Prediction of neoplastic gallbladder polyps in patients with different age level based on preoperative ultrasound: a multi-center retrospective real-world study.

BACKGROUND: The prevalence of neoplastic polyps in gallbladder polyps (GPs) increases sharply with age and is associated with gallbladder carcinoma (GBC). This study aims to predict neoplastic polyps and provide appropriate treatment strategies based on preoperative ultrasound features in patients with different age level. METHODS: According to the age classification of WHO, 1523 patients with GPs who underwent cholecystectomy from January 2015 to December 2019 at 11 tertiary hospitals in China were divided into young adults group (n=622), middle-aged group (n=665) and elderly group (n=236). Linear scoring models were established based on independent risk variables screened by the Logistic regression model in different age groups. The area under ROC (AUC) to evaluate the predictive ability of linear scoring models, long- and short- diameter of GPs. RESULTS: Independent risk factors for neoplastic polyps included the number of polyps, polyp size (long diameter), and fundus in the young adults and elderly groups, while the number of polyps, polyp size (long diameter), and polyp size (short diameter) in the middle-aged groups. In different age groups, the AUCs of its linear scoring model were higher than the AUCs of the long- and short- diameter of GPs for differentiating neoplastic and non-neoplastic polyps (all P<0.05), and Hosmer-Lemeshow goodness of fit test showed that the prediction accuracy of the linear scoring models was higher than the long- and short- diameter of GPs (all P>0.05). CONCLUSION: The linear scoring models of the young adults, middle-aged and elderly groups can effectively distinguish neoplastic polyps from non-neoplastic polyps based on preoperative ultrasound features.

ß-asarone prolongs sleep via regulating the level of glutamate in the PVN.

People of all ages could suffer from sleep disorders, which are increasingly recognized as common manifestations of neurologic disease. Acorus tatarinowii is a herb that has been used in traditional medicine to promote sleep. ß-asarone, as the main component of volatile oil obtained from Acorus tatarinowii, may be the main contributor to the sleeping-promoting efficacy of Acorus tatarinowii. In the study, adult male C57BL/6 mice were administered ß-asarone at 12.5 mg/kg, 25 mg/kg, and 50 mg/kg. Behavioral experiments showed that ß-asarone at 25 mg/kg could significantly improve sleep duration. It was also observed that the proportion of NREM (Non-Rapid Eye Movement) sleep increased considerably after administration of ß-asarone. In the PVN (paraventricular nucleus of hypothalamus) region of the hypothalamus, it was observed that the glutamate content decreased after ß-asarone treatment. At the same time, the expression of VGLUT2 (vesicular glutamate transporters 2) decreased while the expression of GAD65 (glutamic acid decarboxylase 65) and GABARAP (GABA Type A Receptor-Associated Protein) increased in the hypothalamus, suggesting that ß-asarone may suppress arousal by reducing glutamate and promoting transformation of glutamate to the inhibitory neurotransmitter GABA (γ-aminobutyric acid). This study is the first to focus on the association between ß-asarone and sleep, shedding perspectives for pharmacological applications of ß-asarone and providing a new direction for future research.

SPBERE: Boosting span-based pipeline biomedical entity and relation extraction via entity information.

Triplet extraction is one of the fundamental tasks in biomedical text mining. Compared with traditional pipeline approaches, joint methods can alleviate the error propagation problem from entity recognition to relation classification. However, existing methods face challenges in detecting overlapping entities and overlapping relations, which are ubiquitous in biomedical texts. In this work, we propose a novel pipeline method of end-to-end biomedical triplet extraction. In particular, a span-based detection strategy is used to detect the overlapping triplets by enumerating possible candidate spans and entity pairs. The strategy is further used to capture different contextualized representations via an entity model and a relation model, respectively. Furthermore, to enhance interrelation between spans, entity information from the output of the entity model is used to construct the input for the relation model without utilizing any external knowledge. Our approach is evaluated on the drug-drug interaction (DDI) and chemical-protein interaction (CHEMPROT) datasets, exhibiting improvement of the absolute F1-score in relation extraction by 3.5%-3.7% compared prior work. The experimental results highlight the importance of overlapping triplet detection using the span-based approach, acquisition of various contextualized representations via different in-domain pre-trained language models, and early fusion of entity information in the relation model.

A Bayesian network prediction model for gallbladder polyps with malignant potential based on preoperative ultrasound.

