Recurrent spinal atypical teratoid/rhabdoid tumor with pulmonary metastasis.

BACKGROUND: Atypical teratoid/rhabdoid tumors (ATRT) are aggressive pediatric central nervous system malignancies that predominantly affect the brain and have poor survival outcomes. However, spinal ATRT is an uncommon subset of ATRT, and its clinical course and management are poorly understood. CASE: We describe a case of spinal ATRT in a previously healthy 5-year-old girl who initially presented with rapid-onset gait disturbance. Magnetic resonance imaging (MRI) revealed an extramedullary tumor at thoracic level 5 (T5) without bony destruction or metastasis. The patient partially recovered after surgical resection. One month was required for a definitive diagnosis, and the pathology confirmed ATRT characterized by the loss of INI-1 protein expression. Chemoradiotherapy with local irradiation and high-dose chemotherapy with autologous peripheral blood stem cell transplantation led to complete remission and functional recovery for 5 months. However, the condition exhibited progression in the cerebrospinal fluid (CSF) region, resulting in cerebellar, cerebral, and spinal tumor development. Eventually, the disease metastasized to the lungs and disseminated to the entire cerebrospinal cord and fluid. The patient died 15 months after the initial diagnosis. CONCLUSION: This case emphasizes the importance of considering ATRT as a potential diagnostic modality for pediatric spinal cord tumors, enabling prompt multidisciplinary intervention. The heterogeneous appearance of spinal ATRT may make distinguishing it from other spinal tumors difficult, resulting in delayed diagnosis and treatment. The treatment approach for ATRT remains challenging with no established standards. Local irradiation may be preferable to minimize neurodevelopmental effects, and initial craniospinal irradiation may potentially prevent recurrence. Our case emphasizes the likelihood of extracranial metastasis in ATRT, thereby highlighting the importance of a comprehensive assessment of both genetic and epigenetic profiles to identify any factors that may influence the clinical course of this disease. Prompt diagnosis and comprehensive therapeutic strategies are critical for improving outcomes in spinal ATRT patients.

Comparison of laboratory-derived biomagnification factors for hexachlorobenzene in common carp conducted under 9 test conditions.

Nine dietary exposure bioaccumulation fish tests with hexachlorobenzene (HCB) were conducted with common carp to explore how differences in test conditions (different test foods and feeding rates) influenced the lipid-corrected, growth-corrected kinetic biomagnification factor (BMFkgL ) value (BMFkgL = BMFkg × lipid content of test food/lipid content of test fish). The BMFkgL values for HCB differed by approximately a factor of 5 among the tests. The average, median, 95% confidence interval, and coefficient of variation of the BMFkgL values were 0.925, 0.998, 0.578 to 1.27, and 49%, respectively. The BMFkgL value differed markedly between tests conducted using test food with lipid contents of approximately 5 and 15%. Different feeding rates (2 or 3% of body weight/d) had comparatively little effect on the BMFkgL of HCB. The present study revealed that the lipid content of test fish was correlated with the growth-corrected kinetic BMF (BMFkg ) value of HCB but the lipid content of test food was poorly correlated with BMFkg . This lack of correlation might explain the large variations of the BMFkgL values observed. The value of the BMFkg normalized to a fish with a 5% lipid content (defined as the 5% lipid-normalized BMFkg in the present study) did not differ markedly between tests conducted using test food with different lipid contents (5-15%). It is therefore useful to report the 5% lipid-normalized BMFkg as well as the BMFkgL when dietary exposure tests are conducted. Environ Toxicol Chem 2018;37:1032-1039. © 2017 SETAC.

EP300-ZNF384 fusion gene product up-regulates GATA3 gene expression and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells.

ZNF384-related fusion genes are associated with a distinct subgroup of B-cell precursor acute lymphoblastic leukemias in childhood, with a frequency of approximately 3-4%. We previously identified a novel EP300-ZNF384 fusion gene. Patients with the ZNF384-related fusion gene exhibit a hematopoietic stem cell (HSC) gene expression signature and characteristic immunophenotype with negative or low expression of CD10 and aberrant expression of myeloid antigens, such as CD33 and CD13. However, the molecular basis of this pathogenesis remains completely unknown. In the present study, we examined the biological effects of EP300-ZNF384 expression induced by retrovirus-mediated gene transduction in an REH B-cell precursor acute lymphoblastic leukemia cell line, and observed the acquisition of the HSC gene expression signature and an up-regulation of GATA3 gene expression, as assessed by microarray analysis. In contrast, the gene expression profile induced by wild-type ZNF384 in REH cells was significantly different from that by EP300-ZNF384 expression. Together with the results of reporter assays, which revealed the enhancement of GATA3-promoter activity by EP300-ZNF384 expression, these findings suggest that EP300-ZNF384 mediates GATA3 gene expression and may be involved in the acquisition of the HSC gene expression signature and characteristic immunophenotype in B-cell precursor acute lymphoblastic leukemia cells.

Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells.

ATF7IP-PDGFRB is a novel PDGFRB-related fusion gene identified in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with a signature similar to that of Ph1 ALL, so-called Ph-like ALL. When we introduced ATF7IP-PDGFRB, murine Ba/F3 cells acquired the ability to proliferate in an interleukin (IL)-3-independent manner. On the contrary, the expression of wild-type PDGFRB is not sufficient to acquire the ability for IL-3-independent proliferation in Ba/F3 cells. The introduction of ATF7IP-PDGFRB also induces a typical gene expression profile for Ph1-ALL in Ba/F3 cells. A series of biochemical and cell biological experiments revealed the constitutive activation of ATF7IP-PDGFRB as well as downstream signaling molecules, including AKT and MAPK. Although the phosphoinositide 3-kinase inhibitor led to cell death in both cells into which ATF7IP-PDGFRB had been introduced and IL-3-maintained Mock cells, MEK inhibitor selectively led to cell death into which ATF7IP-PDGFRB had been introduced. The introduction of tyrosine to phenylalanine mutations at binding sites of adaptor molecules important in the MAPK pathway located in the PDGFRB portion abolished ATF7IP-PDGFRB-mediated cell transformation, suggesting that MAPK-mediated signals are critical in ATF7IP-PDGFRB-mediated cell transformation. On treatment with tyrosine kinase inhibitors, ATF7IP-PDGFRB-expressing, but not Mock, Ba/F3 cells underwent rapid apoptosis accompanied by reduced phosphorylation of MAPK. Importantly, the sensitivity of ATF7IP-PDGFRB-expressing Ba/F3 cells to imatinib is significantly higher than that of BCR-ABL1-transformed Ba/F3 cells, as assessed by the IC50. Taken together, ATF7IP-PDGFRB has transforming potential via the constitutive activation of MAPK and participates in the pathogenesis of Ph-like ALL. Our observations suggest the therapeutic importance of tyrosine kinase inhibitors and possibly MEK inhibitor for a subset of BCP-ALL harboring PDGFRB-related fusion kinases.

TKI dasatinib monotherapy for a patient with Ph-like ALL bearing ATF7IP/PDGFRB translocation.

We report a 10-year-old male with relapsing Ph-like acute lymphoblastic leukemia (ALL) bearing ATF7IP/PDGFRB translocation. He was refractory to conventional therapy, and was finally treated with single-agent second-generation TKI dasatinib. The therapeutic response was prompt, with the disappearance of minimum residual disease (MRD) based on genomic PCR analysis within 3 months, and he has maintained complete molecular remission for 12 months. This case report describes an early-phase response to TKI monotherapy on Ph-like ALL, and technical tips for MRD monitoring on long-term follow-up.

Uptake and biological effects of synthetic glucocorticoids in common carp (Cyprinus carpio).

Uptake and biological effects of synthetic glucocorticoids (GCs) were analyzed using common carp (Cyprinus carpio). Fish were exposed to clobetasol propionate (CP) or clobetasone butyrate (CB) individually or in mixture at 1 µg L(-1) for 21 days. Bioconcentration factor (BCF) of CB was calculated as 100, and BCF of CP was less than 16. No effects were found in fish erythrocyte and leukocyte numbers and serum glucose levels after exposure to the selected GCs. On the other hand, serum concentrations of free amino acids significantly increased in GC-exposed groups. Thus, exposures to synthetic GCs at relatively low concentrations seemed to cause enhancement of protein degradation and subsequent increase of serum free amino acids without a corresponding increase in serum glucose levels, an effect which might be related to partial induction of gluconeogenesis by GC.

Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1.

