Objective The goal of this study was to investigate the role of endogenous amyloid-β peptide (Aβ) in healthy brain. Methods Long-term potentiation (LTP), a type of synaptic plasticity that is thought to be associated with learning and memory, was examined through extracellular field recordings from the CA1 region of hippocampal slices, whereas behavioral techniques were used to assess contextual fear memory and reference memory. Amyloid precursor protein (APP) expression was reduced through small interfering RNA (siRNA) technique. Results We found that both antirodent Aβ antibody and siRNA against murine APP reduced LTP as well as contextual fear memory and reference memory. These effects were rescued by the addition of human Aβ42, suggesting that endogenously produced Aβ is needed for normal LTP and memory. Furthermore, the effect of endogenous Aβ on plasticity and memory was likely due to regulation of transmitter release, activation of α7-containing nicotinic acetylcholine receptors, and Aβ42 production. Interpretation Endogenous Aβ42 is a critical player in synaptic plasticity and memory within the normal central nervous system. This needs to be taken into consideration when designing therapies aiming at reducing Aβ levels to treat Alzheimer disease.

This phase II trial was conducted to evaluate the safety and efficacy of concurrent gemcitabine and high-intensity focused ultrasound (HIFU) therapy in patients with locally advanced pancreatic cancer. Patients with localized unresectable pancreatic adenocarcinoma in the head or body of the pancreas received gemcitabine (1000 mg/m) intravenously over 30 min on days 1, 8, and 15, and concurrent HIFU therapy on days 1, 3, and 5. The treatment was given every 28 days. Thirty-seven (94.9%) of the 39 patients were assessable for response, and two cases of complete response and 15 cases of partial response were confirmed, giving an overall response rate of 43.6% [95% confidence interval (CI), 28.0-59.2%]. The median follow-up period was 16.5 months (range: 8.0-28.5 months). The median time to progression and overall survival for all patients were 8.4 months (95% CI, 5.4-11.2 months) and 12.6 months (95% CI, 10.2-15.0 months), respectively. The estimates of overall survival at 12 and 24 months were 50.6% (95% CI, 36.7-64.5%) and 17.1% (95%CI, 5.9-28.3%), respectively. A total of 16.2% of patients experienced grade 3/4 neutropenia. Grade 3 thrombocytopaenia was documented in two (5.4%) patients. Grade 3 nausea/vomiting and diarrhea were observed in three (8.1%), and two (5.4%) patients, respectively. Grade 1 or 2 fever was detected in 70.3% of patients. Twenty-eight patients (71.8%) complained of abdominal pain consistent with tumor-related pain before HIFU therapy. Pain was relieved in 22 patients (78.6%). In conclusion, concurrent gemcitabine and HIFU is a tolerated treatment modality with promising activity in patients with previously untreated locally advanced pancreatic cancer.

BackgroundThere is limited information on treatment strategies and monitoring strategies for late antibody-mediated rejection (ABMR) after kidney transplantation.MethodsIn this observational and nonrandomized study, we compared 78 patients diagnosed with late ABMR (>3 months after transplant) who were treated with standard of care steroids/IVIG (n = 38) ± rituximab (n = 40) at our center between March 1, 2013 and December 31, 2016. All patients had follow-up biopsy and donor-specific antibodies (DSA) monitoring within 3 to 12 weeks.ResultsPatients had biopsy 7.3 ± 7 years after transplant and were followed for 15.9 ± 9.6 months after ABMR was diagnosed. Both treatment strategies were associated with a significant decline in DSA, microvascular inflammation (peritubular capillaritis + glomerulitis), and C4d Banff scores. In univariate regression analyses, rituximab, estimated glomerular filtration rate (eGFR), Banff i, t, v, chronicity (interstitial fibrosis + tubular atrophy + fibrous intimal thickening + allograft glomerulopathy) scores on the first biopsy, and eGFR and Banff v score on follow-up biopsy were associated with graft loss. Multivariate analyses retained only rituximab (hazard ratio, 0.23; 95% confidence interval, 0.06-0.84; P = 0.03) and eGFR at follow-up biopsy (0.84; 95% confidence interval, 0.76-0.92; P < 0.001) as significant predictors of graft loss. Kaplan-Meier analyses demonstrated that the benefit associated with rituximab was apparent after 1 year (15% vs 32% graft loss, P = 0.02).ConclusionTreatment of late ABMR with steroids/IVIG ± rituximab was effective in reducing DSA and microcirculation inflammation. The addition of rituximab was associated with better graft survival. Follow-up biopsies could be considered in the management of acute rejection to monitor the effect of therapy. Randomized studies on the best therapeutic options for ABMR are needed.

The cancer cells with bronchioalveolar stem cells phenotype are detectable in adenocarcinoma of the lung and the expression of self-renewal regulatory gene OCT4 in these cells indicated the worse clinical outcomes.