TPD52L2 impacts proliferation, invasiveness and apoptosis of glioblastoma cells via modulation of wnt/ß-catenin/snail signaling.

Intratumoral heterogeneity greatly hinders efficiency of target therapy in glioblastoma (GBM). To decipher the underlying mechanisms of heterogeneity, patient-derived adult GBM cells were separately isolated from margins of T1 gadolinium enhancing tumor lesions (PNCs) and T1 gadolinium enhancing core lesions (ECs). Single clone culture was conducted in ECs and U87MG cell line to screen clones with distinct biological phenotypes. Single cell clones with diverse phenotypes were simultaneously separated from ECs and U87 cell line. PNCs, GCs(H) and U87(H) exhibited longer cellular protrusion than ECs, GCs(L) and U87(L), respectively. Cell strains with longer protrusion exhibited higher invasive ability and lower sensitivity to temozolomide (TMZ) and radiation. Subsequently, TPD52L2 was verified as the functional protein to regulate the cellular heterogeneity by the proteomics analysis. Downregulation of TPD52L2 enhanced cell invasion whereas inhibited cell proliferation rate and sensitivity to chemotherapy in vivo and in vitro, this condition was reversed when TPD52L2 was overexpressed. The invasiveness was facilitated by up-regulating CTNNB1/ß-catenin and SNAI1/Snail mediated EMT process. In addition, the clinical data of 88 GBM cases in our neurosurgery center was analyzed to reveal the influence of TPD52L2 in the prognosis of GBM. Low expression of TPD52L2 exacerbated prognosis of GBM patients received standard radiotherapy plus concomitant and adjuvant TMZ (Stupp strategy). Taken together, TPD52L2 is an important biomarker influencing GBM prognosis.

MACF1 knockdown in glioblastoma multiforme cells increases temozolomide-induced cytotoxicity / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the role of microtubule-actin crosslinking factor 1 (MACF1) in the response of glioma cells to temozolomide (TMZ).</p><p><b>METHODS</b>TMZ was applied to a human gliomablastoma cell line (U87) and changes in the protein expression and cellular localization were determined with Western blot, RT-PCR, and immunofluorescence. The responses of the cells with MACF1 expression knockdown by RNA interference to TMZ were assessed. TMZ-induced effects on MACF1 expression were also assessed by immunohistochemistry in a nude mouse model bearing human glioblastoma xenografts.</p><p><b>RESULTS</b>TMZ resulted in significantly increased MACF1 expression (by about 2 folds) and changes in its localization in the gliomablastoma cells both in vitro and in vivo (P<0.01). Knockdown of MACF1 reduced the proliferation (by 45%) of human glioma cell lines treated with TMZ (P<0.01). TMZ-induced changes in MACF1 expression was accompanied by cytoskeletal rearrangement.</p><p><b>CONCLUSION</b>MACF1 may be a potential therapeutic target for glioblastoma.</p>

MiR-519a functions as a tumor suppressor in glioma by targeting the oncogenic STAT3 pathway.

Glioblastoma (GBM) is among the most aggressive primary brain tumors, with a median survival rate of 12-15 months. MicroRNAs have been implicated in GBM development as oncogenes or tumor suppressors. In this study, we demonstrated that miR-519a expression was frequently downregulated in GBM specimens and cell lines, and that low-levels miR-519a expression significantly correlated with poor outcomes associated with GBM. Analysis of The Cancer Genome Atlas also demonstrated that low miR-519a expression can predict poor clinical outcomes in classical and proneural GBM subtypes. Functionally, re-expression of miR-519a effectively reduced GBM cell proliferation, migration, and invasion. Mechanistically, we confirmed that the signal transducer and activator of transcription 3 (STAT3) 3'-UTR was a putative target of miR-519a, and that re-expression of STAT3 abrogated miR-519a function in GBM cells. Furthermore, we found that STAT3 expression negatively correlated with that of miR-519a in human GBM tissues. These results elucidated the prognostic value and tumor-suppressor role of miR-519a in GBM and further suggested it as a potential therapeutic target for GBM treatment.

