Electrical Stimulation-Based Twitch Exercise Suppresses Progression of Immobilization-Induced Muscle Fibrosis via Downregulation of PGC-1?/VEGF Pathway.

This study aimed to determine whether electrical stimulation-based twitch exercise is effective in inhibiting the progression of immobilization-induced muscle fibrosis. 19 Wistar rats were randomly divided into a control group (n=6), an immobilization group (n=6; with immobilization only), and a Belt group (n=7; with immobilization and twitch exercise through the belt electrode device, beginning 2 weeks after immobilization). The bilateral soleus muscles were harvested after the experimental period. The right soleus muscles were used for histological analysis, and the left soleus muscles were used for biochemical and molecular biological analysis. As a result, in the picrosirius red images, the perimysium and endomysium were thicker in both the immobilization and Belt groups compared to the control group. However, the perimysium and endomysium thickening were suppressed in the Belt group. The hydroxyproline content and alpha-SMA, TGF-beta1, and HIF-1alpha mRNA expressions were significantly higher in the immobilization and belt groups than in the control group. These expressions were significantly lower in the Belt group than in the immobilization group. The capillary-to-myofiber ratio and the mRNA expressions of VEGF and PGC-1alpha were significantly lower in the immobilization and belt groups than in the control group, these were significantly higher in the Belt group than in the immobilization group. From these results, Electrical stimulation-based twitch exercise using the belt electrode device may prevent the progression of immobilization-induced muscle fibrosis caused by downregulating PGC-1alpha/VEGF pathway, we surmised that this intervention strategy might be effective against the progression of muscle contracture. Keywords: Immobilization, Skeletal muscle, Fibrosis, Electrical stimulation-based twitch exercise, PGC-1alpha/VEGF pathway.

Multidisciplinary management of locally recurrent rectal cancer with carbon ion radiotherapy followed by prophylactic removal of the irradiated bowel: a case report.

BACKGROUND: Locally recurrent rectal cancer (LRRC) involving the upper sacrum is typically incurable, and palliative treatment is the only option for most patients, resulting in a poor prognosis and reduced quality of life. Carbon ion radiotherapy (CIRT) has emerged as a promising modality for treating LRRC. This report presents a case of LRRC with sacral involvement that was managed via multidisciplinary therapy incorporating CIRT. CASE PRESENTATION: A 55-year-old male was diagnosed with an anastomotic recurrence of rectal cancer 15 months after undergoing anterior resection. Computed tomography (CT) suggested that the lesion was at an anastomosis site and broadly adherent to the upper sacrum, and colonoscopy confirmed the diagnosis of LRRC. Histopathological examination of the biopsy specimens revealed adenocarcinoma cells and that lesion was genetically RAS-wild. Induction chemotherapy with mFOLFOX6 and panitumumab was used as the first treatment. The recurrent lesion shrank and no signs of distant metastasis were observed after 11 cycles, although the range of the lesions attached to the sacrum remained unchanged. Therefore, we provided CIRT for this inoperable lesion and prophylactically removed the radiation-exposed bowel including the recurrent lesion, because radiation-induced ulcers can cause bleeding and perforation. Despite the presence of considerable fibrosis in the irradiated region, the operation was successful and the postoperative course had no untoward incidents. He is still recurrence-free 24 months following surgery, despite the lack of adjuvant chemotherapy. This is the first report of CIRT followed by CIRT-irradiated bowel removal for an unresectable anastomosis recurrent lesion. CONCLUSIONS: The clinical course of this case suggests that CIRT could be a potentially effective therapeutic option for LRRC involving the bowel, as long as the prophylactic removal of the irradiated bowel is performed at the optimal time. Further research involving larger sample sizes is warranted to validate the findings and conclusions of this case report.

Prognostic and predictive values of tumour budding in stage IV colorectal cancer.

