Drug addiction is considered an aberrant form of learning, and drug-associated memories evoked by the presence of associated stimuli (drug context or drug-related cues) contribute to recurrent craving and reinstatement. Epigenetic changes mediated by DNA methyltransferase (DNMT) have been implicated in the reconsolidation of fear memory. Here, we investigated the role of DNMT activity in the reconsolidation of cocaine-associated memories. Rats were trained over 10 days to intravenously self-administer cocaine by nosepokes. Each injection was paired with a light/tone conditioned stimulus (CS). After acquisition of stable self-administration behaviour, rats underwent nosepoke extinction (10 d) followed by cue-induced reactivation and subsequent cue-induced and cocaine-priming + cue-induced reinstatement tests or subsequently tested to assess the strength of the cocaine-associated cue as a conditioned reinforcer to drive cocaine seeking behaviour. Bilateral intra-basolateral amygdala (BLA) infusion of the DNMT inhibitor5-azacytidine (5-AZA, 1 μg per side) immediately following reactivation decreased subsequent reinstatement induced by cues or cocaine priming as well as cue-maintained cocaine-seeking behaviour. In contrast, delayed intra-BLA infusion of 5-AZA 6 h after reactivation or 5-AZA infusion without reactivation had no effect on subsequent cue-induced reinstatement. These findings indicate that memory reconsolidation for a cocaine-paired stimulus depends critically on DNMT activity in the BLA.
Histone modifications have been implicated in learning and memory. Our previous transcriptome data showed that expression of sirtuins 6 (SIRT6), a member of Histone deacetylases (HDACs) family in the hippocampal cornu ammonis 1 (CA1) was decreased after contextual fear conditioning. However, the role of SIRT6 in the formation of memory is still elusive. In the present study, we found that contextual fear conditioning inhibited translational expression of SIRT6 in the CA1. Microinfusion of lentiviral vector-expressing SIRT6 into theCA1 region selectively enhanced the expression of SIRT6 and impaired the formation of long-term contextual fear memory without affecting short-term fear memory. The overexpression of SIRT6 in the CA1 had no effect on anxiety-like behaviors or locomotor activity. Also, we also found that SIRT6 overexpression significantly inhibited the expression of insulin-like factor 2 (IGF2) and amounts of proteins and/or phosphoproteins (e.g. Akt, pAkt, mTOR and p-mTOR) related to the IGF2 signal pathway in the CA1. These results demonstrate that the overexpression of SIRT6 in the CA1 impaired the formation of long-term fear memory, and SIRT6 in the CA1 may negatively modulate the formation of contextual fear memory via inhibiting the IGF signaling pathway.
Introduction. Patients receiving chemotherapy for breast cancer may be at risk of developing cardiac dysfunction and electrophysiological abnormalities. The aim of this study is to evaluate alterations in electrocardiographic (ECG) parameters in breast cancer patients receiving chemotherapy. Materials and Methods. This was a prospective single-center cohort study conducted in the Fourth Hospital of Hebei Medical University, China. Participants with breast cancer referred for chemotherapy from May 1, 2019, to October 1, 2019, were invited to participate in the study. Standard 12-lead ECG and echocardiography were performed at baseline or before chemotherapy (prechemotherapy) (T0), after 1 cycle (T1), after 3 cycles (T2), and at the end of chemotherapy (T3). Results. A total of 64 patients with diagnosed breast cancer undergoing chemotherapy were included. Echocardiographic parameters showed no significant variation during the entire procedure (all P > 0.05 ). The incidence of abnormal ECG increased from 43.75% at baseline to 65.63% at the end of chemotherapy, of which only the prevalence of fragmented QRS (fQRS) was significantly increased after the drug regimen (26.56% to 53.13%). At the end of the treatment, heart rate, P-wave dispersion, corrected QT interval, T-peak to T-end, RR, SV1, RV5, Sokolow–Lyon index (SLI), and index of cardioelectrophysiological balance deteriorated markedly (all P < 0.05 ). The area under the curve for SLI and QT dispersion (QTd) derived by ECG was 0.710 and 0.606, respectively. The cutoff value with 2.12 of SLI by ECG had a sensitivity of 67.2% and specificity of 71.9% for differentiating patients after therapy from baselines. The cutoff value with 0.55 of QTd had a sensitivity of 60.9% and specificity of 60.9%. Conclusions. The current study demonstrated that ECGs can be used to detect electrophysiological abnormalities in breast cancer patients receiving chemotherapy. ECG changes can reflect subclinical cardiac dysfunction before the echocardiographic abnormalities.
