Impact of sequential (first- to third-generation) EGFR-TKI treatment on corrected QT interval in NSCLC patients.

Objective: To evaluate the impact of sequential (first- to third-generation) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment on top-corrected QT interval (top-QTc) in non-small cell lung cancer (NSCLC) patients. Methods: We retrospectively reviewed the medical records of NSCLC patients undergoing sequential EGFR-TKI treatment at Shanghai Chest Hospital between October 2016 and August 2021. The heart rate (HR), top-QT interval, and top-QTc of their ECGs were extracted from the institutional database and analyzed. Logistic regression was performed to identify predictors for top-QTc prolongation. Results: Overall, 228 patients were enrolled. Compared with baseline (median, 368 ms, same below), both first-generation (376 ms vs. 368 ms, p < 0.001) and sequential third-generation EGFR-TKIs (376 ms vs. 368 ms, p = 0.002) prolonged top-QT interval to a similar extent (p = 0.635). Top-QTc (438 ms vs. 423 ms, p < 0.001) and HR (81 bpm vs.79 bpm, p = 0.008) increased after first-generation EGFR-TKI treatment. Further top-QTc prolongation (453 ms vs. 438 ms, p < 0.001) and HR increase (88 bpm vs. 81 bpm, p < 0.001) occurred after treatment advanced. Notably, as HR elevated during treatment, top-QT interval paradoxically increased rather than decreased, and the top-QTc increased rather than slightly fluctuated. Moreover, such phenomena were more significant after treatment advanced. After adjusting for confounding factors, pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation during sequential third-generation EGFR-TKI treatment. Conclusion: First-generation EGFR-TKI could prolong top-QTc, and sequential third-generation EGFR-TKI induced further prolongation. Top-QT interval paradoxically increased and top-QTc significantly increased as HR elevated, which was more significant after sequential EGFR-TKI treatment. Pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation after sequential EGFR-TKI treatment.

A clinical study on the surgical treatment of simple multiple rib fractures in older adult patients.

Background: The treatment of simple rib fractures in older adults can be divided into surgical treatment and nonsurgical treatment, with indications for surgery presently being unclear. This study was conducted to determine whether older adult individuals with simple multiple rib fractures can benefit from surgical treatment. Methods: A single-center, retrospective study was conducted. All 880 registry-identified patients aged ≥60 years who were admitted to Beijing Jishuitan Hospital with blunt rib fractures between 2013 to 2020 were included. They were divided into 2 groups according to whether internal fixation was performed. After screening of inclusion and exclusion criteria and propensity score matching, there were 226 patients, 113 of whom were placed in the operation group and 113 in the nonoperation group. The demographic characteristics, underlying diseases, number of rib fractures, hospital stay, intensive care unit (ICU) hospital stay, mechanical ventilation duration, fracture comorbidities on admission, pain index, and fracture healing condition were analyzed using chi-squared test and independent samples t test. Results: The pain score and fracture healing time were significantly improved in the operation group (P<0.05), while the duration of painkiller use was significantly shorter in the operation group (P=0.009). However, there was no significant differences in mortality, the incidence of bone nonunion, length of stay in the ICU, or duration of mechanical ventilation between the 2 groups. Conclusions: For patients in the clinical study, internal fixation surgery could reduce fracture healing time and minimize the use of painkillers. Surgical treatment was determined to be safe, as it did not increase the mortality of the older adult patients. For older patients with simple rib fractures who have no contraindications to surgery, internal fixation surgery is recommended.

LncRNA GAS5 Attenuates Cardiac Electrical Remodeling Induced by Rapid Pacing via the miR-27a-3p/HOXa10 Pathway.

Previous studies indicated long non-coding RNAs (lncRNAs) participated in the pathogenesis of atrial fibrillation (AF). However, little is known about the role of lncRNAs in AF-induced electrical remodeling. This study aimed to investigate the regulatory effect of lncRNA GAS5 (GAS5) on the electrical remodeling of neonatal rat cardiomyocytes (NRCMs) induced by rapid pacing (RP). RNA microarray analysis yielded reduced GAS5 level in NRCMs after RP. RT-qPCR, western blot, and immunofluorescence yielded downregulated levels of Nav1.5, Kv4.2, and Cav1.2 after RP, and whole-cell patch-clamp yielded decreased sodium, potassium, and calcium current. Overexpression of GAS5 attenuated electrical remodeling. Bioinformatics tool prediction analysis and dual luciferase reporter assay confirmed a direct negative regulatory effect for miR-27a-3p on lncRNA-GAS5 and HOXa10. Further analysis demonstrated that either miR-27a-3p overexpression or the knockdown of HOXa10 further downregulated Nav1.5, Kv4.2, and Cav1.2 expression. GAS5 overexpression antagonized such effects in Nav1.5 and Kv4.2 but not in Cav1.2. These results indicate that, in RP-treated NRCMs, GAS5 could restore Nav1.5 and Kv4.2 expression via the miR-27a-3p/HOXa10 pathway. However, the mechanism of GAS5 restoring Cav1.2 level remains unclear. Our study suggested that GAS5 regulated cardiac ion channels via the GAS5/miR-27a-3p/HOXa10 pathway and might be a potential therapeutic target for AF.

