BRAF V600E mutation as a novel mechanism of acquired resistance to ALK inhibition in ALK-rearranged lung adenocarcinoma: A case report

Rationale:Patients with lung adenocarcinoma harboring EML4-ALK rearrangements respond well to multiple ALK tyrosine kinase inhibitors (TKIs). However, the tumor will invariably progress due to acquired resistance. Comprehensive genomic profiling appears to be a promising strategy to reveal the underlying molecular mechanisms of ALK-TKIs resistance.Patient concerns:A patient with right lung adenocarcinoma harboring an ALK rearrangement received targeted therapy with multiple ALK-TKIs. He sought for follow-up treatment after his disease progressed again.Diagnosis:The patient had a tumor diagnosed with stage I (T1bN0M0) lung adenocarcinoma.Interventions:Due to the surgical contraindication, the patient did not undergo surgical resection. Instead, he received crizotinib as the first-line therapy with the progression-free survival of 20 months. Then he switched to alectinib treatment, however the disease rapidly progressed again.Outcomes:Next-generation sequencing was performed and revealed that 7 somatic mutations were identified. Among them, 2 mutations, ALK I1171T and BRAF V600E, may be responsible for the resistance of this patient to ALK-TKIs. BRAF V600E mutation may explain the patient''s resistance to lorlatinib.Lessons:We present a case of ALK-rearranged lung adenocarcinoma with acquired resistance to ALK inhibition, in which the BRAF V600E mutation is a novel resistance mechanism. This provides evidence that BRAF V600E mutation is one mechanism of ALK-TKI resistance.     

Theta oscillatory dynamics of inhibitory control,error processing,and post-error adjustments: Neural underpinnings and alcohol-induced dysregulation in social drinkers

Background

Alcohol intoxication impairs inhibitory control, resulting in disinhibited, impulsive behavior. The anterior cingulate cortex (ACC) plays an essential role in a range of executive functions and is sensitive to the effects of alcohol, which contributes to the top-down cognitive dysregulation. This study used a multimodal approach to examine the acute effects of alcohol on the neural underpinnings of inhibitory control, inhibition failures, and neurobehavioral optimization as reflected in trial-to-trial dynamics of post-error adjustments.

Methods

Adult social drinkers served as their own controls by participating in the Go/NoGo task during acute alcohol and placebo conditions in a multi-session, counterbalanced design. Distributed source modeling of the magnetoencephalographic signal was combined with structural magnetic resonance imaging to characterize the spatio-temporal dynamics of inhibitory control in the time-frequency domain.

Results

Successful response inhibition (NoGo) elicited right-lateralized event-related theta power (4 to 7 Hz). Errors elicited a short-latency increase in theta power in the dorsal (dACC), followed by activity in the rostral (rACC), which may underlie an affective “oh, no!” orienting response to errors. Error-related theta in the dACC was associated with subsequent activity of the motor areas on the first post-error trial, suggesting the occurrence of post-error output adjustments. Importantly, a gradual increase of the dACC theta across post-error trials closely tracked improvements in accuracy under placebo, which may reflect cognitive control engagement to optimize response accuracy. In contrast, alcohol increased NoGo commission errors, dysregulated theta during correct NoGo withholding, and abolished the post-error theta enhancement of cognitive control.

Conclusions

Confirming the sensitivity of frontal theta to inhibitory control and error monitoring, the results support functional and temporal dissociation along the dorso-rostral axis of the ACC and the deleterious effects of alcohol on the frontal circuitry subserving top-down regulation. Over time, alcohol-induced disinhibition may give rise to compulsive drinking and contribute to alcohol misuse.     

The therapeutic effect and safety of the drugs for COVID-19: A systematic review and meta-analysis

Background:Coronavirus disease 2019 (COVID-19) has spread almost all regions of the world and caused great loss to the whole body of mankind. Thus, numerous clinical trials were conducted to find specific medicine for COVID-19 recently. However, it remains unanswered whether they are beneficial.Objective:This study aimed to evaluate the efficiency and safety of the COVID-19 medicine.Methods:Studies were determined through searching PubMed, Embase, Cochrane Library, and Medline. The studies of COVID-19 medicine were involved with eligible end points containing mortality, discharge rate, rate of clinical improvement, and rate of serious adverse events.Results:A total of 33 studies involving 37,879 patients were included in our study, whose intervening measures contained three major types of COVID-19 medicine, ACEI/ARB, antiviral medicine, and chloroquine/hydroxychloroquine. Compared to control group, COVID-19 drugs have no distinct effect on mortality (RR, 0.93; 95% CI, 0.79–1.11, P = .43) and discharge rate (RR, 1.06; 95% CI, 0.98–1.14, P = .13). However, antiviral medicine presents the obvious advantage in clinical improvement (RR, 1.11; 95% CI, 1.01–1.23, P < .05). In addition, the serious adverse events rate (RR, 0.75; 95% CI, 0.63–0.88, P < .05) of COVID-19 medicine is lower than control group.Conclusion:The results indicated antiviral medicine was potential specific medicine for COVID-19 treatment by improving clinical symptoms, but it failed to increase the discharge rate and reduce mortality. Chloroquine/hydroxychloroquine and ACEI/ARB had no significant effect on treatment of COVID-19, thus they were not recommended for routine medication. Moreover, more trials are needed to find effective drugs to lower the mortality of COVID-19 patients.     

