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Purpose: Chordoma is a rare bone tumor with a high recurrence rate and limited treatment options. The aim of this study was to identify molecular subtypes of chordoma that may improve clinical management. Experimental Design: We conducted RNA sequencing in 48 tumors from patients with Chinese skull-base chordoma and identified two major molecular subtypes. We then replicated the classification using a NanoString panel in 48 patients with chordoma from North America. Results: Tumors in one subtype were more likely to have somatic mutations and reduced expression in chromatin remodeling genes, such as PBRM1 and SETD2, whereas the other subtype was characterized by the upregulation of genes in epithelial–mesenchymal transition and Sonic Hedgehog pathways. IHC staining of top differentially expressed genes between the two subtypes in 312 patients with Chinese chordoma with long-term follow-up data showed that the expression of some markers such as PTCH1 was significantly associated with survival outcomes. Conclusions: Our findings may improve the understanding of subtype-specific tumorigenesis of chordoma and inform clinical prognostication and targeted options.

Figure S1. A. PBRM1 and SETD2 expression between CC1 and CC2; B. PBRM1 and SETD2 expression between NCC1 and NCC2.

Figure S2. A. Contributions of small indel (ID) signatures (A and E) between CC1 and CC2; B. Number of mutations in small indel (ID) signatures (A and E) between CC1 and CC2.

Figure S5. SNAI1, SNAI3, and TWIST expression in CC1 and CC2 tumors.

Supplementary Legend

Figure S3. Gene expression profiling based on the NanoString panel in 23 skull-base (top) and 25 non-skull-base (bottom) chordoma patients from North America.

Table S1. Genes included in the targeted DNA panel sequencing. Table S2. Differences in clinical characteristics by molecular subtype. Table S3. Distributions of mutation status in PBRM1 and SETD2 by molecular subtype in RNASeq and Nanostring datasets. Table S4. Differentially expressed genes among molecular subtypes. Table S5. GSEA results for up- and down-regulated gene sets comparing CC2 to CC1.

Purpose:Chordoma is a rare bone tumor with a high recurrence rate and limited treatment options. The aim of this study was to identify molecular subtypes of chordoma that may improve clinical management.Experimental Design:We conducted RNA sequencing in 48 tumors from patients with Chinese skull-base chordoma and identified two major molecular subtypes. We then replicated the classification using a NanoString panel in 48 patients with chordoma from North America.Results:Tumors in one subtype were more likely to have somatic mutations and reduced expression in chromatin remodeling genes, such as PBRM1 and SETD2, whereas the other subtype was characterized by the upregulation of genes in epithelial–mesenchymal transition and Sonic Hedgehog pathways. IHC staining of top differentially expressed genes between the two subtypes in 312 patients with Chinese chordoma with long-term follow-up data showed that the expression of some markers such as PTCH1 was significantly associated with survival outcomes.Conclusions:Our findings may improve the understanding of subtype-specific tumorigenesis of chordoma and inform clinical prognostication and targeted options.

Figure S4. Expression of selected markers in relation to overall survival (left) and recurrence-free survival (right) in Chinese chordoma patients with long-term follow-up data. A. CLDN11; B. GLI1; C. EPHA3; D. LEF1.

