The effect of preoperative short-term octreotide treatment to surgery in thyrotropin-secreting pituitary adenomas: a retrospective cohort study.

BACKGROUND: To prevent thyroid storm and ensure surgical safety, it is imperative to regulate excessive thyroid hormone levels in patients with thyrotropin-secreting pituitary adenomas (TSHoma) prior to surgery. Somatostatin analogues (SSAs), such as octreotide, have showed efficacy in shrinking tumors, which may facilitate surgical resection. This retrospective study aimed to investigate the effect of shortterm preoperative octreotide treatment on the surgical outcome of TSHoma. METHODS: A total of 65 TSHoma patients from January 2010 to July 2019 were included in the study. Of these,41 patients received short-term preoperative octreotide (Sandostatin, intermittent subcutaneous injection) treatment and all patients subsequently underwent surgery. The following data were recorded: clinical manifestations, laboratory examinations, sellar region MRI, postoperative pathological and electron microscopy data, intraoperative situation, and follow-up (> 3 months) regarding hormone levels and tumor recurrence. RESULTS: There was no significant difference in the consistency and blood supply of the tumor between patients who received short-term preoperative octreotide treatment and those who did not. Additionally, preoperative short-term octreotide treatment (median of 10 days with a range of 6-18 days) did not significantly improve the rates of gross total resection (GTR) or biochemical remission. Moreover, electron microscopy revealed subcellular level impairments and cell apoptotic in the octreotide treated TSHoma specimens. CONCLUSION: Preoperative octreotide treatment for the purpose of reducing excessive thyroid hormones may not enhance surgical outcomes, and the duration of octreotide treatment needs to be extended to fully benefit from the tumor-shrinking effects of SSAs.

Evidence-based medicine in neurosurgery: an academic publication view.

Although evidence-based medicine (EBM) has been progressively developing for decades in neurosurgery, there remains a lack of data to fully understand this topic. This study was aimed to evaluate extensively EBM related to neurosurgery through the analysis of neurosurgical EBM publications. We searched the Web of Science (WoS) Core Collection database for all EBM publications related to neurosurgery. The number of publications and other information were obtained. Data were extracted from the search results to obtain the following information: document type, countries/territories, funding agencies, organizations, publication year, source of titles, and research area. From among all of the publications, we extracted randomized controlled trials (RCTs) for further analysis at RCT characteristic and funding agencies. According to the search strategy, 6907 publications were related to EBM in neurosurgery. A total of 91 countries/territories participated in neurosurgical EBM publications. English-speaking countries (USA, England, and Canada) contributed most of the publications. "University of Toronto" is the organization which published the most EBM publications. In total, 1654 neurosurgical RCTs were found. We summarize their characteristics and record the highest cited (more than 400) RCTs, which we descript the distribution in different neurosurgical fields and stages. We also found that more than half of the RCTs were directly funded by industrial companies, and government-funded agencies accounted for no more than one fifth of the RCTs. EBM in neurosurgery has a good foundation but also needs to be constantly revised and improved to synchronize with evidence-based medicine development.

Evidence of dysexecutive syndrome in patients with acromegaly.

PURPOSE: This study aimed to explore different aspects of executive function in patients with acromegaly and investigate the cause of dysexecutive syndrome in these patients. METHODS: We conducted five typical executive function tests (Stroop test, verbal fluency [VF] test, Hayling Sentence Completion Test [HSCT], N-back test, and Sustained Attention to Response Task [SART]) on 42 acromegalic patients and 42 strictly matched healthy controls. Comparative analyses were conducted for five major executive function domains. The Dysexecutive Questionnaire (DEX) was used to assess patients' subjective feelings about their executive function. All patients underwent a magnetic resonance imaging (MRI) examination and a blood test to determine their pituitary hormone levels before the tests were performed. RESULTS: The patients exhibited worse results on the Stroop test, VF test, HSCT and N-back test compared to the healthy control group. Moreover, part B of the HSCT and the N-back test performance were negatively correlated with IGF-1 concentrations, and the duration of the disease was significantly associated with the Stroop color task results. CONCLUSIONS: Acromegalic patients were severely impaired in semantic inhibition, executive processing, working memory and executive inhibition, and they have realized a portion of these deficits. A high level of IGF-1, disease duration may contribute to the impairment of specific aspects of executive function.

