p63-microRNA feedback in keratinocyte senescence

We investigated the expression of microRNAs (miRNAs) associated with replicative senescence in human primary keratinocytes. A cohort of miRNAs up-regulated in senescence was identified by genome-wide miRNA profiling, and their change in expression was validated in proliferative versus senescent cells. Among these, miRNA (miR)-138, -181a, -181b, and -130b expression increased with serial passages. miR-138, -181a, and -181b, but not miR-130b, overexpression in proliferating cells was sufficient per se to induce senescence, as evaluated by inhibition of BrdU incorporation and quantification of senescence-activated β-galactosidase staining. We identified Sirt1 as a direct target of miR-138, -181a, and -181b, whereas ΔNp63 expression was inhibited by miR-130b. We also found that ΔNp63α inhibits miR-138, -181a, -181b, and -130b expression by binding directly to p63-responsive elements located in close proximity to the genomic loci of these miRNAs in primary keratinocytes. These findings suggest that changes in miRNA expression, by modulating the levels of regulatory proteins such as p63 and Sirt1, strongly contribute to induction of senescence in primary human keratinocytes, thus linking these two proteins. Our data also indicate that suppression of miR-138, -181a, -181b, and -130b expression is part of a growth-promoting strategy of ΔNp63α in epidermal proliferating cells.     

Immunomodulation in psoriatic arthritis: Focus on cellular and molecular pathways

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis. Pathogenesis is incompletely understood and pathophysiological role of synovium is just beginning to be elucidated. PsA could be considered an enthesal disease and this hypothesis is the link between mechanical stress (entheses) and immunologically active tissue (synovium). Histologically, PsA is characterized by lining layer hyperplasia, diffuse infiltrate of B, T, macrophages and dendritic cells associated with neutrophils' proliferation and angiogenesis. T cells are present, and oligoclonal T-cell expansions have been demonstrated in both skin and synovium. Histological findings are associated with monocyte-derived cytokines expression, as Myeloid-related protein (S100A8/A9). They play an important role in intracellular functions and cytoskeleton–membrane interactions. S100A8/A9 has a role in the propagation and perpetuation of the inflammatory process in patients with psoriasis and PsA, because of an activated monocyte/macrophage system that involve, distal to the skin, the “enthesal-complex.” Complement system can be considered part of the acute phase response as demonstrated by higher plasma levels of C3 and C4 complement components in PsA patients compared with healthy subjects. These abnormal levels are then reverted by anti-TNF drugs. Evidences of efficacy of anti-TNF are expressed by reduction of vascularity and immune cells in synovial tissue. Therefore, innate response generates high concentrations of inflammatory cytokines which promote effector functions of a variety of tissue cells and sustain the characteristic chronicity of synovitis. The challenge will be the development of molecules affecting the balance between innate and adaptive immunity without affecting beneficial functions of the perfect concert of immunological process.     

Recombinant Human Interleukin-1 Receptor Antagonist Provides Cardioprotection During Myocardial Ischemia Reperfusion in the Mouse

Purpose

Acute myocardial infarction (AMI) drives an intense inflammatory response that contributes to infarct healing and cardiac remodeling. Recently, different studies have identified a role of interleukin-1 (IL-1) in the development of adverse cardiac remodeling. However, in animal models of AMI IL-1 has been shown to be cardioprotective in preconditioning, raising the question of clinical safety of therapeutic IL-1 blockade for autoinflammatory diseases or for the prevention or the treatment of AMI. In this study we proposed to evaluate the effects of pretreatment with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on ischemia reperfusion (I/R) injury to the heart.

Methods

RhIL-1Ra was given 4?h or 30?min before the surgical induction of I/R. Left ventricular ejection fraction(LVEF) and infarct size were assessed to determine the effects of the drug pretreatment compared to vehicle treated mice.

Results

RhIL-1Ra, given 4?h or 30?min before the onset of the ischemia, showed marked cardioprotection though preservation of the LVEF (no change vs sham operated mice) and the reduction of the infarct size (?40?% vs vehicle-treated mice). No differences were observed between the two groups of rhIL-1Ra treatment.

Conclusions

IL-1 blockade therapies using rhIL-1Ra prior the onset of AMI protects the myocardium and preserves cardiac function.     

