Publications by authors named "Zhenggang Xiong"

35 Publications

Bioinformatics integrated analysis to investigate candidate biomarkers and associated metabolites in osteosarcoma.

J Orthop Surg Res 2021 Jul 5;16(1):432. Epub 2021 Jul 5.

Department of Orthopedics and Trauma, The Second Hospital of Shandong University, No. 247 Beiyuan Street, Jinan, 250033, China.

Background: This study hoped to explore the potential biomarkers and associated metabolites during osteosarcoma (OS) progression based on bioinformatics integrated analysis.

Methods: Gene expression profiles of GSE28424, including 19 human OS cell lines (OS group) and 4 human normal long bone tissue samples (control group), were downloaded. The differentially expressed genes (DEGs) in OS vs. control were investigated. The enrichment investigation was performed based on DEGs, followed by protein-protein interaction network analysis. Then, the feature genes associated with OS were explored, followed by survival analysis to reveal prognostic genes. The qRT-PCR assay was performed to test the expression of these genes. Finally, the OS-associated metabolites and disease-metabolic network were further investigated.

Results: Totally, 357 DEGs were revealed between the OS vs. control groups. These DEGs, such as CXCL12, were mainly involved in functions like leukocyte migration. Then, totally, 38 feature genes were explored, of which 8 genes showed significant associations with the survival of patients. High expression of CXCL12, CEBPA, SPARCL1, CAT, TUBA1A, and ALDH1A1 was associated with longer survival time, while high expression of CFLAR and STC2 was associated with poor survival. Finally, a disease-metabolic network was constructed with 25 nodes including two disease-associated metabolites cyclophosphamide and bisphenol A (BPA). BPA showed interactions with multiple prognosis-related genes, such as CXCL12 and STC2.

Conclusion: We identified 8 prognosis-related genes in OS. CXCL12 might participate in OS progression via leukocyte migration function. BPA might be an important metabolite interacting with multiple prognosis-related genes.
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http://dx.doi.org/10.1186/s13018-021-02578-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256509PMC
July 2021

Immune-related prognostic genes signatures in the tumor microenvironment of sarcoma.

Math Biosci Eng 2021 03;18(3):2243-2257

Department of Orthopedics and Trauma, The Second Hospital of Shandong University, No. 247 Beiyuan Street, Jinan, 250033, China.

Sarcomas are a heterogeneous group of malignant mesenchymal neoplasms. This study aimed to investigate the immune-related prognostic gene signatures in the tumor microenvironment of sarcoma. The RNA-sequencing data and clinical phenotype data of 260 sarcoma samples and two normal samples were downloaded from The Cancer Genome Atla (TCGA) database. Tumor purity and immune cells infiltration were evaluated by Estimation of Stromal and Immune cells in Malignant Tumors using Expression data (ESTIMATE) deconvolution algorithm. Differentially expressed genes (DEGs) were screened in high vs. low immune score groups. Survival analysis was performed using Kaplan-Meier curve with log-rank test. Tumor infiltrating of immune cells was analyzed by Tumor Immune Estimation Resource (TIMER). High immune score and ESTIMATE score were associated with favorable prognosis. A total of 623 immune DEGs were screened. The majority of these genes (532 genes accounting for 85% of the DEGs) were up-regulated, and these genes were significantly enriched in various immune related biological processed and pathways, such as neutrophil activation, T cell activation, antigen processing and presentation. A total of 146 prognosis-related immune DEGs, and seven hub genes were identified, including B2M, HLA-DRB1, HLA-DRA, HLA-E, LCK, HLA-DPA1, and VAV1. Survival analysis showed that high expression of these genes was associated with a favorable prognosis. There were negative correlations between the expression of these hub genes and tumor purity, while positive correlations between expression of these hub genes and f infiltration levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages and dendritic cells. These results help to stratify patients with different immune subtypes and help to design immunotherapy strategies for these patients in sarcoma.
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http://dx.doi.org/10.3934/mbe.2021113DOI Listing
March 2021

Generation of glioblastoma patient-derived organoids and mouse brain orthotopic xenografts for drug screening.

STAR Protoc 2021 Mar 18;2(1):100345. Epub 2021 Feb 18.

Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA.

Robust patient-derived platforms that recapitulate the cellular and molecular fingerprints of glioblastoma are crucial for developing effective therapies. Here, we describe a chemically defined protocol for 3D culture and propagation of glioblastoma in 3D gliospheres, patient-derived organoids (PDOs), mouse brain orthotopic xenografts (PDOXs), and downstream drug and immunofluorescence assays. This simple-to-follow protocol allows assessing drug sensitivity, on-target activity, and combined drug synergy. Promising therapies can then be validated in PDOXs for translation in precision medicine oncology trials. For complete details on the use and execution of this protocol, please refer to Chadwick et al. (2020) and Patrizii et al. (2018).
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http://dx.doi.org/10.1016/j.xpro.2021.100345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903462PMC
March 2021

Lateral Myelotomy for Resection of a Ruptured Intramedullary Cervico-Thoracic Cavernous Malformation.

Oper Neurosurg (Hagerstown) 2021 03;20(4):E317-E321

Department of Neurological Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey.

Background And Importance: Intramedullary spinal cord cavernous malformations represent 5% to 12% of spinal vascular disease. Most patients present with acute or progressive neurological symptoms, including motor weakness or sensory loss. Surgical resection is the only definitive management and is recommended for symptomatic lesions that are surgically accessible.

Clinical Presentation: A 35-yr-old woman presented with a sudden onset of pain and temperature sensation loss in the left lower extremity. Magnetic resonance imaging of the spine showed a hemorrhage located ventral and slightly lateral to the right of the midline of the spinal cord from C7 through T3. Ultimately, a right lateral myelotomy between the ventral and dorsal roots was performed, and the cavernous malformation was removed. Postoperative imaging confirmed gross total resection of the cavernous malformation.