Construction and validation of a nomogram of risk factors for new-onset atrial fibrillation in advanced lung cancer patients after non-surgical therapy.

Objective: Risk factors of new-onset atrial fibrillation (NOAF) in advanced lung cancer patients are not well defined. We aim to construct and validate a nomogram model between NOAF and advanced lung cancer. Methods: We retrospectively enrolled 19484 patients with Stage III-IV lung cancer undergoing first-line antitumor therapy in Shanghai Chest Hospital between January 2016 and December 2020 (15837 in training set, and 3647 in testing set). Patients with pre-existing AF, valvular heart disease, cardiomyopathy were excluded. Logistic regression analysis and propensity score matching (PSM) were performed to identify predictors of NOAF, and nomogram model was constructed and validated. Results: A total of 1089 patients were included in this study (807 in the training set, and 282 in the testing set). Multivariate logistic regression analysis showed that age, c-reactive protein, centric pulmonary carcinoma, and pericardial effusion were independent risk factors, the last two of which were important independent risk factors as confirmed by PSM analysis. Nomogram included independent risk factors of age, c-reactive protein, centric pulmonary carcinoma, and pericardial effusion. The AUC was 0.716 (95% CI 0.661-0.770) and further evaluation of this model showed that the C-index was 0.716, while the bias-corrected C-index after internal validation was 0.748 in the training set. The calibration curves presented good concordance between the predicted and actual outcomes. Conclusion: Centric pulmonary carcinoma and pericardial effusion were important independent risk factors for NOAF besides common ones in advanced lung cancer patients. Furthermore, the new nomogram model contributed to the prediction of NOAF.

Evaluation of surgical outcomes in elderly patients with rib fractures: A single-centre propensity score matching study.

Background: Rib fractures are the most common injuries in chest trauma. Compared with younger patients, elderly patients with rib fracture have a higher incidence of complications and mortality. A retrospective study was conducted to investigate the effect of internal fixation compared with conservative treatment on the outcome of rib fracture in elderly patients. Material and methods: We used a 1:1 propensity score matching method to perform a retrospective analysis of 703 elderly patients with rib fractures treated in the Thoracic Surgery Department of Beijing Jishuitan Hospital between 2013 and 2020. After matching, the length of hospital stay, death, symptom relief and rib fracture healing were compared between the surgery and the control group. Results: The study included 121 patients receiving SSRF in the surgery group and 121 patients receiving conservative treatment in the control group. The length of hospital stay in the surgery group was significantly longer than that in the conservative group (11.39d vs. 9.48d, p = 0.000). After 9 months of follow-up, the fracture healing rate in the surgery group was significantly higher than that in the control group (96.67% vs. 88.89%, p = 0.020). The fracture healing time (p = 0.000), improvement in pain score (p = 0.000) and duration of pain medication use (p = 0.000) were also significantly better in the surgery group than in the control group. Conclusion: Compared with conservative treatment, surgical treatment can prolong hospital stay to some extent. However, it has the advantages of more rapid healing and lessened pain. For rib fractures in elderly individuals, surgical treatment is a safe and effective option under strict surgical indications and is recommended.

Severe Left Atrial Spontaneous Echo Contrast in Nonvalvular Atrial Fibrillation: Clinical Characteristics and Impact on Ischemic Risk Postablation.

BACKGROUND: Spontaneous echo contrast (SEC) is an important precursor for intracardiac thrombus and stroke. There are very limited data on characteristics of severe SEC and its impact on ischemic risk of nonvalvular atrial fibrillation (NVAF) patients after radiofrequency catheter ablation. METHODS: Transesophageal echocardiography files were reviewed between March 2009 and March 2021 in this monocentric retrospective study. SEC was classified into four levels. The primary endpoint was thromboembolic event (stroke, myocardial infarction, systemic embolism, and ensuing death), and the secondary endpoint included nonischemic mortality and recurrent atrial arrhythmia. RESULTS: Six hundred SEC cases were enrolled and classified into mild SEC group (Grade 1-2, n = 515) and severe SEC group (Grade 3-4, n = 85). Independent risk factors for severe SEC included higher brain natriuretic peptide (BNP), erythrocyte sedimentation rate (ESR), and LAd/∆LVED (LAd = left atrial diameter; ∆LVED = left ventricular end-diastolic diameter - left ventricular end-systolic diameter). The severe SEC group had a higher peri-procedural ischemic event occurrence (7.1 vs. 1.9%, p = 0.007). At a median follow-up of 55 months, the severe SEC group had a lower freedom rate from ischemic events (90.1 vs. 75.3%, p < 0.001); older age and severe SEC were independent risk factors for ischemic events. In patients undergoing redo-procedure (n = 100), a remarkably reduced ESR (17.8 ± 12.0 vs. 28.2 ± 19.0 mm/h, p < 0.001) was observed in patients whose SEC disappeared. CONCLUSION: Higher BNP, ESR, and LAd/∆LVED were the independent predictors for severe SEC. Severe SEC was associated with higher peri-procedural and long-term ischemic risks. ESR and LAd/∆LVED, as indicators of hematological and hemodynamic change, seemed helpful in identifying NVAF patients prone to developing severe SEC.

