Effect of sternocleidomastoid flap repair and endoscopic injection of emulsified adipose tissue stromal vascular fraction in the treatment of refractory cervical anastomotic leak contaminating mediastinum.

Mediastinal infection caused by anastomotic leak is hard to cure, mainly because the poor drainage at the site of mediastinal infection leads to persistent cavity infection, which in turn becomes a refractory mediastinal abscess cavity after minimally invasive esophagectomy (MIE)-McKeown. Herein, we explored sternocleidomastoid (SCM) muscle flaps and emulsified adipose tissue stromal vascular fraction containing adipose-derived stem-cells to address this issue. We studied 10 patients with esophageal cancer who underwent MIE-McKeown + 2-field lymphadenectomy and developed anastomotic and mediastinal leak and received new technology treatment in the Affiliated Cancer Hospital of Zhengzhou University from June 2018 to March 2022. The clinical data and prognosis of the patients were collected and analyzed. A total of 5 patients received this surgery, and no other complications occurred during the perioperative period. Among the 5 patients, 1 patient was partially cured, and 4 patients were completely cured. During the follow-up 3 months postoperatively, all these 5 patients could eat regular food smoothly, and no relapse of leak and mediastinal infection occurred. The new surgical method has achieved good results in the treatment of anastomotic leak. Compared with the traditional thoracotomy, it is a less invasive and feasible surgical approach, which can be used as a supplement to the effective surgical treatment of cervical anastomotic leak contaminating the mediastinum.

Higher baseline serum bilirubin levels are associated with increased risk of early neurological deterioration in women with acute ischemic stroke.

Background and objectives: Early neurological deterioration (END) occurs in up to one-third of patients with acute ischemic stroke (AIS) and associated with poor outcome. The role of serum bilirubin in END remains controversial. This study aims to investigate the association of total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) with END. Methods: This study was a cross-sectional retrospective study with 344 AIS patients enrolled. We retrospectively reviewed consecutive AIS patients with END through a medical record retrieval system and enrolled patients as control randomly from the AIS patients without END at the same period. The bilirubin levels were compared between the END group and No END group. The correlations of bilirubin with END were assessed according to the bilirubin tertiles on the cohort of different genders. Results: In women, as the bilirubin level increased, the occurrence of END showed an increasing trend. The linear association was significant based on the tertiles of all bilirubin types (TBIL p = 0.003; DBIL p = 0.025; IBIL p = 0.025), while in men no similar trend was observed. After adjustment for confounders, higher TBIL (p for trend 0.009) and DBIL (p for trend 0.033) levels were associated with increased risk of END in women. The adjusted OR for T3 relative to T1 was 5.240 (95% CI 1.496-18.347) in TBIL and 3.549 (95% CI 1.089-11.566) in DBIL. Multivariate logistic regression showed that DBIL was independently associated with END in women (OR 1.717, 95% CI 1.106-2.666). The study also found that DBIL was superior to TBIL and IBIL in prediction of END occurrence in women, with greater predictive value. Discussion: There were gender differences in the relationship between bilirubin and END, and DBIL level was positively associated with END occurrence in women, not in men. DBIL had greater incremental predictive value for END than TBIL and IBIL.

Preliminary findings on diagnostic performance of computed tomography perfusion images for intracranial arterial stenosis: a retrospective study.

