Alterations of Myocardial Mitochondrial Morphology and Function in a Canine Model of Premature Ventricular Contractions-Induced Cardiomyopathy.

AIMS: Changes in myocardial mitochondrial morphology and function in premature ventricular contractions (PVCs)-induced cardiomyopathy (PVCCM) remain poorly studied. Here, we investigated the effects of PVCs with different coupling intervals (CIs) on myocardial mitochondrial remodelling in a canine model of PVCCM. METHODS AND RESULTS: Twenty-one beagles underwent pacemaker implantation and were randomised into the sham (n = 7), short-coupled PVCs (SCP, n = 7), and long-coupled PVCs (LCP, n = 7) groups. Right ventricular (RV) apical bigeminy was produced for 12-week to induce PVCCM in the SCP (CI, 250 ms) and LCP (CI, 350 ms) groups. Echocardiography was performed at baseline and biweekly thereafter to evaluate cardiac function. Masson's trichrome staining measured ventricular interstitial fibrosis. The ultrastructural morphology of the myocardial mitochondria was analysed using transmission electron microscopy. Mitochondrial Ca2+ concentration, reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) content, membrane potential, and electron transport chain (ETC) complex activity were measured to assess myocardial mitochondrial function. Twelve-week-PVCs led to left ventricular (LV) enlargement with systolic dysfunction, disrupted mitochondrial morphology, increased mitochondrial Ca2+ concentration and ROS levels, decreased mitochondrial ATP content and membrane potential, and impaired ETC complex activity in both the SCP and LCP groups (all p < 0.01 vs the sham group). Ventricular fibrosis was observed only in canines with LCP. Worse cardiac function and more pronounced abnormalities in mitochondrial morphology and function were observed in the LCP group than to the SCP group (all p < 0.05). CONCLUSION: We demonstrated myocardial mitochondrial abnormalities in dogs with PVCCM, characterised by abnormal mitochondrial morphology, mitochondrial Ca2+ overload, oxidative stress, and impaired mitochondrial energy metabolism. Compared to SCP, long-term LCP exposure resulted in more severe mitochondrial remodelling and cardiac dysfunction in dogs.

Fork coupling directs DNA replication elongation and termination.

DNA replication is initiated at multiple loci to ensure timely duplication of eukaryotic genomes. Sister replication forks progress bidirectionally, and replication terminates when two convergent forks encounter one another. To investigate the coordination of replication forks, we developed a replication-associated in situ HiC method to capture chromatin interactions involving nascent DNA. We identify more than 2000 fountain-like structures of chromatin contacts in human and mouse genomes, indicative of coupling of DNA replication forks. Replication fork interaction not only occurs between sister forks but also involves forks from two distinct origins to predetermine replication termination. Termination-associated chromatin fountains are sensitive to replication stress and lead to coupled forks-associated genomic deletions in cancers. These findings reveal the spatial organization of DNA replication forks within the chromatin context.

Sensorimotor rhythm and muscle activity in patients with stroke using mobile serious games to assist upper extremity rehabilitation.

Introduction: Exercise rehabilitation is crucial for neurological recovery in hemiplegia-induced upper limb dysfunction. Technology-assisted cortical activation in sensorimotor areas has shown potential for restoring motor function. This study assessed the feasibility of mobile serious games for stroke patients' motor rehabilitation. Methods: A dedicated mobile application targeted shoulder, elbow, and wrist training. Twelve stroke survivors attempted a motor task under two conditions: serious mobile game-assisted and conventional rehabilitation. Electroencephalography and electromyography measured the therapy effects. Results: Patients undergoing game-assisted rehabilitation showed stronger event-related desynchronization (ERD) in the contralateral hemisphere's motor perception areas compared to conventional rehabilitation (p < 0.05). RMS was notably higher in game-assisted rehabilitation, particularly in shoulder training (p < 0.05). Discussion: Serious mobile game rehabilitation activated the motor cortex without directly improving muscle activity. This suggests its potential in neurological recovery for stroke patients.

Zero-profile anchored spacer versus conventional plate-cage construct in bilevel anterior cervical discectomy and fusion: a systematic review and meta-analysis.