BACKGROUND: Tumour budding is an important prognostic feature in early-stage colorectal cancer, but its prognostic significance in metastatic disease has not been fully investigated. METHODS: Patients with stage IV disease who had primary colorectal tumour resection without previous chemotherapy or radiotherapy from January 2000 to December 2018 were reviewed retrospectively. Budding was evaluated at the primary site and graded according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) (BD1, low; BD2, intermediate; BD3, high). Patients were categorized by metastatic (M1a, M1b) and resectional (R0/R1, R2/unresected) status. Subgroups were compared for overall (OS) and recurrence-free (RFS) survival in R0/R1 subgroups; R2/unresected patients were evaluated for the rate of tumour progression, based on change in tumour size from baseline. RESULTS: Of 371 patients observed during the study, 362 were analysed. Patients with BD3 had a lower 5-year OS rate than those with BD1 + BD2 (18·4 versus 40·5 per cent; P < 0·001). Survival analyses according to metastatic and resection status also showed that BD3 was associated with shorter OS than BD1 + BD2. In multivariable analysis, BD3 (hazard ratio (HR) 1·51, 95 per cent c.i. 1·11 to 2·10; P = 0·009), T4 status (HR 1·39) and R2/unresected status (HR 3·50) were associated with decreased OS. In the R0/R1 subgroup, the 2-year RFS rate was similar for BD3 and BD1 + BD2 according to metastatic status. There was no significant difference between BD3 and BD1 + BD2 for change in tumour size in the R2/unresected subgroup (P = 0·094). Of 141 patients with initially unresectable metastases who had chemotherapy, 35 achieved conversion from unresectable to resectable status. The conversion rate was significantly higher for BD1 + BD2 than for BD3 (36 versus 18 per cent; P = 0·016). CONCLUSION: Stage IV colorectal cancer with high-grade tumour budding according to ITBCC criteria correlates with poor prognosis.

ANTECEDENTES: La esofaguectomía por cáncer se asocia con un descenso de la calidad de vida relacionada con la salud (health-related quality of life, HRQoL) a largo plazo. El objetivo de este estudio fue evaluar el efecto de las comorbilidades sobre la HRQOL entre pacientes supervivientes de cánceres de esófago o de la unión gastroesofágicas después de 10 años o más. MÉTODOS: Este estudio incluye una cohorte de base poblacional recogida de forma prospectiva que incluía todos los pacientes operados de cáncer de esófago o de la unión gastroesofágica en Suecia en 2001-2005 con seguimiento hasta el 31 de diciembre de 2016. Todos los datos relacionados con las características de los pacientes y del tumor, detalles del tratamiento y HRQoL se recogieron en una base de datos prospectiva. Se utilizaron modelos de regresión multivariable ANCOVA, ajustados por edad, sexo, histología del tumor, estadio, y técnica quirúrgica, para calcular las puntuaciones medias ajustadas con los i.c. del 95% para todas las variables de la HRQoL. RESULTADOS: Un total de 92 (88%) supervivientes respondieron a los cuestionarios. En función del impacto de las comorbilidades en la salud en general, se clasificaron a los pacientes en los grupos de bajo versus alto impacto. Los resultados muestran que los pacientes en el grupo de alto impacto presentaban un descenso clínicamente significativo de la HRQoL y un aumento en el nivel de síntomas, pero las diferencias entre estos dos grupos no fueron estadísticamente significativas. CONCLUSIÓN: A los 10 años de la esofaguectomía por cáncer, las comorbilidades con un alto impacto sobre la salud general siguen contribuyendo en el deterioro de la HRQoL.

Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer.

BACKGROUND: Reduced expression of cluster of differentiation (CD) 133 and cyclo-oxygenase (COX) 2, and increased density of CD8+ tumour-infiltrating lymphocytes, are associated with a favourable tumour response to preoperative chemoradiotherapy (CRT). This study aimed to evaluate these markers in relation to tumour response after preoperative CRT in two rectal cancer cohorts. METHODS: Patients with low rectal cancer who underwent radical resection and preoperative short-term CRT in 2001-2007 (retrospective cohort) and long-term CRT in 2011-2017 (prospective cohort) were analysed. Pretreatment biopsies were stained immunohistochemically using antibodies to determine CD133 and COX-2 expression, and increased CD8+ density. Outcome measures were tumour regression grade (TRG), tumour downstaging and survival. RESULTS: For 95 patients in the retrospective cohort, the incidence of TRG 3-4 was 67 per cent when two or three immunohistochemistry (IHC) features were present, but only 20 per cent when there were fewer features (P < 0·001). The incidence of tumour downstaging was higher in patients with at least two IHC features (43 versus 22 per cent with fewer features; P = 0·029). The 49 patients in the prospective cohort had similar rates to those in the retrospective cohort (TRG 3-4: 76 per cent for two or more IHC features versus 25 per cent with fewer features, P < 0·001; tumour downstaging: 57 versus 25 per cent respectively, P = 0·022). Local recurrence-free survival rates in patients with more or fewer IHC features were similar in the retrospective and prospective cohort (P = 0·058 and P = 0·387 respectively). CONCLUSION: Assessment of CD133, COX-2 and CD8 could be useful in predicting a good response to preoperative CRT in patients with lower rectal cancer undergoing neoadjuvant therapy. Further studies are needed to validate the results in larger cohorts and investigate a survival benefit.

