The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis.

Accumulating evidence underscores the T-cell immune synapse (IS) as a site of intense vesicular trafficking, on which productive signaling and cell activation crucially depend. Although the T-cell antigen receptor (TCR) is known to exploit recycling to accumulate to the IS, the specific pathway that controls this process remains to be elucidated. Here we demonstrate that the small GTPase Rab29 is centrally implicated in TCR trafficking and IS assembly. Rab29 colocalized and interacted with Rab8, Rab11 and IFT20, a component of the intraflagellar transport system that regulates ciliogenesis and participates in TCR recycling in the non-ciliated T cell, as assessed by co-immunoprecipitation and immunofluorescence analysis. Rab29 depletion resulted in the inability of TCRs to undergo recycling to the IS, thereby compromizing IS assembly. Under these conditions, recycling TCRs accumulated in Rab11(+) endosomes that failed to polarize to the IS due to defective Rab29-dependent recruitment of the dynein microtubule motor. Remarkably, Rab29 participates in a similar pathway in ciliated cells to promote primary cilium growth and ciliary localization of Smoothened. These results provide a function for Rab29 as a regulator of receptor recycling and identify this GTPase as a shared participant in IS and primary cilium assembly.

Negative regulation of chemokine receptor signaling and B-cell chemotaxis by p66Shc.

Shc (Src homology 2 domain containing) adaptors are ubiquitous components of the signaling pathways triggered by tyrosine kinase-coupled receptors. In lymphocytes, similar to other cell types, the p52 and p66 isoforms of ShcA/Shc participate in a self-limiting loop where p52Shc acts as a positive regulator of antigen receptor signaling by promoting Ras activation, whereas p66Shc limits this activity by competitively inhibiting p52Shc. Based on the fact that many signaling mediators are shared by antigen and chemokine receptors, including p52Shc, we have assessed the potential implication of p66Shc in the regulation of B-cell responses to chemokines, focusing on the homing receptors CXCR4 (C-X-C chemokine receptor type 4) and CXCR5 (C-X-C chemokine receptor type 5). The results identify p66Shc as a negative regulator of the chemotactic responses triggered by these receptors, including adhesion, polarization and migration. We also provide evidence that this function is dependent on the ability of p66Shc to interact with the chemokine receptors and promote the assembly of an inhibitory complex, which includes the phosphatases SHP-1 (Src homology phosphatase-1) and SHIP-1 (SH2 domain-containing inositol 5'-phosphatase-1), that results in impaired Vav-dependent reorganization of the actin cytoskeleton. This function maps to the phosphorylatable tyrosine residues in the collagen homology 1 (CH1) domain. The results identify p66Shc as a negative regulator of B-cell chemotaxis and suggest a role for this adaptor in the control of B-cell homing.

The CXCL12/CXCR4 axis as a therapeutic target in cancer and HIV-1 infection.

The seven-spanning transmembrane G-protein coupled receptor CXCR4, which specifically binds to the chemokine CXCL12, is expressed on many cell types, including various types of tumour cells. CXCR4 plays a crucial role in organ-specific metastasis, directing migration of malignant cells expressing this receptor toward microenvironments where the cognate ligand is secreted. CXCL12 has a direct growth and survival-promoting effect for various cancer cells and enhances moreover tumour angiogenesis by recruiting endothelial progenitor cells to tumours. Drugs which modulate the CXCL12/CXCR4 axis are therefore promising candidates in anti-cancer therapies. CXCR4 is also a coreceptor for human immunodeficiency virus type 1 (HIV-1) X4 virus and, as such, plays an important role in virus entry into target cells. Hence, antiviral agents that bind to CXCR4 are expected to inhibit HIV-1 entry. Here we review the structure, mechanism of action and biological activity of the main CXCR4 antagonists (peptide inhibitors, non-peptide antagonists, neutralizing antibodies, modified analogues of CXCL12) and agonists (CXCL12 peptide analogues) and discuss the CXCL12/CXCR4 axis as an important target in development of anti-tumoral and anti-HIV-1 therapies.

[Prognosis of stroke patients undergoing intubation and mechanical ventilation]. / Prognosi dei pazienti con ictus sottoposti ad intubazione e ventilazione meccanica.

BACKGROUND: To determine the outcome of patients with acute stroke requiring intubation and mechanical ventilation. DESIGN: review of the medical records of 33 patients with stroke intubated at presentation in hospital and not requiring neurosurgery or angiography. SETTING: intensive care unit (ICU) of a non teaching hospital. INTERVENTIONS: none. MEASUREMENTS: the mean age (SD) was 73.3 (7.7), min 46 max 87, 18 males and 15 females, mean Glasgow coma scale (GCS) (min-max) was 4.5 (3-8). RESULTS: The hospital mortality of intubated patients was 78.7% (26/33), mortality in the ICU was 69.69% (23/33). In survivors: infarction/hemorrhage (INF/HEM) were 4/3, mean age (SD) 75.2 (5.6), males/females 4/3, mean GCS (min-max) 5.2 (3-7), days in the ICU mean (DS) 18 (20.2). In patients who died: INF/HEM were 10/16, mean age (SD) 72.8 (8.2), males/females 14/12, mean GCS (min-max) 4.3 (3-8), days in the ICU mean (DS) 5.5 (8). The difference between groups was significant (p < 0.05) only for ICU staying. The evolution to brain death was observed in 10 cases (30.3%). CONCLUSIONS: The overall prognosis of patients with acute stroke intubated and ventilated at presentation in hospital for deterioration is severe but the observed survival rate is sufficient to justify this treatment even in cases not requiring other invasive procedures like neurosurgery or angiography. A significant fraction of stroke patients is part of the potential organ donors pull.