OBJECTIVES: Computed tomographic perfusion (CTP) can play an auxiliary role in the selection of patients with acute ischemic stroke for endovascular treatment. However, data on CTP in non-stroke patients with intracranial arterial stenosis are scarce. We aimed to investigate images in patients with asymptomatic intracranial arterial stenosis to determine the detection accuracy and interpretation time of large/medium-artery stenosis or occlusion when combining computed tomographic angiography (CTA) and CTP images. METHODS: We retrospectively reviewed 39 patients with asymptomatic intracranial arterial stenosis from our hospital database from January 2021 to August 2023 who underwent head CTP, head CTA, and digital subtraction angiography (DSA). Head CTA images were generated from the CTP data, and the diagnostic performance for each artery was assessed. Two readers independently interpreted the CTA images before and after CTP, and the results were analyzed. RESULTS: After adding CTP maps, the accuracy (area under the curve) of diagnosing internal carotid artery (R1: 0.847 vs. 0.907, R2: 0.776 vs. 0.887), middle cerebral artery (R1: 0.934 vs. 0.933, R2: 0.927 vs. 0.981), anterior cerebral artery (R1: 0.625 vs. 0.750, R2: 0.609 vs. 0.750), vertebral artery (R1: 0.743 vs. 0.764, R2: 0.748 vs. 0.846), and posterior cerebral artery (R1: 0.390 vs. 0.575, R2: 0.390 vs. 0.585) occlusions increased for both readers (p < 0.05). Mean interpretation time (R1: 72.4 ± 6.1 s vs. 67.7 ± 6.4 s, R2: 77.7 ± 3.8 s vs. 72.6 ± 4.7 s) decreased when using a combination of both images both readers (p < 0.001). CONCLUSIONS: The addition of CTP images improved the accuracy of interpreting CTA images and reduced the interpretation time in asymptomatic intracranial arterial stenosis. These findings support the use of CTP imaging in patients with asymptomatic intracranial arterial stenosis.

Efficacy of antiplatelet drugs combined with Argatroban in treating acute ischemic stroke and its impact on patients' coagulation function and neurological function: a preliminary trial.

This retrospective study analyzed the efficacy of combined antiplatelet therapy with Argatroban in treating acute ischemic stroke (AIS) and its impact on patients' coagulation and neurological functions. Clinical data of 113 AIS patients admitted between January 2021 and January 2023 were retrospectively analyzed. Patients were divided into control (n = 56) and observation (n = 57) groups based on treatment interventions. The control group patients were treated with antiplatelet drugs, while the observation group patients received combination therapy with apatinib on the basis of the control group treatment. Compared to the control group, the observation group demonstrated higher clinical efficacy, improved coagulation parameters, reduced stroke severity (measured by NIHSS), enhanced daily living abilities (BI scores), and lowered inflammatory and neural injury markers post-treatment. Adverse reaction incidence was similar between groups. Combining Argatroban with antiplatelet drugs in AIS management showed superior efficacy without increasing adverse effects, suggesting its potential for clinical application.

Sex-biased single-cell genetic landscape in mice with autism spectrum disorder.

Autistic spectrum disorder (ASD) is a male-biased, heterogeneous neurodevelopmental disorder that affects approximately 1%-2% of the population. Prenatal exposure to valproic acid (VPA) is a recognized risk factor for ASD, but the cellular and molecular basis of VPA-induced ASD at the single-cell resolution is unclear. Here, we aim to compare the cellular and molecular differences in the hippocampus between male and female prenatal mice with ASD at the single-cell transcriptomic level. The transcriptomes of more than 45,000 cells are assigned to 12 major cell types, including neurons, glial cells, vascular cells, and immune cells. Cell type-specific genes with altered expression after prenatal VPA exposure are analyzed, and the largest number of differentially expressed genes (DEGs) are found in neurons, choroid plexus epithelial cells, and microglia. In microglia, several pathways related to inflammation are found in both males and females, including the tumor necrosis factor (TNF), nuclear factor kappa B (NF-κB), toll-like receptor (TLR), and mitogen-activated protein kinase (MAPK) signaling pathways, which are important for the induction of autistic-like behavior. Additionally, we note that several X-linked genes, including Bex1, Bex3, and Gria3, were among the male-specific DEGs of neurons. This pioneering study describes the landscape of the transcriptome in the hippocampus of autistic mice. The elucidation of sexual differences could provide innovative strategies for the prevention and treatment of ASD.

Analysis of risk factors for the efficacy of tirofiban in the treatment of acute ischemic stroke.