BACKGROUND: It is important to identify gallbladder polyps (GPs) with malignant potential and avoid unnecessary cholecystectomy by constructing prediction model. The aim of the study is to develop a Bayesian network (BN) prediction model for GPs with malignant potential in a long diameter of 8-15 mm based on preoperative ultrasound. METHODS: The independent risk factors for GPs with malignant potential were screened by χ2 test and Logistic regression model. Prediction model was established and validated using data from 1296 patients with GPs who underwent cholecystectomy from January 2015 to December 2019 at 11 tertiary hospitals in China. A BN model was established based on the independent risk variables. RESULTS: Independent risk factors for GPs with malignant potential included age, number of polyps, polyp size (long diameter), polyp size (short diameter), and fundus. The BN prediction model identified relationships between polyp size (long diameter) and three other variables [polyp size (short diameter), fundus and number of polyps]. Each variable was assigned scores under different status and the probabilities of GPs with malignant potential were classified as [0-0.2), [0.2-0.5), [0.5-0.8) and [0.8-1] according to the total points of [- 337, - 234], [- 197, - 145], [- 123, - 108], and [- 62,500], respectively. The AUC was 77.38% and 75.13%, and the model accuracy was 75.58% and 80.47% for the BN model in the training set and testing set, respectively. CONCLUSION: A BN prediction model was accurate and practical for predicting GPs with malignant potential patients in a long diameter of 8-15 mm undergoing cholecystectomy based on preoperative ultrasound.

A Bayesian network model to predict neoplastic risk for patients with gallbladder polyps larger than 10 mm based on preoperative ultrasound features.

BACKGROUND: Polyp size of 10 mm is insufficient to discriminate neoplastic and non-neoplastic risk in patients with gallbladder polyps (GPs). The aim of the study is to develop a Bayesian network (BN) prediction model to identify neoplastic polyps and create more precise criteria for surgical indications in patients with GPs lager than 10 mm based on preoperative ultrasound features. METHODS: A BN prediction model was established and validated based on the independent risk variables using data from 759 patients with GPs who underwent cholecystectomy from January 2015 to August 2022 at 11 tertiary hospitals in China. The area under receiver operating characteristic curves (AUCs) were used to evaluate the predictive ability of the BN model and current guidelines, and Delong test was used to compare the AUCs. RESULTS: The mean values of polyp cross-sectional area (CSA), long, and short diameter of neoplastic polyps were higher than those of non-neoplastic polyps (P < 0.0001). Independent neoplastic risk factors for GPs included single polyp, polyp CSA ≥ 85 mm 2, fundus with broad base, and medium echogenicity. The accuracy of the BN model established based on the above independent variables was 81.88% and 82.35% in the training and testing sets, respectively. Delong test also showed that the AUCs of the BN model was better than that of JSHBPS, ESGAR, US-reported, and CCBS in training and testing sets, respectively (P < 0.05). CONCLUSION: A Bayesian network model was accurate and practical for predicting neoplastic risk in patients with gallbladder polyps larger than 10 mm based on preoperative ultrasound features.

Clinical significance of prognostic nutritional index (PNI)-monocyte-to-lymphocyte ratio (MLR)-platelet (PLT) score on postoperative outcomes in non-metastatic clear cell renal cell carcinoma.

BACKGROUND: Prognositic nutritional index (PNI), monocyte-to-lymphocyte ratio (MLR) and platelet (PLT) are associated with tumor survival in many human malignancies. Whereas, no study combined PNI-MLR-PLT score and indicated its predictive significance on the prognosis of patients with non-metastatic clear cell renal cell carcinoma (ccRCC). METHODS: In this study, we retrospectively collected the clinicopathological characteristics and prognostic data from 164 cases of non-metastatic ccRCC and aimed to determine the clinical significance of PNI-MLR-PLT score on patients' outcomes after surgery. The optimal cut-off values of PNI (PNI > 47.40 vs PNI < 47.40), MLR (MLR > 0.31 vs MLR < 0.31) and PLT (PLT > 245 vs PLT < 245) were identified with relative operating characteristic (ROC) curve analysis. The PNI-MLR-PLT score system was established by the value of three indexes, each indication was assigned a score of 0 or 1. Overall survival (OS) and metastasis-free survival (MFS) were analyzed using Kaplan-Meier estimate and Cox regression models. RESULTS: The mean follow-up period was 85.67 months. Eight (5.0%) patients died, 4 (2.0%) relapsed, and 7 (4.0%) developed metastasis after surgery. The 3-year OS and MFS rates were 98.2% and 97.6%, and the 5-year OS and MFS rates were both 90.2%. Our results suggested that PNI-MLR-PLT score negatively correlated with pathological T stage and tumor grade. Survival outcomes revealed that lower PNI-MLR-PLT score is associated with inferior OS (P < 0.001) and MFS (P < 0.001) after surgery. Subgroup analysis regarding pathological T stage, tumor grade and surgical modalities obtained consistent results. univariable and multivariable Cox analysis showed that high PNI-MLR-PLT score was the independent protective factor of tumor survival in non-metastatic ccRCC patients. CONCLUSIONS: Our data suggested that PNI-MLR-PLT score could serve as a promising independent prognostic factor in patients with non-metastatic ccRCC.