Does the calcification of adamantinomatous craniopharyngioma resemble the calcium deposition of osteogenesis/odontogenesis?

AIMS: Calcification in adamantinomatous craniopharyngioma (ACP) is troublesome for surgical intervention. The aim of this study was to examine the osteogenic proteins that play important roles in the calcium deposition of the odontogenic/osteogenic tissues in craniopharyngioma. METHODS AND RESULTS: Craniopharyngiomas (n = 89) were investigated for the presence and expression pattern of the osteoinductive/odontoinductive factor bone morphogenetic protein-2 (Bmp2) and two osteoblastic differentiation makers, Runt-related transcription factor-2 (Runx2) and Osterix, using immunohistochemistry and Western blotting. Our results showed that Bmp2, Runx2 and Osterix levels increased in cases with high calcification and correlated positively with the degree of calcification in ACP, whereas they showed little or no expression in squamous papillary craniopharyngioma. In ACP, Bmp2 was expressed primarily in the stellate reticulum and whorl-like array cells; Runx2 and Osterix tended to be expressed in calcification-related epithelia, including whorl-like array cells and epithelia in/around wet keratin and calcification lesions. CONCLUSIONS: Our study indicated, for the first time, that osteogenic factor Bmp2 may play an important role in the calcification of ACP via autocrine or paracrine mechanisms. Given the presence of osteogenic markers (Runx2 and Osterix), craniopharyngioma cells could differentiate into an osteoblast-like lineage, and the process of craniopharyngioma calcification resembles that which occurs in osteogenesis/odontogenesis.

Association between the XRCC1 Arg399Gln polymorphism and risk of cancer: evidence from 297 case-control studies.

BACKGROUND: The Arg399Gln polymorphism in the X-ray cross-complementing group 1 (XRCC1) had been implicated in cancer susceptibility. The previous published data on the association between XRCC1 Arg399Gln polymorphism and cancer risk remained controversial. METHODOLOGY/PRINCIPAL FINDINGS: To derive a more precise estimation of the association between the XRCC1 Arg399Gln polymorphism and overall cancer risk, we performed a meta-analysis of 297 case-control studies, in which a total of 93,941 cases and 121,480 controls were included. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ration [OR] = 1.04, 95% confidence interval [CI] = 1.01-1.07; recessive model: OR = 1.08, 95% CI = 1.03-1.13; additive model: OR = 1.09, 95% CI = 1.04-1.14) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, significantly elevated hepatocellular and breast cancers risk were observed in Asians (dominant model: OR = 1.39, 95% CI = 1.06-1.84) and in Indians (dominant model: OR = 1.64, 95% CI = 1.31-2.04; recessive model: OR = 1.94, 95% CI = 1.09-3.47; additive model: OR = 2.06, 95% CI = 1.50-2.84), respectively. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests the participation of XRCC1 Arg399Gln is a genetic susceptibility for hepatocellular cancer in Asians and breast cancer in Indians. Moreover, our work also points out the importance of new studies for Arg399Gln association in some cancer types, such as glioma, gastric cancer, and oral cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the XRCC1 Arg399Gln polymorphism in cancer development.

Diagnostic characteristics of optic chiasm-hypothalamic glioma and its high misdiagnosis rate / 中华神经医学杂志