BACKGROUND: Zero-profile anchored spacers (ZAS) and plate-cage constructs (PCC) are currently employed when performing anterior cervical discectomy and fusion (ACDF). Nevertheless, the efficacy and safety of both devices in bilevel ACDF remain controversial. The goal of our meta-analysis is to assess the overall long-term efficacy and security among ZAS and PCC in bilevel ACDF. METHODS: A search of four electronic databases was conducted to identify researches that compared ZAS with PCC for bilevel ACDF. Stata MP 17.0 software was used for this meta-analysis. RESULTS: Nine researches with a total of 580 patients were involved. In comparison to PCC, ZAS significantly reduced intraoperative bleeding and postoperative dysphagia rates. No significant differences were found concerning operation time, JOA score, NDI score, cervical Cobb angle, fusion rates, the incidence of adjacent segmental degeneration (ASD) and implant sinking rates at last follow-up. CONCLUSION: Compared to PCC, ZAS achieved similar efficacy and security in bilevel ACDF with respect to operative time, JOA score, NDI score, cervical Cobb angle, fusion rates, implant sinking rates and ASD rates at final follow-up. It is worth noting that ZAS offered considerable benefits over conventional PCC for the reduction of intraoperative bleeding and postoperative dysphagia. Therefore, for patients requiring bilevel ACDF, ZAS seems superior to PCC. Given the limitations of our study, larger prospective randomised controlled trials are needed to establish reliable proof to consolidate our conclusions.

Dapagliflozin attenuates cardiac remodeling and dysfunction in rats with ß-adrenergic receptor overactivation through restoring calcium handling and suppressing cardiomyocyte apoptosis.

Background: Long-term ß-adrenergic receptor (ß-AR) activation can impair myocardial structure and function. Dapagliflozin (DAPA) has been reported to improve clinical prognosis in heart failure patients, whereas the exact mechanism remains unclear. Here, we investigated the effects of DAPA against ß-AR overactivation toxicity and explored the underlying mechanism.Methods and Results: Rats were randomized to receive saline + placebo, isoproterenol (ISO, 5 mg/kg/day, intraperitoneally) + placebo, or ISO + DAPA (1 mg/kg/day, intragastrically) for 2-week. DAPA treatment improved cardiac function, alleviated myocardial fibrosis, prevented cardiomyocytes (CMs) apoptosis, and decreased the expression of ER stress-mediated apoptosis markers in ISO-treated hearts. In isolated CMs, 2-week ISO stimulation resulted in deteriorated kinetics of cellular contraction and relaxation, increased diastolic intracellular Ca2+ level and decay time constant of Ca2+ transient (CaT) but decreased CaT amplitude and sarcoplasmic reticulum (SR) Ca2+ level. However, DAPA treatment prevented abnormal Ca2+ handling and contractile dysfunction in CMs from ISO-treated hearts. Consistently, DAPA treatment upregulated the expression of SR Ca2+-ATPase protein and ryanodine receptor 2 (RyR2) but reduced the expression of phosphorylated-RyR2, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and phosphorylated-CaMKII in ventricles from ISO-treated rats.Conclusion: DAPA prevented myocardial remodeling and cardiac dysfunction in rats with ß-AR overactivation via restoring calcium handling and suppressing ER stress-related CMs apoptosis.

Cohesin maintains replication timing to suppress DNA damage on cancer genes.

Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism underlying its role in tumorigenesis is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks and 147 translocation hotspot genes, co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor disruption. However, damage-induced chromosomal translocations coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes replication stresses induced by excessive DNA replication initiation, resulting in gross DNA damages that may promote tumorigenesis.

Self-locking stand-alone cage versus cage-plate fixation in monosegmental anterior cervical discectomy and fusion with a minimum 2-year follow-up: a systematic review and meta-analysis.