Donor compatibility and performance status affect outcome of allogeneic haematopoietic stem cell transplant in patients with relapsed or refractory acute myeloid leukaemia

We retrospectively analysed 78 patients with relapsed (n?=?38), primary refractory (n?=?34) or untreated (n?=?6) acute myeloid leukaemia (AML) who underwent allogeneic HSCT at our Institution between 2002 and 2011, to verify outcome and to identify factors that can affect long-term outcome. Myeloablative conditioning regimens were used in 48 patients (24 siblings, 24 matched unrelated donor (MUD)), while 30 patients (18 siblings, 12 MUD) received reduced-intensity conditioning. Acute graft versus host disease (GVHD) developed in 37 (47?%) patients, while chronic GVHD occurred in 19 of the 65 evaluable patients (29?%). With a median follow-up time of 5?years, 13 of 78 patients (17?%) are alive and in complete remission (CR), while 64 have died. Cause of death was disease recurrence in 37 patients (58?%), infection in ten patients (16?%) and GVHD in six (9?%). One-year non-relapse mortality was 35?%. In multivariate analysis, performance status ≥80?% WHO and a full-matched donor were associated with a better outcome: these two variables allowed for risk stratification, identifying three groups with significantly different survival after transplant (P?=?0.0001). Considering post-transplant variables, only CR at recovery and development of cGVHD were correlated with a longer survival. Our data confirm the capacity of allogeneic transplant to prolong survival in a significant proportion of extremely high-risk AML patients.     

What is the probability of being too old for salvage transplantation after hepatocellular carcinoma resection?

BackgroundThe strategy of salvage transplantation for patients with hepatocellular carcinoma is based on the premise that tumour recurrence will be still transplantable at the time of recurrence. However, patients can not only present non-transplantable recurrence but can also be over the age limit accepted for transplantation.AimsTo measure the risk of being too old for salvage transplantation of patients resected for hepatocellular carcinoma within Milan criteria.MethodsA Markov simulation model was developed on the basis of published literature.ResultsThe risk of being too old for salvage transplantation depends on the time-span between age at hepatic resection and age limit, and the expected median waiting-time. Patients resected at an age 2 or 3 years below the age limit carry a risk of being too old that overcomes the probability of receiving transplantation. Salvage strategy can cause harm that depends on the tumour characteristics and degree of portal hypertension, becoming maximal for patients with multiple tumours, clinical signs of portal hypertension and increased bilirubin levels.ConclusionsThe best strategy to adopt should be balanced between the risk of being too old and the expected transplant benefit, but salvage strategy could be pursued if it did not turn into significant harm in comparison to primary transplantation.     

International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A Task Force report from the ILAE Commission on Diagnostic Methods

Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug‐resistant temporal lobe epilepsy (TLE). Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome. However, no international consensus about definitions and terminology has been achieved. A task force reviewed previous classification schemes and proposes a system based on semiquantitative hippocampal cell loss patterns that can be applied in any histopathology laboratory. Interobserver and intraobserver agreement studies reached consensus to classify three types in anatomically well‐preserved hippocampal specimens: HS International League Against Epilepsy (ILAE) type 1 refers always to severe neuronal cell loss and gliosis predominantly in CA1 and CA4 regions, compared to CA1 predominant neuronal cell loss and gliosis (HS ILAE type 2), or CA4 predominant neuronal cell loss and gliosis (HS ILAE type 3). Surgical hippocampus specimens obtained from patients with TLE may also show normal content of neurons with reactive gliosis only (no‐HS). HS ILAE type 1 is more often associated with a history of initial precipitating injuries before age 5 years, with early seizure onset, and favorable postsurgical seizure control. CA1 predominant HS ILAE type 2 and CA4 predominant HS ILAE type 3 have been studied less systematically so far, but some reports point to less favorable outcome, and to differences regarding epilepsy history, including age of seizure onset. The proposed international consensus classification will aid in the characterization of specific clinicopathologic syndromes, and explore variability in imaging and electrophysiology findings, and in postsurgical seizure control.     

Adult-onset leukodystrophies from respiratory chain disorders: do they exist?

Respiratory chain disorders (RCDs) have been included in the differential diagnosis of adult-onset leukodystrophies. Here, we first report a 32-year-old female with an atypical, adult-onset, non-syndromic RCD due to a mitochondrial DNA deletion and manifesting as complicated ataxia. A ‘leukodystrophic’ pattern was found on brain MRI, but it was neither isolated nor predominant because of the presence of overt basal ganglia and infratentorial lesions, which led us to the proper diagnosis. Subsequently, we evaluated our series of patients with RCDs in order to verify whether a ‘leukodystrophic’ pattern with little or no involvement of deep grey structures and brainstem may be found in adult-onset RCDs, as reported in children. Among 52 patients with adult-onset RCDs, no case with a ‘leukodystrophic’ pattern was found, apart from three cases with a classical phenotype of mitochondrial neurogastrointestinal encephalopathy. In addition, no case of RCDs was found among six cases of adult-onset leukodystrophy of unknown origin and at least one feature suggestive of mitochondrial disease. The review of the literature was in agreement with these findings. Thus, we provide evidence that, unlike in children, RCDs should not be included in the differential diagnosis of adult-onset leukodystrophies, except when there are additional MRI findings or clinical features which unequivocally point towards a mitochondrial disorder.