OBJECTIVE: To analyse the risk factors for tirofiban efficacy in the early treatment of acute ischemic stroke. METHODS: The clinical data of 204 patients with acute ischemic stroke treated with tirofiban were retrospectively analysed. The early efficacy of tirofiban was assessed by a ≥ 4-point decline in the National Institutes of Health Stroke Scale (NIHSS) score or via the complete disappearance of neurological deficits at the end of ischemic stroke treatment, and patients were divided into an effective groupand an ineffective group. Univariate and multivariate logistic regression analyses were used to compare the differences in clinical data between the two groups. RESULTS: Multivariate logistic regression analysis showed that heavy drinking (OR 0.477, 95% CI 0.249-0.899, P = 0.023), elevated total cholesterol (OR 0.331, 95% CI 0.141-0.734, P = 0.008), NIHSS score at initiation of treatment (OR 1.130, 95% CI 1.026-1.253, P = 0.016) and time from onset to treatment (OR 0.839, 95% CI 0.700-0.979, P = 0.038) were independent risk factors affecting the early efficacy of tirofiban. CONCLUSION: The early curative effect of tirofiban in acute ischemic stroke patients with a heavy drinking history and elevated total cholesterol was poor. In patients with acute ischemic stroke, the higher the NIHSS score was within a certain range (8 < NIHSS ≤15 and the Org 10,172 Trial in the Treatment of Acute Stroke (TOAST) belongs to small-artery occlusion lacunar) at the initiation of treatment and the shorter the time from onset to treatment, the better the early curative effect was.

Safety and efficacy of low-dose and long-course tirofiban in large hemispheric infarction.

Background: The clinical efficacy and safety of tirofiban in the treatment of large hemispheric infarction (LHI) remain controversial. Methods: This study prospectively enrolled patients with acute LHI who were admitted to Putuo Hospital affiliated with Shanghai University of Traditional Chinese Medicine from June 2021 to December 2021. The patients were randomly assigned to the tirofiban group [3-4 µg/(kg·h)] or control group (clopidogrel 75 mg/d). Results: A total of 71 patients with acute LHI were selected: 36 in the tirofiban group and 35 in the control group. The reduction of the NIHSS score in the tirofiban group was 2.92 ± 9.31 at discharge, and that of the control group was -3.23 ± 12.06 (p = 0.021, OR, 0.006; 95% CI, 0.004-0.008). Six patients (16.7%) in tirofiban group and 14 patients (40%) in control group died during hospitalization (p = 0.029, OR, 0.300; 95% CI, 0.099-0.908). There was significant difference in Modified Rankin Scale (mRS) 5-6 scores at 90 days between the two groups (p = 0.023, OR, 0.327; 95% CI, 0.124-0.867). However, there was no significant difference in mRS 0-1 (p = 0.321, OR, 0.972; 95% CI, 0.920-1.027), mRS 2 (p = 0.572, OR, 2.00; 95% CI, 0.173-23.109), mRS 3 (p = 0.225, OR, 2.214; 95% CI, 0.601-8.161), or mRS 4(p = 0.284, OR, 1.859; 95% CI, 0.593-5.825) scores between the two groups. There was no difference in symptomatic intracranial hemorrhage (p = 0.29, OR, 0.305; 95% CI, 0.030-3.081), asymptomatic intracranial hemorrhage (p = 0.123, OR, 0.284; 95% CI, 0.053-1.518). There was a significant difference in systemic bleeding events during hospitalization (p = 0.044, OR, 0.309; 95% CI, 0.096-1.000). Conclusions: Low-dose and long-course tirofiban treatment may significantly improve the early neurological function and reduce the in-hospital mortality in LHI patients. Meanwhile, tirofiban does not increase the risk of any type of bleeding events.

Circ_0007624 suppresses the development of esophageal squamous cell carcinoma via targeting miR-224-5p/CPEB3 to inactivate the EGFR/PI3K/AKT signaling.