[Objective]To investigate the diagnostic characteristics of optic chiasm-hypothalamic glioma (OCHG) and the reasons for its high misdiagnosis rate.[Methods]Retrospective analysis was performed on the clinical features and imaging findings of 32 patients with OCHG,admitted to our hospitals from October 1999 to December 2011 and proved by pathology.Being compared with those features of other diseases in the sellar region,the reasons for high misdiagnosis rate of OCHG were analyzed.[Results] Among the 32 patients,18 were diagnosed correctly before surgery.However,in the other 14,lesions were misdiagnosed as craniopharyngioma in 8,germ cell tumor in 4,pituitary adenoma in 1,and chordoma in 1 with a total misdiagnosis rate reaching 43％.All patients suffered craniotomy surgery for tumor removal.Among the 4 patients misdiagnosed as having germinoma,2 underwent preoperative radiotherapy and 2 performed preoperative EP regimen chemotherapy.According to the features of the CT and MR images,the OCHG were divided into 3 presentations:solid,solid and cyst mixture and round enhanced tumors.The solid lesions (n=10) were easily misdiagnosed as germinoma (4/10,40％);however,the round enhanced tumors (n=5),especially combined with huge calcification (n=4),were extremely easily misdiagnosed as craniopharyngioma (4/5,80％ ).[Conclusion] Comprehensive understanding the growth and image features of OCHG and summing up the misdiagnosis points when comparing to the other diseases in the sellar region are indispensable in improving the presurgical diagnosis accuracy for OCHG.

Intraoperative EMG monitoring in surgery of tumor in the floor of the fourth ventricle / 中华神经医学杂志

Objective To analyze the protective role of intraoperative EMG monitoring in surgical removal of tumors related to the floor of the fourth ventricle and its influencing factors.Methods Intraoperative EMG monitoring was performed during the surgical removal of 32 patients with brain tumor, admitted to our hospital from January 2007 to December 2010; among these 32patients, 11 was conformed as having medulloblastoma, 9 ependymoma, 6 brain stem cavernous hemangioma, 4 brain stem exogenous glioma and 2 hemangioblastoma of the dorsal brain stem. The influencing factors of intraoperative EMG monitoring and the possible damage of cranial nerve nuclei caused by these surgical procedures were analyzed.Results Twenty-one patients enjoyed total removal, 9 sub-total removal and 2 partial removal. Good function protection of patient's posterior cranial nerves was noted in 9 patients, mild impairment in 18 patients, and moderate dysfunction in 5 patients.The influencing factors of EMG monitoring included leaking electric current caused by bipolar coagulation, excessive use of muscle relaxant drugs, changes in depth of anesthesia, and rapid changes of patient′s temperature, saline temperature and blood pressure. Conclusion The intraoperative EMG monitoring can provide evidence about the location of the cranial motor nuclei during the surgical removal of the tumor related to the floor of the fourth ventricle and the function protection of patient’s posterior cranial nerves.

The arachnoid sleeve enveloping the pituitary stalk: anatomical and histologic study.

BACKGROUND: The arachnoid membrane in the suprasellar region may affect the growth pattern of sellar and suprasellar tumors however, the topographic relationships between the pituitary stalk and the surrounding arachnoid membranes remained unclear. OBJECTIVE: The aim of this study was to evaluate the anatomical and histological characteristics of the arachnoid membranes. METHODS: Microsurgical dissection and anatomical observation were performed in 16 formalin-fixed adult cadaver heads. In the other 5 adult cadaver heads, histologic sections of sellar-suprasellar specimens were studied under light microscopy. RESULTS: An arachnoid sleeve enveloping the pituitary stalk of variable length presented in all specimens, which was formed by direct upward extension of the basal arachnoid membrane covering the diaphragma sellae. In the majority of specimens, the arachnoid sleeve was reinforced by the arachnoid trabeculae originating from the basal arachnoid membrane, the Liliequist membrane, and the medial carotid membrane. CONCLUSION: The relationship between the pituitary stalk and the surrounding arachnoid membrane is important in evaluating the growth patterns of the sellar and suprasellar tumors, and their topographical relationships.