Left Atrial Anterior Wall Scar-Related Atrial Tachycardia in Patients after Catheter Ablation or Cardiac Surgery: Electrophysiological Characteristics and Ablation Strategy.

Background: The mechanisms of atrial tachycardia (AT) related to the left atrial anterior wall (LAAW) are complex and can be challenging to map in patients after catheter ablation for atrial fibrillation (AF) or cardiac surgery. We aimed to investigate the electrophysiological characteristics AT and to devise an ablation strategy. Methods and Results: We identified 31 scar-related LAAW reentrant ATs in 22 patients after catheter ablation for AF or cardiac surgery. Activation maps of the left atrium (LA) or both atria were obtained using a high-density mapping system, and the precise mechanism and critical area for each AT were analyzed. Patients were followed up regularly in a clinic. After analyzing the activation and propagation of each AT, the scar-related LAAW ATs were classified into three types, based on mechanisms related to: (1) LAAW conduction gap(s) in 19 LA macro-reentrant ATs; (2) LAAW epicardial connection(s) in 11 LA or bi-atrial ATs; and (3) LAAW local micro-reentry in 1 LAAW AT. Multiple ATs were identified in seven patients. Effective ablation (termination or circuit change of AT) was obtained in 30 ATs by targeting the critical area identified by the mapping system. During 16.0 ± 7.6 months follow-up, recurrent AT occurred in two patients. Conclusions: Three mechanisms of scar-related AT of LAAW were identified, most of which were related to LAAW conduction gaps. Notably, epicardial AT or bi-atrial AT comprised a nonnegligible proportion. A high-density mapping system could make it possible to determine the accurate mechanism of AT and serve as a guide following ablation.

Hydroxamic Acid-Piperidine Conjugate is an Activated Catalyst for Lysine Acetylation under Physiological Conditions.

Lysine acylation of proteins is an essential chemical reaction for posttranslational modification and as a means of protein modification in various applications. N,N-Dimethyl-4-aminopyridine (DMAP) derivatives are widely-used catalysts for lysine acylation of proteins; however, the DMAP moiety mostly exists in a protonated, and thus deactivated, form under physiological conditions due to its basicity. An alternative catalytic motif furnishing higher acylation activity would further broaden the possible applications of chemical lysine acylation. We herein report that the hydroxamic acid-piperidine conjugate Ph-HXA is a more active catalytic motif for lysine acetylation than DMAP under physiological conditions. In contrast to DMAP, the hydroxamic acid moiety is mostly deprotonated under aqueous neutral pH, resulting in a higher concentration of the activated form. The Ph-HXA catalyst is also more tolerant of deactivation by a high concentration of glutathione than DMAP. Therefore, Ph-HXA might be a suitable catalytic motif for target protein-selective and site-selective acetylation in cells.

Ruthenium(II)-Catalyzed Regioselective C-8 Hydroxylation of 1,2,3,4-Tetrahydroquinolines.

Ru(II)-catalyzed chelation-assisted highly regioselective C8-hydroxylation of 1,2,3,4-tretrahydroquinolines has been developed. Various 1,2,3,4-tetrahydroquinolines underwent smooth C8-H hydroxylation with cheap and safe K2S2O8 as the oxidant and oxygen source to furnish the corresponding products in good to excellent yields with high tolerance of the functional groups. The choice of a readily installable and removable N-pyrimidyl directing group is the key to catalysis. Mechanistic studies suggest the involvement of a six-membered ruthenacycle intermediate in the catalytic cycle. The method can also be extended to the direct hydroxylation of other (hetero)arene C-H bonds.

Kinetic analyses and structure-activity relationship studies of synthetic lysine acetylation catalysts.

Lysine acylation of proteins is a crucial chemical reaction, both as a post-translational modification and as a method for bioconjugation. We previously developed a chemical catalyst, DSH, which activates a chemically stable thioester including acyl-CoA, allowing the site-selective lysine acylation of histones under physiological conditions. However, a more active catalyst is required for efficient lysine acylation in more complex biological milieu, such as in living cells, but there are no rational guidelines for developing efficient lysine acylation catalysts for use under physiological conditions as opposed to in organic solvents. We, herein, conducted a kinetic analysis of the ability of DSH and several derivatives to mediate lysine acetylation to better understand the structural elements essential for high acetylation activity under physiological conditions. Interestingly, the obtained trend in reactivity was different from that observed in organic solvents, suggesting that a different principle is necessary for designing chemical catalysts specifically for use under physiological conditions compared to catalysts for use in organic solvents. Based on the obtained information, we identified a new catalyst scaffold with high activity and structural flexibility for further modification to improve this catalyst system.