Conclusion: In this article, we report a highly unusual case of a multisegment, ruptured intramedullary cavernous malformation that was ultimately resected through a lateral myelotomy approach. This case demonstrates that a lateral approach to the spinal cord substance can be utilized for ruptured cavernous malformation, especially if there is hemorrhage at the surface of the spinal cord. This can be used as an entry into the anterolateral compartment of the spinal cord, which would otherwise be regarded as a highly morbid approach due to the sensory deficits induced. We believe this entry point to the spinal cord is feasible in highly select cases such as this.
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http://dx.doi.org/10.1093/ons/opaa417DOI Listing
March 2021

Increased (Pro)renin Receptor Expression in the Hypertensive Human Brain.

Front Physiol 2020 19;11:606811. Epub 2020 Nov 19.

Departments of Pharmacology and Physiology & Cell Biology, University of Nevada, Reno, School of Medicine, Reno, NV, United States.

Overactivation of the renin-angiotensin system (RAS) - a central physiological pathway involved in controlling blood pressure (BP) - leads to hypertension. It is now well-recognized that the central nervous system (CNS) has its own local RAS, and the majority of its components are known to be expressed in the brain. In physiological and pathological states, the (pro)renin receptor (PRR), a novel component of the brain RAS, plays a key role in the formation of angiotensin II (Ang II) and also mediates Ang II-independent PRR signaling. A recent study reported that neuronal PRR activation is a novel mechanism for cardiovascular and metabolic regulation in obesity and diabetes. Expression of the PRR is increased in cardiovascular regulatory nuclei in hypertensive (HTN) animal models and plays an important role in BP regulation in the CNS. To determine the clinical significance of the brain PRR in human hypertension, we investigated whether the PRR is expressed and regulated in the paraventricular nucleus of the hypothalamus (PVN) and rostral ventrolateral medulla (RVLM) - two key cardiovascular regulatory nuclei - in postmortem brain samples of normotensive (NTN) and HTN humans. Here, we report that the PRR is expressed in neurons, but not astrocytes, of the human PVN and RVLM. Notably, PRR immunoreactivity was significantly increased in both the PVN and RVLM of HTN subjects. In addition, PVN-PRR immunoreactivity was positively correlated with systolic BP (sBP) and showed a tendency toward correlation with age but not body mass index (BMI). Collectively, our data provide clinical evidence that the PRR in the PVN and RVLM may be a key molecular player in the neural regulation of BP and cardiovascular and metabolic function in humans.
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http://dx.doi.org/10.3389/fphys.2020.606811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710895PMC
November 2020

Intraventricular pilocytic astrocytoma in an adult patient.

Intractable Rare Dis Res 2020 Nov;9(4):260-262

Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, NJ, USA.

Pilocytic astrocytomas are tumors of the central nervous system mostly during the first two decades of life. Although they are mostly common in the midline structures of children, pilocytic astrocytoma within the ventricular system of an adult is extremely rare. We report a case of a 38-year old woman with obstructive hydrocephalus secondary to a brain tumor within the third ventricle. On histological examination, the tumor exhibited biphasic growth pattern comprising compacted cellular areas with Rosenthal fibers and loose textured microcystic areas with eosinophilic granular bodies. Mitosis or necrosis was not present. Immunohistochemical studies demonstrated glial fibrillary acid protein (GFAP), Olig2, and ATRX positivity as well as NeuN and EMA negativity. Ki67 labeling index was less than 1%. Molecular studies revealed that there are no isocitrate dehydrogenase () gene mutation and mutation. This clinical presentation along with the histologic and molecular findings is consistent with a pilocytic astrocytoma arising in the third ventricle of this adult brain, which indicates that pilocytic astrocytoma can present as an intraventricular tumor in an adult patient and should be routinely included in the differential diagnosis of intraventricular brain neoplasm.
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http://dx.doi.org/10.5582/irdr.2020.03088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586879PMC
November 2020

Cranial intraosseous angiolipoma: case report and literature review.

Intractable Rare Dis Res 2020 Aug;9(3):175-178

Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA.

Angiolipomas are slow-growing, soft tissue tumors consisting of mature adipocytes and thin-walled blood vessels. While most angiolipomas are subcutaneous lesions in the trunk and upper extremities, intraosseous angiolipomas are rare at cranial site. We present the case of a 61-year-old female with an enlarging lesion in the left frontoparietal skull following minor head trauma. Radiography confirmed an expansile, enhancing, spiculated bony lesion in the left frontoparietal calvarium with extension outside the cortex into the soft tissues. She underwent a craniectomy for complete resection of the calvarial mass, which was histologically composed of mature adipocytes and disorganized blood vessels highlighted by an immunophenotype positive for S100 and CD34, respectively, consistent with a cranial intraosseous angiolipoma. The review of the literature that reported five cases of cranial intraosseous angiolipoma with our case representing the sixth case is discussed.
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http://dx.doi.org/10.5582/irdr.2020.03038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441033PMC
August 2020

Intramedullary Spinal Cord Metastasis from Primary Lung Neuroendocrine Carcinoma: A Case Report and Operative Video.

World Neurosurg 2021 01 20;145:426-431. Epub 2020 Aug 20.

Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. Electronic address:

Background: Intramedullary spinal cord metastasis (ISCM) account for a minority of all spinal cord tumors. Rarely, symptoms from ISCM may be the initial presentation of an unknown primary carcinoma. Intramedullary metastasis from a second malignancy or from an unknown neuroendocrine malignancy is extremely rare and has never been reported in the literature. Because of the rarity of these tumors and the low volume of cases, well-defined treatment guidelines do not exist for the management of ISCM. Here we present a rare and one of the first reports of an intramedullary metastatic neuroendocrine tumor.