Circular RNAs (circRNAs) have been confirmed to be involved in the regulation of esophageal squamous cell carcinoma (ESCC) progression. According to GEO datasets (GSE112496 and GSE150476), we identified that circ_0007624 was abnormally down-regulated in ESCC. However, there is still no reports regarding the function and mechanism of circ_0007624 in ESCC development. Here, we found that circ_0007624 was significantly underexpressed in ESCC tissues, and low expression of circ_0007624 was indicative of a poor prognosis. Overexpressing circ_0007624 or silencing miR-224-5p suppressed cell proliferation, metastasis, epithelial-mesenchymal transition (EMT), and promoted apoptosis in vitro. Also, circ_0007624 up-regulation slowed ESCC tumor growth in vivo. Mechanistically, circ_0007624 could serve as a competing endogenous RNA (ceRNA) by sponging miR-224-5p to antagonize its inhibitory effect on the target cytoplasmic polyadenylation element binding protein 3 (CPEB3). Rescue experiments showed that the anti-cancer properity role of circ_0007624 in ESCC is partly reversed by the restoration of miR-224-5p or down-regulation of CPEB3. Furthermore, EGFR/PI3K/AKT pathway was involved in the regulation of circ_0007624/miR-224-5p/CPEB3 axis in ESCC. Together, our findings demonstrate for the first time that circ_0007624/miR-224-5p/CPEB3 suppresses ESCC progression by inactivating EGFR/PI3K/AKT signaling, providing a basis for developing circ_0007624-targeted therapies for ESCC patients.

Older patients more likely to die from cancer-related diseases than younger with stage IA non-small cell lung cancer: a SEER database analysis.

Background: Various reports showed some conflicting data on survival at different ages. This study aimed to investigate the main cause of death in older patients with lung cancer and to perform a comparison with younger patients in order to observe the differences between these two cohorts. Methods: Outcomes of patients with stage IA non-small cell lung cancer (NSCLC) ≤3 cm who underwent lobectomy without induction therapy in the Surveillance, Epidemiology, and End Results-18 (SEER-18; January 2004 to December 2016) database were evaluated using multivariable Cox proportional hazards modeling and propensity score-matched analysis. Results: A total of 16,672 eligible NSCLC cases were found in the SEER database. The number of patients aged ≤60, 61-70, and ≥71 years was 3,930, 6,391, and 6,351, respectively. Among these patient groups, 527 (13.4%), 1,018 (15.9%), and 1,235 (19.4%) died of lung cancer during follow-up, while 357 (9.1%), 964 (15.1%) and 1,579 (25.2%) died of non-lung cancer diseases, respectively. The overall survival (OS) and lung cancer-specific survival (LCSS) rates of younger patients showed a significant survival advantage over older patients. After propensity-score matching (PSM) of patients aged ≤60 and ≥71 years using a ratio of 1:1, we found that 403 (12.9%) and 584 (18.7%) patients in the ≤60 and ≥71 years age groups died of lung cancer, respectively. The OS and LCSS rates of younger patients still exhibited a significant survival advantage over older patients. Conclusions: Older patients with stage IA NSCLC have a worse prognosis compared with younger patients. Also, cancer-related causes were more frequent in older patients than non-cancer-related causes.

Time Course for Benefit and Risk With Ticagrelor and Aspirin in Individuals With Acute Ischemic Stroke or Transient Ischemic Attack Who Carry CYP2C19 Loss-of-Function Alleles: A Secondary Analysis of the CHANCE-2 Randomized Clinical Trial.