We introduced SNX2-ABL1, a novel ABL1-related chimeric transcript lacks SH3 and SH2 domains, into murine Ba/F3 cells and compared their function with that of BCR-ABL1. After the expression of SNX2-ABL1 proteins, Ba/F3 cells acquired an ability to proliferate in an IL-3-independent manner. Upon treatment with both imatinib and dasatinib, BCR-ABL1-expressing Ba/F3 cells underwent rapid apoptosis, whereas SNX2-ABL1-expressing Ba/F3 cells showed poorer sensitivity toward these TKIs and could proliferate in the presence of a low dose of dasatinib. Therefore, other TKIs with a more selective effect against this chimeric kinase should be used for the treatment of patients with SNX2-ABL1+ ALL.

Monitoring impedance changes associated with motility and mitosis of a single cell.

We present a device enabling impedance measurements that probe the motility and mitosis of a single adherent cell in a controlled way. The micrometre-sized electrodes are designed for adhesion of an isolated cell and enhanced sensitivity to cell motion. The electrode surface is switched electro-chemically to favour cell adhesion, and single cells are attracted to the electrode using positive dielectrophoresis. Periods of linear variation in impedance with time correspond to the motility of a single cell adherent to the surface estimated at 0.6 µm h(-1). In the course of our study we observed the impedance changes associated with mitosis of a single cell. Electrical measurements, carried out concomitantly with optical observations, revealed three phases, prophase, metaphase and anaphase in the time variation of the impedance during cell division. Maximal impedance was observed at metaphase with a 20% increase of the impedance. We argue that at mitosis, the changes detected were due to the charge density distribution at the cell surface. Our data demonstrate subtle electrical changes associated with cell motility and for the first time with division at the single-cell level. We speculate that this could open up new avenues for characterizing healthy and pathological cells.

Electrically induced contraction of C2C12 myotubes cultured on a porous membrane-based substrate with muscle tissue-like stiffness.

A porous membrane-based cell culture device was developed to electrically stimulate a confluent monolayer of C2C12 myotubes. The device's cell culture substrate is a microporous alumina membrane-modified by attaching an atelocollagen membrane on the upperside and a hole-spotted poly(dimethylsiloxane) (PDMS) film on the underside. When electric current is generated between the device's Pt ring electrodes--one of which is placed above the cells and the other below the PDMS layer--the focused current at the PDMS hole can electrically stimulate the cells. C2C12 myoblasts were cultured on the substrate and differentiated into myotubes. When the electrical pulses were applied, myotubes started to contract slightly in and near the hole, and that the continuous stimulation increased both the number of stimuli-responding myotubes and the magnitude of the contraction considerably owing to the underlying atelocollagen membrane with muscle tissue-like stiffness. Also, the generation of contractile myotubes on a wider region of the membrane substrate was possible by applying the electrical pulses through the array of holes in the PDMS film. Using the present system, the glucose uptake by contractile myotubes was examined with fluorescence-labeled glucose, 2-NBDG, which displayed a positive correlation between the contractile activity of myotubes and the uptake of 2-NBDG.

Micropatterning contractile C2C12 myotubes embedded in a fibrin gel.

Contractile C(2)C(12) myotube line patterns embedded in a fibrin gel have been developed to afford a physiologically relevant and stable bioassay system. The C(2)C(12) myotube/fibrin gel system was prepared by transferring a myotube monolayer from a glass substrate to a fibrin gel while retaining the original line patterns of myotubes. To endow the myotubes with contractile activity, a series of electrical pulses was applied through a pair of carbon electrodes placed at either side of a fibrin gel separately. The frequency and magnitude of myotube contraction were functions of the pulse frequency and duration, respectively. We found that the myotubes supported by an elastic fibrin gel maintained their line patterns and contractile activities for a longer period of time (1 week) than myotubes adhered on a conventional culture dish.

Localized electrical stimulation to C2C12 myotubes cultured on a porous membrane-based substrate.

We report a porous membrane-based cell culture device that can conduct localized electrical stimulation of a cell monolayer. The device's cell culture substrate is a microporous alumina membrane with an underlying thin poly(dimethylsiloxane) (PDMS) film spotted with holes. When electric current is generated between the device's Pt ring electrodes--one of which is placed above the cells and the other below the PDMS layer--the current density condenses at the holes in the PDMS film, and cells located above the holes can be electrically stimulated. C2C12 cells were confluently cultured on the substrate and were differentiated to myotubes. To control the stimulated area in the substrate, we attempted to seal and reopen the holes of the PDMS film by using an air bubble. Since the current pulse could be effectively blocked at the sealed holes, fluorescent Ca2+ transients, indicative of cellular excitation, were observed from the myotubes located above holes in the open state.

Effects of switching from topical beta-blockers to latanoprost on intraocular pressure in patients with normal-tension glaucoma.

