Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth.

Androgen receptor (AR) functions as a ligand-dependent transcription factor to regulate its downstream signaling for prostate cancer progression. AR complex formation by multiple transcription factors is important for enhancer activity and transcriptional regulation. However, the significance of such collaborative transcription factors has not been fully understood. In this study, we show that Oct1, an AR collaborative factor, coordinates genome-wide AR signaling for prostate cancer growth. Using global analysis by chromatin immunoprecipitation sequencing (ChIP-seq), we found that Oct1 is recruited to AR-binding enhancer/promoter regions and facilitates androgen signaling. Moreover, a major target of AR/Oct1 complex, acyl-CoA synthetase 3 (ACSL3), contributes to tumor growth in nude mice, and its high expression is associated with poor prognosis in prostate cancer patients. Next, we examined the therapeutic effects of pyrrole-imidazole polyamides that target the Oct1-binding sequence identified in the center of the ACSL3 AR-binding site. We observed that treatment with Oct1 polyamide severely blocked the Oct1 binding at the ACSL3 enhancer responsible for its transcriptional activity and ACSL3 induction. In addition, Oct1 polyamides suppressed castration-resistant tumor growth and specifically repressed global Oct1 chromatin association and androgen signaling in prostate cancer cells, with few nonspecific effects on basal promoter activity. Thus, targeting Oct1 binding could be a novel therapeutic strategy for AR-activated castration-resistant prostate cancer.

The Infundibular Recess Passes through the Entire Pituitary Stalk.

BACKGROUND AND PURPOSE: The infundibular recess (IR), commonly illustrated as a V-shaped hollow in the sagittal view, is recognized as a small extension of the third ventricle into the pituitary stalk. The precise morphology of the human IR is unknown. The present study sought to delineate the morphology of the IR using magnetic resonance imaging. MATERIALS AND METHODS: Subjects included 100 patients without acute cerebral infarcts, intracranial hemorrhage, intrasellar or suprasellar cysts, hydrocephalus, inflammatory disease, or brain tumors. Patients with symptoms of increased intracranial pressure, intracranial hypotension, or pituitary dysfunction were excluded. Thin-sliced, seamless T2-weighted sequences involving the optic chiasm, entire pituitary stalk, and pituitary gland were performed in axial and sagittal planes for each patient. The numbers of slices delineating the pituitary stalk and IR were recorded from the axial images and quantified as ratios. RESULTS: The pituitary stalk consistently appeared as a styloid- or cone-shaped structure with variable inclinations toward the third ventricle floor. The IR was delineated as a smoothly tapering, tubular extension of the third ventricle located in the central portion of the pituitary stalk. In 81 % of patients, the IR passed through the entire length of the pituitary stalk and reached the upper surface of the pituitary gland, which was identified in 40 % of the midsagittal images. CONCLUSIONS: The IR is a cerebrospinal fluid-filled canal passing through the center of the pituitary stalk and connects the third ventricle to the pituitary gland. It may function in conjunction with the pituitary gland.

Schwannoma of the nasal septum presenting as a multicentric neuronal tumour.

PROBLEM: Schwannomas (neurilemmomas) are benign primary tumours that arise from Schwann cells. Schwannomas arising from the nasal septum are exceptionally rare. Here, we report a unique case of schwannoma of the nasal septum presenting as a multicentric neuronal tumour. RESULTS: A 40-year old male sustained intermittent left tinnitus. Magnetic resonance imaging revealed masses near the nasal septum and upper cervical cord in addition to a tumour in the left cerebellopontine (CP) angle. The tumour in the nasal septum was completely resected by endoscopic endonasal surgery and diagnosed as a typical schwannoma. The CP angle tumour was treated with stereotactic radiosurgery, while the asymptomatic cord lesion showed no significant growth and remains under observation. CONCLUSION: Endoscopic endonasal surgery is useful for the resection of schwannomas of the nasal septum. Schwannomas of the nasal septum may present as multiple neuronal tumours.

Cranial arachnoid protrusions and contiguous diploic veins in CSF drainage.