Case Description: A 66-year-old woman with a history of breast cancer presented with worsening bilateral lower extremity numbness for 2 months. Imaging revealed an intramedullary spinal cord tumor at the T4 level. The patient underwent microsurgical resection of the intramedullary spinal cord tumor. At operation, the tumor had an exophytic component. Subtotal resection was achieved. Pathology revealed a neuroendocrine metastasis, likely pulmonary in origin. She achieved partial resolution of neurologic symptoms at follow-up.

Conclusions: Neuroendocrine ISCM are rare and lack well-defined treatment guidelines. Care should be individualized in these cases. Whenever feasible, surgical resection should be considered. Despite multidisciplinary care, the prognosis is dismal with limited life expectancy. Larger, multiinstitutional, or national database studies are needed that compare treatment modalities in the management of ISCM to identify the therapy with the best outcomes.
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http://dx.doi.org/10.1016/j.wneu.2020.08.103DOI Listing
January 2021

The effect of bone morphogenetic protein 2 composite materials combined with cannulated screws in treatment of acute displaced femoral neck fractures.

Medicine (Baltimore) 2020 Feb;99(6):e18976

Medical Department, The Second Hospital of Shandong University, Shandong Province, Peoples Republic of China.

The risk of avascular necrosis (AVN) and nonunion after treatment of displaced femoral neck fractures is increased in patients aged <60 years. Therefore we established a new protocol for closed reduction and internal fixation (CRIF) using cannulated screws combined with bone morphogenetic protein 2 (BMP-2) composite materials to treat acute femoral neck fractures.This study enrolled 78 patients with acute femoral neck fractures between April 2014 and September 2016. We treated 46 patients with a mean age of 43.8 years in study group. These patients were treated by CRIF combined with BMP-2 composite materials. In control group, there were 32 patients with a mean age of 42.09 years. The patients were treated by CRIF without BMP-2. The duration between presentation and surgery, operative time, Harris score and complications were recorded.In study group, 43 patients were followed up with an average of 31.3 months. One patient suffered nonunion and three patients presented AVN. In control group, 28 patients were followed up with an average of 32.3 months, the rate of AVN and fracture nonunion were 25% (7/28) and 21.4% (6/28) respectively, significantly higher than those in study group (P < .05).Acute displaced femoral neck fractures can be treated with CRIF and BMP-2 composite materials in a minimally invasive manner. This technique was reproducible and had fewer complications.
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http://dx.doi.org/10.1097/MD.0000000000018976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015652PMC
February 2020

Resection of a posterior fossa arteriovenous malformation complicated by leaked Onyx: a case report and review of literature.

Acta Neurochir (Wien) 2020 04 30;162(4):923-928. Epub 2020 Jan 30.

Department of Neurosurgery, Rutgers-Robert Wood Johnson Medical School and University Hospital, New Brunswick, NJ, USA.

Extravasation of Onyx is a rare complication during embolization of arteriovenous malformations (AVM). We present a case of embolization that was complicated by leakage of Onyx into the cerebellum which was later encountered during surgical excision of the AVM. Our goal is to report this rare event and to outline successful treatment of this complication. The patient's records were reviewed for medical history, laboratory and radiologic workup, and outpatient clinical follow-up. A 62-year-old female presented with Hunt Hess grade 2 and modified Fisher grade 2 subarachnoid hemorrhage (SAH) secondary to ruptured left posterior inferior cerebellar artery (PICA) aneurysm associated with a superior cerebellar vermian AVM. Following endovascular intervention, the aneurysm was completely embolized; however, only 75% of the AVM could be safely obliterated. Extravasation of Onyx from the ruptured aneurysm was noted on her initial angiogram. Elective suboccipital craniectomy was subsequently planned for resection of the residual AVM where the extravasated Onyx posed an operative nuisance during resection. Post-op angiogram confirmed complete resection of the AVM, as well as the bulk of the extravasated Onyx. Patient did well post-operatively, remaining neurologically intact throughout her hospital course. Although infrequently reported in the literature, Onyx extravasation is a potential complication that neurosurgeons should be ready to face. Adherence of Onyx to surrounding parenchyma could hinder optimal surgical resection of AVM and increase complications. Therefore, careful surgical dissection should be performed with special care to delicate neurovasculature. In this case, complete resection of the AVM and Onyx mass was safely achieved.
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http://dx.doi.org/10.1007/s00701-019-04199-3DOI Listing
April 2020

Anaplastic glioneuronal tumor with fusion.

Intractable Rare Dis Res 2019 Nov;8(4):279-282

Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, USA.

Glioneuronal tumors are usually low-grade and have favorable prognosis. The anaplastic glioneuronal tumor with fusion has not yet been documented. This article reports a case of glioneuronal tumor with anaplasia and fusion to illuminate the importance of fusion in high-grade glioneuronal tumors. A ten-year-old boy presented with one year of headache and three months of blurry vision and proptosis. Ophthalmologic evaluation revealed bilateral papilledema. Magnetic resonance imaging showed a large mixed cystic and solid mass in the left frontal lobe of cerebrum. Histologic analysis demonstrated a neoplasm with pseudopapillary growth pattern, focal necrosis, microcalcification, and brisk mitotic activity with a high Ki67 labeling index of focally up to 20%. Immunohistochemical assessment identified a mixed glial and neuronal neoplastic cell population. Molecular studies revealed a fusion. The histological and molecular changes are consistent with an anaplastic glioneuronal tumor with fusion. In view of the fact that the effective, targeted therapies for the tumors with fusion are available, detection of fusion for high-grade glioneuronal tumors is clinically helpful.
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http://dx.doi.org/10.5582/irdr.2019.01118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929590PMC
November 2019

Nocardia amikacinitolerans and cytomegalovirus: distinctive clinical and radiological characterization of the rare etiologies of brain abscesses: report of 2 cases.