Treadmill Exercise Alleviates Cognition Disorder by Activating the FNDC5: Dual Role of Integrin αV/ß5 in Parkinson's Disease.

Parkinson's disease with cognitive impairment (PD-CI) results in several clinical outcomes for which specific treatment is lacking. Although the pathogenesis of PD-CI has not yet been fully elucidated, it is related to neuronal plasticity decline in the hippocampus region. The dopaminergic projections from the substantia nigra to the hippocampus are critical in regulating hippocampal plasticity. Recently, aerobic exercise has been recognized as an effective therapeutic strategy for enhancing plasticity through the secretion of various muscle factors. The exact role of FNDC5-an upregulated, newly identified myokine produced after exercise-in mediating hippocampal plasticity and regional dopaminergic projections in PD-CI remains unclear. In this study, the effect of treadmill exercise on hippocampal synaptic plasticity was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced chronic PD models. The results showed that treadmill exercise substantially alleviated the motor dysfunction, cognition disorder, and dopaminergic neuron degeneration induced by MPTP. Here, we discovered that the quadriceps, serum, and brain FNDC5 levels were lower in PD mice and that intervention with treadmill exercise restored FNDC5 levels. Moreover, treadmill exercise enhanced the synaptic plasticity of hippocampal pyramidal neurons via increased dopamine levels and BDNF in the PD mice. The direct protective effect of FNDC5 is achieved by promoting the secretion of BDNF in the hippocampal neurons via binding the integrin αVß5 receptor, thereby improving synaptic plasticity. Regarding the indirect protection effect, FNDC5 promotes the dopaminergic connection from the substantia nigra to the hippocampus by mediating the interaction between the integrin αVß5 of the hippocampal neurons and the CD90 molecules on the membrane of dopaminergic terminals. Our findings demonstrated that treadmill exercise could effectively alleviate cognitive disorders via the activation of the FNDC5-BDNF pathway and enhance the dopaminergic synaptic connection from SNpc to the hippocampus in the MPTP-induced chronic PD model.

Glycine increased ferroptosis via SAM-mediated GPX4 promoter methylation in rheumatoid arthritis.

OBJECTIVE: Over-proliferation of synovium is a key event of invasive pannus formation and cartilage damage in the progression of RA disease. At the same time, ferroptosis may play a pivotal role in maintaining the balance of proliferation and death of synovium. In this study, we firstly evaluated the ferroptosis level in RA fibroblast-like synoviocytes (FLS) and then explored the role of glycine in ferroptosis. METHODS: Ferroptosis was evaluated in RA synovium and FLS. The therapeutic effect of glycine on RA was evaluated by clinical and histopathological score and cytokine level in a CIA mouse model. The influence of glycine on ferroptosis was evaluated by mitochondrial morphology observation and membrane potential assay in RA FLS. Methylase expression was detected to explore the mechanism behind the effect of glycine on glutathione peroxidase 4 (GPX4) methylation. RESULTS: Compared with healthy controls, ferroptosis decreased in the RA synovium and FLS, with a decrease in Acyl Coenzyme A Synthetase Long Chain 4 (ACSL4) and an increase in Ferritin heavy chain 1 (FTH1), GPX4 and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11). Although both oxidation and antioxidation levels of lipids were higher in RA FLS than in healthy controls, the increase in antioxidation was slightly higher than oxidation. RNA-seq and verification showed that glycine regulated the ferroptosis pathway through increase S-adenosylmethionine (SAM) concentration and decrease the expression of GPX4 and FTH1 by promoting SAM-mediated GPX4 promoter methylation and reducing FTH1 expression in RA FLS. CONCLUSIONS: In summary, we confirmed a decline in ferroptosis in RA and explored that glycine enhanced ferroptosis via SAM-mediated GPX4 promoter methylation and ferritin decrease.