Microsurgical removal of huge tuberculum sellae meningiomas through bi-subfrontal anterior longitudinal fission approach / 南方医科大学学报

<p><b>OBJECTIVE</b>To summary the microsurgical techniques for removal of huge tuberculum sellae meningiomas through the bi-subfrontal anterior longitudinal fission approach.</p><p><b>METHODS</b>Eleven patients with huge tuberculum sellae meningiomas underwent microsurgical removal of the meningiomas between January, 2005 and November, 2009. The microsurgical techniques were summarized, and the factors affecting the prognosis were analyzed.</p><p><b>RESULTS</b>Among all the patients, 5 had Simpson grade I meningioma removal and the other patients had Simpson grade II removal. No death occurred in these patients. Nine patients showed vision improvement after the surgery, one had no significant improvement, and the other one experienced worsening of vision. Transient postoperative diabetes insipidus occurred in 5 cases.</p><p><b>CONCLUSION</b>With satisfactory exposure of Dorsum sellae, bottom of the third ventricle and cavernous sinus, the bi-subfrontal anterior longitudinal fission approach is suggested for treatment of tuberculum sellae meningiomas. The key to improve the GTR and reduce the complication lies in the sequence of the operation, namely resection of the tumoral basement before dissection of the potential arachnoidal space and tuberculum.</p>

Clinical pathology of pineal region tumors / 中华神经医学杂志

Objective To investigate the pathological distribution and clinical characteristics of pineal region tumors (PRTs) with variant pathology.Methods We retrospectively analyzed the clinical and pathological data of 133 patients with PRTs that were performed surgical removal from January 2000 to January 2009 in our hospital.Results Sixty-one patients (45.9%) were diagnosed as having germ cell tumors,17 (12.8%) pineal parenchymal tumors,28 (21.1%) gliomas and 27 (20.2%)other resource tumors.Sex ratio of patients with germ cell tumors,pineal parenchymal tumors and gliomas were 14.25:1 (male:female),2.4:1 and 1.15:1,respectively; their median ages were 15.3,24.7 and 28.1,respectively.The serum immunologic test showed abnormal results in 33 patients; except for 1 with metastatic tumors,the others were diagnosed as having germ cell tumors.Conclusion PRTs have many pathological types and patients with PRTs are mainly diagnosed as having germ cell tumors.Correct diagnosis can not be made by imaging,serum immunologic test or biopsy, thus,obtaining complete clinical specimen during the total tumor removal is very necessary in studying the pathology of PRTs.

Regional anatomy of the diaphragmatic foramen and its clinical significance / 中华神经医学杂志

Objective To perform an anatomical study of the structures around the diaphragmatic foramen and analyze the mechanism of cerebrospinal fluid leak and empty sella(ES).Methods With HE and Masson staining,the structures around the diaphragmatic foramen were observed microscopically on serial histological sections of 8 fetal specimens.The transsphenoidal approach was then simulated in 10 adult cadaver heads,and the structures around the diaphragnmatic foramen were observed under an operating microscope.Results The suprasellar arachnoid adhered tightly to the pia mater covering the upper part of the pituitary stalk,and folded into the sella through the diaphragmatic foramen.On the upper surface of the pituitary gland,the diaphragm adhered to the pia mater of the gland around the foramen,and their histological boundaries could not be distinctly identified on the serial sections.The suprasellar cistern terminated above the foramen due to the restriction by the arachnoid,pia mater and sellae diaphragma.Conclusion The close anatomic relationship between the sellae diaphragm,pia mater,and suprasellar arachnoid is critical to prevention of cerebrospinal fluid leak,and the breach of this anatomic relation,especially in the transsphenoidal approach for pituitary adenoma management that causes excessive traction of the tumor,results in separation or rupture of the arachnoid and pia mater,which can be an important factor contributing to cerebrospinal fluid leak.The separation of the sellae diaphragm,pia mater and the upper surface of the pituitary gland may also play an important role in the occurrence of ES.

