Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method.

N-Hydroxyapiosporamide (N-hydap), a marine product derived from a sponge-associated fungus, has shown promising inhibitory effects on small cell lung cancer (SCLC). However, there is limited understanding of its metabolic pathways and characteristics. This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs), as well as human/rat/mice microsomes, and also the pharmacokinetic properties by HPLC-MS/MS. Additionally, the cocktail probe method was used to investigate the potential to create drug-drug interactions (DDIs). N-Hydap was metabolically unstable in various microsomes after 1 h, with about 50% and 70% of it being eliminated by CYPs and UGTs, respectively. UGT1A3 was the main enzyme involved in glucuronidation (over 80%), making glucuronide the primary metabolite. Despite low bioavailability (0.024%), N-hydap exhibited a higher distribution in the lungs (26.26%), accounting for its efficacy against SCLC. Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity. Furthermore, N-hydap was found to affect the catalytic activity of drug metabolic enzymes (DMEs), particularly increasing the activity of UGT1A3, suggesting potential for DDIs. Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy, toxicity, and potential for DDIs.

[Comparative study of orthopaedic robot-assisted minimally invasive surgery and open surgery for limb osteoid osteoma].

Objective: To compare the accuracy and effectiveness of orthopaedic robot-assisted minimally invasive surgery versus open surgery for limb osteoid osteoma. Methods: A clinical data of 36 patients with limb osteoid osteomas admitted between June 2016 and June 2023 was retrospectively analyzed. Among them, 16 patients underwent orthopaedic robot-assisted minimally invasive surgery (robot-assisted surgery group), and 20 patients underwent tumor resection after lotcated by C-arm X-ray fluoroscopy (open surgery group). There was no significant difference between the two groups in the gender, age, lesion site, tumor nidus diameter, and preoperative pain visual analogue scale (VAS) scores ( P>0.05). The operation time, lesion resection time, intraoperative blood loss, intraoperative fluoroscopy frequency, lesion resection accuracy, and postoperative analgesic use frequency were recorded and compared between the two groups. The VAS scores for pain severity were compared preoperatively and at 3 days and 3 months postoperatively. Results: Compared with the open surgery group, the robot-assisted surgery group had a longer operation time, less intraoperative blood loss, less fluoroscopy frequency, less postoperative analgesic use frequency, and higher lesion resection accuracy ( P<0.05). There was no significant difference in lesion resection time ( P>0.05). All patients were followed up after surgery, with a follow-up period of 3-24 months (median, 12 months) in the two groups. No postoperative complication such as wound infection or fracture occurred in either group during follow-up. No tumor recurrence was observed during follow-up. The VAS scores significantly improved in both groups at 3 days and 3 months after surgery when compared with preoperative value ( P<0.05). The VAS score at 3 days after surgery was significantly lower in robot-assisted surgery group than that in open surgery group ( P<0.05). However, there was no significant difference in VAS scores at 3 months between the two groups ( P>0.05). Conclusion: Compared with open surgery, robot-assisted resection of limb osteoid osteomas has longer operation time, but the accuracy of lesion resection improve, intraoperative blood loss reduce, and early postoperative pain is lighter. It has the advantages of precision and minimally invasive surgery.

[Effectiveness of robot-guided percutaneous fixation and decompression via small incision for advanced thoracolumbar metastases].