Upregulation of p-Smad2 contributes to FAT10-induced oncogenic activities in glioma.

The human leukocyte antigen f-associated transcript 10 (FAT10) has a similar structure and function with ubiquitin, which efficiently mediate proteasome degradation in an ubiquitin-independent manner. FAT10 expression is upregulated in many tumor tissues and plays a vital role in cell cycle regulation and tumor genesis. However, its role in glioma has not been illuminated. The aim of this study was to evaluate the prognostic value of FAT10 and investigate its functional roles in glioma. The expression of FAT10 in glioma patient samples was examined using quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry methods. Glioma cell lines with either FAT10 overexpression or knockdown were created. The effect of FAT10 on glioma cell migration and invasion was investigated using these cells. In the present study, we had shown that FAT10 was elevated significantly in glioma samples and correlated with tumor pathological grade. FAT10 high-expression glioma is associated with a poor clinical prognosis. Overexpression of FAT10 promoted proliferation, invasion, migration, and sphere formation of glioma cells, whereas downregulation of FAT10 had an opposite effect. Overexpression of FAT10 also promoted the growth of glioma cells in vivo. Moreover, FAT10 enhanced the phosphorylation of Smad2, which contributes to FAT10-induced oncogenic activities in glioma. In conclusion, these findings indicate that FAT10 is a critical regulator potential therapeutic target of glioma.

Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21.

Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. Upregulation of lysine (K)-specific demethylase 5B (KDM5B) has been reported in a variety of malignant tumors. However, the impact of KDM5B in glioma remains unclear. The objective of this study was to investigate the expression and prognostic value of KDM5B in glioma. In clinical glioma samples, we found that KDM5B expression was significantly upregulated in cancer lesions compared with normal brain tissues. Kaplan-Meier analysis showed that patients with glioma and higher KDM5B expression tend to have shorter overall survival time. By silencing or overexpressing KDM5B in glioma cells, we found that KDM5B could promote cell growth both in vitro and in vivo. Moreover, we demonstrated that KDM5B promoted glioma proliferation partly via regulation of the expression of p21. Our study provided evidence that KDM5B functions as a novel tumor oncogene in glioma and may be a potential therapeutic target for glioma management.

Differential expression of p42.3 in low- and high-grade gliomas.

BACKGROUND: Malignant gliomas are the most common form of primary malignant brain tumor. It has recently been suggested that genetic changes are involved in the progression of malignant gliomas. In previous studies, a novel gene, p42.3, was characterized as a tumor-specific gene that encodes a mitosis phase-dependent expression protein which is expressed in gastric cancer, but not in matched normal tissues. METHODS: In a series of 200 human brain gliomas and 13 normal tissues, we performed RT-PCR and mRNA in situ hybridization for analysis of p42.3 gene expression in gliomas, including astrocytoma (grade 2), oligoastrocytomas (grade 2), anaplastic oligoastrocytomas (grade 3), glioblastomas (grade 4) and normal tissues. Also, the mRNA expression was detected in gliomas by in situ hybridization. After producing polyclonal antibody to p42.3, we further tested p42.3 protein expression in astrocytomas and glioblastomas by immunohistochemistry and Western blot analysis. RESULTS: Our results demonstrated that overexpression of the p42.3 gene is detected in gliomas, but not in normal brain tissues. Importantly, p42.3 mRNA expression is correlated with the pathological features of gliomas. In addition, p42.3 protein is expressed in both the cytoplasm and the nucleus in astrocytomas, whereas this protein appeared in the cytoplasm in glioblastomas. CONCLUSIONS: These results indicate that p42.3 might be involved in carcinogenesis as a potential molecular marker for malignant gliomas.

Vestibular schwannoma coexisting with dermoid cyst: A case report.