Sleep quality is negatively related to video gaming volume in adults

Most literature on the relationship between video gaming and sleep disturbances has looked at children and adolescents. There is little research on such a relationship in adult samples. The aim of the current study was to investigate the association of video game volume with sleep quality in adults via face‐to‐face interviews using standardized questionnaires. Adults (n = 844, 56.2% women), aged 18–94 years old, participated in the study. Sleep quality was measured using the Pittsburgh Sleep Quality Index, and gaming volume was assessed by asking the hours of gaming on a regular weekday (Mon–Thurs), Friday and weekend day (Sat–Sun). Adjusting for gender, age, educational level, exercise and perceived stress, results of hierarchical regression analyses indicated that video gaming volume was a significant predictor of sleep quality (β = 0.145), fatigue (β = 0.109), insomnia (β = 0.120), bedtime (β = 0.100) and rise time (β = 0.168). Each additional hour of video gaming per day delayed bedtime by 6.9 min (95% confidence interval 2.0–11.9 min) and rise time by 13.8 min (95% confidence interval 7.8–19.7 min). Attributable risk for having poor sleep quality (Pittsburgh Sleep Quality Index > 5) due to gaming >1 h day was 30%. When examining the components of the Pittsburgh Sleep Quality Index using multinomial regression analysis (odds ratios with 95% confidence intervals), gaming volume significantly predicted sleep latency, sleep efficiency and use of sleep medication. In general, findings support the conclusion that gaming volume is negatively related to the overall sleep quality of adults, which might be due to underlying mechanisms of screen exposure and arousal.     

探讨四种肿瘤标志物联合在肺癌诊断中的应用

目的 探讨血清癌胚抗原(CEA)、细胞角蛋白19片段21-1(CYFRA21-1)、神经元特异性烯醇化酶(NSE)和糖类抗原125(CA125)在肺癌患者中的水平及其在肺癌鉴别诊断中的临床价值.方法 随机选取52例肺癌患者、40例良性肺部感染者、40名健康体检者,分为肺癌组、对照组及健康组.采用电化学发光法对三组人群的CEA、CA125、NSE和CYFRA21-1进行检测分析.结果 四种肿瘤标记物水平肺癌组均明显高于对照组以及健康组,差异均有统计学意义(P＜0.05);CEA、CA125、NSE和CYFRA21-1单项检测对肺癌组的敏感度分别为44.23％、38.46％、42.31％和51.92％,四项标记物联合检测敏感度为86.54％;CEA和CA125在腺癌中表达显著高于小细胞肺癌和鳞状细胞癌(P＜0.05);CYFRA21-1在腺癌和鳞状细胞癌中表达明显高于小细胞癌(P＜0.05);NSE在小细胞肺癌中表达较高.结论 四种肿瘤标记物在肺癌诊断中分别具有一定的应用价值,可为肺癌的鉴别诊断提供参考依据,联合检测可显著提高肺癌诊断的灵敏度和准确度,值得临床推广应用.     