Objective: To evaluate the effectiveness of robot-guided percutaneous fixation and decompression via small incision in treatment of advanced thoracolumbar metastases. Methods: A clinical data of 57 patients with advanced thoracolumbar metastases admitted between June 2017 and January 2021 and met the selection criteria was retrospectively analyzed. Among them, 26 cases were treated with robot-guided percutaneous fixation and decompression via small incision (robot-guided group) and 31 cases with traditional open surgery (traditional group). There was no significant difference in gender, age, body mass index, lesion segment, primary tumor site, and preoperative Tokuhashi score, Tomita score, Spinal Instability Neoplastic Score (SINS), visual analogue scale (VAS) score, Oswestry disability index (ODI), Karnofsky score, and Frankel grading between groups ( P>0.05). The operation time, hospital stays, hospital expenses, intraoperative blood loss, postoperative drainage volume, duration of intensive care unit (ICU) stay, blood transfusion, complications, and survival time were compared. The pedicle screw placement accuracy was evaluated according to the Gertzbein-Robbins grading by CT within 4 days after operation. The pain, function, and quality of life were evaluated by VAS score, ODI, Karnofsky score, and Frankel grading. Results: During operation, 257 and 316 screws were implanted in the robot-guided group and the traditional group, respectively; and there was no significant difference in pedicle screw placement accuracy between groups ( P>0.05). Compared with the traditional group, the operation time, hospital stays, duration of ICU stay were significantly shorter, and intraoperative blood loss and postoperative drainage volume were significantly lesser in the robot-guided group ( P<0.05). There was no significant difference in hospital expenses, blood transfusion rate, and complications between groups ( P>0.05). All patients were followed up 8-32 months (mean, 14 months). There was no significant difference in VAS scores between groups at 7 days after operation ( P>0.05), but the robot-guided group was superior to the traditional group at 1 and 3 months after operation ( P<0.05). The postoperative ODI change was significantly better in the robot-guided group than in the traditional group ( P<0.05), and there was no significant difference in the postoperative Karnofsky score change and Frankel grading change when compared to the traditional group ( P>0.05). Median overall survival time was 13 months [95% CI (10.858, 15.142) months] in the robot-guided group and 15 months [95% CI (13.349, 16.651) months] in the traditional group, with no significant difference between groups ( χ 2=0.561, P=0.454) . Conclusion: Compared with traditional open surgery, the robot-guided percutaneous fixation and decompression via small incision can reduce operation time, hospital stays, intraoperative blood loss, blood transfusion, and complications in treatment of advanced thoracolumbar metastases.

Microstructure Study of High-Rank Coal in an Alkaline Solution at the Chengzhuang Mine.

To study the adsorption performance of coal bodies after alkaline solution erosion and the microscopic mechanism of alkali erosion on coal bodies, isothermal adsorption experiments at different pH values and with different numbers of soaking days were conducted on high-order coal bodies from the Chengzhuang mine. The results showed that the adsorption capacity of the coal bodies after alkali leaching was improved compared to that of the original coal, all of which was in accordance with the Langmuir equation. The unit adsorption capacity of coal samples increased gradually with an increase in the number of soaking days and solution pH, reaching the maximum at pH 13 and eight soaking days. The adsorption constant a of the coal sample was positively correlated with the pH, and the number of soaking days was a power exponential function; the adsorption constant b increased gradually with an increase in the pH of the solution and increased first and then decreased with an increase in the number of soaking days. The change in the adsorption of coal samples occurs because the alkaline solution reacts with the minerals in the coal as well as the mineral ions, and the resulting complex gels and precipitates block the pore channels of the coal body, which in turn inhibits the adsorption of gases. The presence of Na, Mg, Al, Si, Ca, Fe, and other elemental compounds detected in the generated sediments verified the mechanism of alkaline solution erosion. The changes in the microscopic pore structure of the coal body were quantified by low-temperature liquid nitrogen adsorption experiments. The small and medium pore volumes of the coal samples reached the maximum values at pH 13 and with eight soaking days, which is in agreement with the conclusion of optimal alkali modification.

The gene spectrum of thalassemia in Yangjiang of western Guangdong Province.

