Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Cav1.3 channels

Ca2+/calmodulin- and voltage-dependent inactivation (CDI and VDI) comprise vital prototypes of Ca2+ channel modulation, rich with biological consequences. Although the events initiating CDI and VDI are known, their downstream mechanisms have eluded consensus. Competing proposals include hinged-lid occlusion of channels, selectivity filter collapse, and allosteric inhibition of the activation gate. Here, novel theory predicts that perturbations of channel activation should alter inactivation in distinctive ways, depending on which hypothesis holds true. Thus, we systematically mutate the activation gate, formed by all S6 segments within CaV1.3. These channels feature robust baseline CDI, and the resulting mutant library exhibits significant diversity of activation, CDI, and VDI. For CDI, a clear and previously unreported pattern emerges: activation-enhancing mutations proportionately weaken inactivation. This outcome substantiates an allosteric CDI mechanism. For VDI, the data implicate a “hinged lid–shield” mechanism, similar to a hinged-lid process, with a previously unrecognized feature. Namely, we detect a “shield” in CaV1.3 channels that is specialized to repel lid closure. These findings reveal long-sought downstream mechanisms of inactivation and may furnish a framework for the understanding of Ca2+ channelopathies involving S6 mutations

Perianeurysmal edema in giant intracranial aneurysms in relation to aneurysm location, size, and partial thrombosis

OBJECT The underlying mechanisms causing intracranial perianeurysmal edema (PAE) are still poorly understood. Since PAE is most frequently observed in giant intracranial aneurysms (GIAs), the authors designed a study to examine the occurrence of PAE in relation to the location, size, and partial thrombosis (PT) of GIAs along with the clinical impact of PAE. METHODS Magnetic resonance imaging data for patients with a diagnosis of unruptured GIA from the international multicenter Giant Intracranial Aneurysm Registry were retrospectively analyzed with regard to location and size of the GIA, PAE volume, and the presence of PT. The occurrence of PAE was correlated to clinical findings. RESULTS Imaging data for 69 GIAs were eligible for inclusion in this study. Perianeurysmal edema was observed in 33.3% of all cases, with the highest frequency in GIAs of the middle cerebral artery (MCA; 68.8%) and the lowest frequency in GIAs of the cavernous internal carotid artery (ICA; 0.0%). Independent predictors of PAE formation were GIA volume (OR 1.13, p = 0.02) and the occurrence of PT (OR 9.84, p = 0.04). Giant intracranial aneurysm location did not predict PAE occurrence. Giant aneurysms with PAE were larger than GIAs without PAE (p < 0.01), and GIA volume correlated with PAE volume (rs = 0.51, p = 0.01). Perianeurysmal edema had no influence on the modified Rankin Scale score (p = 0.30 or the occurrence of aphasia (p = 0.61) or hemiparesis (p = 0.82). CONCLUSIONS Perianeurysmal edema was associated with GIA size and the presence of PT. As no PAE was observed in cavernous ICA aneurysms, even though they exerted mass effect on the brain and also displayed PT, the dura mater may serve as a barrier protecting the brain from PAE formation

Quantifying unruptured giant intracranial aneurysms by measuring diameter and volume--a comparative analysis of 69 cases

Intracranial aneurysms (IA) are usually quantified according to their largest diameter. However, volumetry has recently been increasingly conducted as well, especially in giant intracranial aneurysms (GIAs). Since so far the true value of GIA volumetry is unknown, we designed a trial to examine correlations between GIA diameter and volume with special focus on clinical implications

Stem cell collection and hematological recovery in the Fondazione Italiana Linfomi (FIL) MCL0208 clinical trial

Abstract In the frontline high-dose phase 3 FIL-MCL0208 trial (NCT02354313), 8% of enrolled mantle cell lymphoma (MCL) patients could not be randomised to receive lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) due to inadequate hematological recovery and 52% of those who started LEN, needed a dose reduction due to toxicity. We therefore focused on the role played by CD34 + hematopoietic stem cells (PBSC) harvesting and reinfusion on toxicity and outcome. Overall, 90% (n = 245) of enrolled patients who underwent the first leukapheresis collected ≥ 4 × 106 PBSC/kg, 2.6% (n = 7) mobilized  10 days) was associated with a worse outcome, both in terms of PFS and OS. In conclusion, although the harvesting procedures proved feasible for younger MCL patients, long-lasting cytopenia following ASCT remains a significant issue: this can hinder the administration of effective maintenance therapies, potentially increasing the relapse rate and negatively affecting survival outcomes

The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction – a phase III trial of the German AIO/CAO-V/CAOGI

Abstract Background Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases. Methods This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled. Discussion If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention. Trial registration The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368 ; EudraCT: 2014–002665-30