血清人附睾分泌蛋白4在卵巢上皮性癌中的临床价值

目的 研究血清人附睾蛋白4(HE4)在卵巢恶性肿瘤中的诊断价值.方法 用酶联疫吸附试验方法对卵巢上皮性癌组(54例)、盆腔良性疾病组(60例)、正常组(60例)妇女血清中HE4和CA125进行双盲检测,结果以中位数表示,分析比较两者单独检测诊断卵巢恶性肿瘤的价值.血清HE4和CA125的正常值分别为0～ 140pmol/L和0～ 35KU/L,其中任一指标高于正常即为阳性.结果 ①卵巢上皮性癌组血清HE4和CA125水平分别为142.72pmol/L和136.07KU/L,分别与盆腔良性疾病组(分别为63.72pmol/L和72.20KU/L)和正常组(分别为57.82pmol/L和57.42KU/L)比较,差异均有统计学意义(P＜0.01).②以盆腔良性疾病组作参照人群时,HE4和CA125单独检测的受试者工作特征曲线下面积(ROC-AUC)分别为0.958和0.886,两者比较,差异有统计学意义(P＜0.001).③以ROC曲线最左上方的点130 pmol/L、正常组95％参考值80pmol/L和正常值的上限140pmol/L为界值点,比较HE4单项检测对卵巢上皮性恶性肿瘤的诊断能力,结果显示,界值点为80pmol/L的特异度和阳性预测值均为88％,明显低于界值点为130(分别为93％和90％)和140pmol/L(分别为93％和95％)时的特异度和阳性预测值(P＜0.01).结论 HE4单项检测诊断卵巢上皮性恶性肿瘤的特异度优于CA125单项检测.以140pmol/L为界值点,对卵巢上皮性恶性肿瘤的早期诊断准确率更高,而以130pmol/L为界值点有利于卵巢上皮性恶性肿瘤的筛查、降低漏诊率.     

小细胞肺癌相关肿瘤标志物的研究进展

肺癌是恶性肿瘤死亡的首要原因,而小细胞肺癌是一种未分化、恶性程度高、预后较差的特殊肿瘤,因此早期诊断、早期治疗至关重要.本文对与小细胞肺癌相关的血清肿瘤标志物如:神经元特异性烯醇化酶(NSE)、胃泌素释放肽前体(ProGRP)、嗜铬粒蛋白A(CgA)、CD56和与小细胞肺癌相关的自身抗体进行了如下综述.     

Gas Exchange and Ventilatory Efficiency During Exercise in Pulmonary Vascular Diseases

Background and ObjectiveVentilatory inefficiency (high V′_E/V′CO₂) and resting hypocapnia are common in pulmonary vascular disease and are associated with poor prognosis. Low resting PaCO₂ suggests increased chemosensitivity or an altered PaCO₂ set-point. We aimed to determine the relationships between exercise gas exchange variables reflecting the PaCO₂ set-point, exercise capacity, hemodynamics and V′_E/V′CO₂.MethodsPulmonary arterial hypertension (n = 34), chronic thromboembolic pulmonary hypertension (CTEPH, n = 19) and pulmonary veno-occlusive disease (PVOD, n = 6) patients underwent rest and peak exercise arterial blood gas measurements during cardiopulmonary exercise testing. Patients were grouped according to resting PaCO₂: hypocapnic (PaCO₂ ≤34 mmHg) or normocapnic (PaCO₂ 35–45 mmHg). The PaCO₂ set-point was estimated by the maximal value of end-tidal PCO₂ (maximal P_ETCO₂) between the anaerobic threshold and respiratory compensation point.ResultsThe hypocapnic group (n = 39) had lower resting cardiac index (3.1 ±0.8 vs. 3.7 ±0.7 L/min/m², p < 0.01), lower peak V′O₂ (15.8 ± 3.5 vs. 20.7 ± 4.3 mL/kg/min, p < 0.01), and higher V′_E/V′CO₂ slope (60.6 ± 17.6 vs. 38.2 ± 8.0, p < 0.01). At peak exercise, hypocapic patients had lower PaO₂, higher V_D/V_T and higher P_(a-ET)CO₂. Maximal P_ETCO₂ (r = 0.59) and V_D/V_T (r = −0.59) were more related to cardiac index than PaO₂ or PaCO₂ at rest or peak exercise. Maximal P_ETCO₂ was the strongest correlate of V′_E/V′CO₂ slope (r = −0.86), peak V′O₂ (r = 0.64) and peak work rate (r = 0.49).ConclusionsResting hypocapnia is associated with worse cardiac function, more ventilatory inefficiency and reduced exercise capacity. This could be explained by elevated chemosensitivity and lower PaCO₂ set-point. Maximal P_ETCO₂ may be a useful non-invasive marker of PaCO₂ setpoint and disease severity even with submaximal effort.     

Platelet Glycoprotein IIb/IIIa Integrin Blockade in Coronary Artery Disease: Current State of the Art

Platelets have been shown to play an important role in the pathogenesis of atherosclerosis, acute coronary syndromes, and ischemic complications after percutaneous coronary intervention. Fibrinogen binding via platelet surface glycoprotein (GP) IIb/IIIa receptors constitutes the "final pathway" in platelet aggregation leading to thrombus formation. The GP IIb/IIIa receptor inhibitors, a new class of antiplatelet agents that have emerged in recent years, show great promise in reducing complications of coronary angioplasty and acute coronary syndromes. This review will examine the biology of platelet GP IIb/IIIa receptors, the various classes of GP IIb/IIIa receptor antagonists, the results of the latest clinical trials, and their implications in current clinical practice.