Aumolertinib-based comprehensive treatment for an uncommon site of EGFR exon 20 insertion mutations with multiple metastases non-small cell lung cancer: a case report.

EGFR exon 20 insertion mutation is a rare mutation subtype of EGFR mutations, with no approved treatment in China so far. The clinical treatments of advanced EGFR exon 20 insertion mutations in non-small cell lung cancer (NSCLC) are mainly based on EGFR-TKI, chemotherapy, ICI, and other therapies. However, the efficacy is not satisfactory. Aumolertinib is the third-generation EGFR-TKI independently developed in China, which has shown excellent efficacy and safety in phase 2 and 3 clinical trials. This study aimed to share a case of applying aumolertinib as the core combined with other treatments for a patient with multiple metastases in NSCLC with an uncommon site of EGFR exon 20 insertion mutations. The comprehensive treatment benefited the patient in terms of 10 months of progression-free survival and a significant improvement in quality of life. We discussed whether we could further explore the potential of aumolertinib in treating EGFR exon 20 insertion mutations through this case report.

The role of ER stress and ATP/AMPK in oxidative stress meditated hepatotoxicity induced by citrinin.

Citrinin, a secondary metabolite, can pose serious risks to the environment and organisms, but its hepatotoxic mechanisms are still unclear. Histopathological and ultrastructural results showed that citrinin-induced liver injury in Kunming mice, and the mechanism of citrinin-induced hepatotoxicity was studied in L02 cells. Firstly, citrinin mades L02 cell cycle arrest in G2/M phase by inhibition of cyclin B1, cyclin D1, cyclin-dependent kinases 2 (CDK2), and CDK4 expression. Secondly, citrinin inhibits proliferation and promotes apoptosis of L02 cells via disruption of mitochondria membrane potential, increase Bax/Bcl-2 ration, activation of caspase-3, 9, and enhance lactate dehydrogenase (LDH) release. Then, citrinin inhibits superoxide dismutase (SOD) activity and increases the accumulation of malondialdehyde (MDA) and reactive oxygen species (ROS), resulting oxidative damage in L02 cells; upregulates the protein expression of binding immunoglobulin protein (Bip), C/EBP homologous protein (CHOP), PKR-like ER kinase (PERK) and activating transcription factor6 (ATF6), inducing ER stress in L02 cells; increases the phosphorylation of AMP-activated protein kinase (AMPK) and decreases the content of adenosine-triphosphate (ATP), activating AMPK pathway in L02 cells. Eventually, pretreatment with NAC, an ROS inhibitor, alleviates citrinin-induced cell cycle G2/M arrest and apoptosis by inhibiting ROS-mediated ER stress; pretreatment with 4-PBA, an ER stress inhibitor, reversed ER stress and p-AMPK; pretreatment with dorsomorphin, an AMPK inhibitor, decreases citrinin-induced cell cycle G2/M arrest and apoptosis. In summary, citrinin induces cell cycle arrest and apoptosis to aggravate liver injury by activating ROS-ER stress-AMPK signaling pathway.

Integrative analysis and experiments to explore angiogenesis regulators correlated with poor prognosis, immune infiltration and cancer progression in lung adenocarcinoma.