BACKGROUND AND PURPOSE: Studies have suggested that arachnoid villi or granulations found in the walls of the cranial dural sinuses, olfactory mucosa, and cranial nerve sheaths function as outlets for intracranial CSF. However, their role as CSF outlets has not yet been verified. Here we show that arachnoid protrusions and contiguous diploic veins provide an alternative drainage route for intracranial CSF. MATERIALS AND METHODS: Four hundred patients with intact skull, dura mater, and dural sinuses underwent MR imaging to explore arachnoids protruding into the skull and diploic veins. Patients with symptoms of increased intracranial pressure or intracranial hypotension were excluded. For 15 patients undergoing craniotomy, both peripheral and diploic venous blood was collected. Albumin and the CSF-specific biomarkers were measured by enzyme-linked immunosorbent assay. RESULTS: With MR imaging, arachnoid protrusions into the skull and contiguous diploic veins were consistently identified throughout the cranium with their characteristic appearance depending on the cranial region. In addition, elevated amounts of prostaglandin D synthase and cystatin C were confirmed in diploic veins compared with peripheral venous blood. CONCLUSIONS: Diploic veins are distributed ubiquitously throughout the cranium. A portion of the intracranial CSF may be drained through arachnoid protrusions and contiguous diploic veins.

Prognostic factors for cervical spondylotic amyotrophy: are signs of spinal cord involvement associated with the neurological prognosis?

OBJECTIVES: The purpose of this study was to clarify the prognostic factors for cervical spondylotic amyotrophy (CSA). METHODS: The authors retrospectively reviewed the medical records of 47 consecutive patients with CSA in whom the presence/absence of the pyramidal tract sign was noted. We analyzed whether the age, sex, presence of diabetes mellitus, medication (vitamin B12), type of the most atrophic and impaired muscle, the muscle strength at the presentation, the presence of the pyramidal tract sign, magnetic resonance imaging (MRI) findings, including the presence and number of T2 high signal intensity areas (T2 HIA) in the spinal cord and the conversion to surgery were associated with the recovery of muscle strength in the patients. In addition, we also investigated whether the duration of symptoms before surgery and the type of surgery were associated with the recovery of muscle strength in patients who required conversion to surgical treatment. RESULTS: The presence of T2 HIA on MRI (P=0.002), the number of T2 HIA on MRI (P=0.002) and conversion to surgery (P=0.015) were found to be significantly associated with a poorer recovery at the observational final follow-up. Further, the presence of the pyramidal tract sign (P=0.043) was significantly associated with a poor recovery at the final follow-up after surgery. CONCLUSION: The presence of a high signal intensity change on T2-weighted MRI and the pyramidal tract sign can be used as prognostic factors for patients with CSA.

Detection of antiferromagnetic ordering in heavily doped LaFeAsO(1-x)H(x) pnictide superconductors using nuclear-magnetic-resonance techniques.

We studied double superconducting (SC) domes in LaFeAsO(1-x)H(x) by using 75As and 1H nuclear-magnetic-resonance techniques and unexpectedly discovered that a new antiferromagnetic (AF) phase follows the double SC domes on further H doping, forming a symmetric alignment of AF and SC phases in the electronic phase diagram. We demonstrated that the new AF ordering originates from the nesting between electron pockets, unlike the nesting between electron and hole pockets, as seen in the majority of undoped pnictides. The new AF ordering is derived from the features common to high-Tc pnictides; however, it has not been reported so far for other high-Tc pnictides because of their poor electron doping capability.

Single institutional experience of the treatment of angiosarcoma of the face and scalp.