PCR primers of mRNAs and lncRNAs used for qRT-PCR

IRB of Beijing Tiantan Hospital Affiliated to Medical University

Purpose: To explore the molecular mechanism and prognosis of bone-invasive pituitary adenomas (BIPA).Experimental design: A total of 274 patients with pituitary adenomas were followed up. Transcriptomic microarrays analysis was performed on 10 pituitary adenomas, including five BIPAs and five non-bone-invasive pituitary adenomas (NBIPA). The targeted molecular markers were validated by qRT-PCR, IHC, ELISA, and osteoclast differentiation.Results: Clinical variable analyses revealed a significant correlation between bone invasion and female sex, large tumor volume, non-gross total resection (NGTR), and tumor regrowth. BIPAs had worse progression-free survival (PFS) than did NBIPAs in the NGTR and nonfunctional pituitary adenoma (NFPA) groups. Gene ontology functional and KEGG pathway analyses showed that the biological processes and pathways were primarily immune and inflammatory pathways. Pathway act work showed that osteoclast differentiation pathway was significantly implicated in the pathway network. BIPAs had higher expression of TNFα than that of NBIPAs on IHC. In vitro, TNFα could induce RAW264.7 cells to differentiate into mature osteoclasts, leading to bone destruction. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFα expression.Conclusions: BIPAs had worse PFS than did NBIPAs in the NGTR and NFPA groups. Inflammatory and immune factors play an important role in BIPAs. TNFα can directly induce osteoclast differentiation in BIPAs. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFα expression. TNFα and its related lncRNAs and miRNAs represent potential therapeutic targets for bone-invasive pituitary adenomas in the future. Clin Cancer Res; 24(22); 5757–66. ©2018 AACR.

To explore the clinical features and mechanism of pituitary adenoma associated with vestibular schwannoma (PAVS).The authors retrospectively reviewed pituitary adenoma patients in Beijing Tiantan Hospital from January 1, 2008 to December 31, 2016. A total of two pituitary adenoma samples, 1 vestibular schwannoma sample and one paired pituitary adenoma/blood sample were subjected next-generation sequencing and sanger sequence.A total of 5675 pituitary adenoma patients from January 1, 2008 to December 31, 2016, were retrospectively analyzed; of these, 4 (7%) patients met the criteria of PAVS. Clinical variable analyses revealed significant correlations between PAVS and older age when compared with sporadic pituitary adenoma (SPA) or sporadic vestibular schwannoma (SVS). The authors found that there were 2 germline mutations of XKR3 in 2/4 PAVS patients. Therefore, the authors speculated that XKR3 might be a genetic predisposition factor. The result also showed that there was no NF2 mutation and NF2-related symptom in the 4 PAVS samples.PAVS had a significant correlation with older age when compared with SPA and SVS. XKR3 may be a genetic predisposition factor for PAVS, it represents a therapeutic target for PAVS in the future.

Total 158 gonadotropin-type pituitary adenoma tissue specimens were collected and the expression of ESR1 in gonadotropin-type pituitary adenoma and its association with the overall survival of patients were analyzed. Transcriptome-sequencing data containing 79 cases of gonadotropin-type pituitary adenoma was used to search for all ESR1-related genes. KEGG pathway enrichment analysis was performed to identify the altering pathway and targeting genes. The

Integrase interactor 1 (INI1) loss is associated with a poor prognosis of skull base chordoma, while the molecular mechanism remains generally unclear. Hence, we herein explored the regulatory mechanism underlying INI1 action in skull base chordoma. We exploited transcriptomic sequencing of 48 skull base chordomas to analyze the INI1-correlated genes, and we found that EZH2 was negatively correlated with INI1. As EZH2 regulated the expression of the repressive histone mark H3K27me3, we applied chromatin immunoprecipitation (ChIP) sequencing of H3K27me3 to investigate the downstream molecules involved. ChIP sequencing and ChIP-qPCR revealed that H3K27me3 directly bound to the SIDT1 promoter, and qRT-PCR verified that H3K27me3 suppressed the transcription of SIDT1. The expression of SIDT1 in skull base chordoma was assessed using immunohistochemical staining and its low expression was associated with a poor prognosis in chordoma patients. When the potential tumor-suppressive effects ofSIDT1 were further investigatedby cytologic experiments, our results verified that SIDT1 played a tumor-suppressive role in chordoma both in vitro and in vivo. In conclusion, these findings suggested the INI1-EZH2-H3K27me3-SIDT1 axis as a possible novel therapeutic target in skull base chordoma.