Background: Thalassemia presents a higher incidence in southern China. The objective of this study is to analyze the genotype distribution of thalassemia in Yangjiang, a western city of Guangdong Province in China. Methods: The genotypes of suspected cases with thalassemia were tested by PCR and reverse dot blot (RDB). Unidentified rare thalassemia genotypes of the samples were further ascertained by PCR and direct DNA sequencing. Results: Among 22467 suspected cases with thalassemia, 7658 cases were found with thalassemia genotypes using our PCR-RDB kit. Among these 7658 cases, 5313 cases were found with α-thalassemia (α-thal) alone, --SEA/αα was the most common genotype, accounting for 61.75% of α-thal genotypes, and the following mutations were found: α3.7/αα, -α4.2/αα, αCSα/αα, αWSα/αα, and αQSα/αα. A total of 2032 cases were found with ß-thalassemia (ß-thal) alone. ßCD41-42/ßN, ßIVS-II-654/ßN, and ß-28/ßN accounted for 80.9% of all ß-thal genotypes, and the following genotypes were found: ßCD17/ßN, ßCD71-72/ßN, and ßE/ßN. Compound heterozygotes of ß-thal and ß-thalassemia homozygotes were identified in 11 and five cases, respectively, in this study. α-thal combined with ß-thal was identified in 313 cases, showing 57 genotype combinations of the coincidence of both Hb disorders; one extreme patient had a genotype of --SEA/αWSα and ßCD41-42/ß-28. In addition, four rare α-mutations (--THAI, HKαα, Hb Q-Thailand, and CD31 AGG>AAG) and six rare ß-mutations (CD39 CAG>TAG, IVS-Ⅱ-2 (-T), -90(C>T), Chinese Gγ+(Aγδß)0, CD104 (-G), and CD19 A>G) were also found in this study population. Conclusion: This study provided detailed genotypes of thalassemia in Yangjiang of western Guangdong Province in China and reflected the complexity of genotypes in this high-prevalence region, and this would be valuable for diagnosis and counseling for thalassemia in this area.

Restoration of lipid homeostasis between TG and PE by the LXRα-ATGL/EPT1 axis ameliorates hepatosteatosis.

Converting lipid disturbances in response to energy oversupply into healthy lipid homeostasis is a promising therapy to alleviate hepatosteatosis. Our clinical studies found that a further elevation of triglyceride (TG) in obese patients with the body mass index (BMI) greater than 28 was accompanied by a further reduction of phosphatidylethanolamine (PE). Shorter survival and poor prognosis were shown for the patients with high TG and low PE levels. Liver X receptor alpha (LXRα) knockout mice aggravated high-fat diet (HFD)-induced obesity and lipid disorders, making the TG enrichment and the PE decrease more pronounced according to the liver lipidomics analysis. The RNA-seq from mice liver exhibited that these metabolism disorders were attributed to the decline of Atgl (encoding the TG metabolism enzyme ATGL) and Ept1 (encoding the PE synthesis enzyme EPT1) expression. Mechanistic studies uncovered that LXRα activated the ATGL and EPT1 gene via direct binding to a LXR response element (LXRE) in the promoter. Moreover, both the supplement of PE in statin or fibrate therapy, and the LXRα inducer (oridonin) ameliorated cellular lipid deposition and lipotoxicity. Altogether, restoration of lipid homeostasis of TG and PE via the LXRα-ATGL/EPT1 axis may be a potential approach for the management of hepatosteatosis and metabolic syndrome.

TiRobot-assisted percutaneous kyphoplasty in the management of multilevel (more than three levels) osteoporotic vertebral compression fracture.

PURPOSE: To compare the effectiveness of TiRobot-assisted kyphoplasty with that of the traditional fluoroscopy-assisted approach in treating multilevel osteoporotic vertebral compression fractures. METHODS: In this retrospective study, we collected data from 71 patients (TiRobot-assisted group, n = 39; fluoroscopy-assisted group, n = 32) with multilevel osteoporotic vertebral compression fracture treated with unilateral traditional TiRobot-assisted or fluoroscopy-assisted percutaneous kyphoplasty. The operative time, infusion volume, length of stay (LOS), hospital expenses, visual analog scale (VAS), Oswestry Disability Index (ODI), radiation exposure, puncture deviation, anterior height of diseased vertebrae, local kyphotic angle, bone cement distribution, and bone cement leakage were compared between the TiRobot- and fluoroscopy-assisted groups. RESULTS: Of the 257 treated vertebrae, the average amount of bone cement injected in the TiRobot-assisted (142 vertebrae) and fluoroscopy-assisted (115 vertebrae) groups was 4.6 mL and 4.5 mL, respectively. The VAS score was significantly lower in the TiRobot-assisted group at 24 hours post-operatively (p = 0.006). The X-ray frequency was 34.7 times in the TiRobot-assisted group and 51.7 times in the fluoroscopy-assisted group (p < 0.001). In addition to the operative time, cumulative radiation dose for the surgeon and patient was significantly lower in the TiRobot-assisted group. The hospital expenses of the TiRobot-assisted group were significantly higher (p < 0.001). The puncture deviation and bone cement distribution were better in the TiRobot-assisted group (p < 0.001). Bone cement leakage was found in 18 and 29 cases in the TiRobot- and fluoroscopy-assisted groups, respectively (p = 0.010). One patient in the fluoroscopy-assisted group experienced radiculopathy due to a misplaced puncture but recovered in three months. No radiculopathy was observed in the TiRobot-assisted group. CONCLUSIONS: TiRobot-assisted percutaneous multilevel kyphoplasty is more accurate and has smaller radiometry, a more uniform bone cement distribution, and lower bone cement leakage. This method was therefore accurate and safe.

