Since the initial description of apoptosis, a number of different forms of cell death have been described. In this review we will focus on classic caspase-dependent apoptosis and its variations that contribute to diseases. Over fifty years of research have clarified molecular mechanisms involved in apoptotic signaling as well and shown that alterations of these pathways lead to human diseases. Indeed both reduced and increased apoptosis can result in pathology. More recently these findings have led to the development of therapeutic approaches based on regulation of apoptosis, some of which are in clinical trials or have entered medical practice.
Bcl2-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that interacts with the ATPase domain of the heat shock protein (Hsp) 70 through BAG domain (110–124 amino acids). BAG3 is the only member of the family to be induced by stressful stimuli, mainly through the activity of heat shock factor 1 on bag3 gene promoter. In addition to the BAG domain, BAG3 contains also a WW domain and a proline-rich (PXXP) repeat, that mediate binding to partners different from Hsp70. These multifaceted interactions underlie BAG3 ability to modulate major biological processes, that is, apoptosis, development, cytoskeleton organization and autophagy, thereby mediating cell adaptive responses to stressful stimuli. In normal cells, BAG3 is constitutively present in a very few cell types, including cardiomyocytes and skeletal muscle cells, in which the protein appears to contribute to cell resistance to mechanical stress. A growing body of evidence indicate that BAG3 is instead expressed in several tumor types. In different tumor contexts, BAG3 protein was reported to sustain cell survival, resistance to therapy, and/or motility and metastatization. In some tumor types, down-modulation of BAG3 levels was shown, as a proof-of-principle, to inhibit neoplastic cell growth in animal models. This review attempts to outline the emerging mechanisms that can underlie some of the biological activities of the protein, focusing on implications in tumor progression.
Some studies suggest that patients with cirrhosis have an increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE). Unfortunately, available data on this association are contrasting. It was the objective of this study to perform a systematic review and meta-analysis of literature to evaluate the risk of venous thromboembolism (VTE) associated with cirrhosis. Studies reporting on VTE risk associated with cirrhosis were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. Eleven studies (15 data-sets) showed a significantly increased VTE risk in 695,012 cirrhotic patients as compared with 1,494,660 non-cirrhotic controls (OR: 1.703; 95 %CI: 1.333, 2.175; P<0.0001). These results were confirmed when specifically considering the risk of DVT (7 studies, OR: 2.038; 95 %CI: 1.817, 2.285; P<0.0001) and the risk of PE (5 studies, OR: 1.655; 95 %CI: 1.042, 2.630; p=0.033). The increased VTE risk associated with cirrhosis was consistently confirmed when analysing nine studies reporting adjusted risk estimates (OR: 1.493; 95 %CI: 1.266, 1.762; p<0.0001), and after excluding studies specifically enrolling populations exposed to transient risk factors for VTE (OR: 1.689; 95 %CI: 1.321, 2.160; p<0.0001). Meta-regression models suggested that male gender may significantly impact on the risk of VTE associated with cirrhosis. Results of our meta-analysis suggest that cirrhotic subjects may exhibit an increased risk of VTE. This should be considered to plan specific prevention strategies in this clinical setting.
The immune system seems to play a fundamental role in breast cancer responsiveness to chemotherapy. We investigated two peripheral indicators of immunity/inflammation, i.e. neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in order to reveal a possible relationship with pathological complete response (pCR) in patients with early or locally advanced breast cancer treated with neoadjuvant chemotherapy (NACT).We retrospectively analyzed 373 consecutive patients affected by breast cancer and candidates to NACT. The complete blood cell count before starting NACT was evaluated to calculate NLR and PLR. ROC curve analysis determined threshold values of 2.42 and 104.47 as best cut-off values for NLR and PLR, respectively. The relationships between NLR/PLR and pCR, along with other clinical-pathological characteristics, were evaluated by Pearson's c 2 or Fisher's exact test as appropriate. Univariate and multivariate analyses were performed using a logistic regression model. NLR and PLR were not significantly associated with pCR if analyzed separately. However, when combining NLR and PLR, patients with a NLR low /PLR low profile achieved a significantly higher rate of pCR compared to those with NLR high and/or PLR high (OR 2.29, 95% CI 1.22e4.27, p 0.009). Importantly, the predictive value of NLR low /PLR low was independent from common prognostic factors such as grading, Ki67, and molecular subtypes.The combination of NLR and PLR may reflect patients' immunogenic phenotype. Low levels of both NLR and PLR may thus indicate a status of immune system activation that may predict pCR in breast cancer patients treated with NACT.
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