Hippocampal transcriptomic analyses reveal the potential antiapoptotic mechanism of a novel anticonvulsant agent Q808 on pentylenetetrazol-induced epilepsy in rats.

Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never been reported. In this study, the seizure stage and latency to reach stage 2 of pentylenetetrazol (PTZ) seizure rat model treated with Q808 were investigated. The morphological change and neuronal apoptosis in the hippocampus were detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, respectively. The hippocampal transcriptomic changes were observed using RNA sequencing (RNA-seq). The expression levels of hub genes were verified by quantitative reverse-transcription PCR (qRT-PCR). Results revealed that Q808 could allay the seizure score and prolong the stage 2 latency in seizure rats. The morphological changes of neurons and the number of apoptotic cells in the DG area were diminished by Q808 treatment. RNA-seq analysis revealed eight hub genes, including Map2k3, Nfs1, Chchd4, Hdac6, Siglec5, Slc35d3, Entpd1, and LOC103690108, and nine hub pathways among the control, PTZ, and Q808 groups. Hub gene Nfs1 was involved in the hub pathway sulfur relay system, and Map2k3 was involved in the eight remaining hub pathways, including Amyotrophic lateral sclerosis, Cellular senescence, Fc epsilon RI signaling pathway, GnRH signaling pathway, Influenza A, Rap1 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. qRT-PCR confirmed that the mRNA levels of these hub genes were consistent with the RNA-seq results. Our findings might contribute to further studies exploring the new apoptosis mechanism and actions of Q808.

Oral bacteriome and mycobiome of patients with idiopathic membranous nephropathy with different tongue coatings treated with a Chinese herbal formula.

ETHNOPHARMACOLOGICAL RELEVANCE: Moshen Fuyuan Formula (MSFY) is one of the representative Chinese medicine compound for Idiopathic membranous nephropathy (IMN), that originate from Fang Ji Huang Qi decoction in the Han dynasty. IMN is usually accompanied by different tongue coatings in traditional Chinese medicine (TCM), and tongue microorganisms are important factors affecting the formation of the tongue coating. Recently, oral microbiomes, including bacteria and fungi, have been identified as pivotal factors that contribute to disease development. However, the regulation of oral microbiomes by MSFY has not been defined. AIM OF THE STUDY: In this work, we explore the characteristics of oral bacteria and fungi in IMN patients with different tongue coatings, and clarify the therapeutic effect of MSFY based on oral microbiome. MATERIALS AND METHODS: We enrolled 24 patients with IMN, including 11 with white tongue (IMN-W) and 13 with yellow tongue (IMN-Y), and recruited an additional 10 healthy individuals. Patients with IMN were treated with the MSFY. The oral bacteriome and fungi before and after treatment were detected using full-length 16S rRNA and internal transcribed spacer gene sequencing. RESULTS: The therapeutic effect of MSFY on patients with yellow tongue coating was more significant than that on patients with white tongue coating. In terms of oral bacteriome, Campylobacter bacteria were enriched in patients with yellow tongue and could be a promising biomarker for yellow coating. Enrichment of Veillonella parvula_A may partially account for the therapeutic effect of MSFY. As for oral fungi, Malassezia globosa was enhanced in patients with IMN-W and reduced in patients with IMN-Y. Notably, it was reduced by MSFY. We also found that mycobiome-bacteriome interactions were highly complex and dynamic in patients with IMN. CONCLUSION: The regulation of the dynamic balance between oral fungi and bacteria by MSFY contributes to the treatment of IMN. This study determined the oral bacteriome and mycobiome of patients with IMN with different tongue coatings before and after MSFY treatment, which aids in promoting personalized treatment in clinical TCM and provides direction for investigating the mechanism of Chinese herbal medicines.

Treatment of stellate ganglion block in diseases: Its role and application prospect.

The stellate ganglion (SG), as a type of sympathetic ganglion, consists of the sixth and seventh cervical vertebrae and the first thoracic sympathetic ganglia. SG block (SGB) is a minimally invasive injection that aims to inject low-concentration local anesthetics to induce a broad sympathetic blocking effect near the SG. There have been no changes and progress in the clinical application of SGB since the 1830s due to several potential risks, including hematoma from blood vessel injury, hoarseness from recurrent laryngeal nerve injury, and cardiopulmonary arrest. The feasibility and safety of SGB have greatly improved since the appearance of ultrasound-guided SGB. In recent years, SGB has been widely applied in the field of non-anesthesiology sedation, with significant therapeutic effects on pain, immunological diseases, somnipathy, psychological disorders, arrhythmias, and endocrine diseases. The present study reviews the present application of SGB in clinical practice.