Oridonin restores hepatic lipid homeostasis in an LXRα-ATGL/EPT1 axis-dependent manner.

Hepatosteatosis is characterized by abnormal accumulation of triglycerides (TG), leading to prolonged and chronic inflammatory infiltration. To date, there is still a lack of effective and economical therapies for hepatosteatosis. Oridonin (ORI) is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens. In this paper, we showed that ORI exerted significant protective effects against hepatic steatosis, inflammation and fibrosis, which was dependent on LXRα signaling. It is reported that LXRα regulated lipid homeostasis between triglyceride (TG) and phosphatidylethanolamine (PE) by promoting ATGL and EPT1 expression. Therefore, we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRα-dependent manner, and the results showed the TG reduction and PE elevation. In detail, hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATGL and EPT1 genes, respectively. Taken together, the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRα-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.

Ketamine impairs growth cone and synaptogenesis in human GABAergic projection neurons via GSK-3ß and HDAC6 signaling.

The growth cone guides the axon or dendrite of striatal GABAergic projection neurons that protrude into the midbrain and cortex and form complex neuronal circuits and synaptic networks in a developing brain, aberrant projections and synaptic connections in the striatum related to multiple brain disorders. Previously, we showed that ketamine, an anesthetic, reduced dendritic growth, dendritic branches, and spine density in human striatal GABAergic neurons. However, whether ketamine affects the growth cone, the synaptic connection of growing striatal GABAergic neurons has not been tested. Using human GABAergic projection neurons derived from human inducible pluripotent stem cells (hiPSCs) and embryonic stem cells (ES) in vitro, we tested ketamine effects on the growth cones and synapses in developing GABAergic neurons by assessing the morphometry and the glycogen synthase kinase-3 (GSK-3) and histone deacetylase 6 (HDAC6) pathway. Ketamine exposure impairs growth cone formation, synaptogenesis, dendritic development, and maturation via ketamine-mediated activation of GSK-3 pathways and inhibiting HDAC6, an essential stabilizing protein for dendritic morphogenesis and synapse maturation. Our findings identified a novel ketamine neurotoxic pathway that depends on GSK-3ß and HDAC6 signaling, suggesting that microtubule acetylation is a potential target for reducing ketamine's toxic effect on GABAergic projection neuronal development.

Efficacy and Safety of Apatinib plus Neoadjuvant Chemotherapy for Locally Advanced Esophageal Squamous Cancer: A Phase II Trial.

Evidence for neoadjuvant chemotherapy combined with targeted therapy for locally advanced esophageal squamous cancer (ESCC) is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of apatinib combined with taxol and cisplatin (ATP) for locally advanced ESCC. All patients were cT3-4aN0-3 M0 (IIIb-IVa) stage, which were confirmed by histopathology. Apatinib was taken orally (425 mg/d) for two cycles, followed by one cycle of rest. Taxol was administered at 135 mg/m2 intravenously on day 1, and cisplatin was administered at 20 mg/m2 intravenously on day 1 to day 3. Radical ESCC resection was performed 4 weeks after ATP. The primary endpoint was pathological response rate (pCR). Secondary endpoints were pathologic response rate (MPR), disease-free survival (DFS), overall survival (OS), R0 resection rate, and safety profile. This trial was registered. We evaluated 41 patients for screening from Oct 2018 to July 2020, of whom 39 were enrolled in the study, with a median age of 65 years (range 49-75 years), and 29 (74.4%) were male. Among the 39 patients, 1 was considered unresectable by the multidisciplinary team due to tumor progression, and 38 patients underwent surgery eventually. The median follow-up was 22 months (range 5-29 months), and the follow-up rate was 100%. The 1-year and 2-year OS was 95% and 95%, and the 1-year and 2-year DFS was 85% and 82%, respectively. Thirty-eight (97.3%) successfully underwent R0 resection. Of the 38 evaluable patients, 9 (23.6%) were pCR, and 15 (39.5%) were MPR. The most common ATP-related AEs were nausea (76.9%), leucopenia (53.8%), neutropenia (51.2%) and vomit (51.2%), anemia (41.0%), and hypertension (25.6%). The most frequent grade 3-4 events included leucopenia (15.3%), neutropenia (15.3%), nausea (12.8%), vomit (12.8%), and hypertension (10.2%). No treatment-related death occurred. Neoadjuvant apatinib combined with taxol and cisplatin for locally advanced ESCC showed favorable activity and manageable safety.