Multiple primary intracranial tumors, or the presence of two or more primary intracranial tumors, are a rare clinical occurrence. The current study presents the case of a 28-year-old patient with concurrent left vestibular schwannoma, left cerebellar hemisphere dermoid cyst and craniovertebral junction malformation, specifically basilar invagination and Klippel-Feil syndrome. The patient exhibited symptoms of torticollis and recurrent headaches, with no apparent hearing loss. A far lateral approach was selected for surgical resection to address these complex conditions and achieve gross total resection in a single-stage surgery while preserving both facial and auditory nerve function. Successful gross total resection was achieved and the function of both nerves was effectively preserved. Of note, the coexistence of vestibular schwannoma and dermoid cyst in the same patient has not been documented in the existing literature. The present study provided a comprehensive account of the presentation and progression of this uncommon medical scenario. Furthermore, a surgical principle for the management of multiple primary intracranial tumors was proposed.

Neural substrates of the interaction between effort-expenditure reward decision-making and outcome anticipation.

OBJECTIVE: Reward anticipation is important for future decision-making, possibly due to re-evaluation of prior decisions. However, the exact relationship between reward anticipation and prior effort-expenditure decision-making, and its neural substrates are unknown. METHOD: Thirty-three healthy participants underwent fMRI scanning while performing the Effort-based Pleasure Experience Task (E-pet). Participants were required to make effort-expenditure decisions and anticipate the reward. RESULTS: We found that stronger anticipatory activation at the posterior cingulate cortex was correlated with slower reaction time while making decisions with a high-probability of reward. Moreover, the substantia nigra was significantly activated in the prior decision-making phase, and involved in reward-anticipation in view of its strengthened functional connectivity with the mammillary body and the putamen in trial conditions with a high probability of reward. CONCLUSIONS: These findings support the role of reward anticipation in re-evaluating decisions based on the brain-behaviour correlation. Moreover, the study revealed the neural interaction between reward anticipation and decision-making.

Clinical outcomes and natural history of pediatric brainstem tumors: with 33 cases follow-ups.

The purpose of this study is to investigate the patient characteristics and clinical outcomes of children with pediatric brainstem glioma. Between 2004 and 2009, a total of 42 children were diagnosed with brainstem gliomas at the Neurosurgical Center of Beijing Tiantan Hospital, China. A retrospective study including the 33 patients of this cohort with complete follow-up was conducted in an attempt to better understand clinical outcomes following multidisciplinary treatment modalities for pediatric brainstem gliomas. Investigational variables including clinical presentations, anatomical distribution, radiological findings, and clinical outcomes were analyzed. Survival time difference was computed using a Kaplan-Meier method with a log-rank test between groups. The Cox proportional hazards regression model was utilized in the multivariate analysis to determine the independent prognostic factors. Overall median survival of the entire series of patients was 11 months with a 1-year actuarial survival rate of 43.6 %. In nine patients who received no treatment after diagnosis, all patients expired within 8 months with a median time of 3.5 months. On univariate analysis, the following variables including older age at diagnosis, higher Karnofsky Performance Status score at diagnosis, the lower pathological grade, surgical resection modality, increasing diagnostic latency, and focal growth pattern were associated with better survival. On multivariate analysis, only the last two variables were associated with survival advantage. Focal pediatric brainstem gliomas amenable to a surgical resection are likely to achieve a prolonged survival. Clinical trials on larger number of patients are of importance in further understanding this spectrum of devastating diseases.

Bioprinting and its Use in Tumor-On-A-Chip Technology for Cancer Drug Screening: A Review.

The rising global incidence of cancer and high attrition rates of anticancer drugs make it imperative to design novel screening platforms to increase the success rate of chemotherapeutic agents. Advances in cell culture models from two-dimensional to three-dimensional platforms, along with microfluidics, have resulted in the creation of tumor-on-a-chip technology, which enables high-throughput molecular screening and helps to simulate the dynamic tumor microenvironment. Furthermore, advancements in bioprinting have allowed the structural and physiological aspects of the tumor to be recreated accurately and help to mimic cell-cell interactions and cell-extracellular matrix. This paper provides a comprehensive review of three-dimensional bioprinting to fabricate a tumor-on-a-chip platform to advance the discovery and screening of anticancer agents and provides a perspective on the challenges and future directions associated with the adoption of this technology to advance cancer research.

