N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer's disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk.

BACKGROUND: Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer's disease (AD). The natural psychedelic N, N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti-AD potential through protecting neuronal ER-mitochondrial interplay. METHODS: 3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aß accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated. RESULTS: chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aß accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD. CONCLUSION: The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.

Acupuncture for chemotherapy-associated insomnia in breast cancer patients: an assessor-participant blinded, randomized, sham-controlled trial.

BACKGROUND: Insomnia is a highly prevalent symptom occurred during and post-chemotherapy. Acupuncture may have beneficial effects in the management of chemotherapy-associated insomnia. This study was conducted to determine the efficacy and safety of acupuncture in improving chemotherapy-associated insomnia in breast cancer patients. METHODS: This assessor-participant blinded, randomized, sham-controlled trial was conducted from November 2019 to January 2022 (follow-up completed July 2022). Participants were referred by oncologists from two Hong Kong hospitals. Assessments and interventions were conducted at the outpatient clinic of School of Chinese Medicine, the University of Hong Kong. The 138 breast cancer patients with chemotherapy-associated insomnia were randomly assigned to receive either 15 sessions of active acupuncture regimen by combining needling into body acupoints and acupressure on auricular acupoints or sham acupuncture control (69 each) for 18 weeks, followed by 24 weeks of follow-up. The primary outcome was measured using Insomnia Severity Index (ISI). Secondary outcomes included the Pittsburgh Sleep Quality Index, Actiwatch and sleep diary for sleep parameters, depression and anxiety, fatigue and pain, and quality of life. RESULTS: There were 87.7% (121/138) participants who completed the primary endpoint (week-6). The active acupuncture regimen was not superior to the sham control in reducing ISI score from baseline to 6 weeks (mean difference: - 0.4, 95% CI - 1.8-1.1; P = 0.609), but produced short-term treatment and long-term follow-up better outcomes in improving sleep onset latency, total sleep time, sleep efficiency, anxiety, depression, and quality of life. Participants of the active acupuncture group had a pronouncedly higher cessation rate of sleeping medications than the sham control (56.5% vs. 14.3%, P = 0.011). All treatment-related adverse events were mild. No participants discontinued treatments due to adverse events. CONCLUSION: The active acupuncture regimen could be considered as an effective option for the management of chemotherapy-associated insomnia. It also could serve as a tapering approach to reduce and even replace the use of sleeping medications in breast cancer patients. Trial registration Clinicaltrials.gov : NCT04144309. Registered 30 October 2019.

Adjuvant Chemotherapy Guided by Molecular Profiling and Improved Outcomes in Early Stage, Non-Small-Cell Lung Cancer.

INTRODUCTION: Many early stage non-small-cell lung cancer (NSCLC) patients who are not considered candidates for adjuvant treatment according to current guidelines do harbor occult metastasis, and have disease recurrence despite complete resection. Although National Comprehensive Cancer Network (NCCN) guidelines suggest clinicopathologic characteristics to identify high-risk patients for adjuvant intervention, molecular profiling more accurately predicts 5-year survival. Early evidence of clinical benefit from application of this molecular-based management strategy, however, has not been reported. PATIENTS AND METHODS: An internationally validated, prognostic, 14-gene quantitative polymerase chain reaction expression assay was used to stratify risk prospectively in 100 consecutive patients with stage IA, IB, and IIA nonsquamous NSCLC. Kaplan-Meyer estimates, log rank analysis, and Cox regression were used to compare disease-free survival (DFS) between high-risk patients who did or did not elect adjuvant chemotherapy. RESULTS: Forty-eight patients (48%) were deemed high-risk according to molecular testing and 36 (36%) met NCCN high-risk criteria; risk designations were discordant in 34 (34%) of all patients. Estimated 5-year DFS was 48.9% among molecular high-risk patients who did not undertake adjuvant chemotherapy, 93.8% among untreated molecular low-risk patients, and 91.7% in molecular high-risk patients who did undergo chemotherapy (P = .004). In contrast, DFS was only 75.2% in untreated NCCN low-risk patients, and 61.9% in untreated NCCN high-risk patients (P = .183). CONCLUSION: This prospective, nonrandomized study provides initial evidence that high-risk designation according to the 14-gene prognostic assay also predicts benefit from adjuvant chemotherapy for very early stage NSCLC, and further supports the superiority of molecular stratification over current NCCN criteria at identifying high-risk patients.