new ligand of GHS-R

BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages

The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential

Autoimmune Hepatitis: Factors Involved in Initiation and Methods of Diagnosis and Treatment

Autoimmune hepatitis is an acute or mostly chronic liver disease that can affect both adults and children and has a clear prevalence for the female sex. A definite etiology has not been established, but it is known that genetic predisposing profiles and exogenous trigger factors are involved. The main diagnostic criteria include typical histological features, the occurrence of serum auto-antibodies, and increased levels of transaminases and gamma-globulins. Instances of autoimmune hepatitis sharing features with other autoimmune liver diseases have also been observed. An imbalance of the immune system with persistent activation of effector T cells has been emphasized to account for the sustained liver injury. Clinical manifestations are variable both at presentation and throughout the course of the disease, ranging from an asymptomatic state or the occurrence of non-specific symptoms to the features of end-stage liver disease such as jaundice, ascites, and gastrointestinal bleeding. A clinical and biochemical remission is achieved in at least 80% of patients receiving corticosteroids with or without the addition of azathioprine. Alternative therapeutic schedules have been proposed for unresponsive and intolerant patients. Given that relapse often occurs after therapy withdrawal, maintenance treatment is usually required

Preliminary Study on the Significance of BRCA1 and PARP1 Immunohistochemical Expression in Ovarian Cancer

Role of BRCA1 and PARP1 has been studied by immunohistochemistry in a cohort of ovarian cancers. Their expression has been related to overall survival and disease free disease. Objective: To investigate the clinical outcome of an heterogeneous population of ovarian cancers as respect to immunohistochemical expression of BRCA1 and PARP1 in order to identify a histological threshold for positivity and negativity and to predict possible candidates to anti-PARP therapy. Material and methods: 97 cases of ovarian cancers were collected in a multicentre study and immunohistochemically tested for BRCA1 and PARP1. The immunohistochemical expression of BRCA1 and PARP1 was studied on formalin-fixed and paraffin-embedded samples. Overall survival and disease free survival were evaluated. Statistical analysis was performed including cancers of all types and a subgroup of high grade serous carcinoma that represents the predominant histotype. Results: A possible threshold to discriminate positive and negative cases has been proposed. BRCA1 and PARP1 immunohistochemical expression did not significantly correlate with overall survival. The evaluation of survival for the combinations of BRCA1+/-, PARP1+/- showed a longer patient survival when the positivity and negativity were in contrast compared to when they were in agreement. Conclusions: Although BRCA1 and PARP1 expression do not appear to be correlated with overall survival, further investigation and follow-up together with a larger number of cases could clarify the function; the standardised immunohistochemical method could better select the patient group sensitive to PARP1 inhibitors

An homologue of the human 100 kD protein (p100) is differentially expressed by Histoplasma capsulatum during infection of murine macrophages

Using differential display reverse transcription-PCR (DDRT-PCR) we have identified several sequences that are specifically expressed by Histoplasma capsulatum during infection of murine macrophages (MPhi). Here, we report the characterization of a clone, pHc12, identified as a differentially expressed gene 1 hour after infection of MPhi. Screening of a cDNA library of H. capsulatum allowed us to isolate a clone, pHc12-E, that contains the complete coding sequence. We show that after infection the level of transcription of this gene increases about 5 fold. Analysis of its sequence revealed the presence of an open reading frame of 890 aa (ORF890) that shares respectively 30 and 33% identity with human and Caenorhabditis elegans p100 kD and rat p105 kD co-activator proteins. Using the two-dimensional Hydrophobic Cluster Analysis (HCA) method, we showed that H. capsulatum ORF890 and p100 kD co-activator proteins are clearly related. The H. capsulatum protein consists of a four-fold repeated module (domains I to IV) like the p100 kD co-activator proteins, whose three-dimensional (3D) structure is related to staphylococcal thermonuclease, followed by a modified fifth "hybrid" domain which partially resembles the structure of the tudor domain found in multiple copies in the Drosophila melanogaster tudor protein. These data strongly suggest that ORF890 is homologous to human p100 kD and that this protein, named Hcp100, may play an essential role during infection by co-activating the expression of specific genes

Dynamics of GH secretion during incremental exercise in obesity, before and after a short period of training at different work-loads

International audience<b>Background</b>. Growth hormone (GH) is normally sensitive to physical exercise. Intensity and duration of exercise, fitness as well as age, all can influence GH response to exercise. In obesity, GH secretion is decreased both in basal conditions and in response to exercise. <b>Objective</b>. To analyse the dynamics of GH response to a progressive cycloergometric test conducted up to exhaustion in adult normal subjects and obese patients, after a reconditioning program at different workloads. <b>Design and methods</b>. We studied 8 lean subjects (4 males, mean age 34.3 yrs, range 26-47 yrs, mean BMI 22.1 kg/m²). GH was sampled at baseline and during the last 30 s of each power output increase. Anaerobic threshold (AT) was detected by the V-slope method. The same test was carried out in 16 obese subjects (7 males, mean age 39.1 yrs, range 20-59 yrs, mean BMI 35.8 kg/m²) and repeated after a 4-week reconditioning program consisting of aerobic workout (Group A, 8 subjects, 3 males, mean age 40.5 yrs, range 22-59 yrs, mean BMI 33.6 kg/m²), and aerobic plus anaerobic work (group B, 8 subjects, 4 males, mean age 37.6 yrs, range 20-56 yrs, mean BMI 38.0 kg/m²) for 6 days/wk, with no dietary restrictions. <b>Results</b>. Mean exercise peak occurred at higher intensity in controls (140 vs. 110 W, p<0.05) and AT exceeded at higher work outputs than in obese subjects (102 vs. 74 W, p<0.05). In controls, GH response to exercise was prompt and further sustained after AT; in obese subjects, GH increased slowly and unsignificantly before AT, thereafter it increased to lower levels than in controls (p<0.001). Following the reconditioning period, both Group A and Group B of obese subjects failed to improve exercise performance as well as GH response to exercise before AT; beyond AT, a greater GH response to exercise occurred in Group B than Group A (7.59 ± 0.32 μg/l at peak of exercise) with significantly different Delta AUCs following AT: 30.5 ± 12 μg-min/l in the Group A vs 124.2 ± 38 μg-min/l in the Group B, p < 0.05. <b>Conclusions</b>. Our results confirm the blunted GH response to exercise in obese adults when compared to lean counterparts. With obesity, aerobic training poorly increases the GH response beyond AT while supplemental anaerobic workload appears to increase GH response beyond AT. These observations may have implications for prescription of physical exercise, which is one of the recommendations in the management of obesity