Importance: Dual antiplatelet therapy (DAPT) with ticagrelor and aspirin has been found to be effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA) in individuals who carry CYP2C19 loss-of-function (LOF) alleles; however, uncertainties remain about the time course of benefit and risk with ticagrelor and aspirin in these patients. Objective: To obtain time-course estimates of efficacy and risk with ticagrelor and aspirin after minor stroke or TIA in individuals with CYP2C19 LOF alleles. Design, Setting, and Participants: The Ticagrelor or Clopidogrel With Aspirin in High-risk Patients With Acute Nondisabling Cerebrovascular Events II (CHANCE-2) randomized clinical trial enrolled patients 40 years and older from 202 hospitals in China with acute minor stroke or TIA who carried CYP2C19 LOF alleles between September 23, 2019, and March 22, 2021, and were followed up for 90 days. All 6412 patients enrolled in the CHANCE-2 trial were included in this secondary analysis. Data were analyzed in October 2021. Interventions: Ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2-90) or clopidogrel (300 mg on day 1 followed by 75 mg daily on days 2-90). All patients received aspirin (75-300 mg on day 1 followed by 75 mg daily for 21 days). Main Outcomes and Measures: The efficacy outcome was major ischemic event, defined as the composite of ischemic stroke or nonhemorrhagic death. Safety outcomes included moderate to severe bleeding and any bleeding. Results: A total of 6412 patients were included (3205 in the ticagrelor and aspirin group and 3207 in the clopidogrel and aspirin group). The median (IQR) age was 65 (57-71) years, and 4242 patients (66%) were men. The reduction of major ischemic events with ticagrelor and aspirin predominately occurred in the first week (absolute risk reduction, 1.34%; 95% CI, 0.29 to 2.39) and attenuated but remained in the next 3 weeks (absolute risk reduction in the second week, 0.11%; 95% CI, -0.24 to 0.45; absolute risk reduction in the third week, 0.14%; 95% CI, -0.11 to 0.38; absolute risk reduction in the fourth week, 0.04%; 95% CI, -0.18 to 0.25). The risk of moderate to severe bleeding was consistently low in the ticagrelor and aspirin group. The absolute increase in any bleeding seen in the first week (0.87%; 95% CI, 0.25 to 1.50) remained in the next 3 weeks (absolute increase in the second week, 1.21%; 95% CI, 0.75 to 1.68; absolute increase in the third week, 0.33%; 95% CI, -0.05 to 0.72; absolute increase in the fourth week, 0.23%; 95% CI, -0.03 to 0.49). Conclusion and Relevance: Among patients with minor stroke or TIA who carried CYP2C19 LOF alleles, benefit with ticagrelor and aspirin was present predominately in the first week, with additional small benefit accruing in the next 2 weeks.

Predictive model of postoperative pneumonia after neoadjuvant immunochemotherapy for esophageal cancer.

Background: Postoperative pneumonia (PP) is the most common pulmonary complication of esophagectomy. It is of great importance to identify any high-risk factors and prevent pulmonary complications to improve the prognosis of patients with esophageal cancer undergoing esophagectomy. Thus, we established a predictive model of PP in patients with neoadjuvant immunochemotherapy for resectable esophageal squamous cell carcinoma (ESCC), and provide suggestions for the best strategy for the perioperative period of the patients. Method: We retrospectively analyzed 78 patients who underwent esophagectomy for squamous cell carcinoma after neoadjuvant immunochemotherapy between September 2019 and August 2021.We used the "glmnet" language package in R to perform least absolute shrinkage and selection operator (LASSO) regression to screen the best predictors of PP, and nomograms predicting PP were constructed utilizing screened factors. The performance of nomograms was internally validated by calibration curves, concordance index (C-index), and the Brier score for overall performance. Results: Twenty-six patients (33.3%) had postoperative pneumonia. After LASSO regression, the factors that were independently associated with PP were diffusing capacity of the lungs for carbon monoxide (DLCO) (P=0.0002), white blood cell (WBC) difference before vs. after neoadjuvant immunochemotherapy (P=0.0133). We constructed a prediction model, plotted the nomogram, and verified its accuracy. Its Brier score was 0.147, its calibration slope was 0.98, and its C-index was 0.85 (95% CI: 0.75-0.95). Internal validation demonstrated a good discrimination power that the actual probability corresponds closely with the predicted probability. Conclusions: Our prediction model can predict the possibility of PP in patients with neoadjuvant immunochemotherapy for resectable esophageal squamous cell carcinoma and may facilitate physicians' efforts to reduce the incidence of postoperative pneumonia.

Circular RNA hsa_circ_0000277 promotes tumor progression and DDP resistance in esophageal squamous cell carcinoma.