Sex differences in major cardiovascular outcomes and fractures in patients with subclinical thyroid dysfunction: a systematic review and meta-analysis.

OBJECTIVE: To evaluate whether sex differences in the associations of subclinical hypothyroidism (SH) and subclinical hyperthyroidism (SCH) with the risks of major adverse cardiovascular events (MACE) and fractures. METHODS: The PubMed, EmBase, and Cochrane Library databases were searched for eligible studies from inception until November 2021. The relative risk (RR) ratio with the 95% confidence interval (CI) was used to identify sex differences in the associations of SH and SCH with the risks of MACE and fractures. All analyses were performed using a random-effects model. RESULTS: Twenty-four cohort studies (in 3,480,682 patients) were selected for meta-analysis. There were no sex differences in the associations of SH and SCH with the risks of atrial fibrillation, all-cause mortality, cardiac death, coronary heart disease, heart failure, MACE, stroke, fracture. Subgroup analyses indicated a greater risk of MACE in men than in women with SH if follow-up was ≥10.0 years (RR ratio 2.44; 95% CI 1.17-5.10; P = 0.017). The risk of any fracture was greater in men than in women with SH if follow-up was <10.0 years (RR ratio 1.17; 95% CI 1.03-1.34; P = 0.017) and in studies with a high level of adjustment (RR ratio 1.16; 95% CI 1.02-1.32; P = 0.022). However, the risk of hip fracture was lower in men than in women with SH on pooling of studies with low adjustment (RR ratio 0.53; 95% CI 0.29-0.97; P = 0.039). CONCLUSIONS: There may be sex-related differences in the risks of MACE, any fracture, and hip fracture in patients with SH.

A prognostic risk model for glioma patients by systematic evaluation of genomic variations.

The overall survival rate of gliomas has not significantly improved despite new effective treatments, mainly due to tumor heterogeneity and drug delivery. Here, we perform an integrated clinic-genomic analysis of 1, 477 glioma patients from a Chinese cohort and a TCGA cohort and propose a potential prognostic model for gliomas. We identify that SBS11 and SBS23 mutational signatures are associated with glioma recurrence and indicate worse prognosis only in low-grade type of gliomas and IDH-Mut subtype. We also identify 42 genomic features associated with distinct clinical outcome and successfully used ten of these to develop a prognostic risk model of gliomas. The high-risk glioma patients with shortened survival were characterized by high level of frequent copy number alterations including PTEN, CDKN2A/B deletion, EGFR amplification, less IDH1 or CIC gene mutations, high infiltration levels of immunosuppressive cells and activation of G2M checkpoint and Oxidative phosphorylation oncogenic pathway.

AluScan: a method for genome-wide scanning of sequence and structure variations in the human genome.

BACKGROUND: To complement next-generation sequencing technologies, there is a pressing need for efficient pre-sequencing capture methods with reduced costs and DNA requirement. The Alu family of short interspersed nucleotide elements is the most abundant type of transposable elements in the human genome and a recognized source of genome instability. With over one million Alu elements distributed throughout the genome, they are well positioned to facilitate genome-wide sequence amplification and capture of regions likely to harbor genetic variation hotspots of biological relevance. RESULTS: Here we report on the use of inter-Alu PCR with an enhanced range of amplicons in conjunction with next-generation sequencing to generate an Alu-anchored scan, or 'AluScan', of DNA sequences between Alu transposons, where Alu consensus sequence-based 'H-type' PCR primers that elongate outward from the head of an Alu element are combined with 'T-type' primers elongating from the poly-A containing tail to achieve huge amplicon range. To illustrate the method, glioma DNA was compared with white blood cell control DNA of the same patient by means of AluScan. The over 10 Mb sequences obtained, derived from more than 8,000 genes spread over all the chromosomes, revealed a highly reproducible capture of genomic sequences enriched in genic sequences and cancer candidate gene regions. Requiring only sub-micrograms of sample DNA, the power of AluScan as a discovery tool for genetic variations was demonstrated by the identification of 357 instances of loss of heterozygosity, 341 somatic indels, 274 somatic SNVs, and seven potential somatic SNV hotspots between control and glioma DNA. CONCLUSIONS: AluScan, implemented with just a small number of H-type and T-type inter-Alu PCR primers, provides an effective capture of a diversity of genome-wide sequences for analysis. The method, by enabling an examination of gene-enriched regions containing exons, introns, and intergenic sequences with modest capture and sequencing costs, computation workload and DNA sample requirement is particularly well suited for accelerating the discovery of somatic mutations, as well as analysis of disease-predisposing germline polymorphisms, by making possible the comparative genome-wide scanning of DNA sequences from large human cohorts.

