The role of extended synaptotagmin at membrane contact sites in cancer research.

Membrane contact sites (MCSs) are adjacent locations between the membranes of two different organelles and play important roles in various physiological processes, including cellular calcium and lipid signaling. In cancer research, MCSs have been proposed to regulate tumor metabolism and fate, contributing to tumor progression, and this function could be exploited for tumor therapy. However, there is little evidence on how MCSs are involved in cancer progression. In this review, we use extended synaptotagmins (E-Syts) as an entry point to describe how MCSs affect cancer progression and may be used as new diagnostic biomarkers. We then introduced the role of E-Syt and its related pathways in calcium and lipid signaling, aiming to explain how MCSs affect tumor proliferation, progression, metastasis, apoptosis, drug resistance, and treatment through calcium and lipid signaling. Generally, this review will facilitate the understanding of the complex contact biology of cancer cells.

Organoid drug screening report for a non-small cell lung cancer patient with EGFR gene mutation negativity: A case report and review of the literature.

Patients with non-small cell lung cancer (NSCLC) who carry epidermal growth factor receptor (EGFR) mutations can benefit significantly from EGFR tyrosine kinase inhibitors (EGFR TKIs). However, it is unclear whether patients without EGFR mutations cannot benefit from these drugs. Patient-derived tumor organoids (PDOs) are reliable in vitro tumor models that can be used in drug screening. In this paper, we report an Asian female NSCLC patient without EGFR mutation. Her tumor biopsy specimen was used to establish PDOs. The treatment effect was significantly improved by anti-tumor therapy guided by organoid drug screening.

Safety and efficacy of three enteral feeding strategies in patients with severe stroke in China (OPENS): a multicentre, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: Early enteral nutrition is crucial for preventing malnutrition and improving outcomes in patients with severe stroke, but previous trials have provided conflicting results regarding the optimal nutritional strategy. We aimed to compare the efficacy and safety of three enteral feeding strategies in patients with severe stroke. METHODS: The Optimizing Early Enteral Nutrition in Severe Stroke (OPENS) study was a multicentre, investigator-initiated, prospective, open-label, randomised controlled trial, with blinded outcome assessment, in 16 tertiary and district general hospitals in the west of China. Adult patients with acute severe ischaemic or haemorrhagic stroke (Glasgow Coma Scale score ≤12 or National Institutes of Health Stroke Scale score ≥11 on admission) who were expected to receive enteral nutrition for more than 7 days were randomly assigned (1:1:1) to full enteral nutrition (70-100% of estimated caloric requirements), modified full enteral nutrition (full enteral nutrition plus prokinetic agents), or hypocaloric enteral nutrition (40-60% of estimated caloric requirements) via a centralised web-based randomisation system. The assigned nutrition was initiated within 24 h after enrolment and continued for 7 days. The computer-generated randomisation sequence was prepared by a statistician not involved with the rest of the study. Randomisation was done with an automated permuted block size of six. The allocation was unblinded to participants and investigators. The primary efficacy outcome was the proportion of participants with poor outcome (modified Rankin Scale score ≥3) at day 90 and the prespecified primary safety outcome was mortality at day 90, assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02982668. FINDINGS: Between Jan 15, 2017, and Sept 23, 2020, 321 patients were randomly assigned (107 in each group) and 315 patients (175 [56%] men, median age 71 years, IQR 60-78) were included in the final analysis. The study was terminated ahead of schedule on Sept 23, 2020, because a significant difference between groups was detected in mortality. The proportion of participants with poor outcomes at 90 days did not differ (modified full enteral nutrition 86 [82%] of 105 patients vs full enteral nutrition 85 [80%] of 106 patients, adjusted odds ratio [OR] 0·87, 95% CI 0·41-1·86, p=0·721; hypocaloric enteral nutrition 76 [73%] of 104 patients vs full enteral nutrition 0·61, 0·30-1·27, p=0·186; hypocaloric enteral nutrition vs modified full enteral nutrition 0·70, 0·34-1·46, p=0·340). Hypocaloric enteral nutrition showed significantly higher 90-day mortality than did modified full enteral nutrition (35 [34%] of 104 patients vs 18 [17%] of 105 patients, adjusted OR 2·89, 95% CI 1·46-5·72; p=0·0023), whereas the difference was not significant between hypocaloric enteral nutrition and full enteral nutrition (24 [23%] of 106 patients; adjusted OR 1·92, 95% CI 1·00-3·69; p=0·049), and between modified full enteral nutrition and full enteral nutrition (adjusted OR 0·61, 0·29-1·28; p=0·187). The most common adverse event was pneumonia, the incidence of which showed no significant difference among groups (full enteral nutrition 82 [78%] of 105 patients, modified full enteral nutrition 83 [81%] of 103 patients, hypocaloric enteral nutrition 78 [75%] of 104 patients; p=0·625). INTERPRETATION: In the early phase of severe stroke, modified full enteral nutrition or hypocaloric enteral nutrition did not significantly reduce the risk of a poor outcomes compared with full enteral nutrition over a 90-day period. Hypocaloric enteral nutrition might be associated with increased mortality compared with modified full enteral nutrition. Further studies are needed to investigate whether modified full enteral nutrition might be the optimal strategy. FUNDING: Shaanxi province Key Research and Development Project.