BACKGROUND: Circular RNAs (circRNAs) are well-known regulators of cancer progression and chemoresistance in various types of cancers. This study was performed to investigate the function of hsa_circ_0000277 in esophageal squamous cell carcinoma (ESCC). METHODS: RNA levels were analyzed via the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8) assay was applied to determine cell proliferation and half maximal inhibitory concentration (IC50) of cisplatin (DDP). Colony formation ability was evaluated by colony formation assay. Cell cycle and apoptosis were measured using flow cytometry. RNA immunoprecipitation (RIP), pull-down assay and dual-luciferase reporter assays were performed for target interaction analysis. The protein levels were determined through western blot. Xenograft models were established for researching hsa_circ_0000277 function in vivo. RESULTS: Hsa_circ_0000277 expression was increased in ESCC cells and tissues, and it had important clinical significance. Downregulation of hsa_circ_0000277 repressed ESCC cell proliferation, colony formation, cell cycle, and DDP resistance. Hsa_circ_0000277 acted as a microRNA-873-5p (miR-873-5p) sponge and Sry-related high-mobility group box 4 (SOX4) was validated as a target of miR-873-5p. Moreover, hsa_circ_0000277/miR-873-5p axis and miR-873-5p/SOX4 axis regulated ESCC cell progression and DDP resistance. Hsa_circ_0000277/miR-873-5p axis activated SOX4/Wnt/ß-catenin signaling pathway. Hsa_circ_0000277 facilitated tumorigenesis and DDP resistance by miR-873-5p/SOX4 axis in vivo. CONCLUSION: These findings unraveled that hsa_circ_0000277 promoted ESCC progression and DDP resistance via miR-873-5p/SOX4/Wnt/ß-catenin axis, showing a specific molecular mechanism of carcinogenesis and chemoresistance in ESCC.

ß-arrestin-2 alleviates rheumatoid arthritis injury by suppressing NLRP3 inflammasome activation and NF- κB pathway in macrophages.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder that inflicts damage to the joints of the hands and wrist. The aim of this study was to investigate the protective effect of ß-Arrestin-2 (ßArr2) on RA in vivo and in vitro. The ßArr2 adenovirus (ßArr2-Ad) or the control (Con-Ad) was injected into the ankle joint cavity of collagen-induced arthritis (CIA) mice. According to the results, an improvement was shown in the symptoms and pathological injury of RA after an upregulation of ßArr2. Correspondingly, the inflammatory response was attenuated, as evidenced by the decreased serum pro-inflammatory cytokines levels and NF-κB pathway-related proteins. Nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome activation was inhibited in CIA mice treated with ßArr2-Ad injection, as reflected by the diminished IL-18 level and declined protein levels of inflammasome components in the ankle joint. Likewise, the anti-inflammatory effect of macrophages was also validated by in vitro experiments. In summary, ßArr2 effectively ameliorates ankle inflammation in CIA mice via NF-κB/NLRP3 inflammasome, providing theoretical and clinical basis for RA therapy.

Association between the inclination angle of the proximal tibiofibular joint surface and medial compartment knee osteoarthritis.

BACKGROUND: Fibular support for the lateral tibial plateau through the proximal tibiofibular joint (PTFJ) results in nonuniform settlement of the tibial plateau in middle-aged and elderly persons and may lead to medial compartment knee osteoarthritis. However, the inclination angle of the PTFJ surface varies widely and may affect nonuniform settlement. The purpose of this case-control study was to assess the association between the inclination angle of the PTFJ surface and medial compartment knee osteoarthritis. METHODS: The fibular inclination angle (FIA) and tibial inclination angle (TIA) of the PTFJ surface were measured using radiographs. Differences of FIA and TIA among groups were assessed with t tests and the odds ratios (ORs) for risk factors of medial compartment knee osteoarthritis were calculated with binary logistic regression analysis. RESULTS: Forty patients and 40 control participants were included in this case-control study. Patients had both a lower FIA (P=0.005) and TIA (P=0.000) than the controls, and logistic regression analysis showed that FIA (OR =7.000) and TIA (OR =17.000) were risk factors for medial compartment knee osteoarthritis. CONCLUSIONS: A lower inclination angle of the PTFJ surface is associated with a risk of medial compartment knee osteoarthritis. Clinically, early prevention of medial compartment knee osteoarthritis should be considered for middle-aged and elderly persons with low PTFJ inclination angles.

Glycosylation of ß1 subunit plays a pivotal role in the toxin sensitivity and activation of BK channels.