[The Mechanism of Artesunate Combined with Cytarabine and/or Daunorubicin on the Apoptosis of MV4-11 MLL-rearranged Acute Myeloid Leukemia Cell Line].

OBJECTIVE: To investigate the effect and mechanism of artesunate (ARTS) combined with cytarabine(Ara-C) and/or daunorubicin (DNR) on the proliferation and apoptosis of MV4-11 human mixed-lineage leukemia rearranged（MLL-r） acute myeloid leukemia (AML) cell line. METHODS: CCK-8 assay was used to detect the proliferation effect of individual or in combination of ARTS, DNR, Ara-C on MV4-11 cells. The IC50 of ARTS, DNR and Ara-C was calculated separately. The cell apoptosis and expression of receptors DR4 and DR5 were detected by flow cytometry. Western blot was used to detect the expression of Caspase-3 and Caspase-9 in each groups. RESULTS: The inhibition effect of ARTS, Ara-C and DNR on the proliferation of MV4-11 were all dose-dependently (r=0.99, 0.90 and 0.97, respectively). The IC50 of ARTS, Ara-C and DNR on MV4-11 for 48 hours were 0.31 µg/ml, 1.43 µmol/L and 22.47 nmol/L, respectively. At the dose of ARTS 0.3 µg/ml， Ara-C 1.0 µmol/L and DNR 15 nmol/L, the proliferation rate for 48 hours of the tri-combination treatment was significantly lower than that of the bi-combination treatment, while both were significantly lower than that of the individual treatment (all P＜0.05). In terms of bi-combination treatment, the cells proliferation rate for 48 hours of the ARTS+Ara-C group was significantly lower than that of the ARTS+DNR group, while both were significantly lower than that of the Ara-C+DNR group (all P＜0.05). The cooperativity index (CI) of bi- and tri-combination treatment were all less than 1. After 48 hours of drug action, the cell apoptosis rate of the ARTS+DNR+Ara-C group was significantly higher than that of the Ara-C+DNR group, while both were significantly higher than that of the ARTS+DNR group (all P＜0.05). Meanwhile, the was no statistical difference between the cells apoptotic rate of the ARTS+DNR+Ara-C group and the ARTS+Ara-C group (P>0.05). The expression of DR4 and DR5 also showed no difference between control group and drug group. Compared with the DNR+Ara-C group, the expressions of Caspase-3 were significantly down-regulated in both the ARTS+DNR+Ara-C group and the ARTS+Ara-C group (all P＜0.05). The down-regulation of Caspase-3 expression was the most significantly in the combination group of three drugs, while the Caspase-9 expressions in different groups showed no apparent change. CONCLUSION: The in vitro study showed that tri-combination of ARTS+Ara-C+DNR and bi-combination of ARTS+Ara-C could inhibit the proliferation and promote apoptosis of MV4-11 cell line. The inhibition effect of these two combinations were significantly superior to that of the traditional Ara-C+DNR treatment. The mechanism underlying this finding may be identified by the down regulation of Caspase-3, while no altered expression was observed of Caspase-9, DR4 and DR5.

Simultaneous stabilization/solidification of arsenic in acidic wastewater and tin mine tailings with synthetic multiple solid waste base geopolymer.