[Study on the meningoima using FT-mid-IR spectroscopy].

In the present investigation, 24 cases of meningoima tissues (including 12 cases of benign tumor and 12 cases of malignant tumor 12) were detected using FT-mid-IR spectroscopy linked with attenuated total reflectance (ATR) accessory. These FTIR spectra obtained from the above-mentioned meningoima tissues were analyzed and compared. Significant differences were found in the spectral features of different kinds of meningoima tissues for example fibrous type meningoima and endothelioid meningoima; and for the same type of meningoima tissues the significant differences in the spectram features can be also observed with the increase of grade malignancy. The malignant tumor can be distinguished primarily from benign tumor by the changes of position, shape and intensity of infrared absorption bands, particularly in the ranges of 1 000-1 500 cm(-1). The results show that the peak position of the bands (such as 1 160 cm(-1)) can be used to distinguish the characteristic of meningoima which are in agreement with the pathological results. The accuracy is larger than 85%. These results demonstrate that FT-mid-IR spectroscopy exhibits prospect to develop a novel, non-invasive and rapid method for the diagnosis the brain tumors.

Two-bone flap craniotomy for the transpetrosal-presigmoid approach to avoid a bony defect in the periauricular area after surgery on petroclival lesions: technical note.

The authors describe a two-bone-flap craniotomy technique to avoid the bone defect caused by the transpetrosal-presigmoid approach. Briefly, this technique includes three steps. The first step is to elevate a temporoparietal bone flap located superiorly to the transverse and sigmoid sinuses. The second step is to dissect the transverse and sigmoid sinuses away from the bone by inserting a gelatin sponge. This maneuver provides hemostasis and protects the sinuses from injury. The third step is to cut a second bone flap including part of the temporal bone and the outer table of the mastoid bone with a high-speed drill system. After the operation, the two bone flaps are fixed in place with titanium osteosynthesis fixation material. This approach provides a simple, easy, and safe technique for the transpetrosal-presigmoid approach. The technique has been performed in 83 patients treated for petroclival neoplasms with excellent cosmetic results.

[Preservation of pituitary stalk in the microsurgery of giant pituitary adenoma and its significance].

OBJECTIVE: To investigate and elucidate how to preserve the pituitary stalk in the microsurgery of giant pituitary adenoma (GPA) and its clinical significance. METHODS: 45 GPA patients, 23 males and 22 female; aged 40.8, including 12 cases of invasive pituitary adenoma (IPA) underwent craniotomy based on the respective preoperative neuroradiological imaging characteristics. The anatomical relationship between the pituitary stalk and tumor was recorded. The methods to protect the pituitary stalk were summarized. RESULTS: Total tumor excision was achieved in 25 patients (55.5%), near-total resection was done in 12 (26.7%), and subtotal resection in 8 (17.8%). During the surgical proceeding, the pituitary stalk was distinguished from the tumor and preserved well in all 33 cases with non-invasive giant pituitary adenoma. On the contrary, in the 12 cases of invasive giant pituitary adenoma (IPA) the pituitary stalk was visualized in only 7 cases. In the patients with visualized pituitary stalks 4 pituitary stalks were not identified very well. In most cases (91%) the pituitary stalks were located laterally (on the left or right side) or supero-posterior to the tumor, only a few were located anteriorly. In all 12 IPA patients 2 cases of postoperative hemorrhage occurred associated with remnant tumor and immediate hematoma evacuation was performed, however, one patient died due to hypothalamus injury. CONCLUSION: Pituitary stalk has various anatomical relationships to the entity of GPA; most are located lateral or supero-posterior to the tumor. However, the relationship between the stalk and tumor is not clear in IPA. Identifying and preserving the pituitary stalk well during surgical manipulation will be beneficial to get an excellent outcome.