BACKGROUND: Currently, self-locking stand-alone cages (SSC) are commonly applied in anterior cervical discectomy and fusion (ACDF), as are cage-plate constructs (CPC). However, it remains controversial concerning the long-term effectiveness of both apparatuses. Our purpose is to compare long-term effectiveness of SSC with CPC in monosegmental ACDF. METHODS: Four electronic databases were queried to identify studies comparing SSC versus CPC in monosegmental ACDF. The meta-analysis was carried out with the use of the Stata MP 17.0 software package. RESULTS: Ten trials with 979 patients were included. Compared to CPC, SSC significantly reduced operative time, intraoperative blood loss, duration of hospitalisation, cervical Cobb angle at final follow-up, 1-month postoperative dysphagia rate, and incidence of adjacent segment degeneration (ASD) at final follow-up. No significant difference was found regarding 1-month postoperative cervical Cobb angle, JOA scores, NDI scores, fusion rate and cage subsidence rate at final follow-up. CONCLUSION: Both devices achieved similar long-term effectiveness in monosegmental ACDF regarding JOA scores, NDI scores, fusion rate and cage subsidence rate. SSC had significant advantages over CPC in reducing surgical duration, intraoperative bleeding, duration of hospitalisation, as well as rates of dysphagia and ASD after surgery. Therefore, SSC is a better option than CPC in monosegmental ACDF. However, SSC is inferior to CPC in maintaining cervical curvature at long-term follow-up. Whether radiological changes affect clinical symptoms needs confirmation in trials with longer follow-up.

Key Mutant Genes and Biological Pathways Involved in Aspirin Resistance in the Residents of the Chinese Plateau Area.

INTRODUCTION: Aspirin is used to prevent and treat cardiovascular diseases; however, some patients develop aspirin resistance. AIM: We aimed to explore the potential molecular mechanisms underlying aspirin resistance in people living in the Chinese plateau area. METHODS: In total, 91 participants receiving aspirin treatment from the Qinghai plateau area were divided into the aspirin resistance and aspirin sensitivity groups. Genotyping was performed using the Sequence MASSarray. Differentially mutated genes between the two groups were analyzed using MAfTools. The annotation of differentially mutated genes was conducted based on the Metascape database. RESULTS AND DISCUSSION: In total, 48 differential SNP and 22 differential InDel mutant genes between the aspirin resistance and aspirin sensitivity groups were screened using Fisher's exact test (P < 0.05). After the χ2 test, a total of SNP mutant genes, including ZFPL1 and TLR3, and 19 InDel mutant genes were found to be differentially expressed between the two groups (P < 0.05). Functional analysis revealed that these differential SNP mutations were mainly enriched in aspirin resistance pathways, such as the Wnt signaling pathway. Furthermore, these genes were related to many diseases, including various aspirin indications. CONCLUSION: This study identified several genes and pathways that could be involved in arachidonic acid metabolic processes and aspirin resistance progression, which will provide a theoretical understanding of the molecular mechanism of aspirin resistance.

CT-based assessment of sarcopenia for differentiating wild-type from mutant-type gastrointestinal stromal tumor.

Non-invasive prediction for KIT/PDGFRA status in GIST is a challenging problem. This study aims to evaluate whether CT based sarcopenia could differentiate KIT/PDGFRA wild-type gastrointestinal stromal tumor (wt-GIST) from the mutant-type GIST (mu-GIST), and to evaluate genetic features of GIST. A total of 174 patients with GIST (wt-GIST = 52) were retrospectively identified between January 2011 to October 2019. A sarcopenia nomogram was constructed by multivariate logistic regression. The performance of the nomogram was evaluated by discrimination, calibration curve, and decision curve. Genomic data was obtained from our own specimens and also from the open databases cBioPortal. Data was analyzed by R version 3.6.1 and clusterProfiler ( http://cbioportal.org/msk-impact ). There were significantly higher incidence (75.0% vs. 48.4%) and more severe sarcopenia in patients with wt-GIST than in patients with mu-GIST. Multivariate logistic regression analysis showed that sarcopenia score (fitted based on age, gender and skeletal muscle index), and muscle fat index were independent predictors for higher risk of wt-GIST (P < 0.05 for both the training and validation cohorts). Our sarcopenia nomogram achieved a promising efficiency with an AUC of 0.879 for the training cohort, and 0.9099 for the validation cohort with a satisfying consistency in the calibration curve. Favorable clinical usefulness was observed using decision curve analysis. The additional gene sequencing analysis based on both our data and the external data demonstrated aberrant signal pathways being closely associated with sarcopenia in the wt-GIST. Our study supported the use of CT-based assessment of sarcopenia in differentiating the wt-GIST from the mu-GIST preoperatively.

Tubeimoside I Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating SIRT3.