Rationale: Wellens syndrome is a comprehensive electrocardiographic (ECG) diagnosis that combines medical history with characteristic ECG changes. These changes, characterized by biphasic T-wave inversions or symmetric and deep T-wave inversions in the anterior precordial leads, often indicate that the left anterior descending coronary artery is at a high risk of severe stenosis. Chemotherapy-related cardiovascular toxicity refers to damage to the cardiovascular system caused by chemotherapeutic drugs, which is unpredictable and may occur during or after chemotherapy. Patient concerns: In this case report, a 41-year-old male patient with cholangiocarcinoma received sequential adjuvant chemotherapy with gemcitabine/nanoparticle albumin–bound paclitaxel and gemcitabine/cisplatin. This patient presented with recurrent brief chest pain episodes after the third dose of gemcitabine/cisplatin, and the characteristic T-wave morphological changes were captured in routine ECG monitoring prior to the 6th dose. Diagnoses: Acute coronary syndrome due to chemotherapy-related cardiovascular toxicity was diagnosed on the basis of characteristic ECG changes. Interventions: The patient underwent coronary angiography, which revealed diffuse stenosis of up to 95% in the middle segment of the left anterior descending coronary artery. Stents were implanted in the stenotic segment for vascular reconstruction. Outcomes: The patient’s chest pain was completely resolved, and electrocardiography returned to normal. Lessons: Cardiovascular toxicity during chemotherapy in patients with cancer may be life threatening. This rare case highlights the importance of identifying the characteristic ECG pattern of the Wellens syndrome by monitoring electrocardiography during chemotherapy. Immediate and accurate identification of the morphological ECG features of Wellens syndrome with a slight elevation of the ST-segment is related to patient prognosis.
Funding Acknowledgements Type of funding sources: None. Background Patients receiving chemotherapy for breast cancer (BC) may develop cardiac electrophysiological abnormalities. The aim of this study is to examined possible alterations in cardiac electrophysiological parameters detected by three-dimensional vectorcardiograms (3D-VCGs) in BC patients who received chemotherapy. Methods This was a prospective single-center cohort study conducted. Patients with BC referred for chemotherapy from May 1, 2019, to October 1, 2019 were invited to participate in the study. 3D-VCG and echocardiography were recorded at rest four times (baseline, after the first cycle, after third cycles and at the end of the regimen, respectively). Results A total of 63 patients were included. Compared with baseline, decreases in 3-dimensional maximum T vector magnitude (TVM) (0.29 ± 0.10 vs. 0.25 ± 0.10mV; p < 0.05) and 3-dimensional T/QRS ratio (0.26 ± 0.11 vs. 0.21 ± 0.11; p < 0.05) were observed by the end of chemotherapy regimen, while echocardiographic parameters showed no significant variation before and after chemotherapy (all P > 0.05). Maximum TVM showed a significant positive correlation with left ventricular ejection fraction (LVEF) (all p < 0.05). Furthermore, the cut-off value with 0.23 of 3-dimensional T/QRS ratio (the area under the curve [AUC] 0.725) for differentiating LVEF reduction ≥10% following initiation of chemotherapy. The AUC of the front plane T/QRS ratio and horizontal plane T/QRS ratio for the detection of an LVEF reduction ≥10% was 0.725 and 0.763, respectively. Conclusions 3D-VCGs can be used to detect electrophysiological abnormalities in BC patients receiving chemotherapy. Subclinical cardiac dysfunction can be revealed by 3D-VCGs before alterations in traditional echocardiographic parameters.
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