Efficacy of vertebral augmentation in the treatment of osteoporotic vertebral compression fractures: a systematic review and meta-analysis.

BACKGROUND: Percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) are common vertebral augmentation (VA) procedures for the treatment of osteoporotic vertebral compression fractures (OVCF), each with their own advantages and disadvantages. In recent years, the development of new implant-assisted technologies has provided a breakthrough in VA. This study systematically evaluated and meta-analyzed the reports on new implant-assisted VA techniques in recent years, so as to provide evidence for clinical diagnosis and treatment. METHODS: The PubMed, Embase, Ovid, and SpringerLink databases were searched for randomized controlled studies on VA in the treatment of OVCF. In this study, patients in the experimental group were treated with PVP using the new implant-assisted VA technique, while patients in the control group were treated with PKP. Bias assessment was conducted using the tool integrated with the Revman 5.4 software, and meta-analysis was carried out to compare the mid-term postoperative pain relief, functional status, quality of life, and cement extravasation between the two groups (each presented with a forest plot). RESULTS: Eight articles were finally included in the selection, involving a total of 1,027 patients. PVP surgery using the new implant-assisted VA technique was superior to PKP surgery in relieving postoperative pain [mean difference (MD) =-3.77, 95% CI: -5.63, -1.92, P<0.0001] and improving the postoperative Oswestry Disability Index (ODI) score (MD =-1.59, 95% CI: -3.01, -0.16, P=0.03). However, it was not significantly different from PKP surgery in improving postoperative quality of life (MD =-0.27, 95% CI: -3.55, 3.01, P=0.87), and the cement extravasation rate was significantly lower than that of PKP surgery [odd ratio (OR) =0.38, 95% CI: 0.19, 0.74, P=0.004]. DISCUSSION: The new implant-assisted VA technique can significantly relieve pain, reduce clinical symptoms, improve postoperative quality of life, and significantly reduce the problem of cement extravasation. However, this new technology is still evolving, and more high-quality randomized controlled studies on this topic are needed to provide stronger evidence.

A meta-analysis and systematic review of the therapeutic effects of arthroscopy combined with intra-articular injection of sodium hyaluronate in the treatment of knee osteoarthritis.