Cardiotoxicity linked to doxorubicin (DOX) is primarily caused by inflammation, oxidative stress, and apoptosis. The role of tubeimoside I (TBM) in DOX-induced cardiotoxicity remains ambiguous, despite growing evidence that it could reduce inflammation, oxidative stress, and apoptosis in various diseases. This study was designed to investigate the role of TBM in DOX-induced cardiotoxicity and uncover the underlying mechanisms. H9c2 cell line and C57BL/6 mice were used to construct an in vitro and in vivo model of DOX-induced myocardial injury, respectively. We observed that DOX treatment provoked inflammation, oxidative stress, and cardiomyocyte apoptosis, which were significantly alleviated by TBM administration. Mechanistically, TBM attenuated DOX-induced downregulation of sirtuin 3 (SIRT3), and SIRT3 inhibition abrogated the beneficial effects of TBM both in vitro and in vivo. In conclusion, TBM eased inflammation, oxidative stress, and apoptosis in DOX-induced cardiotoxicity by increasing the expression of SIRT3, suggesting that it holds great promise for treating DOX-induced cardiac injury.

Chronic catestatin treatment reduces atrial fibrillation susceptibility via improving calcium handling in post-infarction heart failure rats.

BACKGROUND: Abnormal Ca2+ handling is a pivotal element of atrial fibrillation (AF) substrates. Catestatin (CST) modulates intracellular Ca2+ handling in cardiomyocytes (CMs). We investigated the effects of CST administration on atrial Ca2+ handling and AF susceptibility in rats with post-infarction heart failure (HF). METHODS: Myocardial infarction (MI) was established by ligation of the left anterior descending coronary artery in rats. Two-week later, rats with post-infarction HF were randomly treated with saline (MI group) or CST (MI + CST group) for 4-week. Cellular Ca2+ imaging was performed by incubating atrial CMs with Fura-2 AM. An in vitro electrophysiological study was performed to assess the vulnerability to action potential duration (APD) alternans and AF. Ca2+ handling proteins expression was determined using western blotting. RESULTS: In atrial CMs, compared with the sham group, the sarcoplasmic reticulum (SR) Ca2+ load, Ca2+ transient (CaT) amplitude, and threshold for Ca2+ alternans were significantly decreased, but the diastolic intracellular Ca2+ level, SR Ca2+ leakage, and spontaneous Ca2+ events were markedly increased in the MI group. However, CST attenuated these Ca2+-handling abnormalities induced by post-infarction HF. Moreover, vulnerability to atrial APD alternans and AF was significantly increased in isolated hearts from the MI group compared to the sham group, whereas all effects were prevented by CST. CST treatment also preserved SR Ca2+-ATPase protein expression but decreased the protein levels of phosphorylated-ryanodine receptor 2 and phosphorylated-Ca2+/calmodulin-dependent protein kinase II in atria from post-infarction HF rats. CONCLUSION: Chronic CST treatment reduces AF vulnerability in rats with MI-induced HF by improving Ca2+ handling.

Relationship between CYP2C19 Polymorphism and Clopidogrel Resistance in Patients with Coronary Heart Disease and Ischemic Stroke in China.

Objective: Clopidogrel is widely used for preventing ischemic complications related to cardiovascular diseases. However, many patients experience clopidogrel resistance (CR). The polymorphisms of CYP2C19 have been implicated in CR, but CYP2C19 polymorphism considerably varies with both ethnic group and geographical location. This study aimed to investigate the association between CYP2C19 polymorphisms and clopidogrel resistance (CR) in patients with coronary heart disease and ischemic stroke among Han and Tibetan populations in Qinghai Province, China. Methods: From June 2019 to January 2020, patients who were diagnosed with coronary heart disease or cerebral infarction in internal medicine of Qinghai Provincial People's Hospital and had taken dual antiplatelet drugs were included in this study. Blood was collected and routine items were completed. Whole exome sequencing was performed for CYP2C19 genetic polymorphisms of CYP2C19∗2 (rs4244285), CYP2C19∗3 (rs4986893), and CYP2C19∗17 (rs12248560). Results: A total of 91 patients with coronary heart disease or cerebral infarction (67 Han people (65.99 ± 12.25 years old) and 24 Tibetan (63.6324 Tib years old)) including 52 cases with CR and 39 cases with non-CR were enrolled in this study. For the Han population, the differences in age, glycosylated hemoglobin, activated partial thromboplastin time (APTT), gender, aspirin resistance, and diabetes were significant between the CR and non-CR groups. For the Tibetan population, the two groups showed no significant difference in all indicators. There was no significant difference between CR and non-CR groups for all genotypes (CYP2C19 ∗2, ∗3, and ∗17) in either Han or Tibetan populations. For the Han populations, age, APTT, and aspirin resistance were significantly correlated with CR. Conclusion: The present study indicated that CYP2C19∗2, CYP2C19∗3, and CYP2C19∗17 alleles were not correlated with CR for both Han and Tibetan populations in Qinghai Province, while age, APTT, and aspirin resistance were independent risk factors of CR in this region.