The application analysis of 8F ultrafine chest drainage tube for thoracoscopic lobectomy of lung cancer.

BACKGROUND: Currently, thoracoscopic lobectomy is widely used in clinical practice, and postoperative placement of ultrafine drainage tube has advantages of reducing postoperative pain and accelerating postoperative recovery in patients. This study aimed to investigate the feasibility and safety of placement of 8F ultrafine chest drainage tube after thoracoscopic lobectomy and its superiority over traditional 24F chest drainage tube. METHODS: A retrospective data analysis was conducted in 169 patients who underwent placement of 8F ultrafine chest drainage tube or 24F chest drainage tube with thoracoscopic lobectomy for lung cancer from January 2018 to December 2019. Propensity score matching (PSM) was used to reduce bias between the experimental group and the control group. After PSM, 134 patients (67 per group) were enrolled. The drainage time, the total drainage volume, postoperative hospital stay, postoperative pain score and postoperative complication of both groups were analyzed and compared. RESULTS: Compared to group B, group A had lower pain scores on postoperative days 1, 2 and 3 (3.72 ± 0.65point vs 3.94 ± 0.67point, P = 0.027; 2.72 ± 0.93point vs 3.13 ± 1.04point, P = 0.016; and 1.87 ± 0.65point vs 2.39 ± 1.22point, P = 0.005), shorter drainage time (4.25 ± 1.79d vs 6.04 ± 1.96d, P = 0.000), fewer drainage volume (1100.42 ± 701.57 ml vs 1369.39 ± 624.25 ml, P = 0.021); and shorter postoperative hospital stay (8.46 ± 2.48d vs 9.37 ± 1.70d, P = 0.014). Postoperative complications such as subcutaneous emphysema, pulmonary infection, atelectasis, chest tube reinsertion and intrathoracic hemorrhage showed no differences between both groups (P > 0.05). CONCLUSION: Compared with 24F chest drainage tube, the application of an 8F ultrafine chest drainage tube after thoracoscopic lobectomy has significantly shortened the drainage time, reduced the total drainage volume, reduced the postoperative pain degree, shortened the hospital day, and effectively detected postoperative intrathoracic hemorrhage. So, it is considered as an effective, safe and reliable drainage method.

Treatment of intrathoracic anastomotic leak after esophagectomy with the sump drainage tube.