Angiogenesis is the process of capillary sprouting from pre-existing vessels and it plays a critical role in the carcinogenic process of lung adenocarcinoma (LUAD). However, the association of angiogenesis regulators with the prognosis and progression of LUAD needs to be further elucidated. In this study, we adopted differential expression analysis, Cox proportional hazards (PH) regression analysis and experimental validation to identify angiogenesis regulators correlated with a poor prognosis, immune infiltration and cancer progression in LUAD. These results showed that the diagnostic and prognostic models based on COL5A2 and EPHB2 served as independent biomarkers with superior predictive ability. The patients in the high-risk group exhibited a worse prognosis in the TCGA cohort (P < 0.001, HR = 1.72, 95% CI 1.28-2.30), GSE310210 cohort (P = 0.005, HR = 2.87, 95% CI 1.46-5.61), and GSE31019 cohort (P = 0.01, HR = 2.14, 95% CI 1.19-3.86) than patients in the low-risk group. The high prognostic risk patients had a higher TMB (P < 0.001); higher fractions of M0 macrophages, neutrophils, NK cells resting, and T cells CD4 memory activated (P < 0.05); and higher expression of immune checkpoints PD-1, PDL-1, PDL-2, and B7H3 (P < 0.001). Patients in the high-risk group were more sensitive to chemotherapeutic drugs and molecular targeted drugs such as cisplatin, doxorubicin, gefitinib, and bosutinib (P < 0.0001). In addition, inhibition of COL5A2 and EPHB2 effectively suppressed the proliferation and migration of LUAD cells. The current study identified angiogenesis regulators as potential biomarkers and therapeutic targets for LUAD and may help to further optimize cancer therapy.

Long-Term Efficacy of T3 Versus T3+T4 Thoracoscopic Sympathectomy for Concurrent Palmar and Plantar Hyperhidrosis.

BACKGROUND: More than 50% of patients with palmar hyperhidrosis (PAH) also have plantar hyperhidrosis (PLH). We compared the long-term results of T3 sympathectomy with those of combined T3+T4 sympathectomy among patients with concurrent PAH and PLH. MATERIALS AND METHODS: We retrospectively analyzed the records of patients with concurrent PAH and PLH who underwent T3 alone or T3+T4 sympathectomy from January 1, 2012, to December 31, 2017. Preoperative and postoperative sweating (hyperhidrosis index) was evaluated through questionnaires, physical examination, and outpatient follow-up. The relief rates and hyperhidrosis index were used as outcome measures to compare the efficacy of the two approaches. Patients' satisfaction and side effects were also evaluated. RESULTS: Of the 220 eligible patients, 60 underwent T3 sympathectomy (T3 group), and 160 underwent T3+T4 sympathectomy (T3+T4 group). Compared with the T3 group, the T3+T4 group showed higher symptom relief rates both for PAH (98.75% versus 93.33%, P = 0.048) and PLH (65.63% versus 46.67%, P = 0.01), and a greater postoperative decrease in both hyperhidrosis indices. The rate of severe compensatory hyperhidrosis also increased (10% versus 5%, P = 0.197), although the rates of overall satisfaction were comparable between the groups. The incidence of postoperative pneumothorax requiring chest tube placement and postoperative neuralgia was also similar. There were no cases of perioperative death, secondary operation, wound infection, or Horner syndrome in either group. CONCLUSIONS: Compared with T3 alone, T3+T4 sympathectomy achieved a higher symptom relief rate and a lower hyperhidrosis index. T3+T4 sympathectomy may be a choice for the treatment of concurrent PAH and PLH; however, patients need to be informed that this kind of surgery may increase the risk of compensatory sweating.

Enhanced Propulsion of Urease-Powered Micromotors by Multilayered Assembly of Ureases on Janus Magnetic Microparticles.

Enzyme-powered micro/nanomotors propelled by biocompatible fuels generally show a weak propulsive force, which greatly limits their applications in complex biological environments. Herein, we have developed a novel and versatile approach to significantly enhance the propulsion of enzyme-powered micromotors by multilayered assembly of enzymes. As an example, multilayers of biotinylated ureases (BU) were asymmetrically immobilized on biotinylated Janus Au/magnetic microparticles (MMPs) with the assistance of streptavidin (SA). When the mass ratio of BU into SA and the amount of BU used in the assembly process are increased, the amount of urease immobilized on the biotinylated Janus Au/MMPs increased monotonously while the migration speed of the micromotor was augmented gradually until a saturated value. The as-optimized micromotors can be self-propelled with an average speed up to about 21.5 ± 0.8 µm/s at physiological urea concentrations (10 mM), which is five times faster than that of the monolayered counterparts and two times faster than that of the previously reported values. Owing to the enhanced thrust, the micromotors can move in liquids with viscosities similar to that of blood. In addition, with the inherent magnetic property of MMPs, the micromotors can exhibit fast magnetic separation and controllable motion direction by external magnetic fields. Our results provide a new pathway for designing high-efficient enzyme-powered micro/nanomotors and thereby promote their biomedical applications.

Synthesis of Antitricyclic Morpholine Derivatives through Iodine(III)-Mediated Intramolecular Umpolung Cycloaddition of Olefins.