BACKGROUND: Knee osteoarthritis (KOA) causes joint pain and dysfunction that severely affects the patient's ability to walk. Arthroscopy combined with intraarticular injection of sodium hyaluronate can slow the development of knee osteoarthritis, but there is a lack of rigorous evidence-based medicine evaluation, and it has not been recognized by some scholars at home and abroad. This paper analyzed the clinical efficacy of arthroscopy combined with intraarticular injection of sodium hyaluronate in slowing knee osteoarthritis based on Lysholm score. METHODS: Randomized control trials of arthroscopy combined with intra-articular injection of sodium hyaluronate in the treatment of KOA on Chinese and English databases were retrieved using the following search terms: "knee osteoarthritis", "arthroscopic debridement of the joint", "articular cavity", and "sodium hyaluronate". The quality of the literature was evaluated using the Rev Man 5.3 software. RESULTS: Twelve literatures were included in the meta-analysis. Regarding Newcastle-Ottawa Scale (NOS) score, of the 12 literatures, 7 literatures (58.33%) scored 6-9 points, 3 literatures (25%) scored 3-5 points, and 2 literatures (16.67%) scored 0-2 points. With a random effects model used for analysis, the Lysholm score after 1 month of combined treatment was significantly higher than that before treatment [mean difference (MD) =30.65, 95% confidence interval (CI): 19.44, 41.86, P<0.01]. Further, after 3 months of combination treatment, the Lysholm score was significantly higher than that before treatment (MD =24.04, 95% CI: 13.75, 34.32, P<0.01), and the same trend was also observed after 6 months (MD =20.41, 95% CI: 14.43, 26.40, P<0.01) and after 12 months (MD =20.86, 95% CI: 8.99, 32.72, P<0.01) of combination treatment. Overall, the combined treatment achieved significantly better clinical therapeutic effects than the single treatments in the control group [odds ratio (OR) =7.51, 95% CI: 4.84, 11.65, P<0.01]. DISCUSSION: This meta-analysis has confirmed that arthroscopy combined with intra-articular injection of sodium hyaluronate demonstrates significant clinical therapeutic effects in the treatment of KOA. This combination treatment can significantly improve knee joint function, relieve clinical symptoms, and improve patients' quality of life.

Study on the Critical Value of Residual Gas Content Based on the Difference of Adsorption Structure between Soft and Hard Coal.

In view of the difference of the adsorption structure between soft and hard coal, there is a big difference in the critical value of the inspection index for the regional outburst risk caused by the gas content. For the coal seams with soft and hard coal stratification, the model of gas content in the equilibrium state was established first, and the microscopic parameters of different rank coals were determined by the low-temperature liquid nitrogen adsorption test and mercury intrusion test. Then, the adsorption capacity of coal samples was determined by the adsorption test. Finally, the residual gas content of the coal seam in the equilibrium state was calculated based on the adsorbed gas content, and the critical value of prediction indexes of regional outburst based on the residual gas content was studied. The results show that for the same metamorphic degree, the specific surface area of soft coal is larger than that of hard coal. However, under the same gas pressure, the residual gas content of hard coal of anthracite and lean coal is greater than that of soft coal with the same metamorphic degree, while that of meager-lean coal and gas-fat coal is opposite. It is suggested to adopt the small value (rounded) of the measured gas content of soft and hard coal at 0.74 MPa as the critical value of the residual gas content in the regional effect test from the economic perspective. It is of great significance to determine the critical standard of the residual gas content in the regional effect test according to local conditions for reducing the cost of outburst prevention work.

HDAC6 is critical for ketamine-induced impairment of dendritic and spine growth in GABAergic projection neurons.

Ketamine is widely used in infants and children for anesthesia; both anesthetic and sub-anesthetic doses of ketamine have been reported to preferentially inhibit the GABAergic neurons. Medium spiny neurons (MSNs), the GABAergic projection neurons in the striatum, are vulnerable to anesthetic exposure in the newborn brain. Growth of dendrites requires a deacetylase to remove acetyl from tubulin in the growth cone to destabilize the tubulin. Histone deacetylase 6 (HDAC6) affects microtubule dynamics, which are involved in neurite elongation. In this study we used a human induced pluripotent stem cells (iPSCs)-derived striatal GABA neuron system to investigate the effects of ketamine on HDAC6 and the morphological development of MSNs. We showed that exposure to ketamine (1-500 µM) decreased dendritic growth, dendrite branches, and dendritic spine density in MSNs in a time- and concentration-dependent manner. We revealed that ketamine treatment concentration-dependently inhibited the expression of HDAC6 or aberrantly translocated HDAC6 into the nucleus. Ketamine inhibition on HDAC6 resulted in α-tubulin hyperacetylation, consequently increasing the stability of microtubules and delaying the dendritic growth of MSNs. Finally, we showed that the effects of a single-dose exposure on MSNs were reversible and lasted for at least 10 days. This study reveals a novel role of HDAC6 as a regulator for ketamine-induced deficits in the morphological development of MSNs and provides an innovative method for prevention and treatment with respect to ketamine clinical applications.

Prognosis of rectal neuroendocrine tumors after endoscopic resection: a single-center retrospective study.