Pituitary adenoma and meningioma are two of the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease, the tumorigenesis of which remains unclear. Therefore, the aim of the present study was to investigate the tumorigenesis of PAM. A total of 8,197 patients with pituitary adenoma were analyzed. Furthermore, the clinical data of 57 patients with PAM were compared with patients with multiple endocrine neoplasia 1 (MEN-1) syndrome. Whole exome sequencing (WES) was performed on 23 samples from patients with PAM and the germline mutation was verified by Sanger sequencing. The age of tumor penetrance (age of patients at diagnosis) for PAM was significantly higher than that for patients with MEN-1. Compared with MEN-1 patients, there was a significant association between PAM and female sex (P=0.004). Clonal analysis and phylogenetic tree construction suggested that the pituitary adenoma and meningioma in PAM don't originate from a common progenitor. WES revealed that 5/23 PAM samples had the recurrent germline mutation MEN1 c.1523G>A; p.G508D, which may be a genetic risk factor for PAM. Compared with patients with sporadic pituitary adenoma, the difference was statistically significant (P=0.0004). Compared with wild-type MEN1, there was a significant association between the MEN1 mutation and recurrence of pituitary adenoma, young age and larger diameter of the meningioma. The present study indicated that germline mutations in MEN1 may be associated with the tumorigenesis of PAM.

Objectives SWI/SNF‐related matrix‐associated actin‐dependent regulator of chromatin subfamily B member 1 (SMARCB1) loss is associated with a poor prognosis in chordoma, while the mechanism remains largely unclear. Here, we aim to explore the function and regulatory mechanisms of SMARCB1 in chordoma. Materials and Methods The effect of SMARCB1 on chordoma cells was investigated in vitro and in vivo. Chromatin immunoprecipitation (ChIP) sequencing was used to investigate the mechanisms of SMARCB1 in chordoma. The association between SMARCB1 and autophagy was validated by Western blot, immunofluorescence and transmission electron microscopy. In addition, the ATG5 expression in chordoma tissue was assessed using immunohistochemistry and correlated with patient survival. Results SMARCB1 inhibited the malignant phenotype of chordoma cells in vitro and in vivo, supporting a tumour suppressor role of SMARCB1 in chordoma. ATG5‐mediated autophagy was identified as a potential downstream pathway of SMARCB1. Mechanistically, SMARCB1 bound directly to the ATG5 promoter and epigenetically inhibited its transcription, which decreased ATG5 expression and impaired autophagy. Additionally, autophagy inhibitor chloroquine had a potential anti‐cancer effect on chordoma cells in vitro. Moreover, high ATG5 expression was observed in recurrent chordoma patients, which independently correlated with adverse outcomes. Conclusions Taken together, our results revealed that the SMARCB1/ATG5 axis is a promising therapeutic target for chordoma and autophagy inhibitors may be effective agents for chordoma treatment., SMARCB1 bound directly to the promoter region of ATG5 and epigenetically inhibited transcription of ATG5, which impaired autophagy. Our finding highlights that the SMARCB1/ATG5 axis is a promising therapeutic target for chordoma and autophagy inhibitors may be effective agents for chordoma treatment.

Mingxuan Li,1,&ast; Yutao Shen,1,&ast; Yujia Xiong,1,&ast; Jiwei Bai,2 Shuai Wang,1 Chuzhong Li,1 Yazhuo Zhang1– 5 1Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Beijing Institute for Brain Disorders Brain Tumor Center, Beijing, People’s Republic of China; 4China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; 5Key Laboratory of Central Nervous System Injury Research, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yazhuo Zhang Email zyz2004520@yeah.netObjective: Accumulating studies report that levels of mean corpuscular volume (MCV) and red cell distribution width (RDW) are associated with outcomes in cancer patients, while studies including MCV and RDW in chordoma are lacking so far. Therefore, our study aims to investigate the prognostic impact of MCV and RDW on survival in skull base chordoma patients.Methods: Levels of preoperative MCV and RDW in 187 primary skull base chordoma patients were collected. X-tile software was used to find the cutoff values of MCV and RDW. Progression-free survival (PFS) and overall survival (OS) analyses were performed using the Kaplan–Meier methods, Cox analysis, and nomogram model.Results: Low MCV level (MCV < 84.2) was more commonly observed in classical chordoma patients (p=0.022). High RDW level (RDW≥ 12.7) was correlated with older patient age (p=0.022) and a tough tumor texture (p=0.035). Low MCV level and high RDW level were associated with poor PFS (p=0.045 and 0.007, respectively) and OS (p=0.023 and < 0.001, respectively). Multivariate Cox analysis demonstrated that RDW was an independent prognostic indicator for both PFS (p=0.001) and OS (p< 0.001). Importantly, a nomogram based on RDW and clinical predictors showed satisfactory performance for PFS and OS prediction (concordance index, C-index: 0.684 and 0.744, respectively).Conclusion: Our data was first to reveal the prognostic role of RDW in skull base chordoma, and identified the use of RDW may contribute to a more accurate prognosis judgment and personalized treatment decision.Keywords: skull base chordoma, mean corpuscular volume, red cell distribution width, survival analysis, biomarker