Stabilization/Solidification (S/S) is considered as a feasible technology for the treatment of arsenic (As) in acidic wastewater (AW) and tin mine tailings (TMTs); however, high cost, high carbon footprint, and strict reaction conditions are the main limitations. Herein, a novel alkali-activated geopolymer material (AAGM) for S/S As was synthesized by combining AW, TMT, gypsum (GP), and metakaolin (MK). At room temperature, an initial As concentration of 3914 mg/L, a NaOH content of 4.98%, and an MK content of 20% decreased the As leaching concentration to 1.55 mg/L (<5 mg/L). The main S/S mechanisms of As included physical encapsulation of C-(A)-S-H and geopolymer structures, ion exchange of ettringite, and formation of Fe-As and Ca-As precipitates. Further studies showed that increasing initial As concentration and MK content facilitated the formation of Ca-As precipitates and C-(A)-S-H gels. The semi-dynamic leaching tests revealed that the leaching mechanism of As was surface wash-off. The effective diffusion coefficients of the samples were less than 10-13 cm2/s, and the respective leachability indexes were greater than 9, indicating that AAGM was effective in preventing the leaching of As. Therefore, this study provides a green and low cost solution for the synergistic utilization of AW, TMT, GP, and MK.

Enhanced Antibacterial and Osteogenic Properties of Graphene Oxide Loaded with Berberine on Biomedical Titanium.

Internal implants are widely used in most orthopedic surgeries, of which titanium and its alloys are most widely used owing to the excellent corrosiveness resistance, low elastic modulus and good biocompatibility. However, implant failure still occurs for that titanium and its alloys themselves do not own antibacterial and osteogenic properties. In this work, we successfully fabricated berberine-loaded graphene oxide (GO) on the surface of biomedical titanium and systematically investigated its capabilities of antibacteria and osteogenesis. In vitro results showed that berberine had low antibacterial activity, but GO loaded with berberine on titanium (Ber&GO@Ti) exhibited superior antibacterial activity against Staphylococcus aureus (S. aureus) with the synergistic effect of GO and berberine. Meanwhile, Ber&GO@Ti performed satisfactory cytocompatibility and was capable of promoting osteogenic differentiation of MC3T3-E1 cells. In the vivo experiment, Ber&GO@Ti showed excellent antibacterial properties and inflammatory cells e.g., neutrophils had seldom been found. No visceral toxicity had been found. This multifunctional coating showed great potential in orthopedic implants.

Effect of Training Data Volume on Performance of Convolutional Neural Network Pneumothorax Classifiers.

Large datasets with high-quality labels required to train deep neural networks are challenging to obtain in the radiology domain. This work investigates the effect of training dataset size on the performance of deep learning classifiers, focusing on chest radiograph pneumothorax detection as a proxy visual task in the radiology domain. Two open-source datasets (ChestX-ray14 and CheXpert) comprising 291,454 images were merged and convolutional neural networks trained with stepwise increase in training dataset sizes. Model iterations at each dataset volume were evaluated on an external test set of 525 emergency department chest radiographs. Learning curve analysis was performed to fit the observed AUCs for all models generated. For all three network architectures tested, model AUCs and accuracy increased rapidly from 2 × 103 to 20 × 103 training samples, with more gradual increase until the maximum training dataset size of 291 × 103 images. AUCs for models trained with the maximum tested dataset size of 291 × 103 images were significantly higher than models trained with 20 × 103 images: ResNet-50: AUC20k = 0.86, AUC291k = 0.95, p < 0.001; DenseNet-121 AUC20k = 0.85, AUC291k = 0.93, p < 0.001; EfficientNet AUC20k = 0.92, AUC 291 k = 0.98, p < 0.001. Our study established learning curves describing the relationship between dataset training size and model performance of deep learning convolutional neural networks applied to a typical radiology binary classification task. These curves suggest a point of diminishing performance returns for increasing training data volumes, which algorithm developers should consider given the high costs of obtaining and labelling radiology data.

Hippocampus RNA Sequencing of Pentylenetetrazole-Kindled Rats and Upon Treatment of Novel Chemical Q808.