Neurosurg Focus 2019 08;47(2):E18

Departments of1Neurosurgery and.

Central nervous system infections in immunosuppressed patients are rare but potentially lethal complications that require swift diagnoses and intervention. While the differential diagnosis for new lesions on neuroradiological imaging of immunosuppressed patients typically includes infections and neoplasms, image-based heuristics to differentiate the two has been shown to have variable reliability.The authors describe 2 rare CNS infections in immunocompromised patients with atypical physical and radiological presentations. In the first case, a 59-year-old man, who had recently undergone a renal transplantation, was found to have multifocal Nocardia amikacinitolerans abscesses masquerading as neoplasms on diffusion-weighted imaging (DWI); in the second case, a 33-year-old man with suspected recurrent Hodgkin's lymphoma was found to have a nonpyogenic abscess with cytomegalovirus (CMV) encephalitis.As per review of the literature, this appears to be the first case of brain abscess caused by N. amikacinitolerans, a recently isolated superbug. Despite confirmation through brain biopsy later on in case 1, the initial radiological appearance was atypical, showing subtle diffusion restriction on DWI. Similarly, the authors present a case of CMV encephalitis that presented as a ring-enhancing lesion, which is extremely rare. Both cases draw attention to the reliability of neuroimaging in differentiating an abscess from a neoplasm.
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http://dx.doi.org/10.3171/2019.5.FOCUS19284DOI Listing
August 2019

Neurosurgical and Scalp Reconstructive Challenges During Craniotomy in the Setting of Cutis Verticis Gyrata.

World Neurosurg 2019 05 11;125:392-397. Epub 2019 Feb 11.

Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. Electronic address:

Background: Cutis verticis gyrata (CVG) is a rare condition of the scalp in which thickening of the dermis induces rigid folds and furrows resembling the cerebral cortex. Two forms of primary CVG exist: essential, in which CVG is the only presenting problem, and nonessential, in which the scalp condition occurs along with neuropsychiatric ailments. CVG can also occur secondary to a variety of causes including inflammatory, neoplastic, and metabolic conditions or drug use. A review of the available literature, including description of the epidemiology, pathophysiology, histology, and typical management of CVG, is provided. However, we identified no literature describing the complications of CVG in the setting of a craniotomy.

Case Report: The patient presented here is a 54-year-old man with CVG who presented with occlusion of the M2/M2 branches of the middle cerebral artery, resulting in malignant cerebral edema, requiring emergent management via decompressive craniectomy. Because of the thickening of the scalp, skin incision was complicated by bleeding and difficulty in achieving hemostasis using Raney clips. Plastic surgery was consulted intraoperatively for assistance with complex closure of the wound in a multilayered fashion. Despite this, the patient's postoperative course was complicated by cerebrospinal fluid leakage due to difficulty in approximating the incision during closure. Subsequent cranioplasty was performed jointly between neurosurgery and plastic surgery.

Conclusions: Despite its rarity, CVG is an important issue for neurosurgeons to understand as it can present complications in performing craniotomy, most notably during the scalp exposure and closure. CVG may also complicate the postoperative course if adequate approximation of the tissues cannot be achieved, resulting in wound infection and/or cerebrospinal fluid leak. The presented patient benefited from a combined neurosurgical and plastic surgical approach that was implemented intraoperatively and continued through the postoperative stages and the subsequent cranioplasty.
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http://dx.doi.org/10.1016/j.wneu.2019.01.217DOI Listing
May 2019

Somatostatin Receptor Ligand Therapy-A Potential Therapy for Neurocytoma.

J Clin Endocrinol Metab 2019 06;104(6):2395-2402

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.

Context: Neurocytoma (NC) is a rare, low-grade tumor of the central nervous system, with a 10-year survival rate of 90% and local control rate of 74%. However, 25% of NCs will be atypical, with an elevated Ki-67 labeling index >2%, and will exhibit a more aggressive course, with a high propensity for local recurrence and/or craniospinal dissemination. Although no standard treatment regimen exists for these atypical cases, adjuvant stereotactic or conventional radiotherapy and/or chemotherapy have been typically offered but have yielded inconsistent results.

Case Description: We have described the case of a patient with a vasopressin-secreting atypical NC of the sellar and cavernous sinus region. After subtotal resection via endoscopic transsphenoidal surgery, the residual tumor showed increased fluorodeoxyglucose uptake and high somatostatin receptor (SSTR) expression on a 68Ga-DOTA-TATE positron emission tomography/CT scan. Somatostatin receptor ligand (SRL) therapy with lanreotide (120 mg every 28 days) was initiated. Four years later, the residual tumor was stable with decreased fluorodeoxyglucose tumor uptake. Immunocytochemical SSTR2 and SSTR5 expression >80% was further confirmed in a series of NC tissues.

Conclusions: To the best of our knowledge, we have described the first use of SRL therapy for an atypical NC. Our results support consideration of adjuvant SRL therapy for NC refractory to surgical removal. Our findings further raise the possibility of SSTR-directed peptide receptor radionuclide therapy as NC therapy.
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http://dx.doi.org/10.1210/jc.2018-02419DOI Listing
June 2019

Increased (pro)renin receptor expression in the subfornical organ of hypertensive humans.

Am J Physiol Heart Circ Physiol 2018 04 22;314(4):H796-H804. Epub 2017 Dec 22.

Departments of Pharmacology, Physiology, and Cell Biology; Center for Cardiovascular Research, School of Medicine, University of Nevada , Reno, Nevada.