BACKGROUND: The efficacy of endoscopic resection in patients with rectal neuroendocrine tumors (NETs) which are less than 20 mm in diameter remains unclear. This study aimed to investigate the efficacy and outcomes of different types of endoscopic resection in patients with NETs. METHODS: We performed a retrospective analysis and follow-up on 98 patients who underwent endoscopic resection for rectal NETs between August 2010 and October 2019 at Guangdong Provincial People's Hospital, China. The lesions were preoperatively classified according to their endoscopic morphology and measured by endoscopic ultrasound. Patients were divided into modified endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) groups depending on the endoscopic treatment they received. The en bloc resection rate, histopathological complete resection rate, and the complication rate of the 2 groups were evaluated after the operation. The risk factors for incomplete resection were also analyzed. RESULTS: The average diameter of the 98 NETs was 6.29±2.90 mm (range, 2-15 mm). The en bloc resection rate of the modified EMR and ESD treatment groups was 97.2% (35/36) and 100% (62/62), respectively. The histopathological complete resection rate was 86.1% (31/36) and 87.1% (54/62), respectively. No tumor recurrence or tumor-related death occurred. There were no statistically significant differences in the rate of histopathological complete resection, perforation, or delayed hemorrhage between the 2 groups (P>0.05). Multivariate analysis demonstrated that the depth of tumor invasion (P=0.007) and tumor diameter (P<0.001) were independent risk factors for histopathological complete resection. CONCLUSIONS: Modified EMR and ESD are safe and effective endoscopic approaches for the resection of rectal NETs ≤15 mm in diameter. Endoscopic resection requires a comprehensive preoperative evaluation of risk factors including the depth of tumor invasion and tumor diameter.

Activation of the Notch signaling pathway in the anterior cingulate cortex is involved in the pathological process of neuropathic pain.

Plastic changes in the anterior cingulate cortex (ACC) are critical in pain hypersensitivity caused by peripheral nerves injury. The Notch signaling pathway has been shown to regulate synaptic differentiation and transmission. Therefore, this study was to investigate the function of the Notch signaling pathway in the ACC during nociceptive transmission induced by neuropathic pain. We adopted Western blotting, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) microinjections, RNA interference targeting Notch1, Hairy and enhancer of split (Hes) 1 or Hes5, electrophysiological recordings, and behavioral tests to verify the link between Notch signaling in ACC and neuropathic pain with adult male Sprague-Dawley rats. Levels of the Notch intracellular domain were increased in ACC on day 7 after chronic constriction injury surgery or spared nerve injury. Meanwhile, the mRNA level of the downstream effector of Notch signaling Hes1 was increased, whereas the level of Hes5 mRNA did not change. Microinjection of DAPT, a γ-secretase (a key enzyme involved in Notch pathway) inhibitor, into ACC significantly reversed neuropathic pain behaviors. Intra-ACC injection of short hairpin RNA-Notch reduced Notch intracellular domain expression and decreased the potentiation of synaptic transmission in the ACC. Moreover, pain perceptions were also alleviated in rats subjected to chronic constriction injury or spared nerve injury. This process was mainly mediated by the downstream effector Hes1, but not Hes5. Based on these results, the activation of the Notch/Hes1 signaling pathway in the ACC participates in the development of neuropathic pain, indicating that the Notch pathway may be a new therapeutic target for treating chronic pain.

Dynamic mechanical properties of structural anisotropic coal under low and medium strain rates.

The static mechanical properties of coal rock show anisotropism, which makes the permeability have anisotropic characteristics partly. The dynamic impact mechanical characteristics of structural anisotropic coal under low and medium strain rates were studied by using self-made vertical Split Hopkinson Bar (SHPB) equipment. The peak stress, the strain rate, dynamic elastic modulus and failure characteristics of raw coal with three coring directions were analyzed under the influence of five impact loads and structural anisotropy. The peak stress increases linearly with impact load, and the maximum strain rate and the dynamic elastic modulus increase exponentially with impact load. The coal samples display anisotropic mechanical characteristics. The values of maximum strain rate, peak stress and dynamic elastic modulus are ranked with directions by the perpendicular to bedding direction (Z direction), the parallel to bedding direction (X direction), and the oblique 45° to bedding direction (Y direction). Dynamic mechanical properties of structural anisotropic coal provide a theoretical basis for gas seepage in far-blasting field.