A (diacetoxyiodo)benzene-mediated intramolecular cycloaddition of olefins to construct tricyclic morpholines is presented. A series of substituted tricyclic morpholines were obtained in one-step simple operation under mild conditions, and the NMR studies were employed to see the interaction of reactants. The studies on stereochemistry showed that transformation of Z-alkene was inhibited, which is interpreted by density functional theory calculations on Z- and E-transition state models, and only E-alkene resulted in an anticycloaddition product, which is testified by a single-crystal X-ray diffraction analysis.

LIMK2 acts as an oncogene in bladder cancer and its functional SNP in the microRNA-135a binding site affects bladder cancer risk.

LIM kinases modulate multiple aspects of cancer development, including cell proliferation and survival. As the mechanisms of LIMK-associated tumorigenesis are still unclear, we analyzed the tumorigenic functions of LIM kinase 2 (LIMK2) in human bladder cancer (BC) and explored whether the newly identified LIMK2 3´-UTR SNP rs2073859 (G-to-A allele) is correlated with clinical features. Expression levels of LIMK2 in 38 human BC tissues and eight cell lines were examined using quantitative real-time PCR and immunohistochemistry. LIMK2 was overexpressed in most BC tissues (27/38, 71%) and BC-derived cell lines (6/8), and was more frequently overexpessed in high-grade than low-grade BC (80% vs. 47%). The effects of LIMK2 on BC cell proliferation, survival and migration, were studied by overexpression and RNA interference approaches in vitro and in vivo. LIMK2 overexpression promoted proliferation, migration and invasion of BC cells, while LIMK2 depletion inhibited cell invasion and viability and induced growth arrest in vitro and in vivo. PCR-Restriction Fragment Length Polymorphism (RFLP) was used to genotype LIMK2 SNP rs2073859 and multivariate logistic regression applied to assess the relationship between allele frequency and clinical features in 139 BC patients. Functional analyses localized SNP rs2073859 within the microRNA-135a seed-binding region and revealed significantly lower LIMK2 G allele expression. The frequency of A genotypes (AG + AA) was higher in the BC group than normal controls and correlated with risks of high-grade and high-stage BC. In conclusion, LIMK2 may function as an oncogene in human BC, while allele-specific regulation by microRNA-135a may influence disease risk.

Thoracoscopic Treatment of Giant Pulmonary Bullae.

BACKGROUND: Giant pulmonary bullae (GPB) is rare. The aim of this study was to evaluate the functional results of video-assisted thoracic surgery (VATS) in the treatment of GPB and the factors associated with complications following VATS resection for GPB. MATERIALS AND METHODS: From January 2010 to January 2015, 44 GPB patients underwent surgery with VATS. Individual GPB patient characteristics and surgical outcomes were evaluated. The patients were separated into two groups (an emphysematous group and a nonemphysematous group), and differences between the respective groups were investigated. RESULTS: Although there were no mortalities within a 30-d postoperative period among the 44 GPB patients treated surgically with VATS, 28 experienced postoperative complications, of which the most common were air leaks. VATS for GPB resulted in obvious improvements in symptoms and lung function in the majority of cases. Among 26 patients with preoperative dyspnea, the symptoms of 22 patients (84.62%) improved after treatment with VATS resection for GPB, and the mean forced expiratory volume in 1 s increased from 2.24 L preoperatively to 2.5 L postoperatively (P = 0.02). The complication rate of patients aged >48 y, who smoked and had emphysema, was significantly higher than that of those who did not smoke and did not have emphysema (79.2% versus 45%, P = 0.019; 85.7% versus 25%, P < 0.05; 88% versus 31.6%, P < 0.05). These characteristics could be associated with complications. CONCLUSIONS: VATS resection is a safe and effective treatment for GPB and leads to improvements in symptoms and lung function. Patients >48 y, who smoked and had emphysema, were more likely to experience postoperative complications. There could be a relationship between these characteristics and the patients' postoperative complications.

A Comparative Investigation of Proton Conductivities for Two Metal-Organic Frameworks under Water and Aqua-Ammonia Vapors.