The central nervous system plays an important role in essential hypertension in humans and in animal models of hypertension through modulation of sympathetic activity and Na and body fluid homeostasis. Data from animal models of hypertension suggest that the renin-angiotensin system in the subfornical organ (SFO) of the brain is critical for hypertension development. We recently reported that the brain (pro)renin receptor (PRR) is a novel component of the brain renin-angiotensin system and could be a key initiator of the pathogenesis of hypertension. Here, we examined the expression level and cellular distribution of PRR in the SFO of postmortem human brains to assess its association with the pathogenesis of human hypertension. Postmortem SFO tissues were collected from hypertensive and normotensive human subjects. Immunolabeling for the PRR and a retrospective analysis of clinical data were performed. We found that human PRR was prominently expressed in most neurons and microglia, but not in astrocytes, in the SFO. Importantly, PRR levels in the SFO were elevated in hypertensive subjects. Moreover, PRR immunoreactivity was significantly correlated with systolic blood pressure but not body weight, age, or diastolic blood pressure. Interestingly, this correlation was independent of antihypertensive drug therapy. Our data indicate that PRR in the SFO may be a key molecular player in the pathogenesis of human hypertension and, as such, could be an important focus of efforts to understand the neurogenic origin of hypertension. NEW & NOTEWORTHY This study provides evidence that, in the subfornical organ of the human brain, the (pro)renin receptor is expressed in neurons and microglia cells but not in astrocytes. More importantly, (pro)renin receptor immunoreactivity in the subfornical organ is increased in hypertensive humans and is significantly correlated with systolic blood pressure.
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http://dx.doi.org/10.1152/ajpheart.00616.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966774PMC
April 2018

Anaplastic myxopapillary ependymoma in an infant: Case report and literature review.

Intractable Rare Dis Res 2017 May;6(2):128-131

Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.

A 7-month-old boy presented with gastrointestinal disturbance, mild neurologic deficit of the left lower extremity and levo-scoliosis of the thoracic spine. Magnetic resonance imaging demonstrated a large intramedullary lesion involving the thoracic spine, from level T1 to T11. Histologic analysis showed a glial tumor with fibrillary processes arranged in radial pattern around mucoid fibrovascular cores with a high proliferative index (focally up to 80%) and prominent vascular endothelial hyperplasia. These findings were consistent with an anaplastic myxopapillary ependymoma. Subtotal resection was performed a T3-T10 laminoplasty. A ventricular shunt was placed, and the patient subsequently received chemoradiation therapy. To date, this is the second case of a myxopapillary ependymoma with high-grade anaplastic features and the first case in an infant reported in the literature.
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http://dx.doi.org/10.5582/irdr.2017.01015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451745PMC
May 2017

Overexpression of Eg5 correlates with high grade astrocytic neoplasm.

J Neurooncol 2016 Jan 11;126(1):77-80. Epub 2015 Oct 11.

Section of Neuropathology, Department of Pathology, Tulane University School of Medicine, 1430 Tulane Ave., SL-79, New Orleans, LA, 70112-2632, USA.

To investigate the relationship between Eg5 and histopathological grade of astrocytoma, Eg5 expression was evaluated by immunohistochemical examination on 88 specimens including 25 cases of glioblastoma (WHO grade IV), 22 cases of anaplastic astrocytoma (WHO grade III), 20 cases of diffuse astrocytoma (WHO grade II), and 21 cases of pilocytic astrocytoma (WHO grade I). The histopathological characteristics and Eg5 expression level of each tumor were assessed and statistically analyzed. Astrocytic tumors exhibited significant correlation of expression of Eg5 with higher WHO histopathological grades (p < 0.001). Eg5 is expressed in 51-98% (mean 76.88%) of neoplastic cells in glioblastoma, 34-57% (mean 43.59%) of neoplastic cells in anaplastic astrocytoma, 6-36% (mean 18.60%) of neoplastic cells in diffuse astrocytoma, and 2-28% (mean 13.48%) of neoplastic cells in pilocytic astrocytoma. In conclusion, overexpression of Eg5 associates with high-grade astrocytic neoplasm, and it may represent an independent diagnostic and prognostic factor in grading astrocytic tumors and predicting prognosis of astrocytic tumor patients.
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http://dx.doi.org/10.1007/s11060-015-1954-3DOI Listing
January 2016

The first association of a primary amebic meningoencephalitis death with culturable Naegleria fowleri in tap water from a US treated public drinking water system.

Clin Infect Dis 2015 Apr 16;60(8):e36-42. Epub 2015 Jan 16.

Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: Naegleria fowleri is a climate-sensitive, thermophilic ameba found in warm, freshwater lakes and rivers. Primary amebic meningoencephalitis (PAM), which is almost universally fatal, occurs when N. fowleri-containing water enters the nose, typically during swimming, and migrates to the brain via the olfactory nerve. In August 2013, a 4-year-old boy died of meningoencephalitis of unknown etiology in a Louisiana hospital.

Methods: Clinical and environmental testing and a case investigation were initiated to determine the cause of death and to identify potential exposures.

Results: Based on testing of cerebrospinal fluid and brain specimens, the child was diagnosed with PAM. His only reported water exposure was tap water; in particular, tap water that was used to supply water to a lawn water slide on which the child had played extensively prior to becoming ill. Water samples were collected from both the home and the water distribution system that supplied the home and tested; N. fowleri was identified in water samples from both the home and the water distribution system.

Conclusions: This case is the first reported PAM death associated with culturable N. fowleri in tap water from a US treated drinking water system. This case occurred in the context of an expanding geographic range for PAM beyond southern states, with recent case reports from Minnesota, Kansas, and Indiana. This case also highlights the role of adequate disinfection throughout drinking water distribution systems and the importance of maintaining vigilance when operating drinking water systems using source waters with elevated temperatures.
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http://dx.doi.org/10.1093/cid/civ017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627687PMC
April 2015

Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

Hypertension 2015 Feb 24;65(2):352-61. Epub 2014 Nov 24.