The expression of genes altered in epilepsy remains incomplete, particularly in the hippocampus, which exhibits exquisite vulnerability to epilepsy. Q808 is an innovation chemical compound that has potent anti-convulsant effect. Exploring its mechanism can not only explore the pathogenesis of epilepsy but also provide a theoretical basis for its clinical application. The present study aimed to use RNA sequencing (RNA-seq) to reveal the gene transcriptomic profile of chronic pentylenetetrazole (PTZ)-kindled seizure rats and the difference of the PTZ model rat before and after treatment with Q808. Quantitative real-time PCR (qRT-PCR) was performed to validate the RNA-seq results. The protein level was estimated with Western blot. Hippocampal transcriptomic analysis showed that 289 differentially expressed genes (DEGs) were confirmed in the PTZ-kindled seizure group compared with the vehicle control. Gene cluster analysis identified most of the DEGs linked to neuronal apoptosis, neurogenesis, neuronal projections, and neurotransmitter regulation. After analysis across the three groups, 23 hub genes and 21 pathways were identified, and qRT-PCR analysis confirmed that most of the mRNA levels of hub genes were consistent with the RNA-seq results. Q808 treatment increased the level of ACE, a GABA-related protein. Our analysis showed the comprehensive compendium of genes and pathways differentially expressed for PTZ-kindled seizure rats and upon Q808 treatment in PTZ-kindled seizure, which may provide a theoretical basis to explore the mechanism and unique efficacy of Q808 and the pathophysiology of epilepsy in the future.

The effect of a novel anticonvulsant chemical Q808 on gut microbiota and hippocampus neurotransmitters in pentylenetetrazole-induced seizures in rats.

BACKGROUND: The gut microbiota can modulate brain function and behavior and is increasingly recognized as an important factor in mediating the risk of epilepsy and the effects of seizure interventions. Drug therapy is one of the factors that influence the composition of the intestinal microbiota. Q808 is an innovative chemical with strong anticonvulsant activity and low neurotoxicity. However, studies evaluating the effect of Q808 on gut microbial communities are lacking. In this study, we aimed to evaluate the anticonvulsant activity of Q808 on a pentylenetetrazol (PTZ)-induced seizure model and analyze and compare the intestinal microbiota composition of non-PTZ vehicle control group, the PTZ-induced seizure model rats with and without Q808, through 16S rDNA sequencing. Neurotransmitter levels in the hippocampus were quantitatively estimated using HPLC-MS. RESULTS: The results suggest that Q808 effectively alleviates seizures in chronic PTZ-kindled model rats. Additionally, based on the analyzed abundance of the gut microbiota, dysbacteriosis of model rats was found to be corrected after Q808 treatment at the phylum level. The unique bacterial taxa (e.g., Lactobacillus) that are associated with acetylcholine production, were significantly increased. Several short-chain fatty acids (SCFAs)-producing bacteria, including Roseburia, Alloprevptella, Prevotellaceae_NK3B31_group, Prevotellaceae_UCG-001, and Prevotella_9, were enriched. In the hippocampus, the contents of acetylcholine increased, whereas the levels of 3-methoxytyramine, glutamine, and 5-hydroxyindole acetic acid (5-HIAA) decreased after Q808 treatment. CONCLUSIONS: This study demonstrates that Q808 can be used to remodel the dysbiosis of the gut microbiome and influence neurotransmitter levels in the hippocampus of PTZ-induced seizure model rats. We hope that these novel findings prompt further research on the interaction between gut microbiota and seizures and the mechanism of Q808.

Red mud-metakaolin based cementitious material for remediation of arsenic pollution: Stabilization mechanism and leaching behavior of arsenic in lollingite.

The proper treatment of lollingite is of great significance due to its rapid oxidation leading to release of arsenic into the environment. Herein, a green multi-solid waste geopolymer, consisting of red mud, metakaolin, blast furnace slag, and flue gas desulfurization gypsum, was developed. The obtained red mud-metakaolin-based (RMM) geopolymer demonstrated good arsenic retention capability. The results showed that the replacement of SO42- in ettringite with AsO42- via ion exchange, formation of Ca-As and Fe-As precipitates, and physical encapsulation with aluminosilicate gel were the main mechanisms that prevented the release of arsenic. Further dissolution of ettringite in RMM was alleviated by adding a suitable amount of Ca(OH)2 and controlling the pH of the leachate. TCLP results verified that RMM materials possessed an outstanding ability to stabilize arsenic, with a leaching rate below the permitted value of 5 mg/L for safe disposal. The low leachability of the RMM geopolymers (<0.50 mg/L) is potentially related to the pH buffering capacity of the hydration products at a pH range of 2-5. RMM geopolymers showed a high compressive strength (>15 MPa) and low arsenic leaching concentration (<2.66 mg/L) after 28 days of curing. These results demonstrate the potential of RMM geopolymers to be utilized as an environmentally friendly backfilling cementitious material for sustainable remediation of arsenic pollution.