The pituitary gland is a small but important organ located in the base of the brain. Although mostly noncancerous, pituitary adenomas (PAs) can cause serious health problems such as headaches, visual field defects, double vision, and hypopituitarism by invasion of regional structures. Nonfunctioning PAs (NFPAs) approximately account for one-third of PAs manifested by no circulating hormone hypersecretion. Lipid reprogramming has been recognized as a hallmark of tumor cells and proven to play a crucial role in tumorigenesis. However, the lipid molecular pathogenesis of NFPAs has remained obscure to date. To uncover lipid alterations that may contribute to the development of NFPAs and define their molecular characteristics, we investigated tissue lipids of patients with NFPAs including eight null cell adenomas (NCAs) and eight oncocytomas (OCMs) and of five normal pituitary glands as the control (Ctrl) using nontargeted lipidomics based on ultrahigh-performance liquid chromatography-Orbitrap Q-Exactive HF mass spectrometry. The lipidomic results were further validated in another set of subjects consisting of 8 NCAs, 10 OCMs, and 6 Ctrls to define crucial lipids discriminating NFPAs from the normal pituitary tumors. Lipidomic analyses revealed that OCM showed more pronounced changes in lipid compositions than NCA and Ctrl. As expected, mitochondria abundant cardiolipins were remarkably increased in OCM, which was accordant with the biochemical evidence of mitochondria hyperplasia in OCM. Significantly increased levels of phospholipids (PLs), especially arachidonic acid (AA)-enriched PLs, were unique characteristics of lipid profiling in OCM vs Ctrl. Our results indicate that AA-PLs may have diagnostic potential for OCM.

Background Pituitary adenoma and meningioma are the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease and the clinical features and mechanisms of PAM are unclear. Methods We summarized the clinical data of 57 PAM patients and compared with sporadic pituitary adenoma (SPA) and sporadic meningioma (SM). 5 pituitary adenomas of PAM and 5 SPAs were performed ceRNA microarray. qRT-PCR, Western Blot, siMEN1 and rapamycin inhibition experiment were validated for ceRNA microarray. Results Clinical variable analyses revealed that significant correlations between PAM and female sex as well as older age when compared with SPA and significant correlations between PAM and transitional meningioma as well as older age when compared with SM. Additionally, the characteristics of PAM were significantly different for MEN1 patients. Functional experiments showed lower expression of MEN1 can upregulate mTOR signaling, in accordance with the result of ceRNA microarray. Rapamycin treatment promotes apoptosis in primary pituitary adenoma and meningioma cells of PAM. Conclusions MEN1 plays an important role in PAM by upregulating mTOR signaling pathway. Rapamycin represents a potential therapeutic strategy for PAM in the future.