BACKGROUND: Intrathoracic esophagogastric anastomotic leak is one of the deadliest complications after esophagectomy. In recent years, we have implemented new method for the treatment of intrathoracic esophagogastric anastomotic leak with the nasogastric placement of sump drainage tube through fistula into abscess cavity. The aim of this study is to compare the efficacy of the new method and conventional therapies for intrathoracic anastomotic leak after esophagectomy. METHOD: Esophagectomy and esophagogastric anastomotic procedures were performed in 875 patients at our institution from January 2008 to December 2019. Of these patients, 43(4.9%) patients developed intrathoracic anastomotic leaks postoperatively were enrolled into our study and their clinical data were retrospectively assessed. 20 (47%) patients from January 2008 to December 2012 received conventional treatments (group 1) known as the traditional "three-tube method", and 23 (53%) patients from January 2013 to December 2019 received new treatments (group 2), consisted of conventional therapies and the nasogastric placement of sump drainage tube through fistula into abscess cavity. RESULTS: The presence of intrathoracic anastomotic leak was proven by contrast esophagography in 43 patients (4.9%). Among them, The average duration of chest tube was 47 days in group 1 and 28 days in group 2. The average length of leak treatment was 52 days in group 1 and 35 days in group 2. The average length of postoperative hospital stay was 56 days in group 1 and 39 days in group 2, respectively. 7(35%) patients among 20 patients died from intrathoracic anastomotic leak in group 1; and 3(13%) patients among 23 patients died from intrathoracic anastomotic leak in group 2. Compared with the conventional treatments (group 1), The average duration of chest tube was significantly decreased in the new treatments (group 2) (P < 0.01), as well as the length of leak treatment (P < 0.05) and the length of postoperative hospital stay (P < 0.01). However, there was no significant difference in the mortality rate (P = 0.148 > 0.05). CONCLUSION: In conclusion, Our results showed this method of the nasogastric placement of sump drainage tube through fistula appears to be an safe, effective, technically feasible treatment option for intrathoracic esophagogastric anastomotic leak. The efficacy and feasibility could be further investigated with a well-designed and large-scale RCT research.

Long non-coding RNA SPRY4-IT1 as a promising indicator for three field lymph-node dissection of thoracic esophageal carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma(ESCC) is one of the most common tumors worldwide. Esophagectomy with three-field lymph node dissection(3FLND) is the radical surgical procedure for esophageal cancer. However, 3FLND is not widely used due to it's higher mortality rate and higher incidence of postoperative complications. There is an urgent need to identify novel biomarkers that can guide the most proper lymph-node dissection in esophageal cancer patients. METHOD: Ninety-two patients with thoracic ESCC undergoing 3FLND were enrolled into our study from the Department of Thoracic Surgery of the Fourth Hospital affiliated to the Hebei Medical University and Hebei General Hospital between Jun 2011 and Dec 2015. Retrospectively collected data from these 92 patients was used to explore the relationship between the lymph-node metastasis、recurrence and the SPRY4-IT1 expression level and to determine whether 3FLND should be performed in patients with thoracic ESCC. RESULTS: The findings revealed that the SPRY4-IT1 expression was significantly higher in esophageal cancer tissues than in adjacent noncancerous tissues. (P < 0.01). Furthermore, the high expression of SPRY4-IT1 was significantly correlated with tumor differentiation (P = 0.029), T classification (P = 0.013), lymph node metastasis(P = 0.022) and pathological stage (P = 0.001). The increased expression of SPRY4-IT1 was associated with a higher risk of cervical and superior mediastinal lymph-node metastasis(P = 0.039).However, no significant association was observed between the risk of cervical and superior mediastinal lymph-node recurrence and the SPRY4-IT1 expression level in the thoracic ESCC patients performed 3FLND(P = 0.509). CONCLUSIONS: Our data support the assumption that the high expression of SPRY4-IT1 is associated with a high risk of lymph node metastasis and it has potential application as a indicator for guiding on three-field lymph node dissection in patients with thoracic ESCC. Randomized controlled trials with a large cohort of patients will be needed to confirm this conclusion in the future.

Clinical application and observation of single-port inflatable mediastinoscopy combined with laparoscopy for radical esophagectomy in esophageal squamous cell carcinoma.