From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.).

We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.114.04458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902274PMC
February 2015

20(S)-protopanaxadiol inhibition of progression and growth of castration-resistant prostate cancer.

PLoS One 2014 6;9(11):e111201. Epub 2014 Nov 6.

College of Life Sciences, Jilin University, Changchun, China; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America; National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, China.

Castration-resistant progression of prostate cancer after androgen deprivation therapies remains the most critical challenge in the clinical management of prostate cancer. Resurgent androgen receptor (AR) activity is an established driver of castration-resistant progression, and upregulation of the full-length AR (AR-FL) and constitutively-active AR splice variants (AR-Vs) has been implicated to contribute to the resurgent AR activity. We reported previously that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) can reduce the abundance of both AR-FL and AR-Vs. In the present study, we further showed that the effect of PPD on AR expression and target genes was independent of androgen. PPD treatment resulted in a suppression of ligand-independent AR transactivation. Moreover, PPD delayed castration-resistant regrowth of LNCaP xenograft tumors after androgen deprivation and inhibited the growth of castration-resistant 22Rv1 xenograft tumors with endogenous expression of AR-FL and AR-Vs. This was accompanied by a decline in serum prostate-specific antigen levels as well as a decrease in AR levels and mitoses in the tumors. Notably, the 22Rv1 xenograft tumors were resistant to growth inhibition by the next-generation anti-androgen enzalutamide. The present study represents the first to show the preclinical efficacy of PPD in inhibiting castration-resistant progression and growth of prostate cancer. The findings provide a rationale for further developing PPD or its analogues for prostate cancer therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111201PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222907PMC
July 2015

Histiocytic meningioma: A distinctive subtype of meningioma?

Intractable Rare Dis Res 2014 May;3(2):57-9

Tulane University School of Medicine, New Orleans, USA;

Meningioma with extensive histiocytic changes is rare. We describe a case of histiocytic meningioma which occurred in a 55-year-old woman. The patient had a progressive headache and a decline in fine motor coordination and memory for the past four years. Magnetic resonance imaging demonstrated a well-demarcated, dura-based and contrast-enhancing mass lesion in the right superior frontoparietal region. Histopathologically, the tumor showed neoplastic meningothelial proliferation with extensive and multifocal histiocytic infiltration. The histiocytic component constituted approximately half of the entire tumor. Immunohistochemically, both meningothelial and histiocytic cells showed immunoreactivity for epithelial membrane antigen (EMA), while the histiocytic cells were also positive for CD4 and CD68. In addition, there were scattered S100-positive histiocytes throughout the tumor. Proliferative index highlighted by Ki67 immunostain was 1.6%. There were no high-grade changes such as frequent mitoses, necrosis, or brain parenchymal invasion in the specimen. With review of the literature, we propose that this type of meningioma should be considered as a separate subtype of meningioma. The biological basis and differential diagnosis are discussed.
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http://dx.doi.org/10.5582/irdr.2014.01007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204537PMC
May 2014

Interleukin-17 promotes development of castration-resistant prostate cancer potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.

Prostate 2014 Jun 1;74(8):869-79. Epub 2014 Apr 1.

Department of Structural & Cellular Biology, Tulane University, New Orleans, Louisiana.

Background: Interleukin-17 (IL-17) has been demonstrated to promote formation and growth of hormone-naïve prostate adenocarcinoma in mice. IL-17's role in development of castration-resistant prostate cancer is unknown. In the present study, we investigated IL-17's role in castration-resistant prostate cancer in a mouse model.

Methods: IL-17 receptor C (IL-17RC) deficient mice were interbred with Pten conditional mutant mice to produce RC(+) mice that maintained IL-17RC expression and RC(-) mice that were IL-17RC deficient. Male RC(+) and RC(-) mice were Pten-null and were castrated at 16 weeks of age when invasive prostate cancer had already formed. At 30 weeks of age, all male mice were analyzed for the prostate phenotypes.

Results: RC(-) mice displayed prostates that were smaller than RC(+) mice. Approximately 23% of prostatic glands in RC(-) mice, in contrast to 65% of prostatic glands in RC(+) mice, developed invasive adenocarcinomas. Compared to castrate RC(+) mice, castrate RC(-) mouse prostate had lower rates of cellular proliferation and higher rates of apoptosis as well as lower levels of MMP7, YBX1, MTA1, and UBE2C proteins. In addition, castrate RC(-) mouse prostate had less angiogenesis, which was associated with decreased levels of COX-2 and VEGF. Moreover, castrate RC(-) mouse prostate had fewer inflammatory cells including lymphocytes, myeloid-derived suppressor cells, and macrophages.

Conclusions: Taken together, our findings suggest that IL-17 promotes development of invasive prostate adenocarcinomas under castrate conditions, potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.
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http://dx.doi.org/10.1002/pros.22805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063299PMC
June 2014

Insulin and IGF1 enhance IL-17-induced chemokine expression through a GSK3B-dependent mechanism: a new target for melatonin's anti-inflammatory action.

J Pineal Res 2013 Nov 20;55(4):377-87. Epub 2013 Aug 20.

Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA.