Chemical degradation is one of the crucial methods for the remediation of hydrophobic organic compounds (HOCs) in soil/sediment. The sequestration effect of black carbon (BC) can affect the adsorption state of HOCs, thereby affecting their chemical degradability. Our study focused on the chemical degradability of 2-Chlorobiphenyl (PCB1) sequestrated on the typical BC (fly ash (FC), soot (SC), low-temperature biochar (BC400) and high-temperature biochar (BC900)) by iron-nickel bimetallic nanomaterials (nZVI/Ni) based on TENAX desorption technology. The results showed that PCB1 adsorbed in various states were simultaneously dechlorinated by nZVI/Ni. Specifically, rapid-desorption-state PCB1 tended to degrade more easily than resistant-desorption-state PCB1. Moreover, the degradation mechanism varied according to the type of BC. In the case of FC and SC, the degradation rate was lower than the desorption rate for the PCB1 in rapid and slow desorption states, and the degradation rate of PCB1 in the resistant desorption state was negligible. The PCB1 on FC and SC was first desorbed from BC and then degraded. However, in terms of BC400 and BC900, the degradation rate was higher than the desorption rate, and the degradation rate of the resistant-desorption-state PCB1 was 1.4 × 10−2 h−1 and 4.1 × 10−2 h−1, respectively. The graphitized structure of BC900 can directly transfer electrons, so more than 90% of the resistant-desorption-state PCB1 could be degraded. In addition, BC may affect the longevity of nZVI/Ni, thereby affecting its degradability. Therefore, the chemical degradability of BC-adsorbed HOCs should be comprehensively evaluated based on the adsorption state and the properties of BC.

Black carbon (BC) plays a crucial role in the migration, transformation, and remediation of hydrophobic organics (HOCs) in soil/sediment. Previous studies mainly focus on the sorption characteristic of BC, while the chemical degradability of HOCs, which is affected by sequestration and catalytic effects of BC, has not yet been systematically studied. In this study, the dechlorination process of 2-chlorobiphenyl (PCB1), adsorbed on BC prepared at different pyrolysis temperatures, by bimetal modified nano zero-valent iron (nZVI/Pd) was investigated. The results showed that, on the one hand, adsorption limited the dechlorination process. PCB1 in the resistant desorption state exhibited lower degradation efficiency than that in other adsorption state. On the other hand, the catalysis of high-temperature BC reduced the inhibition of adsorption on dechlorination to some extent. As the pyrolysis temperature rose from 400 °C to 900 °C, the degradation efficiency of adsorbed PCB1 within 48 h improved from 53.5% to 95.3%, and the rate constant (kobs) increased from 0.104 h−1 to 0.197 h−1. High-temperature BC promoted the electrons release of Fe0 and the generation of [H], and its conductivity improved the electron utilization efficiency so that the dechlorination reaction could proceed both on the surface of nZVI/Pd particles and BC, thereby promoting the dechlorination of PCB1. Therefore, adsorption effect dominated degradability of PCB1 sequestrated by low-temperature BC, while for high-temperature BC, synergistic catalytic effect played a dominant role. These findings indicate that reductive efficiency of nZVI should be systematically evaluated according to different types of BC in soil/sediment.

There are few studies on the mechanism of pituitary adenoma (PA) destroying bone. The current study aimed to investigate the role of MEG8/miR-454-3p/TNF-α in bone-invasive pituitary adenomas (BIPAs). In this study, we report that lncRNA MEG8 and TNF-α are upregulated in BIPA tissues while miR-454-3p is downregulated, which is associated with poor progression-free survival (PFS). Functional assays revealed the role of up-regulated MEG8 and down-regulated miR-454-3p in promoting bone destruction. Mechanistically, MEG8 promotes TNF-α expression by sponging miR-454-3p, which ultimately leads to the occurrence of bone destruction. The mechanism is confirmed in vivo and in vitro. Therefore, our data illustrated a new regulatory mechanism of MEG8/miR-454-3p/TNF-α in BIPAs. It may provide a useful strategy for diagnosis and treatment for BIPA patients.