Neolignans from Piper betle Have Synergistic Activity against Antibiotic-Resistant Staphylococcus aureus.

A phytochemical investigation of an extract of the leaves of Piper betle, guided by a synergistic antibacterial screen, led to the isolation and structural elucidation of 10 new neolignans, Pibeneolignan A-J (1-10), together with 11 known compounds. The structures and absolute configurations of the new compounds were elucidated on the basis of spectroscopic data, single-crystal X-ray diffraction analysis, and experimental and calculated ECD investigations. Compounds 1 and 2 are new naturally occurring neolignan skeletons, based on the cyclohept-2-ene-1,4-dione framework. We propose that these natural products are biosynthetically formed from bicyclic [3.2.1] neolignans by oxidative cleavage and ring opening at C-1' and C-2'. Among these compounds, 9, 13, 15, and 16, in combination with norfloxacin against an effluxing S. aureus strain (SA1199B), exhibited significant synergistic activity with fractional inhibitory concentration indices (FICIs) of 0.078, 0.156, 0.125, and 0.25, respectively. Bacterial growth curves, ethidium bromide (EtBr) efflux, and qRt-PCR were further employed to verify their synergistic antibacterial mechanism. Furthermore, computational molecular modeling suggested the binding of compounds 14-17 and 19 to the active site of the modeled structure of the NorA efflux pump, which is the main efflux pump in SA1199B.

How much space of the spinal canal should be restored by hoisting the vertebrae-OPLL complex for sufficient decompression in anterior controllable antedisplacement and fusion? A multicenter clinical radiological study.

BACKGROUND CONTEXT: Anterior controllable antedisplacement and fusion (ACAF) is a novel surgical technique for the treatment of ossification of the posterior longitudinal ligament (OPLL). Its prognostic factors for decompression have not been well studied. Additionally, no detailed radiological standard has been set for hoisting the vertebrae-OPLL complex (VOC) in ACAF. PURPOSE: To identify the possible prognostic factors for decompression outcomes after ACAF for cervical OPLL, to determine the critical value of radiological parameters for predicting good outcomes, and to establish a radiological standard for hoisting the VOC in ACAF. STUDY DESIGN: This was a retrospective multicenter study. PATIENT SAMPLE: A total of 121 consecutive patients with OPLL who underwent ACAF at a point between January 2017 and June 2018 at any one of seven facilities and were monitored for at least 1 year afterward were enrolled in a multicenter study. OUTCOME MEASURES: Japanese Orthopedic Association (JOA) scores, recovery rate (RR) of neurologic function, and surgical complications were used to determine the effectiveness of ACAF. METHODS: Patients were divided into two groups according to their RR for neurologic function. Patients with an RR of ≥50% and an RR of <50% were designated as having good and poor decompression outcomes, respectively. The relationship between various possible prognostic factors and decompression outcomes was assessed by univariate and multivariate analysis. The receiver operating characteristic curve was used to determine the optimal cutoff value of the radiological parameters for prediction of good decompression outcomes. Next, the patients were redivided into three groups according to the cutoff value of the selected radiological parameter (postoperative anteroposterior canal diameter [APD] ratio). Patients with postoperative APD ratios of ≤80.7%, 80.7%-100%, and ≥100% were defined as members of the incomplete, optimal, and excessive antedisplacement groups, respectively. Differences in decompression outcomes among the three groups were compared to verify the reliability of the postoperative APD ratio and assess the necessity of excessive antedisplacement. RESULTS: Multivariate logistic regression analysis showed that patients' age at surgery (odds ratio [OR]=1.18; 95% confidence interval [CI]=1.08-1.29; p<.01) and postoperative APD ratio (OR=0.83; 95% CI=0.77-0.90; p<.01) were independently associated with decompression outcomes. The optimal cutoff point of the postoperative APD ratio was calculated at 80.7%, with 86.2% sensitivity and 73.5% specificity. There were no significant differences in the postoperative JOA scores and RRs between the excessive antedisplacement group and optimal antedisplacement group (p>.05). However, a lower incidence of cerebrospinal fluid leakage and screw slippage was observed in the optimal antedisplacement group (p<.05). CONCLUSIONS: Patients' age at surgery and their postoperative APD ratio are the two prognostic factors of decompression outcomes after ACAF. The postoperative APD ratio is also the most accurate radiological parameter for predicting good outcomes. Our findings suggest that it is essential for neurologic recovery to restore the spinal canal to more than 80.7% of its original size (postoperative APD ratio >80.7%), and restoration to less than its original size (postoperative APD ratio <100%) will help reduce the incidence of surgical complications. This may serve as a valuable reference for establishment of a radiological standard for hoisting the VOC in ACAF.