OBJECTIVE: Angiosarcoma is a rare malignant neoplasm with a poor prognosis. A retrospective study was performed to accumulate radiotherapy (RT) data. METHODS: Data from 17 patients with angiosarcoma of the face and scalp (AFS) who were treated with definitive RT between January 1999 and July 2011 were retrospectively analysed. The total radiation dose was 70 Gy, and the fractional doses were 2.0-2.5 Gy. Combined with RT, chemotherapy using docetaxel alone, recombinant interleukin-2 immunotherapy alone and both of these was performed in 10, 4 and 2 patients, respectively. Three patients underwent limited surgery before RT. RESULTS: The response rate was 82%, and the median overall survival (OS) rate was 26 months. Locoregional relapse alone, distant metastasis alone and both of these were confirmed in 4, 5 and 4 patients, respectively. Patients treated with docetaxel showed a better prognosis (p=0.0477), a distant metastasis-free rate (p=0.0063) and a better in-field control rate, although the last was not statistically significant (p=0.1645). CONCLUSION: Definitive RT combined with docetaxel chemotherapy provided an effective approach for treating AFS. ADVANCES IN KNOWLEDGE: Since patients treated with chemoradiotherpy using docetaxel showed better OS and distant metastasis-free rates than those who did not receive docetaxel, it was warranted to continue use of docetaxel. In chemoradiotherapy at a dose of 70 Gy using docetaxel, 2-year in-field control rate was 67%.

Magnetic resonance imaging appearance of primary spinal extradural Ewing's sarcoma: case report and literature review.

PURPOSE: Primary spinal extradural Ewing's sarcoma (PSEES) or primitive neuroectodermal tumor (PNET) is uncommon. The present study summarizes the magnetic resonance (MR) imaging appearance of PSEES. METHODS: Literature search from 1994 to 2012 with our representative case presentation. RESULTS: Twenty-one patients, 12 males and 9 females, aged 3 weeks to 44 years, were identified. The thoracic spine was most frequently affected, followed by the cervical, cervicothoracic, and thoracolumbar spine. Superior-inferior extension of lesions was three vertebral levels in 7, two in 7, five in 4, four in 1, one in 1 and unknown in 1. PSEESs appeared isointense in 9 cases, hypointense in 2, hyperintense in 1, and no description in 9 on T1-weighted imaging, while hyperintense in 6, hypointense in 3, heterogeneous in 1, and no description in 11 on T2-weighted imaging. Varying enhancement was noted in 13 cases (62 %), with no description of contrast study in the other 8 cases. Dumbbell-shaped configuration of PSEES was found in 5 cases, foraminal widening in 4, and erosions or scalloping of the adjacent vertebral bodies in 4. CONCLUSION: The MR imaging appearance of PSEESs is indistinguishable from other tumors. PSEES should be assumed as the differential diagnosis of spinal extradural tumors in pediatric, adolescent, and young adult patients, and prompt surgical exploration should be performed.

Solitary spinal extradural plasmacytoma: a case report and literature review.

Solitary spinal extradural plasmacytoma (SSEP) is a rare but distinct form of plasma cell disorder. The clinical picture and treatment of SSEP are reviewed using the seven previously reported cases. The three male and four female patients were aged 40-85 years. The location was cervical spine in one patient, cervicothoracic in one, thoracic in two, thoracolumbar in one, lumbar in one, and extensive involvement in one. Progressive paraparesis and sensory disturbance were the predominant symptoms. Neuroimaging showed a compressive extradural mass lesion in the dorsal spinal canal without findings of local bone destructive changes in all cases. Four of five patients who underwent decompressive surgical maneuver and tumor resection showed neurological improvement. Immunoglobulin (IgG) kappa subtype was the most predominant histological type, followed by IgD lambda and IgA kappa subtypes. SSEP should be included in the differential diagnosis of an extradural tumor located in the dorsal spinal canal without associated bony changes. Surgery may be effective for symptomatic relief.

Tumor-intrinsic and tumor-extrinsic factors impacting hsp90- targeted therapy.

In 1994 the first heat shock protein 90 (Hsp90) inhibitor was identified and Hsp90 was reported to be a target for anticancer therapeutics. In the past 18 years there have been 17 distinct Hsp90 inhibitors entered into clinical trial, and the small molecule Hsp90 inhibitors have been highly valuable as probes of the role of Hsp90 and its client proteins in cancer. Although no Hsp90 inhibitor has achieved regulatory approval, recently there has been significant progress in Hsp90 inhibitor clinical development, and in the past year RECIST responses have been documented in HER2-positive breast cancer and EML4-ALK-positive non-small cell lung cancer. All of the clinical Hsp90 inhibitors studied to date are specific in their target, i.e. they bind exclusively to Hsp90 and two related heat shock proteins. However, Hsp90 inhibitors are markedly pleiotropic, causing degradation of over 200 client proteins and impacting critical multiprotein complexes. Furthermore, it has only recently been appreciated that Hsp90 inhibitors can, paradoxically, cause transient activation of the protein kinase clients they are chaperoning, resulting in initiation of signal transduction and significant physiological events in both tumor and tumor microenvironment. An additional area of recent progress in Hsp90 research is in studies of the posttranslational modifications of Hsp90 itself and Hsp90 co-chaperone proteins. Together, a picture is emerging in which the impact of Hsp90 inhibitors is shaped by the tumor intracellular and extracellular milieu, and in which Hsp90 inhibitors impact tumor and host on a microenvironmental and systems level. Here we review the tumor intrinsic and extrinsic factors that impact the efficacy of small molecules engaging the Hsp90 chaperone machine.