Experiment and Modeling of Permeability under Different Impact Loads in a Structural Anisotropic Coal Body.

A mount of bedding and cleat in a coal body causes that the mechanical property and gas permeability are anisotropic in a coal seam, partly. To reveal the permeability change law of the impacted coal, a self-developed vertical split Hopkinson pressure bar (SHPB) device is used to carry out the dynamic impact mechanical property tests of coal samples in three different coring directions under five impact loads and then the permeability of the impacted coal samples is measured by a permeability measuring instrument under different gas pressures. Finally, a calculation model for the anisotropic coal permeability is established to analyze the permeability distribution law in any direction with different angles to the bedding plane. The results show that with an increase in impact height the dynamic peak stress of coal samples increases gradually, which shows a linear growth relationship. The permeability of the impacted coal samples is much larger than that of raw coal samples, and the bigger the impact load, the larger the permeability. Moreover, under the same impact load and gas pressure, the permeability is the largest in parallel to the bedding direction, followed by that in oblique 45° to the bedding direction, and the smallest in perpendicular to the bedding direction. The permeability calculated by the anisotropic model in oblique 45° to the bedding direction is in good agreement with the measured results, and the errors are no more than 10%, which will provide a theoretical basis for the permeability distribution law of the coal seam after deep-hole blasting.

Optimal layout of blasting holes in structural anisotropic coal seam.

Compared with the idealized isotropic coal seam, the effectively cracking distances of deep-hole pre-splitting blasting in different directions have significant difference in the structural anisotropy of coal seam. In this paper, based on the test results of coal mechanical parameters in different coring directions, the blasting crack distances in these coring directions of coal seam are theoretically calculated and analyzed, and then a new method of blasthole layout in coal seam is designed and the blasting crack effect is investigated according to the test data of gas drainage. The research results show that both compressive strength and tensile strength of the direction of perpendicular to bedding are larger than that in other directions, especially parallel to bedding. The blasting crack distances of calculation results are in great agreement with that of underground in-situ measurement, so the blasting crack zone caused by the differences of mechanical properties in different directions can be approximately treated as an ellipse. Comparing the conventional method of blasthole layout, the blasting crack effect with new method has greatly enhanced the methane concentration and gas drainage quantity. Pure methane quantities with the new method and conventional method are about 2.8 times and 1.67 times as large as that before blasting, and pure methane quantity with the new method is about 1.46 times that with the conventional method. Therefore, considering the anisotropic characteristics of coal seams, the reasonable blasthole layout plays an important role for enhancing gas drainage in low permeability and outburst working face.

Effect of sevoflurane preconditioning on astrocytic dynamics and neural network formation after cerebral ischemia and reperfusion in rats.

Astrocytes, the major component of blood-brain barriers, have presented paradoxical profiles after cerebral ischemia and reperfusion in vivo and in vitro. Our previous study showed that sevoflurane preconditioning improved the integrity of blood-brain barriers after ischemia and reperfusion injury in rats. This led us to investigate the effects of sevoflurane preconditioning on the astrocytic dynamics in ischemia and reperfusion rats, in order to explore astrocytic cell-based mechanisms of sevoflurane preconditioning. In the present study, 2,3,5-triphenyltetrazolium chloride staining and Garcia behavioral scores were utilized to evaluate cerebral infarction and neurological outcome from day 1 to day 3 after transient middle cerebral artery occlusion surgery. Using immunofluorescent staining, we found that sevoflurane preconditioning substantially promoted the astrocytic activation and migration from the penumbra to the infarct with microglial activation from day 3 after middle cerebral artery occlusion. The formation of astrocytic scaffolds facilitated neuroblasts migrating from the subventricular zone to the lesion sites on day 14 after injury. Neural networks increased in the infarct of sevoflurane preconditioned rats, consistent with decreased infarct volume and improved neurological scores after ischemia and reperfusion injury. These findings demonstrate that sevoflurane preconditioning confers neuroprotection, not only by accelerating astrocytic spatial and temporal dynamics, but also providing astrocytic scaffolds for neuroblasts migration to ischemic regions, which facilitates neural reconstruction after brain ischemia.