CRISPR/Cas9-induced structural variations expand in T lymphocytes in vivo.

CRISPR/Cas9 has been adapted to disrupt endogenous genes in adoptive T-lymphocyte therapy to prevent graft-versus-host disease. However, genome editing also generates prevalent deleterious structural variations (SVs), including chromosomal translocations and large deletions, raising safety concerns about reinfused T cells. Here, we dynamically monitored the progression of SVs in a mouse model of T-cell receptor (TCR)-transgenic T-cell adoptive transfer, mimicking TCR T therapeutics. Remarkably, CRISPR/Cas9-induced SVs persist and undergo clonal expansion in vivo after three weeks or even two months, evidenced by high enrichment and low junctional diversity of identified SVs post infusion. Specifically, we detected 128 expanded translocations, with 20 615 as the highest number of amplicons. The identified SVs are stochastically selected among different individuals and show an inconspicuous locus preference. Similar to SVs, viral DNA integrations are routinely detected in edited T cells and also undergo clonal expansion. The persistent SVs and viral DNA integrations in the infused T cells may constantly threaten genome integrity, drawing immediate attention to the safety of CRISPR/Cas9-engineered T cells mediated immunotherapy.

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling.

BACKGROUND: Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF. METHODS: Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM. RESULTS: High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy. CONCLUSION: DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

Antiarrhythmic effects and mechanisms of sodium-glucose cotransporter 2 inhibitors: A mini review.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new type of oral hypoglycaemic agent with good cardiovascular protective effects. There are several lines of clinical evidence suggest that SGLT2i can significantly reduce the risks of heart failure, cardiovascular death, and delay the progression of chronic kidney disease. In addition, recent basic and clinical studies have also reported that SGLT2i also has good anti-arrhythmic effects. However, the exact mechanism is poorly understood. The aim of this review is to summarize recent clinical findings, studies of laboratory animals, and related study about this aspect of the antiarrhythmic effects of SGLT2i, to further explore its underlying mechanisms, safety, and prospects for clinical applications of it.

Lower Expression of TWEAK is Associated with Poor Survival and Dysregulate TIICs in Lung Adenocarcinoma.

Background: Lung cancer remains the leading cause of cancer death worldwide, and the most subtype is lung adenocarcinoma (LUAD). Tumor-infiltrating immune cells (TIICs) greatly impact the prognosis of LUAD. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), signal via its receptor fibroblast growth factor-inducible 14 (Fn14), dysregulates immune cell recruitment within tumor environment, thus promoting the progression of autoimmune diseases and cancer. We aimed to explore its role in LUAD. Methods: The expression level of TWEAK was explored in Tumor Immune Estimation Resource 2.0 (TIMER2.0) and Oncomine databases. The Tumor Immune Dysfunction and Exclusion (TIDE) and Lung Cancer Explorer (LCE) databases were applied to evaluate the survival in correlation to TWEAK expression. TIICs were assessed with TIMER2.0 and TIDE datasets. The expression of TWEAK protein was detected in LUAD cell lines and also in tissue samples from LUAD patients via western blotting or combination with immunochemistry. Results: Our results showed that TWEAK was downregulated in LUAD tumors compared to normal tissues in TIMER2.0, Oncomine, cell lines, and clinical specimens. Poor survival was uncovered in lower TWEAK expression of LUAD patients in LCE (meta - HR = 0.84 [95% CI, 0.76-0.92]) and TCGA (Continuous Z = -1.97, p = 0.0486) and GSE13213@PRECOG (Continuous Z = -4.25, p = 2.12e - 5) in TIDE. Multiple tumor-infiltrating immune cells (TIICs) were found closely correlated with TWEAK expression in LUAD, especially hematopoietic stem cell (Rho = 0.505, p = 2.78e - 33), common lymphoid progenitor (Rho = -0.504, p = 3.79e - 33), and myeloid-derived suppressor cells (MDSCs) (Rho = -0.615, p = 1.36e - 52). Conclusion: Lower level of TWEAK was linked with poor survival and aberrant recruitment and phenotype of TIICs in LUAD, which might motivate immune escape and weaken the effects of immunotherapy.

