ABSTRACT
The neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still in debate. Long COVID manifests with "brain diseases" and the cause of these brain dysfunction is mysterious. Here, we analyze 34 age- and underlying disease-matched COVID-19 or non-COVID-19 human brains. SARS-CoV-2 RNA, nucleocapsid, and spike proteins are present in neurons of the cognitive centers of all COVID-19 patients, with its non-structural protein NSF2 detected in adult cases but not in the infant case, indicating viral replications in mature neurons. In adult COVID-19 patients without underlying neurodegeneration, SARS-CoV-2 infection triggers A{beta} and p-tau deposition, degenerating neurons, microglia activation, and increased cytokine, in some cases with A{beta} plaques and p-tau pretangles. The number of SARS-CoV-2+ cells is higher in patients with neurodegenerative diseases than in those without such conditions. SARS-CoV-2 further activates microglia and induces A{beta} and p-tau deposits in non-Alzheimers neurodegenerative disease patients. SARS-CoV-2 infects mature neurons derived from inducible pluripotent stem cells from healthy and Alzheimers disease (AD) individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers AD-like gene programs in healthy neurons and exacerbates AD neuropathology. An AD infectious etiology gene signature is identified through SARS-CoV-2 infection and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, our data suggest that SARS-CoV-2 invades the brain and activates an AD-like program.
ABSTRACT
Objective TO evaluate the efficacy and safety of three adjuvant chemotherapy regimens after curative resection for stage III colorectal cancer,and present clinical evidence for proper choice.Methods 256 cases with stage Ⅲ colorectal cancer randomized to receive de Gramont,modified FOLFOX4(mFOLFOX4) and XELOX regimens.3-year disease-free survival(DFS) and overall survival(OS) were compared within the three groups and subgroups.Therapeutic adverse events were recorded and analyzed with Kaplan-Meier.Results Compared with de Gramont regimen,mFOLFOX4 and XELOX had superior efficacy.The two former could significantly improve 3-year DFS(79.7% vs.66.2%,P=0.015;81.5% vs.66.2%,P=0.004) and medium survival time(40.2 mon vs.37.8 mon,P=0.024;41.4 mon vs.37.8 mon,P=0.014).Meanwhile they could respectively decrease the ratio of recurrence risk 18%(P=0.024) and 21%(P=0.003).The relative benefit of mFOLFOX4 versus XELOX didn't differ for 3-year DFS [hazard ratio(HR): 0.84,95% confidence interval(CI): 0.79～1.12,P=0.13] and OS(HR: 0.87,95%CI: 0.84~1.06,P=0.54).In advanced analysis of DFS in subgroup,XELOX had better trend of survival advantage.mFOLFOX4 had higher adverse events within these regimens,especially in grade 3 or 4 neutropenia and peripheral neurologic adverse events.Conclusion XELOX maintains its efficacy and safety ratio in advanced colorectal cancer.Patients have good tolerance and compliance.The regiment is deserved to be applied in clinic.