Effects of denervation at ileocecal junction and ileocecal resection in dogs.

BACKGROUND: To investigate neural regulation at the ileocecal junction (ICJ) and motility changes after ileocecal resection (ICR). Previous studies showed normal basal motility at the ICJ directly by force transducers in dogs, but these observations were limited to normal contractile activity. METHODS: Continuous strain gauge recordings of stomach, terminal ileum, ileocecal sphincter (ICS), and colon were performed in dogs. The dogs were divided into four groups, namely control (CONT), extrinsic denervation at ICJ (ED), intrinsic denervation at ICJ (ID), and ICR groups. Colonic activity was recorded 2 h before a meal, in the early postprandial period (first 2 h), and in the late postprandial period (4-6 h after a meal). The meal lasted 5 min. KEY RESULTS: Motility index was significantly increased at the ICS (P = 0.0056) and proximal colon (P = 0.0059) after feeding. However, such changes were not observed in the ED and ID groups. The amplitude of contractions at proximal colon in the interdigestive state was significantly decreased by ED. In the ID and ICR groups, the numbers of nonmigrating contractions were significantly decreased (P < 0.05), and colonic migrating motor complex (CMMC) ratio was significantly higher than that of the CONT group (P < 0.001). The dogs in these two groups had diarrhea. CONCLUSIONS & INFERENCES: Gastrocolonic response at the ICJ may require both intrinsic and extrinsic innervation. When ID was performed, CMMC ratio increased. As a result, intraluminal water absorption may have decreased. ID may be one of the causes of diarrhea after ICR.

E/N-cadherin switch mediates cancer progression via TGF-ß-induced epithelial-to-mesenchymal transition in extrahepatic cholangiocarcinoma.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a fundamental process governing not only morphogenesis in multicellular organisms, but also cancer progression. During EMT, epithelial cadherin (E-cadherin) is downregulated while neural cadherin (N-cadherin) is upregulated, referred to as 'cadherin switch'. This study aimed to investigate whether cadherin switch promotes cancer progression in cholangiocarcinoma (CC). METHODS: CC cell lines were examined for migration, invasion, and morphological changes with typical EMT-induced model using recombinant TGF-ß1. The changes in E-cadherin and N-cadherin expression were investigated during EMT. We also examined E-cadherin and N-cadherin expression in resected specimens from extrahepatic CC patients (n=38), and the associations with clinicopathological factors and survival rates. RESULTS: TGF-ß1 treatment activated cell migration, invasion, and fibroblastic morphological changes, especially in extrahepatic CC HuCCT-1 cells. These changes occurred with E-cadherin downregulation and N-cadherin upregulation, that is, cadherin switch. Patients with low E-cadherin expression had a significantly lower survival rate than patients with high E-cadherin expression (P=0.0059). Patients with decreasing E-cadherin and increasing N-cadherin expression had a significantly lower survival rate than patients with increasing E-cadherin and decreasing N-cadherin expression (P=0.017). CONCLUSION: Cadherin switch promotes cancer progression via TGF-ß-induced EMT in extrahepatic CC, suggesting a target for elucidating the mechanisms of invasion and metastasis in extrahepatic CC.

Direct impact analysis of multi-leaf collimator leaf position errors on dose distributions in volumetric modulated arc therapy: a pass rate calculation between measured planar doses with and without the position errors.