BACKGROUND: Transthoracic esophagectomy is a crucial independent risk factor for the incidence of postoperative cardiopulmonary complications in elderly or comorbid patients. To reduce postoperative cardiopulmonary complications and promote postoperative recovery. We made an attempt to adopt the single-port inflatable mediastinoscopy combined with laparoscopy for radical esophagectomy in esophageal cancer to observe the clinical application and effect. METHOD: Data of patients with esophageal carcinoma were collected in the Hebei General Hospital from May 2018 to November 2019. The operation time, surgical blood loss, the number of dissected lymph nodes, duration of drainage tube, duration of time on the ventilator, the length of stay in ICU, postoperative complications, the length of postoperative hospital stay were collected to assess the safety and feasibility of the single-port inflatable mediastinoscopy combined with laparoscopy for radical esophagectomy in esophageal cancer. RESULTS: A total of 22 patients with esophageal cancer were analyzed in our research. There were no cases of conversion to thoracotomy、perioperative death or postoperative cardiopulmonary complications. The average operation time of all enrolled patients was 4.26 ± 0.52 h、The surgical blood loss was 142 ± 36.50 ml、The amount of dissected lymph nodes were 21.6 ± 4.2、The duration of drainage tube was 5.8 ± 2.5 days、The duration of time on the ventilator was 6.5 ± 3.4 h、The length of stay in ICU was 1.2 ± 0.4 days、The postoperative hospital stay was 12.6 ± 2.5 days. Among all the enrolled patients, one patient (4.5%) developed anastomotic fistula on the third day after surgery. Anastomotic stricture was found in 5 patients (22.7%). Pleural effusion was found in 4 cases (18.2%). Recurrent laryngeal nerve injury caused hoarseness or cough after drinking water in 3 cases (13.6%).There was one patient (4.5%) of conversion to laparotomy as the patient had serious peritoneal adhesion. All of the patients were discharged successfully. CONCLUSION: Our results showed that this surgery of single-port inflatable mediastinoscopy combined with laparoscopy for radical esophagectomy in esophageal squamous cell carcinoma is safe and feasible. The feasibility and safety could be further and better investigated with a RCT to achieve more conclusive results.

miR-181b inhibits chemoresistance in cisplatin-resistant H446 small cell lung cancer cells by targeting Bcl-2.

INTRODUCTION: MicroRNAs (miRNAs) are a group of small non-coding RNAs that affect multiple aspects of tumor biology including chemo resistance. miR-181b has been reported to modulate multidrug resistance in non-small cell lung cancer cells. This study was undertaken to determine the role of miR-181b in chemo resistance of small cell lung cancer cells. MATERIAL AND METHODS: This study was undertaken to determine the role of miR-181b in chemoresistance of small cell lung cancer cells with use of qRt-PCR, WB, bioinformatics analysis, and double luciferase reporter system. RESULTS: Our data showed that miR-181b was significantly downregulated in cisplatin-resistant H446 small cell lung cancer cells, compared to parental cells, compared to parental cells. Ectopic expression of miR-181b inhibited cell proliferation and invasion in cisplatin-resistant H446 cells (p = 0.023). Moreover, overexpression of miR-181b increased the susceptibility of cisplatin-resistant H446 cells to cisplatin. Mechanistic investigations demonstrated that miR-181b inhibited B-cell lymphoma-2 (Bcl-2) expression by binding to the 3'-untranslated region. Overexpression of Bcl-2 reversed miR-181b-mediated chemo sensitization, which is accompanied by a reduced apoptotic response. CONCLUSIONS: Taken together, this work demonstrated that miR-181b might have the ability to overcome chemo resistance of small cell lung cancer cells, and restoration of this miRNA may represent a potential therapeutic strategy for improving chemo sensitivity in small cell lung cancer.

Effectiveness and safety of valsartan/amlodipine in hypertensive patients with stroke: China Status II subanalysis.