Background Bioleaching has been attracting attention in the recent years as an emerging sediment heavy metal pollution remediation technology. However, the use of sulfur powder as sulfur substrate causes the problem of “post-acidification”, and the free bioleaching functional bacteria which are susceptible to environmental impact during reactor operation cannot be used efficiently for multiple rounds. These problems can be solved if the sulfur substrate and the bioleaching functional bacteria can be recycled simultaneously after bioleaching. A new kind of sulfur substrate, the laboratory-made sulfur-covered biochar particles, was used in the bioleaching experiment, compared with sulfur powder and sulfur powder mixed with the surfactant rhamnolipid. Results The sulfur-covered biochar particles exhibited superior bioleaching performance, including faster acidification rate, SO42− production rate and heavy metal bioleaching rate, and higher heavy metal solubilization percentage (Ni 33.76%; Cu 66.16%; Zn 65.494%), which resulted from the acceleration of bioleaching reaction by the bioleaching functional bacteria immobilized on the biochar surface. Otherwise, the sulfur-covered biochar particles could be reused in the second round, and the heavy metal solubilization percentage (Ni 32.84%, Cu 69.93%, Zn 67.17%) was comparable with that of the first round. Nevertheless, the sulfur content became the main limiting factor causing poor bioleaching performance during the third round. Sulfur mixed with the surfactant rhamnolipid did not show significant effect in promoting acidification and heavy metal solubilization due to high levels of organic matter and the impact of the low pH value. Conclusion The research indicated the laboratory-made sulfur-covered biochar particles could realize the dual immobilization of the bioleaching functional bacteria and the sulfur substrate to support their recycling and reuse in the second bioleaching round. In the future research, the way to maintain the reuse of the sulfur-covered biochar particles for more rounds will be explored.

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics., The genetic basis of prolactinomas remains poorly understood. Here, the authors find a recurrent hotspot somatic mutation in the splicing factor 3 subunit B1 (SF3B1R625H) in prolactinomas, and show that this mutation causes aberrant splicing of ESRRG mRNA leading to up-regulation of prolactin.

Background Bioleaching has been attracting attention recent years as an emerging sediment heavy metal pollution remediation technology. However, the use of sulfur powder as sulfur substrate causes the problem of “post-acidification”, and the free bioleaching functional bacteria which are susceptible to environmental impact during reactor operation cannot be used efficiently for multiple rounds. These problems can be solved if the sulfur substrate and the bioleaching functional bacteria can be recycled simultaneously after bioleaching. A new kind of sulfur substrate, the laboratory-made sulfur-covered biochar particles, were used in the bioleaching experiment, compared with sulfur powder and sulfur powder mixed with the surfactant rhamnolipid. Results The sulfur-covered biochar particles exhibited superior bioleaching performance, including faster acidification rate, SO 4 2- production rate and heavy metal bioleaching rate, and higher heavy metal solubilization percentage (Ni 33.76%; Cu 66.16%; Zn 65.494%), which was resulted from the acceleration of bioleaching reaction by the bioleaching functional bacteria immobilized on the biochar surface. Otherwise, the sulfur-covered biochar particles could be reused in the second round, and the heavy metal solubilization percentage (Ni32.84%, Cu69.93%, Zn67.17%) was comparable with that of the first round. Nevertheless, the sulfur content became the main limiting factor causing poor bioleaching performance during the third round. The sulfur mixed with the surfactant rhamnolipid did not show significant effect in promoting acidification and heavy metal solubilization due to high levels of organic matter and the impact of the low pH value. Conclusion The research indicated the laboratory-made sulfur-covered biochar particles could realize the dual immobilization of the bioleaching functional bacteria and the sulfur substrate to support their recycling and reuse in the second bioleaching round. In the future research, the way to maintain the reuse of the sulfur-covered biochar particle for more rounds will be explored.

Additional file 1: Fig. S1. Amount of heavy metal leached from the sediment during the bioleaching process. Fig. S2. Infrared spectrum analysis of bamboo biochar. Fig. S3. Amount of heavy metal leached from the sediment during the second and the third round of bioleaching.