CacyBP/SIP promotes tumor progression by regulating apoptosis and arresting the cell cycle in osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone tumor in pediatric and adolescent patients. The calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) performs an essential function in cell proliferation and apoptosis. The present study investigated the effect of CacyBP/SIP in OS cell proliferation and apoptosis. CacyBP/SIP mRNA expression levels were evaluated in four OS cell lines by quantitative PCR. CacyBP/SIP expression was downregulated in Saos-2 cells using a lentivirus transfection system and the transfection efficiency was analyzed. The effects of CacyBP/SIP downregulation on Saos-2 cell proliferation and colony-formation ability were evaluated by MTT and colony-formation assays. The effect of CacyBP/SIP knockdown on Saos-2 cell cycle and apoptosis was analyzed by flow cytometry cell sorting. The Cancer Genome Atlas (TCGA) data was analyzed for validation. Human OS cell lines Saos-2, MG-63, HOS and U20S expressed CacyBP/SIP mRNA. CacyBP/SIP knockdown significantly inhibited cell proliferation and colony-formation ability. G1/S phase arrest was induced by CacyBP/SIP downregulation, which also resulted in the downregulation of CDK and cyclins and the upregulation of p21. In addition, CacyBP/SIP downregulation induced Saos-2 cell apoptosis mediated by Bax and Bcl-2. High expression of CacyBP/SIP was significantly associated with poor prognosis in TCGA sarcoma database. Thus, CacyBP/SIP performs important functions in the proliferation and apoptosis of human OS cells.

The screening and identification of internalized nanobody against EpCAM / 药学学报

Epithelial cell adhesion molecule (EpCAM) is a popular target for cancer therapy. In this research, 3 nanobodies with high specificity and endocytosis activity against EpCAM were developed, which provides a basis for the study of immunotoxin based on EpCAM. In our preliminary experiments, we have immunized a camel with EpCAM-Fc antigen and constructed a high-quality phage display library. Seventeen nanobodies with different complementarity determining region (CDR) 3 sequences have been screened after 3 rounds of biopanning by phage display technology. The animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Fudan University School of Pharmacy. After purification, 7 nanobodies showed high cell binding activity by fluorescent activated cell sorting (FACS) identification. Furthermore, 3 nanobodies presented high endocytosis activity based on FACS and laser confocal microscopy, which also showed high affinity to EpCAM measured by ForteBio. According to this study, we aimed to provide a novel alternative approach to the EpCAM-targeted therapy and to provide guidance for the study of nanobody based immunotoxins for other targets.

Short-term Preoperative Denosumab With Surgery in Unresectable or Recurrent Giant Cell Tumor of Bone.