AIMS: The effects of switching from topical beta-blockers (beta) to latanoprost (LA) on intraocular pressure (IOP) and IOP-reduction rate (IOP-RR) in patients with normal-tension glaucoma (NTG) were investigated. SUBJECTS AND METHODS: Sixty (60) NTG patients (60 eyes) were divided into three equal groups receiving carteolol hydrochloride (group A), nipradilol (group B), and betaxolol hydrochloride (group C) twice-daily for 3 months. The drugs were changed to topical LA administered once-daily for the next 3 months. RESULTS: Baseline IOP was 14.4 +/- 0.9, 14.6 +/- 0.6, and 14.6 +/- 0.9 mmHg in groups A, B, and C, respectively. At 3 months, IOP was 12.4 +/- 0.6, 13.4 +/- 0.6, and 12.9 +/- 0.8 mmHg and 10.5 +/- 0.5, 11.1 +/- 0.8, and 11.7 +/- 0.8 mmHg at 6 months in groups A, B, and C, respectively. At 3 months, IOP-RR was 10.4 +/- 5.5, 9.5 +/- 2.6, and 10.8 +/- 4.7% and 24.1 +/- 4.3, 22.9 +/- 5.9, and 19.4 +/- 3.8% at 6 months in groups A, B, and C, respectively. The groups did not significantly differ in the first 3 months regarding IOP and IOP-RR. Switching to LA significantly decreased IOP and increased IOP-RR in all groups. CONCLUSION: In NTG patients, LA reduced IOP more effectively than the beta tested.

Electrodeposition of anchored polypyrrole film on microelectrodes and stimulation of cultured cardiac myocytes.

The electrically conducting polymer polypyrrole (PPy) was electrochemically deposited onto Pt microelectrodes on a polyimide (PI) substrate. Pre-modification of the PI surface with a self-assembled monolayer of octadecyltrichlorosilane-induced anisotropic lateral growth of PPy along the PI surface and enhanced adhesive strength of the PPy film. The lateral growth of PPy film around the electrode anchored the whole film to the substrate. External stimulation of cultured cardiac myocytes was carried out using the PPy-coated microelectrode. The myocytes on the microelectrode substrate were electrically conjugated to form a sheet, and showed synchronized beating upon stimulation. The threshold charge for effective stimulation of a 0.8 cm(2) sheet of myocytes was around 0.2 microC, roughly corresponding to a membrane depolarization of 250 mV.

[Blurred vision after instillation of topical carbonic anhydrase inhibitor].

PURPOSE: The aim of this study was to compare brinzolamide with dorzolamide in regard to blurred vision after instillation. We also compared saline with two topical carbonic anhydrase inhibitor drugs. SUBJECTS AND METHODS: The study population comprised 21 healthy volunteers whose best corrected visual acuity was 1.0 or better. Brinzolamide 1% or dorzolamide 1% was applied to one eye the contralateral eye was exposed to the other drug. At 30 sec after instillation, visual acuity was measured every 30 sec until best visual acuity was recovered. Because visual acuity can fluctuate widely with blinking, subjects blinked for 5 sec before visual acuity measurement. As control, we applied saline alone to both eyes of 14 subjects and measured the change in visual acuity in the same way. Subjective sensations in each eye were recorded after measurement. RESULTS: Average visual acuity every 30 sec for 5 min was 0.41, 0.56, 0.68, 0.86, 0.87, 0.96, 1.04, 1.08, 1.11, and 1.12 after dorzolamide instillation, and 0.28, 0.42, 0.60, 0.69, 0.81, 0.91, 0.93, 0.99, 1.06, and 1.10 after brinzolamide instillation. In contrast, the average visual acuity after saline instillation for 2 min was 1.09, 1.13, 1.16 and 1.16. Of the 21 subjects, 15 (71.4%) felt moderate or severe irritation when dorzolamide was instilled; 2 (9.5%) felt moderate or severe irritation when brinzolamide was instilled. CONCLUSIONS: Both brinzolamide and dorzolamide caused significantly prolonged blurring of vision, from 30 sec to 2 or 3 min after instillation, as compared with saline only. The average visual acuity after brinzolamide instillation was lower than after dorzolamide for 5 min after instillation, although there was no significant difference. Judging from the subjects' sensations, it is suggested that with dorzolamide the prolonged blurred vision was due to reflex tearing from irritation, as explained above, whereas with brinzolamide it was due to opaque tears on the ocular surface.

