The Naturally Processed CD95L Elicits a c-Yes/Calcium/PI3K-Driven Cell Migration Pathway

Patients affected by chronic inflammatory disorders display high amounts of soluble CD95L. This homotrimeric ligand arises from the cleavage by metalloproteases of its membrane-bound counterpart, a strong apoptotic inducer. In contrast, the naturally processed CD95L is viewed as an apoptotic antagonist competing with its membrane counterpart for binding to CD95. Recent reports pinpointed that activation of CD95 may attract myeloid and tumoral cells, which display resistance to the CD95-mediated apoptotic signal. However, all these studies were performed using chimeric CD95Ls (oligomerized forms), which behave as the membrane-bound ligand and not as the naturally processed CD95L. Herein, we examine the biological effects of the metalloprotease-cleaved CD95L on CD95-sensitive activated T-lymphocytes. We demonstrate that cleaved CD95L (cl-CD95L), found increased in sera of systemic lupus erythematosus (SLE) patients as compared to that of healthy individuals, promotes the formation of migrating pseudopods at the leading edge of which the death receptor CD95 is capped (confocal microscopy). Using different migration assays (wound healing/Boyden Chamber/endothelial transmigration), we uncover that cl-CD95L promotes cell migration through a c-yes/Ca2+/PI3K-driven signaling pathway, which relies on the formation of a CD95-containing complex designated the MISC for Motility-Inducing Signaling Complex. These findings revisit the role of the metalloprotease-cleaved CD95L and emphasize that the increase in cl-CD95L observed in patients affected by chronic inflammatory disorders may fuel the local or systemic tissue damage by promoting tissue-filtration of immune cells

Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFb signaling, p53 and beta-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy

Educational action in the rehabilitation of severe acquired brain injuries: the role of self-awareness

Severe acquired brain injuries (ABI) cause a range of short-or long-term limitations in physical and neuropsychological abilities. The aim of rehabilitation is to promote the harmonious development of the individual through collaboration between medical and educational sciences, involved in the educability of the whole person, in which the aim is not only functional recovery but also social- reintegration. This “functional synergy” permits the development of the person, and establishes an indissoluble link between functions and attitudes, thus allowing the achievement of the greater possible autonomy. In this way classical and pedagogical rehabilitation may be combined in a single concept of educational action. To realize this integrated educational process it is important to evaluate and promote awareness development, based on the possibilities of brain plasticity and on the presence of multiple intelligences skillfully in- tertwined each other. Therefore, self-awareness plays a prime role in educational actions for the rehabilitation of persons with severe ABI

Changes in Caregivers Lifestyle after Severe Acquired Brain Injury: A Preliminary Investigation.

INTRODUCTION: Severe acquired brain injury (sABI) is considered the most common cause of death and disability worldwide. sABI patients are supported by their caregivers who often exhibit high rates of psychological distress, mood disorders, and changes in relationship dynamics and family roles. OBJECTIVES: To explore lifestyle changes of caregivers of sABI patients during the postacute rehabilitation, by investigating possible differences between primary and secondary caregivers. Primary caregivers spend most of the time with the patient, providing daily care and taking most responsibility for the day-to-day decisions, while secondary caregivers are those who provide additional support. METHODS: Three hundred forty-seven caregivers of sABI patients were asked to fill in an unpublished self-report questionnaire to explore their possible lifestyles changes. RESULTS: A statistically significant difference was found between primary and secondary caregivers in time spent in informal caregiving (p<0.001). The primary caregivers reduced all leisure activities compared to secondary carers (p<0.05). CONCLUSIONS: By comparing the percentage of leisure activities performed by caregivers before and after the patient's sABI onset, all caregivers showed high percentages of changes in lifestyle and habits, even though primary caregivers reported more negative lifestyle changes than secondary caregivers. Further studies are needed to investigate needs and burden experienced by caregivers of sABI patients during the postacute rehabilitation phase, also in relation to the patients' outcome, to address support interventions for them and improve their quality of life

Metacognitive unawareness correlates with executive function impairment after severe traumatic brain injury

The aim of this study was to evaluate clinical, neuropsychological, and functional differences between severe traumatic brain injury (TBI) outpatients with good and/or heightened metacognitive self-awareness (SA) and those with impaired metacognitive SA, assessed by the Patient Competency Rating Scale (PCRS). Fifty-two outpatients were recruited from a neurorehabilitation hospital based on the following inclusion criteria: 1) age ≥ 15 years; 2) diagnosis of severe TBI; 3) availability of neuroimaging data; 4) post-traumatic amnesia resolution; 5) provision of informed consent. Measures: A neuropsychological battery was used to evaluate attention, memory and executive functions. SA was assessed by the PCRS, which was administered to patients and close family members. Patients were divided into two groups representing those with and without SA. Patients with poor SA had more problems than those with good SA in some components of the executive system, as indicated by the high percentage of perseverative errors and responses they made on the Wisconsin Card Sorting Test. Moreover, a decrease in metacognitive SA correlated signifi cantly with time to follow commands (TFC). This study suggests the importance of integrating an overall assessment of cognitive functions with a specifi c evaluation of SA to treat self-awareness and executive functions together during the rehabilitation proces

Attention deficits in stroke patients: The role of lesion characteristics, time from stroke, and concomitant neuropsychological deficits

Attention impairments are frequent in stroke patients with important consequences on the rehabilitation outcomes and quality of life. The aim of the study was to perform a comprehensive assessment of selective and intensive attention processes in a large population of brain-damaged patients, evaluating the influence of the side and site of the brain lesion, the time from stroke, and the concomitant presence of aphasia or neglect. We assessed 204 patients with a first unilateral brain lesion and 42 healthy individuals with three subtests of the Test of Attentional Performance (TAP): Alertness, Go-No Go, and Divided Attention. 44.4% of patients had an impairment in both intensive and selective aspects of attention, 5.6% had deficits only in the intensive component, and 31.8% had deficits only in selective tasks. More than 80% of the patients fell below the cut-off point on at least one task. Patients with a right hemispheric lesion (RHL) were more impaired than patients with a left hemispheric lesion (LHL) especially in tonic and phasic alertness. Patients with total anterior infarcts (TACI) presented the worst profile compared to other stroke subtypes, with a difference between total and lacunar subtypes in the Alertness test, independent of the presence of warning. Patients in the chronic phase had shorter RTs than acute patients only in the Alertness test. In patients with LHL, the presence of aphasia was associated with a greater deficit in selective attention. In patients with RHL, the presence of unilateral neglect was associated with impaired alertness and selective attention. Attention deficits are common after a unilateral first stroke. In keeping with the hierarchical organization of attention functions, results confirm the important role of the right hemisphere for the intensive components of attention, also highlighting the involvement of left hemisphere functioning for the selective aspects, possibly indicating a role of its linguistic functions