BACKGROUND: The accessory ß1 subunits, regulating the pharmacological and biophysical properties of BK channels, always undergo post-translational modifications, especially glycosylation. To date, it remains elusive whether the glycosylation contributes to the regulation of BK channels by ß1 subunits. METHODS: Herein, we combined the electrophysiological approach with molecular mutations and biochemical manipulation to investigate the function roles of N-glycosylation in ß1 subunits. RESULTS: The results show that deglycosylation of ß1 subunits through double-site mutations (ß1 N80A/N142A or ß1 N80Q/N142Q) could significantly increase the inhibitory potency of iberiotoxin, a specific BK channel blocker. The deglycosylated channels also have a different sensitivity to martentoxin, another BK channel modulator with some remarkable effects as reported before. On the contrary to enhancing effects of martentoxin on glycosylated BK channels under the presence of cytoplasmic Ca2+, deglycosylated channels were not affected by the toxin. However, the deglycosylated channels were surprisingly inhibited by martentoxin under the absence of cytoplasmic Ca2+, while the glycosylated channels were not inhibited under this same condition. In addition, wild type BK (α+ß1) channels treated with PNGase F also showed the same trend of pharmacological results to the mutants. Similar to this modulation of glycosylation on BK channel pharmacology, the deglycosylated forms of the channels were activated at a faster speed than the glycosylated ones. However, the V1/2 and slope were not changed by the glycosylation. CONCLUSION: The present study reveals that glycosylation is an indispensable determinant of the modulation of ß1-subunit on BK channel pharmacology and its activation. The loss of glycosylation of ß1 subunits could lead to the dysfunction of BK channel, resulting in a pathological state.

THAP9-AS1/miR-133b/SOX4 positive feedback loop facilitates the progression of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in the digestive system with a high incidence and poor prognosis. Long non-coding RNAs (LncRNA) have been reported to be closely associated with the occurrence and development of various human cancers. Data from GSE89102 shows an increase of THAP9-AS1 expression in ESCC. However, its functions and mechanisms underlying ESCC progression remain to be investigated. In this study, we found that THAP9-AS1 was overexpressed in ESCC tissues and cells. High THAP9-AS1 expression was positively correlated with tumor size, TNM stage, lymph node metastasis, and worse prognosis. Functionally, depletion of THAP9-AS1 suppressed cell proliferation, migration, and invasion, while enhanced apoptosis in vitro. Consistently, knockdown of THAP9-AS1 inhibited xenograft tumor growth in vivo. Mechanistically, THAP9-AS1 could serve as a competing endogenous RNA (ceRNA) for miR-133b, resulting in the upregulation of SOX4. Reciprocally, SOX4 bound to the promoter region of THAP9-AS1 to activate its transcription. Moreover, the anti-tumor property induced by THAP9-AS1 knockdown was significantly impaired due to miR-133b downregulation or SOX4 overexpression. Taken together, our study reveals a positive feedback loop of THAP9-AS1/miR-133b/SOX4 to facilitate ESCC progression, providing a potential molecular target to fight against ESCC.

Adjuvant treatment can improve prognosis in patients with non-small cell lung cancer ≤3 cm after sublobectomy: a propensity score analysis.

BACKGROUND: Numerous retrospective studies have reported that sublobectomy has a poorer prognosis than lobectomy in patients with early-stage lung cancer. The purpose of this study was to determine whether adjuvant treatment could improve the prognosis of patients with non-small cell lung cancer (NSCLC) ≤3 cm after sublobectomy. METHODS: We collected data from 17,763 patients with T1N0M0 NSCLC after surgery from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Kaplan-Meier curves were generated to compare the overall survival (OS) rates and the lung cancer-specific survival (LCSS) rates. Cox proportional hazards regressions were performed to discover the independent risk factors for both the OS and LCSS rates. RESULTS: Lobectomy was performed in 12,428 cases and sublobectomy was performed in 5,335 cases. In the sublobectomy group, among the 394 patients treated with adjuvant therapy, larger tumor diameter, a lower number of lymph node dissections, and more wedge resections were observed in the patients treated with adjuvant therapy. In the subsequent survival analysis, the OS and LCSS rates of adjuvant therapy patients showed a significant survival advantage over those treated with sublobectomy alone (P<0.05). The survival analysis was performed again after propensity match scoring, generating similar results (P<0.05). There was still a significant difference in OS between adjuvant therapy and lobectomy alone (P<0.05). CONCLUSIONS: Chemoradiotherapy can improve the OS of patients with NSCLC ≤3 cm after sublobectomy and reduce death caused by tumors. Therefore, when patients cannot tolerate lobectomy or are given inappropriate sublobectomy, adjuvant therapy can improve the prognosis of patients.