Obesity is a chronic inflammation with increased serum levels of insulin, insulin-like growth factor 1 (IGF1), and interleukin-17 (IL-17). The objective of this study was to test a hypothesis that insulin and IGF1 enhance IL-17-induced expression of inflammatory chemokines/cytokines through a glycogen synthase kinase 3β (GSK3B)-dependent mechanism, which can be inhibited by melatonin. We found that insulin/IGF1 and lithium chloride enhanced IL-17-induced expression of C-X-C motif ligand 1 (Cxcl1) and C-C motif ligand 20 (Ccl20) in the Gsk3b(+/+) , but not in Gsk3b(-/-) mouse embryonic fibroblast (MEF) cells. IL-17 induced higher levels of Cxcl1 and Ccl20 in the Gsk3b(-/-) MEF cells, compared with the Gsk3b(+/+) MEF cells. Insulin and IGF1 activated Akt to phosphorylate GSK3B at serine 9, thus inhibiting GSK3B activity. Melatonin inhibited Akt activation, thus decreasing P-GSK3B at serine 9 (i.e., increasing GSK3B activity) and subsequently inhibiting expression of Cxcl1 and Ccl20 that was induced either by IL-17 alone or by a combination of insulin and IL-17. Melatonin's inhibitory effects were only observed in the Gsk3b(+/+) , but in not Gsk3b(-/-) MEF cells. Melatonin also inhibited expression of Cxcl1, Ccl20, and Il-6 that was induced by a combination of insulin and IL-17 in the mouse prostatic tissues. Further, nighttime human blood, which contained high physiologic levels of melatonin, decreased expression of Cxcl1, Ccl20, and Il-6 in the PC3 human prostate cancer xenograft tumors. Our data support our hypothesis and suggest that melatonin may be used to dampen IL-17-mediated inflammation that is enhanced by the increased levels of insulin and IGF1 in obesity.
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http://dx.doi.org/10.1111/jpi.12084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797167PMC
November 2013

20(S)-protopanaxadiol-aglycone downregulation of the full-length and splice variants of androgen receptor.

Int J Cancer 2013 Mar 20;132(6):1277-87. Epub 2012 Aug 20.

Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA 70112, USA.

As a public health problem, prostate cancer engenders huge economic and life-quality burden. Developing effective chemopreventive regimens to alleviate the burden remains a major challenge. Androgen signaling is vital to the development and progression of prostate cancer. Targeting androgen signaling via blocking the production of the potent ligand dihydrotestosterone has been shown to decrease prostate cancer incidence. However, the potential of increasing the incidence of high-grade prostate cancers has been a concern. Mechanisms of disease progression after the intervention may include increased expression of androgen receptor (AR) in prostate tissue and expression of the constitutively active AR splice variants (AR-Vs) lacking the ligand-binding domain. Thus, novel agents targeting the receptor, preferentially both the full-length and AR-Vs, are urgently needed. In the present study, we show that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) effectively downregulates the expression and activity of both the full-length AR and AR-Vs. The effects of PPD on AR and AR-Vs are manifested by an immediate drop in proteins followed by a reduction in transcripts, attributed to PPD induction of proteasome-mediated degradation and inhibition of the transcription of the AR gene. We further show that although PPD inhibits the growth as well as AR expression and activity in LNCaP xenograft tumors, the morphology and AR expression in normal prostates are not affected. This study is the first to show that PPD suppresses androgen signaling through downregulating both the full-length AR and AR-Vs, and provides strong rationale for further developing PPD as a promising agent for the prevention and/or treatment of prostate cancer.
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http://dx.doi.org/10.1002/ijc.27754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509250PMC
March 2013

Asperger's syndrome with unusual cerebral pathology: Case report and literature review.

Intractable Rare Dis Res 2012 May;1(2):92-4

Department of Pathology, Tulane University School of Medicine, New Orleans, LA, USA; ; Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA, USA.

A case of Asperger's syndrome with unusual cerebral pathological changes is reported. A 22-year-old male had been having diagnostic Asperger's syndrome since the age of eight and had epilepsy during the past two years. Radiological studies revealed a focal intra-axial cortical and subcortical cerebral lesion with hyper-intensity and non-enhancing contrast in the left frontal lobe. Histological and immunohistochemical studies demonstrated that the lesion consisted of cortical laminar disorganization, neuronal dysmorphism and increased heterotopic neurons in sub-cortical white matter. To our knowledge, this is the first case of Asperger's syndrome with focal cerebral pathological abnormalities rather than mini-columnar changes and the gyrial malformation reported in the literature.
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http://dx.doi.org/10.5582/irdr.2012.v1.2.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204558PMC
May 2012

Interleukin-17 promotes formation and growth of prostate adenocarcinoma in mouse models.

Cancer Res 2012 May 28;72(10):2589-99. Epub 2012 Mar 28.

Department of Structural & Cellular Biology, School of Medicine, New Orleans, LA, USA.

The contributions of interleukin (IL)-17 to cancer remain unclear and somewhat controversial. We took a genetic approach to explore its role in prostate cancers by interbreeding IL-17 receptor C (IL-17RC)-deficient mice with mice that are conditionally mutant for PTEN, one established preclinical model for prostate cancer. Mice that were IL-17RC-deficient (IL-17RC(-)) displayed prostates that were smaller than mice that maintained IL-17RC expression (IL-17RC(+)). In addition, IL-17RC(-) mice developed a reduced number of invasive prostate adenocarcinomas with lower rates of cellular proliferation and higher apoptosis than IL-17RC(+) mice. Moreover, the fibromuscular stroma surrounding prostatic glands was relatively thicker in IL-17RC(-) mice and was associated with decreased matrix metalloproteinase (Mmp)7 expression and increased Timp1, 2, and 4 expression, whereas administration of recombinant mouse IL-17 induced prostatic expression of Mmp7. Taken together, our results suggested that IL-17 promotes the formation and growth of prostate adenocarcinoma, and that an IL-17-MMP7 signaling axis is required for the transition of prostatic intraepithelial neoplasia to frank adenocarcinoma.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-3795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665158PMC
May 2012

Methylseleninic acid enhances paclitaxel efficacy for the treatment of triple-negative breast cancer.

PLoS One 2012 14;7(2):e31539. Epub 2012 Feb 14.

Departments of Structural and Cellular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.