High blood pressure (BP) is a major risk factor associated with stroke in China. This is a subanalysis of patients from the China Status II study, aimed to evaluate the effectiveness and safety of valsartan/amlodipine (Val/Aml) single-pill combination (SPC) in hypertensive patients with different stroke subtypes (hemorrhagic, ischemic, or mixed).China Status II was a multicenter, postmarketing, prospective observational study in hypertensive patients uncontrolled on monotherapy. The study was an 8-week open-label treatment period with 2 4-week follow-ups. Change in BP from baseline to weeks 4 and 8, BP control rate, and response rate at weeks 4 and 8, and safety of 8-week treatment with Val/Aml (80/5 mg) were assessed.A total of 565 hypertensive patients with different types of stroke were analyzed in this China Status II substudy. Significant mean sitting systolic/diastolic BP (MSSBP/MSDBP) reductions from baseline to week 8 were observed across all stroke subtypes (P < .0001). At week 8, percentages of patients achieving MSSBP response (≥20 mm Hg reduction from baseline) were 76.3%, 74.4%, and 85.7%, MSDBP response (≥10 mm Hg reduction from baseline) were 67.8%, 65.9%, and 64.3%, and BP control (<140/90 mm Hg) were 74.6%, 80.5%, and 92.9%, in the hemorrhagic, ischemic, and mixed stroke subgroups, respectively. Adverse events (AEs) and serious AEs were reported in 5 patients (1%) and 1 patient (0.2%), respectively, in the ischemic stroke subgroup, while no AEs were reported in hemorrhagic and mixed stroke subgroups.Val/Aml SPC was effective in hypertensive patients with different stroke subtypes and was well tolerated.

Synthesis and Cytotoxicity of N-Substituted Dibenzo[a,j]xanthene-3,11-dicarboxamide Derivatives.

In order to study the structure-activity relationships of xanthene derivatives, four series of N-substituted 14-aryl-14H-dibenzo[a,j]xanthene-3,11-dicarboxamide derivatives were synthesized. The structures of all compounds were identified by ¹H-NMR, HR-MS and IR spectra, in which compounds 6a-h were further identified by 13C-NMR spectra. The in vitro antitumor activity of the synthesized compounds was tested by MTT assay. Most of them displayed strong inhibitory activity on human hepatocellular carcinoma cell lines (SK-HEP-1, HepG2 and SMMC-7721 cells) and acute promyelocytic leukemia NB4 cells. Compounds 6c-6e exhibited significant inhibitory activity against NB4 cells with IC50 values of 0.52 µM and 0.76 µM, respectively, much lower than 5.31 µM of the positive control As2O3.

A "signal on" protection-displacement-hybridization-based electrochemical hepatitis B virus gene sequence sensor with high sensitivity and peculiar adjustable specificity.

One "signal on" electrochemical sensing strategy was constructed for the detection of a specific hepatitis B virus (HBV) gene sequence based on the protection-displacement-hybridization-based (PDHB) signaling mechanism. This sensing system is composed of three probes, one capturing probe (CP) and one assistant probe (AP) which are co-immobilized on the Au electrode surface, and one 3-methylene blue (MB) modified signaling probe (SP) free in the detection solution. One duplex are formed between AP and SP with the target, a specific HBV gene sequence, hybridizing with CP. This structure can drive the MB labels close to the electrode surface, thereby producing a large detection current. Two electrochemical testing techniques, alternating current voltammetry (ACV) and cyclic voltammetry (CV), were used for characterizing the sensor. Under the optimized conditions, the proposed sensor exhibits a high sensitivity with the detection limit of ∼5fM for the target. When used for the discrimination of point mutation, the sensor also features an outstanding ability and its peculiar high adjustability.

Optimized total thoracoscopic and laparoscopic esophagectomy for esophageal cancer.