Prospective investigation of folic acid supplements before and during early pregnancy and paediatric and adult cancers in the Chinese children and families cohort: a pilot study in a sample of rural and urban families.

OBJECTIVE: To determine the feasibility of long-term prospective follow-up and ascertainment of cancer in offspring and mothers from the 1993-1995 Chinese Community Intervention Program that provided folic acid supplements before and during early pregnancy to reduce neural tube defects. DESIGN: Feasibility pilot study for a prospective cohort study. SETTING: Families residing during 2012-2013 in one rural and one urban county from 21 counties in 3 provinces in China included in the Community Intervention Program campaign. PARTICIPANTS: The feasibility study targeted 560 families, including 280 from the rural and 280 from the urban county included in the large original study; about half of mothers in each group had taken and half had not taken folic acid supplements. INTERVENTION: The planned new study is observational. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary: incidence of paediatric cancers in offspring; secondary: other chronic diseases in offspring and chronic diseases in mothers RESULTS: Only 3.4% of pilot study families could not be found, 3.9% had moved out of the study area and 8.8% refused to participate. Interviews were completed by 82% of mothers, 79% of fathers and 83% of offspring in the 560 families. Almost all mothers and offspring who were interviewed also participated in anthropometric measurements. We found notable urban-rural differences in sociodemographic and lifestyle characteristics of the parents, but fewer differences among the offspring. In eight catchment area hospitals, we identified a broad range of paediatric cancers diagnosed during 1994-2013, although paediatric brain tumours, lymphomas and rarer cancers were likely under-represented. CONCLUSIONS: Overall, 20 years after the original Community Intervention Program, the pilot study achieved high levels of follow-up and family member interview participation, and identified substantial numbers of paediatric malignancies during 1994-2013 in catchment area hospitals. Next steps and strategies for overcoming limitations are described.

Different aspects of dysexecutive syndrome in patients with moyamoya disease and its clinical subtypes.

OBJECTIVE Dysexecutive syndrome is common in patients with moyamoya disease (MMD), a chronic cerebrovascular disease that is characterized by stenosis of the bilateral internal carotid arteries and progressive collateral revascularization, and MMD can be classified as ischemic or hemorrhagic according to the disease presentation and history. In this study, the authors aimed to determine which aspects of executive function are impaired in patients with MMD, in addition to the specific dysexecutive functions present among its clinical subtypes and the mechanisms underlying dysexecutive function in these patients. METHODS The authors administered 5 typical executive function tests (the Stroop test, the Hayling Sentence Completion Test [HSCT], the verbal fluency [VF] test, the N-back test, and the Sustained Attention to Response Task [SART]) to 49 patients with MMD and 47 IQ-, age-, education-, and social status-matched healthy controls. The dysexecutive questionnaire (DEX) was also used to assess participants' subjective feelings about their executive function. A total of 39 of the patients were evaluated by CT perfusion (CTP) before the assessments were performed, and the correlations among the performances of the patients on the above tests with the parameters of cerebral blood volume, cerebral blood flow (CBF), mean transit time (MTT), and time-to-peak (TTP) in the frontal lobes of these patients were also analyzed. RESULTS Many aspects of executive function in the patients with MMD were significantly poorer than those in the healthy controls, and the patients performed particularly poorer on the VF test, HSCT, N-back test, and SART. The patients with hemorrhagic MMD exhibited worse executive inhibition, executive processing, and semantic inhibition compared with those with ischemic MMD, but the latter group presented a worse working memory and poorer sustained attention. There were no significant differences in the DEX scores between the patients with MMD and healthy controls. The other findings were as follows: CBF was significantly positively correlated with the number correct on part B of the HSCT (r = 0.481, p = 0.01) and accuracy on the 0-back task of the N-back (r = 0.346, p = 0.031); MTT was significantly positively correlated with accuracy on the 2-back task of the N-back (r = 0.349, p = 0.034) and factor 5 of the DEX (r = 0.359, p = 0.032); and TTP was significantly positively correlated with the number correct on part B of the HSCT (r = 0.402, p = 0.034) and the 1-back reaction time of the N-back (r = 0.356, p = 0.026). CONCLUSIONS The patients with MMD exhibited impairments in semantic inhibition, executive processing, working memory, and sustained attention, but they were not aware of these deficits. Moreover, differences in dysexecutive function existed between the different subtypes of MMD. Hypoperfusion of the frontal lobe may be related to working memory and semantic inhibition impairments in patients with MMD.