Sediment bioleaching using a sulfur substrate is a promising approach to the removal of heavy metals. Compared with commercial sulfur powder used as the sulfur substrate, agricultural sulfur soil conditioners may reduce secondary pollution and facilitate the reuse of sediment. This study explored the bioleaching effect of three agricultural sulfur soil conditioners, including sulfur-coated urea, bentonite sulfur, and bio-sulfur, and the bioleaching potential of the indigenous sediment bacteria. The results showed that the sulfur-coated urea had a comparable bioleaching effect with sulfur powder (Ni 35.35%, Cu 74.27%, Zn 69.92%) and the highest maximum bioleaching rate because of the additional nitrogen. The bentonite sulfur leached the least but increased the proportion of the residual state due to its adsorption of heavy metal. Similar changes to the microbial flora structure and bioleaching mechanism were found with the use of sulfur powder, sulfur-coated urea, and bentonite sulfur as the bioleaching substrate. There was no significant difference between the indigenous bacteria and the sludge-enriched bacteria in the bioleaching effect except for bio-sulfur, which only performed well with the sludge-enriched bacteria. In the absence of inoculum, the bio-sulfur hindered the bioleaching process due to high levels of organic matter. This study provides insights into the practical application of bioleaching heavy metal removal technology from the perspective of sulfur substrate selection.

Pituitary adenoma and meningioma are two of the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease, the tumorigenesis of which remains unclear. Therefore, the aim of the present study was to investigate the tumorigenesis of PAM. A total of 8,197 patients with pituitary adenoma were analyzed. Furthermore, the clinical data of 57 patients with PAM were compared with patients with multiple endocrine neoplasia 1 (MEN-1) syndrome. Whole exome sequencing (WES) was performed on 23 samples from patients with PAM and the germline mutation was verified by Sanger sequencing. The age of tumor penetrance (age of patients at diagnosis) for PAM was significantly higher than that for patients with MEN-1. Compared with MEN-1 patients, there was a significant association between PAM and female sex (P=0.004). Clonal analysis and phylogenetic tree construction suggested that the pituitary adenoma and meningioma in PAM don't originate from a common progenitor. WES revealed that 5/23 PAM samples had the recurrent germline mutation MEN1 c.1523G>A; p.G508D, which may be a genetic risk factor for PAM. Compared with patients with sporadic pituitary adenoma, the difference was statistically significant (P=0.0004). Compared with wild-type MEN1, there was a significant association between the MEN1 mutation and recurrence of pituitary adenoma, young age and larger diameter of the meningioma. The present study indicated that germline mutations in MEN1 may be associated with the tumorigenesis of PAM.

Additional file 1: Table S1. Clinical information of ceRNA microarray.

Clinical non-functioning pituitary adenoma (NFPA) accounts for >30% of all pituitary adenomas, and the recurrence rate is notably high. The ability to predict tumour recurrence during initial surgery will aid in determining if adjunctive therapy is required to reduce recurrence. With the aim of developing a circular RNA (circRNA) signature to improve prognosis prediction in NFPA, the present study examined the circRNA expression profiles in 73 patients with NFPA from Beijing Tiantan Hospital using high-throughput RNA chip technology. The dataset was randomly separated into a training group and a test group using an R program. In the training group (n=37), a Cox proportional hazards regression model was used to analyse the genes associated with the recurrence and progression-free survival (PFS) of patients with NFPA. Meanwhile, a random survival forest algorithm, Kaplan-Meier and receiver operating characteristic curve (ROC) analyses were used to determine the multi-circRNA signature with the largest area under the ROC curve (AUROC) and verify its efficacy in the test group (n=36). In the training and test groups, the signatures of two circRNAs (hsa_circ_0000066 and hsa_circ_0069707) were specifically associated with the PFS of patients with NFPA (log-rank P