Our investigation on the proton conductivities of two water-stable isostructural 3D Co(II) MOFs, {[Co3(DMPhIDC)2(H2O)6]·2H2O}n (1) [DMPhH3IDC = 2-(3,4-dimethylphenyl)-imidazole-4,5-dicarboxylic acid] and {[Co3(m-BrPhIDC)2(H2O)6]·2H2O} (2) [m-BrPhH3IDC = 2-(m-bromophenyl)-imidazole-4,5-dicarboxylic acid], under water or aqua-ammonia vapor shows that the optimized proton conductivities of both 1 and 2 under aqua-ammonia vapor are 4.41 × 10-3 S·cm-1 and 5.07 × 10-4 S·cm-1 (at aqua-ammonia vapor from 1.5 M NH3·H2O solution and 100 °C), respectively, which are approximately 1 order of magnitude greater than those maximum values (8.91 × 10-4 S·cm-1 and 7.64 × 10-5 S·cm-1) under water vapor (at 98% RH and 100 °C). The plausible proton pathways and mechanisms of the MOFs have been proposed in terms of the structural analyses, activation energy calculations, water and NH3 vapor absorptions, and PXRD determinations.

T-2 Toxin Exposure Induces Apoptosis in TM3 Cells by Inhibiting Mammalian Target of Rapamycin/Serine/Threonine Protein Kinase(mTORC2/AKT) to Promote Ca2+Production.

Although mTOR (the mammalian target of rapamycin) can regulate intracellular free Ca2+concentration in normal cultured podocytes, it remains elusive as to how mTORC2/AKT-mediated Ca2+participates in the process of T-2 toxin-induced apoptosis. The potential signaling responsible for intracellular Ca2+ concentration changes was investigated using immunoblot assays in an in vitro model of TM3 cell injury induced by T-2 toxin. Changes in Ca2+ were assessed using the Ca2+-sensitive fluorescent indictor dye Fura 2-AM. The cytotoxicity of TM3 cells was assessed with an MTT bioassay, and apoptosis was measured using Annexin V-FITC staining. Following T-2 toxin treatment, the growth of cells, phospho-mTORSer2481, phospho-mTORSer2448, and phospho-AktSer473 were significantly decreased in a time-dependent manner, whereas Ca2+ and apoptosis were increased. T-2 toxin-induced apoptosis was prevented by BAPTA-AM (a Ca2+chelator) and MHY1485 (an mTOR activator), and the application of mTOR activator MHY1485 also prevented the increase of intracellular free Ca2+concentration in TM3 cells. Our results strongly suggest that T-2 toxin exposure induces apoptosis in TM3 cells by inhibiting mTORC2/AKT to promote Ca2+ production.

Retraction: Yang, C., et al. miR-126 Functions as a Tumor Suppressor in Osteosarcoma by Targeting Sox2. Int. J. Mol. Sci. 2014, 15, 423-437, doi:10.3390/ijms15010423.

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A New Perspective for Osteosarcoma Therapy: Proteasome Inhibition by MLN9708/2238 Successfully Induces Apoptosis and Cell Cycle Arrest and Attenuates the Invasion Ability of Osteosarcoma Cells in Vitro.

BACKGROUND: The proteasome exists in all eukaryotic cells and provides the main route of intracellular proteins degradation involved in cell growth and apoptosis. Proteasome inhibition could block protein degradation pathways and disturb regulatory networks, possibly leading to profound effects on cell growth, particularly in cancer cells. A proteasome inhibitor with an appropriate toxicity index for malignant cells rather than normal cells would be an attractive anticancer therapy. METHODS: The human osteosarcoma (OS) cell lines MG-63 and Saos-2 and normal osteoblast cells were used to study the antitumour activity of the proteasome inhibitor MLN9708/2238. RESULTS: MLN2238 inhibited cell growth, induced cell cycle arrest and apoptosis, and attenuated the invasion abilities of MG-63 and Saos-2 cells, with little cytotoxicity to normal cells. In addition, MLN2238 promoted antitumour mechanisms including the accumulation of E2F1, P53, P21 and other negative G2/M checkpoint proteins; up-regulated the relative expression ratio of BAX/BCL-2, APAF-1 and pro-apoptotic proteins of the BCL-2 family; triggered mitochondrial outer membrane permeabilization (MOMP); down-regulated BCL-2 and XIAP; activated caspase3/8/9; and suppressed MMP2/9 expression and secretion levels. CONCLUSIONS: The proteasome may be a novel biochemical target for OS treatment in vitro. Our study provides a promising mechanistic framework for MLN9708/2238 in OS treatment, supporting its clinical development.