Glycosylation of ß1 subunit plays a pivotal role in the toxin sensitivity and activation of BK channels

The accessory ß1 subunits, regulating the pharmacological and biophysical properties of BK channels, always undergo post-translational modifications, especially glycosylation. To date, it remains elusive whether the glycosylation contributes to the regulation of BK channels by ß1 subunits. Methods: Herein, we combined the electrophysiological approach with molecular mutations and biochemical manipulation to investigate the function roles of N-glycosylation in ß1 subunits. Results: The results show that deglycosylation of ß1 subunits through double-site mutations (ß1 N80A/N142A or ß1 N80Q/N142Q) could significantly increase the inhibitory potency of iberiotoxin, a specific BK channel blocker. The deglycosylated channels also have a different sensitivity to martentoxin, another BK channel modulator with some remarkable effects as reported before. On the contrary to enhancing effects of martentoxin on glycosylated BK channels under the presence of cytoplasmic Ca2+, deglycosylated channels were not affected by the toxin. However, the deglycosylated channels were surprisingly inhibited by martentoxin under the absence of cytoplasmic Ca2+, while the glycosylated channels were not inhibited under this same condition. In addition, wild type BK (α+ß1) channels treated with PNGase F also showed the same trend of pharmacological results to the mutants. Similar to this modulation of glycosylation on BK channel pharmacology, the deglycosylated forms of the channels were activated at a faster speed than the glycosylated ones. However, the V1/2 and slope were not changed by the glycosylation. Conclusion: The present study reveals that glycosylation is an indispensable determinant of the modulation of ß1-subunit on BK channel pharmacology and its activation. The loss of glycosylation of ß1 subunits could lead to the dysfunction of BK channel, resulting in a pathological state.(AU)

Corrigendum: Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond.

[This corrects the article DOI: 10.3389/fnins.2019.01393.].

Neuroprotective effects of lithium on a chronic MPTP mouse model of Parkinson's disease via regulation of α­synuclein methylation.

The pathological process of Parkinson's disease (PD) is closely associated with the death of nigral neurons, for which an effective treatment has yet to be found. Lithium, one of the most widely certified anticonvulsant and mood­stabilizing agents, exhibits evident neuroprotective effects in the treatment of epilepsy and bipolar disorder. In the present study, the neuroprotective mechanisms by which lithium acts on a chronic 1­methyl­4­phenyl­1,2,3,6­tetrahydropyridine (MPTP) mouse model of PD were investigated by employing animal behavioral tests, immunohistochemistry, RT­PCR, and western blotting. The results revealed that, in open field tests, lithium treatment counteracted the reduction in movement distance as well as activity time induced by MPTP administration. The compound could also prolong the drop time of MPTP­treated mice in rotarod tests. Moreover, lithium treatment corrected the loss of nigral neurons, the increase of α­synuclein (SNCA) in substantia nigra as well as in the striatum of MPTP­treated mice, and decreased the methylation of SNCA intron 1 in DNA from the same regions. Furthermore, marked changes were observed in the expression of miRNAs including miR­148a, a potential inhibitor of DNMT1, in the MPTP­treated mice. These results suggested that the early application of lithium was important for alleviating the behavioral deficits experienced in the PD model, and that the neuroprotective action of lithium was achieved through a lithium­triggered miRNA regulation mechanism. Essentially, our findings indicated that lithium may be beneficial in the prevention and treatment of PD through the regulation of α­synuclein methylation.