ANTECEDENTES: La expresión reducida de CD133 and COX-2, y un aumento en la densidad de los linfocitos infiltrantes del tumor CD8+ se han asociado recientemente con una respuesta favorable del tumor a la quimiorradioterapia preoperatoria (preoperative chemoradiotherapy, CRT). Este estudio evaluó estos marcadores respecto a la respuesta del tumor tras CRT preoperatoria en dos cohortes de cáncer colorrectal. MÉTODOS: Se analizaron pacientes con cáncer de recto bajo sometidos a resección radical y CRT preoperatoria de corta duración entre 2001-2007 (cohorte retrospectiva) y CRT de larga duración entre 2011-2017 (cohorte prospectiva). Se realizó tinción inmunohistoquímica (immunohistochemical, IHC) con anticuerpos para CD133, COX-2 y CD8 en las biopsias previas al tratamiento. Las características de interés incluyeron la disminución en las expresiones de CD133 y COX-2, y la densidad aumentada de CD8+. Las variables de interés fueron los grados de regresión tumoral (tumour regression grades, TRG) de acuerdo con Rödel, la reducción del estadio tumoral y las supervivencias. RESULTADOS: La cohorte retrospectiva incluyó 95 pacientes. En este subgrupo, la incidencia de TRGs 3-4 fue del 66,7% en pacientes con dos o tres características de la IHC, mientras que solo fue del 20,0% en pacientes con ninguna o con una característica (P < 0,001). Además, la incidencia de disminución del estadio tumoral fue más alta en pacientes que mostraban al menos dos características IHC (43,3%) que en los controles (21,5%; P = 0,029). En la cohorte prospectiva se incluyeron 49 pacientes y la incidencia de estos hallazgos fue similar (TRG 3-4, 76,2% en ≥ 2 características IHC versus 25,0% en los controles, P < 0,001; disminución del estadio tumoral, 57,1% en ≥ 2 características IHC versus 25,0% en los controles, P = 0,022). La supervivencia libre de recidiva local fue similar en las cohortes retrospectiva y prospectiva, cuando se compararon subgrupos de acuerdo con las características IHC (P = 0,058 y 0,387, respectivamente) CONCLUSIÓN: Este estudio sugiere que la evaluación de CD133, COX-2 y CD8 podría ser útil para la predicción de una buena respuesta a la CRT preoperatoria en pacientes con cáncer de recto bajo sometidos a tratamiento neoadyuvante. Se necesitan estudios adicionales para validar los resultados en amplias cohortes e investigar el beneficio en la supervivencia.

The relationship between the daily step counts and low back pain during pregnancy.

PURPOSE: To investigate the relationship between the change of daily step counts and low back pain (LBP) during pregnancy. Materials and METHODS: Pregnant women at less than eight weeks of gestation (WG) were recruited. Daily step counts were measured with a pedometer. To assess LBP, the Oswestry disability index (ODI) score was recorded. Thirty-six individuals were divided into the LBP and non-LBP groups. The effect of step counts on LBP between the two groups was analyzed. RESULTS: At 16-19 WG, step counts were not considerably changed in the non-LBP group but were significantly increased in the LBP group. At 24-27 and 32-35 WG, step counts were increased in the non-LBP group but were significantly decreased in the LBP group. CONCLUSIONS: Acute increase of daily step counts in early pregnancy is a risk for LBP, and gradual increases of step counts after mid-pregnancy is recommended for women.

Spin-electricity conversion induced by spin injection into topological insulators.

We report successful spin injection into the surface states of topological insulators by using a spin pumping technique. By measuring the voltage that shows up across the samples as a result of spin pumping, we demonstrate that a spin-electricity conversion effect takes place in the surface states of bulk-insulating topological insulators Bi(1.5)Sb(0.5)Te(1.7)Se(1.3) and Sn-doped Bi(2)Te(2)Se. In this process, the injected spins are converted into a charge current along the Hall direction due to the spin-momentum locking on the surface state.

Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

Prognostic impact of histological categorisation of epithelial-mesenchymal transition in colorectal cancer.

BACKGROUND: The crosstalk between cancer cells and stroma is involved in the acquired capability for metastasis through the induction of epithelial-mesenchymal transition (EMT). We aimed to clarify the prognostic value of the histological category of EMT in colorectal cancer (CRC). METHODS: Tumour EMT was graded into one of three histological categories on the basis of integrated assessment of poorly differentiated clusters and pro-EMT desmoplasia at the leading edge of the primary tumour (Histology(EMT)). Stage II and III CRC patients (cohort 1, N=500) and stage IV patients (cohort 2, N=196) were retrospectively analysed. RESULTS: In cohort 1, patients were stratified into three groups with widely different disease-free survival rates (95%, 83% and 39%) on the basis of Histology(EMT) (P<0.0001). In cohort 2, Histology(EMT) significantly stratified overall survival of patients irrespective of metasectomy. Multivariate analyses indicated that Histology(EMT) had a strong prognostic impact independent of staging factors. Statistically, Histology(EMT) had a better prognostic stratification power than T and N stages; however, in cohort 2, the power of M substage was superior. CONCLUSIONS: A histological model to categorise EMT by integrated assessment of dedifferentiation and desmoplastic environment is a potent prognostic index independent of staging factors.