[Relationship between compliance and background factors of glaucoma patients].

PURPOSE: To obtain useful information for the improvement of patient compliance in the medical treatment of glaucoma. SUBJECTS AND METHODS: An unsigned attitude survey on glaucoma and eye drops was conducted with 431 glaucoma patients. Correlation between compliance and individual(objective and subjective) factors was investigated. Objective factors were age, sex, number of eye drop products, duration of disease, and degree of visual field defects. Subjective factors were "stinging sensation with application of eye drops" and "worry about blindness". RESULTS: Thirty-eight percent of the glaucoma patients were compliant, instilling eye drops at the right time and with good technique. For the factor "duration of disease", patients who had glaucoma for 6-10 years had the best compliance. Compliance became poorer with an increasing number of eye drop products. In the subjective factors, less pain and worry led patients to better compliance. CONCLUSION: To improve compliance with medical treatment, we should categorize patients based on objective factors, eliminating their pain and worry, and instructing them not only in the frequency of instillation but also in the technique of administration.

Latanoprost nonresponders with open-angle glaucoma in the Japanese population.

PURPOSE: As some patients show little response to latanoprost, one of the most powerful topical glaucoma medications, we investigated the incidence and clinical profiles of latanoprost nonresponders (LNR) in the Japanese population. METHODS: We examined 62 glaucoma patients (62 eyes) who had received only latanoprost for more than 3 months. Their mean age was 63.8 +/- 1.8 years; the mean observation period was 9.7 +/- 0.4 months. At 1, 3, 6, and 12 months, their intraocular pressure (IOP) was measured, and the IOP reduction rate (RR) and the rate of LNR, defined as RR of 10% or less, were calculated. We statistically analyzed clinical factors involved in the LNR status of our study population. RESULTS: At 1, 3, 6, and 12 months, RR was 20.1 +/- 2.0%, 18.8 +/- 2.3%, 21.1 +/- 2.8%, and 23.0 +/- 2.6%, respectively. At the same time points, the LNR incidence was 23.1%, 28.1%, 23.5%, and 31.8%, respectively, and significantly higher in patients whose baseline IOP was less than 15 mmHg. Patient sex and age and the glaucoma type played no significant role in the LNR status. CONCLUSIONS: The incidence of LNR in the Japanese population, including normal-tension glaucoma (NTG) patients, is higher than among European or American patients. Only low baseline IOP was a significant clinical factor among LNR.

[A case of severe glaucoma with pseudopemphigoid successfully treated by filtration surgery using amniotic membrane].

BACKGROUND: It is necessary to decrease topical anti-glaucoma medication for severe glaucoma with pseudopemphigoid caused by anti-glaucoma eye drops. Glaucoma filtrating surgery is often needed instead of medication, but the prognosis is poor because it induces scar fomation and makes the filtrating bleb vanish. CASE: An 85-year-old male patient with exfoliation syndrome had twice undergone glaucoma surgery about ten years previously. His intra-ocular pressure (IOP) was high despite topical anti-glaucoma medication. At the first examination in our hospital, he had severe superficial punctate keratopathy, blephariticshortening and symblepharon, and we therefore diagnosed severe pseudopemphigoid induced by anti-glaucoma eye drops. Because his IOP could not be controlled by topical and general medication, we conducted a glaucoma filtrating operation using amniotic membrane. CONCLUSION: The administration of oral anti-inflammatory drugs before and after surgery and the use of amniotic membrane prevented post-operative scar formation and the progress of symblepharon, resulting in the successful control of IOP after surgery.

[Assessment of retention and drug-release of ophthalmic ointment on the ocular surface].

PURPOSE: The dynamics of ophthalmic ointment on the ocular surface were investigated using a fluorescent ointment. METHODS: Ten healthy volunteers were enrolled. Ointment (1.0 cm length, 0.05 g) containing 0.1% flavin adenine dinucleotide sodium was squeezed out from the tube and placed in the left lower conjunctival sac. The eyes were then closed for 30 seconds and permitted to blink naturally. Two examinations including observation of tear film lipid layer interference pattern and fluorophotometric measurement of fluorescence intensity, both at the center of the cornea, were performed before examination and at 1, 3, 6, 9, 12, 15, 30, 60 minutes after instillation. RESULTS: In all cases, even 1 hour after instillation, tear film interference patterns were observed, and fluorescence intensity greater than before instillation, was present. CONCLUSION: Ointment placed in the conjunctival sac is thought to remain and release agents on the ocular surface for at least one hour.