OBJECTIVE: The purpose of this retrospective study was to evaluate the clinical and oncological results of combination treatment of short-term preoperative denosumab (the receptor activator of nuclear factor kappa-B ligand inhibitor) with surgery in unresectable or recurrent cases of giant cell tumor of the bone (GCTB). METHODS: Between 2016 and 2018, 11 eligible patients (1 man, 10 women, mean age 38.1 years) with grade 3 GCTB were treated with a combination of short-term (six doses) preoperative denosumab and surgery in a single institution. The clinical, radiological, and pathological alteration after the denosumab treatment were compared. The oncological results of the combination therapy were also recorded. Meanwhile, adverse effects or complications of denosumab, if any, were reported. RESULTS: The median follow-up time after surgical procedure was 30 months (range 13-45 months). After 3-4 denosumab injections, pain relief was observed in all patients. In two spine patients, the neurological status improved after four doses of treatment. Intraoperatively, the margin of the tumor became clear and the intensity of the tumor increased while the blood supply around and within the lesion decreased. Within the lesion, the typically soft and loose tissue were replaced by the tough and dense fibro-osseous tissue. The mean diameter of the lesion before and after treatment was 61.55 ± 22.49 mm and 51.81 ± 21.12 mm, respectively, and the T-score was 1.02 (P = 0.32). Variable calcification was observed at the periphery and within the lesion. A total of three patients experienced local recurrence in this study. In the resection group, only one extremity patient had soft tissue recurrence that was treated with en-bloc excision. In the curettage group, two of three sacral tumor patients had local occurrence. Both refused re-operation and restarted the monthly denosumab injection thereafter, and the lesions remained stable at the final follow up. Finally, no adverse effects or complications related to denosumab treatment were found. CONCLUSION: For the unresectable or recurrent GCTB cases, short-term (six doses) preoperative use of denosumab improved clinical symptoms, decreased the tumor size, and increased the tumor density. The changes in tumors, in turn, simplified the tumor removal manipulation and, subsequently, decreased the local recurrence for the resection surgery. For the curettage, the denosumab-induced changes had mixed impacts, and shorter term (fewer than six doses) usage may be more appropriate. Our six-dose regime was deemed safe, while the safety of long-term use remains unknown.

[Clinical Efficacy of R-EDOCH Protocol in the Treatment of Newly Diagnosed Double Expression Lymphoma].

OBJECTIVE: To investigate the clinical efficacy of R-EDOCH protocol in the treatment of newly diagnosed double expression lymphoma. METHODS: The clinical data of 51 patients with newly diagnosed double expression lymphoma treated by R-EDOCH protocol were retrospectively analyzed in the period from May 2012 to October 2017, then overall remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) rate and total survival (OS) rate were evaluated; moreover the patients were grouped according to IPI score and whether accepting hematopoietic stem cell transplantation(HSCT) and the clinical efficacy was compared. RESULTS: The ORR was 96.08% (49/51) and DCR was 100.00% (51/51) in all patients. Six cases out of 51 patients (11.76%) relapsed and progressed during the followed-up. The followed-up showed that 2 year-PFS rate and OS rate were 84.31% (43/51) and 94.12% (48/51) respectively. The ORR, SD rate, 2 year-PFS rate and OS rate in the patients with IPI 0-2 and 3-5 scores were no statistically different(p>0.05); the 2 year-PFS and OS rates between patients in subgroup of IPI 0-2 and 3-5 scores also were not statistically different (p>0.05), no matter whether the patients received auto-HSCT or not. The comparison of 2 year-PFS and OS rates in auto-HSCT patients and non-auto-HSCT patients showed no statistical difference(p>0.05). CONCLUSION: The R-EDOCH protocol in treatment of newly diagnosed double expression lymphoma possess the good overall clinical efficacy, the combination of R-EDOCH with auto-HSCT displays ascending trend of PFS.

Protective Effects of Apocynum venetum Against Pirarubicin-Induced Cardiotoxicity.

Pirarubicin (THP) is an anthracycline antibiotic, frequently used for the treatment of various human cancers. Unfortunately, the clinical effectiveness of THP is limited by its dose-related cardiotoxicity. Apocynum leaf extract is an extract of the dried leaves of Apocynum venetum L. (a member of the Apocynaceae family, AVLE) that has many positive effects on the cardiovascular system and is widely consumed as tea in China. In this study we established a cardiactoxicity rat model, which showed that pretreatment with AVLE attenuated THP-induced myocardial histopathological injury, electrocardiogram abnormalities, and cardiac dysfunction. AVLE also significantly reduced serum levels of malondialdehyde (MDA), brain natriuretic peptide (BNP), creatine kinase (CK-MB), cardiac troponin (CTnT), and lactate dehydrogenase (LDH); and increased serum superoxide dismutase (SOD) levels. Treatment with AVLE or dexrazoxane (DZR) resulted in an increase Cytochrome C (cytc) in the mitochondria and reduced Cytc and cleaved-caspase-3 levels (p<0.05) in cytoplasm. We also found that AVLE significantly reduced voltage-dependent anion channel 1 (VDAC1), adenosine nucleotide transporter 1 (ANT1), and cyclophilin D (CYPD) mRNA expression (p<0.05). Furthermore, AVLE appeared to exert therapeutic effects in a dose-dependent manner. Our study suggests the anti-oxidant and anti-apoptotic properties of AVLE may be responsible for the observed cardioprotective effects.