We propose a new method for analyzing the direct impact of multi-leaf collimator (MLC) leaf position errors on dose distributions in volumetric modulated arc therapy (VMAT). The technique makes use of the following processes. Systematic leaf position errors are generated by directly changing a leaf offset in a linac controller; dose distributions are measured by a two-dimensional diode array; pass rates of the dose difference between measured planar doses with and without the position errors are calculated as a function of the leaf position error. Three different treatment planning systems (TPSs) were employed to create VMAT plans for five prostate cancer cases and the pass rates were compared between the TPSs under various leaf position errors. The impact of the leaf position errors on dose distributions depended upon the final optimization result from each TPS, which was explained by the correlation between the dose error and the average leaf gap width. The presented method determines leaf position tolerances for VMAT delivery for each TPS, which may facilitate establishing a VMAT quality assurance program in a radiotherapy facility.

Integration of cap analysis of gene expression and chromatin immunoprecipitation analysis on array reveals genome-wide androgen receptor signaling in prostate cancer cells.

The androgen receptor (AR) is a critical transcriptional factor that contributes to the development and the progression of prostate cancer (PCa) by regulating the transcription of various target genes. Genome-wide screening of androgen target genes provides useful information to understand a global view of AR-mediated gene network in PCa. In this study, we performed 5'-cap analysis of gene expression (CAGE) to determine androgen-regulated transcription start sites (TSSs) and chromatin immunoprecipitation (ChIP) on array (ChIP-chip) analysis to identify AR binding sites (ARBSs) and histone H3 acetylated (AcH3) sites in the human genome. CAGE determined 13 110 distinct, androgen-regulated TSSs (P<0.01), and ChIP-chip analysis identified 2872 androgen-dependent ARBSs (P<1e-5) and 25 945 AcH3 sites (P<1e-4). Both androgen-regulated coding genes and noncoding RNAs, including microRNAs (miRNAs) were determined as androgen target genes. Besides prototypic androgen-regulated TSSs in annotated gene promoter regions, there are many androgen-dependent TSSs that are widely distributed throughout the genome, including those in antisense (AS) direction of RefSeq genes. Several pairs of sense/antisense promoters were newly identified within single RefSeq gene regions. The integration of CAGE and ChIP-chip analyses successfully identified a cluster of androgen-inducible miRNAs, as exemplified by the miR-125b-2 cluster on chromosome 21. Notably, the number of androgen-upregulated genes was larger in LNCaP cells treated with R1881 for 24 h than for 6 h, and the percentage of androgen-upregulated genes accompanied with adjacent ARBSs was also much higher in cells treated with R1881 for 24 h than 6 h. On the basis of the Oncomine database, the majority of androgen-upregulated genes containing adjacent ARBSs and CAGE tag clusters in our study were previously confirmed as androgen target genes in PCa. The integrated high-throughput genome analyses of CAGE and ChIP-chip provide useful information for elucidating the AR-mediated transcriptional network that contributes to the development and progression of PCa.

Correlation between colonic motility and defecatory disorders after anterior resection of the rectum in canine models.

The objective of this study was to describe the correlation between changes in colonic motility and defecatory disorders in four experimental canine models, with an emphasis on denervation. Therefore, we constructed a model by dividing 20 healthy mongrel dogs into four groups, i.e. control, denervation, transection and anterior resection of the rectum (AR) (denervation plus transection), and focused on the correlation between colonic motility and defecatory disorders by counting the colonic migrating motor complexes (CMMCs) and colonic non-migrating motor complexes (CNMCs). Gastrointestinal and colonic contractile activities were continuously recorded on a computer with strain gauge force transducers. The dogs' feces were checked daily, and their consistency was recorded as normal, semisolid, or watery. Compared with the control group, the transection group showed elongation of the propagation time (P < 0.05), and the mean motility index of colonic contractile activity at C4 and C5 in the denervation group was greater than that in the control group (P < 0.05). The AR group showed three features of colonic motility: (i) elongation of the mean CMMC cycle (P < 0.05); (ii) shortening of the propagation time (P < 0.05); and (iii) increment of the number of CNMCs. Concerning fecal consistency, the AR group only showed watery diarrhoea. In conclusion, we revealed the existence of a correlation between defecatory disorders and changes in colonic motility. Increased knowledge among colorectal surgeons of the changes in colonic motility that occur following colorectal surgery is very important and could lead to the curtailment of defecatory disorders among patients.