BACKGROUND: Total thoracoscopic and laparoscopic esophagectomy (TLE) has attracted attention with the advantage of better operative field and minimal wound for the esophageal cancer. However, various severe complications are also reported during the TLE such as cervical anastomotic leakage, chylothorax, and tracheal injury. The aim of this study was to introduce a new optimized TLE procedure for the esophageal cancer and assess its safety and clinical effects. METHODS: We retrospectively collected the clinical data of 30 patients with esophageal cancer who underwent optimized TLE procedures between January 2014 and December 2014. The optimized TLE procedures mainly include as follows: (1) 50 ml of sesame oil-milk mixture (1:1) is injected via gastric tube after endotracheal intubation; (2) patients are intubated with a single lumen endotracheal tube; (3) patients were positioned at 150° in the left prone position rather than lateral decubitus position; and (4) duodenal feeding tube was not placed intraoperatively and however triple lumen nasojejunal feeding tube was placed on the second postoperative day under imaging guidance. Operation time, amount of blood loss, number of dissected nodes, length of hospital stays, and complications were recorded. RESULTS: The mean operation time of the optimized TLE group was 202.13 ± 13.74 min. The mean visible blood loss of the optimized TLE group was 300.00 ± 120.12 ml. The postoperative hospital stays in the optimized TLE group were 16.27 ± 4.51 days. The number of dissected nodes in the optimized TLE group was 13.57 ± 2.76. The postoperative complications for the optimized TLE procedure were seen in one case (3.3%). CONCLUSIONS: The method of optimized TLE is an effective, reliable, and safe procedure for the treatment of esophageal cancer, which provide favorable outcomes in terms of operation time, blood loss, length of hospital stays, the number the dissected nodes, and reduced incidence of postoperative complications compared to previous literatures. Further studies with a large number of samples are warranted.

[Clinical observation of the γ-globulin levels when Benign paroxysmal positional vertigo is attacking].

OBJECTIVE: To observe the characteristics of serum protein in patients with benign paroxysmal positional vertigo (BPPV) during the symptomatic period. METHOD: Fifty-five patients with BPPV and 58 control subjects were enrolled in the study. All the patients underwent the Dixe-Hallpike and Roll maneuver to confirm the type of BPPV. The average time of onset was (1.0 ± 0.8)days in the group of BPPV. The clinical features and the laboratory tests of serum protein electrophoresis, blood counts, and liver and kidney function were performed in both groups. RESULT: The levels of serum albumin (Alb), α1 globulin, α2 globulin and ß globulin of BPPV group did not differ statistically in the two groups (P > 0.05); The γ-globulin levels were significantly higher in patients with BPPV than in controls (P < 0.05). CONCLUSION: The γ-globulin levels are increased when BPPV is attacking.

Using the synergism strategy for highly sensitive and specific electrochemical sensing of Streptococcus pneumoniae Lyt-1 gene sequence.

With the help of the interaction mode of capture probe-target-signal probe (CP-T-SP), an electrochemical sensing method based on the synergism strategy of dual-hybridized signaling probes modified with 6 MB (methylene blue), background suppression and large surface area Au electrode is developed for the detection of Streptococcus pneumoniae (S. pneumoniae) Lyt-1 gene sequence. The proposed sensor features a very low detection limit (LOD) of ∼0.5 fM for the target. This method also exhibits highly versatility and can apply to the construction of other sensors for the analysis of similar designated pathogenic bacteria gene sequence (PBGS).

Design, synthesis and anticancer activity of N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide.

A series of novel N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide, three N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthene-3,11-dimethanamine derivatives and their intermediates 14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxylic acid, were synthesized, and the structures of which were characterized by (1)H-NMR, (13)C-NMR, high resolution (HR)-MS, and IR spectra. The antitumor activities of these molecules were evaluated on five cancer cell lines. The results of in vitro assay against human hepatocellular carcinoma cell lines (SK-HEP-1 and HepG2 and SMMC-7721 cells), acute promyelocytic leukemia NB4 cells and uterine cervix cancer HeLa cells, show several compounds to be endowed with cytotoxicity in micromolar to submicromolar range. The carboxamide derivatives 6c and 6e exhibitted good inhibition on NB4 cancer cells, and the IC(50) values of which were 0.82 µM and 0.96 µM, respectively, much lower than 5.01 µM of the positive control As(2)O(3). Flow cytometric analysis results revealed that compounds 6e and 6f may induce tumor cell apoptosis.