Clinical Efficacy of R-EDOCH Protocol in the Treatment of Newly Diagnosed Double Expression Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical efficacy of R-EDOCH protocol in the treatment of newly diagnosed double expression lymphoma.@*METHODS@#The clinical data of 51 patients with newly diagnosed double expression lymphoma treated by R-EDOCH protocol were retrospectively analyzed in the period from May 2012 to October 2017, then overall remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) rate and total survival (OS) rate were evaluated; moreover the patients were grouped according to IPI score and whether accepting hematopoietic stem cell transplantation(HSCT) and the clinical efficacy was compared.@*RESULTS@#The ORR was 96.08% (49/51) and DCR was 100.00% (51/51) in all patients. Six cases out of 51 patients (11.76%) relapsed and progressed during the followed-up. The followed-up showed that 2 year-PFS rate and OS rate were 84.31% (43/51) and 94.12% (48/51) respectively. The ORR, SD rate, 2 year-PFS rate and OS rate in the patients with IPI 0-2 and 3-5 scores were no statistically different(p>0.05); the 2 year-PFS and OS rates between patients in subgroup of IPI 0-2 and 3-5 scores also were not statistically different (p>0.05), no matter whether the patients received auto-HSCT or not. The comparison of 2 year-PFS and OS rates in auto-HSCT patients and non-auto-HSCT patients showed no statistical difference(p>0.05).@*CONCLUSION@#The R-EDOCH protocol in treatment of newly diagnosed double expression lymphoma possess the good overall clinical efficacy, the combination of R-EDOCH with auto-HSCT displays ascending trend of PFS.

Current Study of the Mechanism of Action of the Potential Anti-Epileptic Agent Q808.

Our previous study showed that the anticonvulsant Q808 might be effective against seizures induced by maximal electroshock, pentylenetetrazole (PTZ), isoniazid (ISO), thiosemicarbazide (THIO), and 3-mercaptopropionic acid (3-MP). In the present study, we explored the possible mechanism of action of Q808. Results obtained with high-performance liquid chromatography (HPLC) suggest that Q808 may affect neurotransmitter content in the brain, by specifically increasing GABA content in the rat hippocampus at doses of 40 mg/kg and 80 mg/kg, and by reducing the content of glutamate and glutamine in the rat thalamus at a dose of 80 mg/kg. Intriguingly, there were no changes in the neurotransmitter content in the cortex in response to Q808. In vitro brain slice electrophysiological studies showed that 10-5 M Q808 enhanced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in corn cells of the CA1 area of the hippocampus, and had no effect on the amplitude of sIPSCs, the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), or γ-aminobutyric acid (GABA) receptor-mediated currents in primary cultured hippocampal neurons. These findings suggest that the antiepileptic activity of Q808 may be due to its ability to increase the amount of GABA between synapses, without affecting the function of GABA receptors.

HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells.

Glycolysis is a typical conduit for energy metabolism in pancreatic cancer (PC) due to the hypoxic microenviroment. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis. The aim of the present study was to explore the mechanism of interactions between hypoxia, HIF-1/2α and LDHA, and the function of LDHA on PC cells by analyzing 244 PC and paratumor specimens. It was found that LDHA was over-expressed and related to tumor stages. The result of in vitro study demonstrated that hypoxia induced LDHA expression. To explore the relationship between HIF and LDHA, chromatin immunoprecipitation assay and luciferase assay were performed. The result showed that HIF-1/2α bound to LDHA at 89bp under the hypoxic condition. Furthermore, knockdown of endogenous HIF-1α and HIF-2α decreased the LDHA expression even in the hypoxic condition, which was accompanied with a significant decrease in lactate production and glucose utilization (p < 0.01). Immunofluorescence in the 244 specimens showed that HIF-1/2α was over-expressed and associated with LDHA over-expression (p < 0.0001). Forced expression of LDHA promoted the growth and migration of PC cells, while knocking down the expression of LDHA inhibited the cell growth and migration markedly. In summary, the present study proved that HIF1/2α could activate LDHA expression in human PC cells, and high expression of LDHA promoted the growth and migration of PC cells.