Clinical features of Symptomatic Rathke's cleft cyst and its surgical treatment / 中华神经医学杂志

Objective To explore the management of endocrine disturbance related to Symptomatic Rathke's cleft cysts (RCCs) in both pre- and post-operation, as well as the risk factors for the recurrence of RCCs after the operation. Methods The clinical manifestations, radiological and pathologic features, treatment, and surgical outcomes of 11 cases of symptomatic RCCs were reviewed retrospectively. Results Headache recovered in 100% of patients and visual disturbance improved in 83.3%, and Amenorrhea and/or galactorrhea recovered or improved in 66.7% of patients. However, diabetes insipidus and panhypopituitarism did not improve postoperatively. Transcranial surgery was performed in 6 patients and transsphenoidal surgery in 5 patients. No recurrence occurred in transcranial radical resected cases while 2 of 5 subtotally removed cases recurred with an average follow-up of 34.5 months. Inflammation was present in two of the recurrent cases. Conclusion RCCs is a rare pathology with a wide specctrum of clinical and radiological features. Accurate preoperative diagnosis can be difficult. Endocrine disturbance should be evaluated both pre- and post-operatively, and proper hormones replacement therapy is mandatory in these selected patients, Removing as much as possible and multiple biopsies around the cyst wall will be helpful in accurate diagnosis, especially of cases showing atypical pathologic findings, and special attention should be paid to follow-up examination.

Microsurgical anatomy of the perforating arteries in the superior space of the internal carotid artery through a pterional approach / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the microanatomy of the perforating arteries in the superior space of the internal carotid artery visualized through a pterional approach.</p><p><b>METHODS</b>Twelve (24 sides) perfused cadaver heads were dissected via the pterional approach, and the perforating arteries in the superior space of the internal carotid artery were studied under microscope. The diameter, course and distribution in the anterior perforated substance of the perforating arteries were recorded.</p><p><b>RESULTS</b>All the perforating arteries exposed lied on the side of the brain tissue. The carotid bifurcation on 8 sides had perforating arteries, and 11 sides showed medial lenticulostriate artery of the middle cerebral arteries, with short course and overlapped with another perforating arteries upon entry into the anterior perforated substance. On 4 sides, the medial lenticulostriate artery coincided with the perforating arteries in A1. All 24 sides showed middle lenticulostriate artery and lateral lenticulostriate artery of the middle cerebral arteries. Most of the lenticulostriate arteries originated from the anterior segment of the bifurcation of the middle cerebral arteries. The earlier bifurcation occurred in M1 of the middle cerebral arteries, the more perforating arteries originated. On 22 sides, the anterior cerebral arteries had perforating arteries with many branches, and fewer perforating arteries in a main artery were associated with greater diameter of them.</p><p><b>CONCLUSION</b>The superior space of the internal carotid artery allows a space for operation, and in some cases, part of the medial leticulostriate arteries and A1 perforating arteries can be severed to obtain larger space for the operation.</p>

Anatomical study of venous spaces in transsphenoidal approach for cavernous sinus surgery / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the anatomical and morphological characteristics of the venous spaces involved in surgery via transsphenoidal approach to the cavernous sinus (CS).</p><p><b>METHODS</b>Ten fixed cadaver heads (six male, four female) with red and blue latex injected in the arteries and veins, respectively, were used to perform the transsphenoidal approach. The anterior wall of the sphenoidal sinus and the floor of sellar turcica were opened as much as possible to expose the dura mater at the sellar floor and the inferior wall of CS, and the location of the anterior and inferior intercavernous sinuses were observed carefully. All the spaces of CS were observed and measured. According to the observations, the venous spaces available for operation were identified and analyzed.</p><p><b>RESULTS</b>In all the cadaver heads, 4 anterior and 5 inferior intercavernous sinuses were found, with the former locating below the optic protuberance, while the latter situated at the turn of the sellar protuberance at the clival indentation. CS was subdivided into medial space, inferolateral space, and dorsolateral space.</p><p><b>CONCLUSIONS</b>In transsphenoidal approach, opening of anterior and inferior intercavernous sinus is liable to result in intra- and postoperative venous bleeding, and understanding of the location of the intercavernous sinus and appropriate utilization of these CS may help reduce intraoperative vascular and nerve injury.</p>