Functional failure of tau contributes to age-dependent, iron-mediated neurotoxicity, and as iron accumulates in ischemic stroke tissue, we hypothesized that tau failure may exaggerate ischemia-reperfusion-related toxicity. Indeed, unilateral, transient middle cerebral artery occlusion (MCAO) suppressed hemispheric tau and increased iron levels in young (3-month-old) mice and rats. Wild-type mice were protected by iron-targeted interventions: ceruloplasmin and amyloid precursor protein ectodomain, as well as ferroptosis inhibitors. At this age, tau-knockout mice did not express elevated brain iron and were protected against hemispheric reperfusion injury following MCAO, indicating that tau suppression may prevent ferroptosis. However, the accelerated age-dependent brain iron accumulation that occurs in tau-knockout mice at 12 months of age negated the protective benefit of tau suppression against MCAO-induced focal cerebral ischemia-reperfusion injury. The protective benefit of tau knockout was revived in older mice by iron-targeting interventions. These findings introduce tau-iron interaction as a pleiotropic modulator of ferroptosis and ischemic stroke outcome.

No abstract

Accumulation evidence shows that β-amyloid (Aβ) is a neurotoxic and accumulation of Aβ is responsible for the pathology of Alzheimer's disease (AD). However, it is currently not fully understood what makes Aβ toxic and accumulated. Previous studies demonstrate that Aβ is a suitable substrate for glycation, producing one form of the advanced glycation endproducts (AGEs). We speculated that Aβ-AGE formation may exacerbate the neurotoxicity. To explore whether the Aβ-AGE is more toxic than the authentic Aβ and to understand the molecular mechanisms, we synthesized glycated Aβ by incubating Aβ with methylglyoxal (MG) in vitro and identified the formation of glycated Aβ by fluorescence spectrophotometer. Then, we treated the primary hippocampal neurons cultured 8 days in vitro with Aβ-AGE or Aβ for 24 h. We observed that glycation exacerbated neurotoxicity of Aβ with upregulation of receptor for AGE (RAGE) and activation of glycogen synthase kinase-3 (GSK-3), whereas simultaneous application of RAGE antibody or GSK-3 inhibitor reversed the neuronal damages aggravated by glycated Aβ. Thereafter, we found that Aβ is also glycated with an age-dependent elevation of AGEs in Tg2576 mice, whereas inhibition of Aβ-AGE formation by subcutaneously infusion of aminoguanidine for 3 months significantly rescued the early cognitive deficit in mice. Our data reveal for the first time that the glycated Aβ is more toxic. We propose that the glycated Aβ with the altered secondary structure may be a more suitable ligand than Aβ for RAGE and subsequent activation of GSK-3 that can lead to cascade pathologies of AD, therefore glycated Aβ may be a new therapeutic target for AD.

Allogeneic hematopoietic SCT is indicated for children whose disease demonstrates dismal prognosis with chemotherapy. This study aims to analyse the most recent outcomes of unmanipulated haploidentical (HID) HSCT for paediatric patients with acute leukaemia. Those from matched sibling donors (MSD) HSCT provided a parallel cohort to illustrate the benefits of HID. Conditioning regimen was modified BuCy2. Anti-thymoglobulin was used for HID. Mobilised marrow and blood stem cells were used as the grafts. All patients in HID achieved neutrophil recovery and 96.7% platelet recovery. In HID, the incidences of acute GVHD 3-4 and extensive chronic GVHD were 14.3 and 26.6%. Play-performance score 90-100% was recorded in 79.7% of all survivors. The 5-year leukaemia-free survival (LFS) in CR1, CR2, beyond CR2 or non-remission were 68.9%, 56.6%, 22.2% and 82.5%, 59.4%, 42.9% for ALL and AML, respectively. In MSD group, LFS for ALL and AML in CR1 were 62.5 and 71.7%. Outcomes of the HID HSCT for paediatric patients with acute leukaemia showed benefits that were similar to those of the parallel cohort of MSD HSCT. 3,4 Hence, the domestic indications for allogeneic HSCT in paediatric patients with acute leukaemia cover more subtypes of disease. 5 For paediatric patients requiring allogeneic HSCT, it is widely accepted that grafts from matched sibling donors (MSDs) result in the best outcomes among various sources of stem cells. For patients lacking a suitable HLA-compatible related donor, alternative options include unrelated donors or umbilical cord blood followed by a haploidentical donor (HID) among family members. At present, there is no international or regional consensus or recommendation to guide alternative options for alternative donors. Haematopoietic cells from relatives who are HLA HID are an immediate almost available source of grafts for HSCT candidates. For HSCT with related HIDs, extensive T-cell depletion or CD34 þ cell selection in vitro, mega-dose infusion and other supportive techniques have increased the rate of engraftment, reduced TRM and improved survival. 6,7 The latest reports of T-cell depletion HSCT from HID parental donors showed improved outcomes in the recent treatment era, with 5-year OS rates of 65% and 74% for very high-risk ALL and AML patients, respectively. 8 At our institution, promising results with unmanipulated, HID HSCT have been achieved in adult patients without ex vivo T-cell depletion, demonstrating outcomes similar to those with MSDs and well-matched unrelated HSCT. 9,10 The short-term efficacy and

The role of donor lymphocyte infusion (DLI) in the prophylaxis of relapse has not been defined. We retrospectively analyzed the data from 88 patients with advanced-stage acute leukemia after HLA-mismatched/haploidentical hematopoietic SCT (HSCT) whose treatment did (n ¼ 61) or did not (n ¼ 27) include granulocyte CSF (GCSF)-primed PBPCs infusion (GPBPCI). The two groups were compared with respect to relapse and OS. Further, a detailed analysis of risk factors was performed. The 2-year cumulative incidence of relapse in patients receiving prophylactic GPBPCI and not receiving prophylactic GPBPCI were 36% and 55% (P ¼ 0.017), respectively. Estimated survival at 3 years was 31% for patients receiving prophylactic GPBPCI and 11% for patients not receiving prophylactic GPBPCI (P ¼ 0.001). The three-year probability of leukemia-free survival was also higher in patients who received prophylactic GPBPCI (22%) compared with patients who did not (11%) (P ¼ 0.003). Multivariate analysis for relapse showed that use of prophylactic GPBPCI after transplantation was an independent prognostic factor (P ¼ 0.025).Higher OS was associated with use of prophylactic GPBPCI (P ¼ 0.002), AML (P ¼ 0.027) and female sex (P ¼ 0.023). Our results suggest that use of prophylactic GPBPCI may increase survival of patients with advanced-stage acute leukemia who receive HLA-mismatched/haploidentical HSCT. INTRODUCTIONHematopoietic SCT (HSCT) is one of the best options, and sometimes the only option, for the treatment of leukemia, particularly for patients with advanced-stage leukemia. Yet, the relapse rate is still very high for patients with advanced-stage leukemia who are treated by HSCT.1 --3 Sierra et al. 1 reported that the cumulative incidences of relapse after T-replete HSCT from unrelated donors were 44% during relapse (n ¼ 81) and 63% during primary induction failure (n ¼ 16) for AML patients. Aversa et al.2 reported a relapse incidence of 51% for 38 relapsed, acute leukemia patients who were undergoing haplo-identical HSCT. Our own data showed that the 2-yr probability of relapse in highrisk group was 51.5% for ALL patients.