3D morphological assessment of occlusal treatment by measuring dental casts with a micro-focus X-ray CT.

The analysis of occlusal relationship is important for the success of dental treatment. Three-dimensional (3D) computer models of upper and lower dental casts can play a significant role. In this study, we proposed and applied a new method in actual clinical assessment to measure dental casts with occlusal relationship by using a micro-focus X-ray CT system. We examined the modelling accuracy by comparing multiple 3D images taken by shifting the dental cast position. Modelling accuracy was confirmed as 0.03 mm. One occlusal treatment in clinical practice was selected as a case example. The dental casts and bite impression, taken before treatment, were scanned and the occlusal contacts and distance distribution between the upper and lower casts were visualized by a coloured map and overlaid on the computer models. Distances between the upper and lower casts of selected points were compared before and after the treatment. Initially, the subject had early contact on the anterior teeth, where distance was measured as 0.04 mm, and only one area measured less than 0.15 mm. After treatment, five areas measured less than 0.15 mm. Also, by comparing the dental cast models taken before and after occlusal adjustment of the tooth, the position and amount of adjustment were visualized. We successfully demonstrated the quantitative clinical assessment of occlusal treatment.

A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion.

Heat shock protein 90 (Hsp90) is a molecular chaperone that maintains function of numerous intracellular signaling nodes utilized by cancer cells for proliferation and survival. Hsp90 is also detected on the plasma membrane of tumor cells and its expression has been suggested to correlate with metastatic potential. Given the abundance and diverse functions of the intracellular pool of this protein, the precise contribution of cell surface Hsp90 to cell motility and tumor metastasis remains to be determined. In this study we utilized the small molecule DMAG-N-oxide, a novel cell-impermeable Hsp90 inhibitor, to specifically examine the role of cell surface Hsp90 in cell motility. We observed that, while not affecting intracellular Hsp90 function, DMAG-N-oxide significantly retarded tumor cell migration and integrin/extracellular matrix-dependent cytoskeletal reorganization. Concomitant with these findings, targeting cell surface Hsp90 significantly inhibited tumor cell motility and invasion in vitro, and had a dramatic impact on melanoma cell lung colonization in vivo. These data indicate that cell surface Hsp90 plays an important role in modulating cancer cell migration that is independent of the function of the intracellular Hsp90 pool, and that small molecule inhibitors of surface Hsp90 may provide a new approach to targeting the metastatic phenotype.

Experimental results and early clinical experience with an easy method for intracorporeal knot tying using a novel laparoscopic needleholder.

BACKGROUND: Intracorporeal suturing and knot tying are among the most difficult procedures in laparoscopic operations. An easy and inexpensive method for intracorporeal instrumental ligation with a modified laparoscopic needle driver is presented. METHODS: The needle driver developed in this study has a novel mechanism that can fix the suturing thread in a hook at the distal site of the holder's jaw hinge. This hook projects out from the rod only when the jaw of the holder is open. After the needle is removed from the tissue using the grasper, the needle driver is placed under the grasper, which the surgeon manipulates by the left hand. Then the thread is hooked on the needle driver by withdrawal of the driver with the jaw opening. The tip of the needle driver is moved over the shaft of the grasper by keeping the thread on the hook. The thread is entwined during a series of crossing movements of the rods of the forceps. The short tail of the suture material is gripped and tied up as a first throw of ligation. The side edge of the jaw, used for thread cutting, is sharpened by grinding. RESULTS: When the angle of the forceps is set at 90 degrees in the box trainer, no difference in terms of ligation time and degree of error is observed between the hook and conventional C-loop methods. In the case of the 30 degree forceps angle, the novel method is superior to the conventional method. CONCLUSION: The novel needle driver provides an easy and inexpensive method for performing an intracorporeal ligation, particularly in a case involving a sharp axis angle of the forceps. More clinical experience is necessary for evaluation of this method, but it has potential advantages in laparoscopic operations.