Crizotinib in Sarcomatous Malignancies Harboring ALK Fusion With a Definitive Partner(s): Response and Efficacy.

Sarcoma or sarcomatoid malignancies are a set of mesenchymal-origin malignancies with vast heterogeneity in clinical and molecular characteristics. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase oncoprotein expressed by several tumors, including sarcomas. Crizotinib is an effective ALK inhibitor. In this review paper, we summarized findings from the literature regarding the use of crizotinib for the treatment of sarcoma and sarcomatoid malignancies harboring ALK fusions with definitive partners (with the given gene(s) name) from the years 2010 to 2021.One hundred and four articles were retrieved and after exclusion, 28 studies containing 33 patients were finally selected. All 33 patients were treated with crizotinib. Among the 33 cases, 19 were adult patients, 11 were pediatric patients, and 3 cases did not have data on age and/or gender. Most cases had a primary abdominal lesion (16/30), followed by thoracic (10/30), trunk (3/30), retroperitoneal (1/30), and one case of right medial thigh (case 7). Stage IV disease was reported in 76.7% (23/30) of patients. The objective response rate and disease control rate was 86.7% (26/30) and 96.7% (29/30), respectively, which were assessed on average of 8 weeks after crizotinib initiation. Rapid improvement of symptoms was observed within one to two weeks in some cases including patients with extensive diseases or poor performance. There was no difference in crizotinib response between pediatrics and adult cases. Crizotinib is effective; however, surgery remains the mainstay of therapy, with newer evidence showing concurrent crizotinib with surgery conferring long-term overall survival. However, we should still be cognizant of the heterogeneous landscape of crizotinib efficacy and its associated fatal adverse events.

Analysis of the Reactivity of Aspirin and Clopidogrel and Its Influencing Factors in Patients with Coronary Heart Disease at High Altitude.

OBJECTIVE: To evaluate the efficacy of dual-antiplatelet treatment (DAPT) in patients with coronary heart disease (CHD) at high altitude by using thrombelastogram (TEG) and to analyze the related biochemical factors affecting drug reactivity. METHODS: Totally 118 CHD patients who admitted to the Qinghai People's Hospital from September 2019 to September 2020 were enrolled in the group. Those people have lived in Qinghai for a long time. Seven days after DAPT, venous blood was collected on an empty stomach in the early morning of the next day; blood routine, coagulation function, and biochemical items were tested. Thrombelastogram (TEG) was used to draw curves to calculate platelet, coagulation and fibrinolysis functions, and drug inhibition rate. Patients were divided into the aspirin resistance (AR) group, clopidogrel resistance (CR) group, dual-antiplatelet drug resistance (DAR) group, and drug-sensitive group according to different inhibition rates. The drug efficacy was analyzed, and the clinical data, biochemical indexes, and TEG parameters of each group were compared to identify the risk factors of drug resistance. RESULTS: Those 118 CHD patients at high altitude were incorporated into the study, ranging from 38 to 84 years of age, including 81 males (68.64%) and 37 females (31.36%). The platelet function and coagulation-fibrinolysis function were detected by TEG, and MATHROMBI, MAADP, and MAAA were higher than the reference range. There were 82 cases (69.49%) of drug resistance, 36 cases (32.53%) of drug sensitivity, 17 cases (14.41%) of AR alone, and 16 cases (12.71%) of CR alone. There was no significant difference in age, gender, BMI, oxygen saturation, TG, GFR, and history of diabetes and hypertension between ACS and CCS groups (P > 0.05). PLT and FIB in the ACS group were higher than those in the CCS group, and the difference was statistically significant (P < 0.05). In addition, MATHROMBIN, MAFIBRIN, E, A, A30, and coagulation composite index were also higher than those in the CCS group, with a statistically significant difference (P < 0.05). Univariate analysis and logistic regression analysis suggested that age, HbA1c, FBG, and diabetes were the main factors of drug resistance. CONCLUSION: Antiplatelet drugs aspirin and clopidogrel resistance are associated with increased age, elevated HbA1c and FBG, and diabetes. Therefore, it is necessary to take reasonable treatment measures based on the actual situation of patients.