Purpose: To explore the molecular mechanism and prognosis of bone-invasive pituitary adenomas (BIPA). Experimental design: A total of 274 patients with pituitary adenomas were followed up. Transcriptomic microarrays analysis was performed on 10 pituitary adenomas, including five BIPAs and five non-bone-invasive pituitary adenomas (NBIPA). The targeted molecular markers were validated by qRT-PCR, IHC, ELISA, and osteoclast differentiation. Results: Clinical variable analyses revealed a significant correlation between bone invasion and female sex, large tumor volume, non-gross total resection (NGTR), and tumor regrowth. BIPAs had worse progression-free survival (PFS) than did NBIPAs in the NGTR and nonfunctional pituitary adenoma (NFPA) groups. Gene ontology functional and KEGG pathway analyses showed that the biological processes and pathways were primarily immune and inflammatory pathways. Pathway act work showed that osteoclast differentiation pathway was significantly implicated in the pathway network. BIPAs had higher expression of TNFα than that of NBIPAs on IHC. In vitro, TNFα could induce RAW264.7 cells to differentiate into mature osteoclasts, leading to bone destruction. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFα expression. Conclusions: BIPAs had worse PFS than did NBIPAs in the NGTR and NFPA groups. Inflammatory and immune factors play an important role in BIPAs. TNFα can directly induce osteoclast differentiation in BIPAs. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFα expression. TNFα and its related lncRNAs and miRNAs represent potential therapeutic targets for bone-invasive pituitary adenomas in the future. Clin Cancer Res; 24(22); 5757–66. ©2018 AACR.

A post-operative central nervous system infection (PCNSI) is a dangerous complication after cranial surgery. Although a large number of neurosurgical procedures are performed in hospitals in China, PCNSI-related data from this country are rarely reported. To address this issue, we examined the incidence of PCNSI after cranial surgery, the potential risk factors, and the offending etiologic agents in a large Chinese population. The medical records and post-operative courses for patients >16 years of age who underwent elective or emergency cranial surgeries between May 2010 and May 2012 and who survived for >7 days were reviewed retrospectively. Pre-operative data, surgery-related records, and post-operative variables were evaluated as risk factors for PCNSI after cranial surgery. Among 1,470 surgeries, 1,340 were craniotomies and 130 involved the cerebrospinal fluid (CSF). There were 109 patients with PCNSIs, resulting in a total infection rate of 7.4 %. The dominant Gram-positive organism isolated (Staphylococcus aureus) was the most common pathogen isolated. Based on multivariate analysis, the risk of PCNSI was increased by a CSF leak [odds ratio (OR), 3.545; 95 % confidence interval (CI), 2.053-6.122; p < 0.001], CSF drainage of any kind (OR, 2.858; 95 % CI, 1.577-5.181; p = 0.001), subsequent short-term surgery (OR, 2.224; 95 % CI, 1.229-4.024; p = 0.008), and surgery duration (OR, 1.331; 95 % CI, 1.230-1.440; p < 0.001). PCNSI remains a critical problem for neurosurgeons in China. CSF leakage, CSF drainage of any kind, subsequent short-term surgery, and surgery duration were major risk factors, indicating that surgery-focused management might be the most effective way to minimize the risk for PCNSI after cranial surgery.

The work proposed is a laboratory investigation of the AnSBR (Anaerobic Sequencing Batch Reactors) for treatment of a synthetic coal conversion wastewater. Two different strategies will be pursued. First, an AnSBR will be operated to simulate the Anaerobic Up-flow Sludge Blanket Reactor in an attempt to develop a readily settleable granular sludge. Second, operating strategies will be sought to optimize treatment, without attempting to develop settleable granular sludge. These systems will require development of more elaborate decanting mechanisms, probably including use of tube settler technology. We will use: (1) screening tests to identify compounds which are amenable to anaerobic degradation; (2) to determine those which are toxic or have an inhibitory effect; and (3) to identify the dilution required to achieve anaerobic degradation of the synthetic waste water; acclimation tests of organisms collected from different sources to the synthetic coal conversion wastewater; and Automatic Laboratory AnSBR studies. A 4-liter reactor will be operated to maintain a settleable granular anaerobic sludge when treating the synthetic coal conversion wastewater. 72 refs., 238 figs., 22 tabs.