A major challenge in breast cancer therapy is the lack of an effective therapeutic option for a particularly aggressive subtype of breast cancer, triple-negative breast cancer. Here we provide the first preclinical evidence that a second-generation selenium compound, methylseleninic acid, significantly enhances the anticancer efficacy of paclitaxel in triple-negative breast cancer. Through combination-index value calculation, we demonstrated that methylseleninic acid synergistically enhanced the growth inhibitory effect of paclitaxel in triple-negative breast cancer cells. The synergism was attributable to more pronounced induction of caspase-mediated apoptosis, arrest of cell cycle progression at the G2/M checkpoint, and inhibition of cell proliferation. Treatment of SCID mice bearing MDA-MB-231 triple-negative breast cancer xenografts for four weeks with methylseleninic acid (4.5 mg/kg/day, orally) and paclitaxel (10 mg/kg/week, through intraperitoneal injection) resulted in a more pronounced inhibition of tumor growth compared with either agent alone. The attenuated tumor growth correlated with a decrease in tumor cell proliferation and an induction of apoptosis. The in vivo study also indicated the safety of using methylseleninic acid in the combination regime. Our findings thus provide strong justification for the further development of methylseleninic acid and paclitaxel combination therapy for the treatment of triple-negative breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031539PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279411PMC
July 2012

Berberine suppresses androgen receptor signaling in prostate cancer.

Mol Cancer Ther 2011 Aug 25;10(8):1346-56. Epub 2011 May 25.

Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.

The androgen receptor (AR) is critical in the normal development and function of the prostate, as well as in prostate carcinogenesis. Androgen deprivation therapy is the mainstay in the treatment of advanced prostate cancer; however, after an initial response, the disease inevitably progresses to castration-resistant prostate cancer (CRPC). Recent evidence suggests that continued AR activation, sometimes in a ligand-independent manner, is commonly associated with the development of CRPC. Thus, novel agents targeting the AR are urgently needed as a strategic step in developing new therapies for this disease state. In this study, we investigated the effect of berberine on AR signaling in prostate cancer. We report that berberine decreased the transcriptional activity of AR. Berberine did not affect AR mRNA expression, but induced AR protein degradation. Several ligand-binding, domain-truncated AR splice variants have been identified, and these variants are believed to promote the development of CRPC in patients. Interestingly, we found that these variants were more susceptible to berberine-induced degradation than the full-length AR. Furthermore, although the growth of LNCaP xenografts in nude mice was inhibited by berberine, and AR expression was reduced in the tumors, the morphology and AR expression in normal prostates were not affected. This study is the first to show that berberine suppresses AR signaling and suggests that berberine, or its derivatives, presents a promising agent for the prevention and/or treatment of prostate cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-10-0985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154574PMC
August 2011

Mammary myofibrosarcoma: case report and literature review.

Breast J 2011 May-Jun;17(3):300-4. Epub 2011 Mar 24.

Department of Pathology, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112, USA.

A case of myofibrosarcoma of breast is reported. A female patient aged 81 years presented with a mammary mass lesion. Histologically, the tumor consisted of neoplastic spindle cells arranged in fascicles and with variably cellularity and hyalinization. Immunohistochemical studies showed expression of vimentin, smooth-muscle actin, and Bcl-2, but not desmin, S-100, C-kit, or CD34. Proliferative index identified by Ki67 was approximately 30%. Electron microscopy revealed variable amount of rough endoplasmic reticulum, myofilaments, fibronexus junctions, and fibronectin fibrils. The histological, immunohistochemical, and ultrastructural features of this tumor were consistent with myofibrosarcoma. This case will be one of the very few cases of ultrastructurally confirmed mammary myofibrosarcoma reported in the literature and contributes to the recognition of this rare mammary malignant neoplasm. The literature on mammary myofibrosarcoma and its differential diagnosis is also reviewed.
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http://dx.doi.org/10.1111/j.1524-4741.2011.01070.xDOI Listing
August 2011

Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples.

Clin Cancer Res 2008 Jan;14(2):488-93

Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1732, USA.

Purpose: Epidermal growth factor receptor variant III (EGFRvIII) is an oncogenic, constitutively active mutant form of the EGFR that is commonly expressed in glioblastoma and is also detected in a number of epithelial cancers. EGFRvIII presents a unique antigenic target for anti-EGFRvIII vaccines and it has been shown to modulate response to EGFR kinase inhibitor therapy. Thus, detection in clinical samples may be warranted. Existing patents preclude the use of anti-EGFRvIII antibodies for clinical detection. Further, frozen tissue is not routinely available, particularly for patients treated in the community. Thus, detection of EGFRvIII in formalin-fixed paraffin-embedded (FFPE) clinical samples is a major challenge.

Experimental Design: We developed a real-time reverse transcription-PCR (RT-PCR) assay for detecting EGFRvIII in FFPE samples and analyzed 59 FFPE glioblastoma clinical samples with paired frozen tissue from the same surgical resection. We assessed EGFRvIII protein expression by immunohistochemistry using two distinct specific anti-EGFRvIII antibodies and examined EGFR gene amplification by fluorescence in situ hybridization.

Results: The FFPE RT-PCR assay detected EGFRvIII in 16 of 59 (27%) samples, exclusively in cases with EGFR amplification, consistent with the expected frequency of this alteration. The FFPE RT-PCR assay was more sensitive and specific for detecting EGFRvIII than either of the two antibodies alone, or in combination, with a sensitivity of 93% (95% confidence interval, 0.78-1.00) and a specificity of 98% (95% confidence interval, 0.93-1.00).

Conclusion: This assay will facilitate accurate assessment of EGFRvIII in clinical samples and may aid in the development of strategies for stratifying patients for EGFRvIII-directed therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-1966DOI Listing
January 2008
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