SET and MYND domain-containing protein 3 is overexpressed in human glioma and contributes to tumorigenicity.

SET and MYND domain-containing protein 3 (SMYD3) is a histone H3 lysine 4 (H3K4) di- and tri-methyltransferase that forms a transcriptional complex with RNA polymerase II and plays an important role in early embryonic lineage commitment through the activation of lineage-specific genes. SMYD3 activates the transcription of oncogenes and cell cycle genes in gastric and breast cancer cells. However, the contribution of SMYD3 in glioma tumorigenesis remains unknown. Here, we determined the expression of SMYD3 and assessed its clinical significance in human glioma. We found that SMYD3 was overexpressed in human glioma but not in normal brain tissue. The level of SMYD3 protein expression in human glioma tissues was directly correlated with the glioma grade. The level of SMYD3 protein expression in human glioma tissues was inversely correlated with patient survival. Enforced SMYD3 expression promoted glioma LN-18 cell proliferation. Inhibition of SMYD3 expression in glioma T98G cells suppressed their anchorage­independent growth in vitro and tumorigenicity in vivo. Furthermore, we found that SMYD3 regulated the expression of p53 protein, which is essential in SMYD3­induced cell growth in glioma cells. These results showed that SMYD3 is overexpressed in human glioma and contributes to glioma tumorigenicity through p53. Therefore, SMYD3 may be a new potential therapeutic target for human malignant glioma.

Glioma Association and Balancing Selection of ZFPM2.

ZFPM2, encoding a zinc finger protein and abundantly expressed in the brain, uterus and smooth muscles, plays important roles in cardiac and gonadal development. Abnormal expression of ZFPM2 in ovarian tumors and neuroblastoma has been reported but hitherto its genetic association with cancer and effects on gliomas have not been studied. In the present study, the hexamer insertion-deletion polymorphism rs71305152, located within a large haplotype block spanning intron 1 to intron 3 of ZFPM2, was genotyped in Chinese cohorts of glioma (n = 350), non-glioma cancer (n = 354) and healthy control (n = 463) by direct sequencing and length polymorphism in gel electrophoresis, and ZFPM2 expression in glioma tissues (n = 69) of different grades was quantified by real-time RT-PCR. Moreover, potential natural selection pressure acting on the gene was investigated. Disease-association analysis showed that the overall genotype of rs71305152 was significantly associated with gliomas (P = 0.016), and the heterozygous genotype compared to the combined homozygous genotypes was less frequent in gliomas than in controls (P = 0.005) or non-glioma cancers (P = 0.020). ZFPM2 mRNA expression was negatively correlated with the grades of gliomas (P = 0.002), with higher expression levels in the low-grade gliomas. In the astrocytoma subtype, higher ZFPM2 expression was also correlated with the rs71305152 heterozygous genotype (P = 0.028). In addition, summary statistics tests gave highly positive values, demonstrating that the gene is under the influence of balancing selection. These findings suggest that ZFPM2 is a glioma susceptibility gene, its genotype and expression showing associations with incidence and severity, respectively. Moreover, the balancing selection acting on ZFPM2 may be related to the important roles it has to play in multiple organ development or associated disease etiology.