Unidirectional spin-wave heat conveyer.

When energy is introduced into a region of matter, it heats up and the local temperature increases. This energy spontaneously diffuses away from the heated region. In general, heat should flow from warmer to cooler regions and it is not possible to externally change the direction of heat conduction. Here we show a magnetically controllable heat flow caused by a spin-wave current. The direction of the flow can be switched by applying a magnetic field. When microwave energy is applied to a region of ferrimagnetic Y3Fe5O12, an end of the magnet far from this region is found to be heated in a controlled manner and a negative temperature gradient towards it is formed. This is due to unidirectional energy transfer by the excitation of spin-wave modes without time-reversal symmetry and to the conversion of spin waves into heat. When a Y3Fe5O12 film with low damping coefficients is used, spin waves are observed to emit heat at the sample end up to 10 mm away from the excitation source. The magnetically controlled remote heating we observe is directly applicable to the fabrication of a heat-flow controller.

Spin Hall magnetoresistance induced by a nonequilibrium proximity effect.

We report anisotropic magnetoresistance in Pt|Y(3)Fe(5)O(12) bilayers. In spite of Y(3)Fe(5)O(12) being a very good electrical insulator, the resistance of the Pt layer reflects its magnetization direction. The effect persists even when a Cu layer is inserted between Pt and Y(3)Fe(5)O(12), excluding the contribution of induced equilibrium magnetization at the interface. Instead, we show that the effect originates from concerted actions of the direct and inverse spin Hall effects and therefore call it "spin Hall magnetoresistance."

Pedometer-Based Behavioral Change Program Can Improve Dependency in Sedentary Older Adults: A Randomized Controlled Trial.

BACKGROUND: Recent studies suggested that pedometer-based walking programs are applicable to older adults. OBJECTIVES: The purpose of this study was to evaluate the use of pedometer in sedentary older adults to improve physical activity, fear of falling, physical performance, and leg muscle mass. DESIGN: This was a pilot randomized controlled trial (RCT). SETTING AND PARTICIPANTS: Eighty-seven community dwelling sedentary older adults living in Japan. INTERVENTION: The intervention group (n=43) received a pedometer-based behavioural change program for 6 months, while the control group (n=44) did not. The participants in the intervention group were instructed to increase their mean daily steps by 10% each month. Thus, at the end of 6 months, participants in the intervention group were expected to have 77 % more daily steps than their baseline step counts. Written activity logs were monthly averaged to determine whether the participants were achieving their goal. MEASUREMENTS: Outcome measures were physical activity, fear of falling, physical performances, and leg muscle mass. RESULTS: In this 6-month trial 40 older adults (93%) completed the pedometer protocol with good adherence. In the intervention group, average daily steps were increased by 83.4% (from 20311323 to 3726 1607) during the study period, but not in the control group (from 20471698 to 22671837). The pedometer-based behavioral change program was more effective to improve their physical activity, fear of falling, locomotive function, and leg muscle mass than control (P<0.05). CONCLUSION: These results suggested that the pedometer-based behavioral change program can effectively improve the physical activity, fear of falling, physical performance, and leg muscle mass in sedentary older adults.

Nutritional Supplementation during Resistance Training Improved Skeletal Muscle Mass in Community-Dwelling Frail Older Adults.

OBJECTIVE: Sarcopenia, the age-related loss of skeletal muscle mass, is highly prevalent in older adults. The aim of this study was to investigate the effects of the combination of resistance training and multinutrients supplementation (including vitamin D and protein) on muscle mass and physical performance in frail older adults. METHODS: This trial was conducted in Japanese frail older adults (n=77), which underwent a standardized protocol of a 3-month physical exercise intervention. The sample population was divided into two groups, according to the adoption (S/Ex: n = 38) or not (Ex: n = 39) of the additional multinutrient supplementation. The outcome measures of interest for the present analyses were the skeletal muscle mass index (SMI) and several physical performance tests. RESULTS: Participants in S/Ex group had significant improvements for the outcome measures, including SMI and maximum walking time (P<0.05), compared to those in Ex group. The prevalence of sarcopenia decreased from 65.7% to 42.9% in S/Ex group, while that in Ex group remained unchanged (68.6% to 68.6%) (relative risk = 1.60, 95% CI: 1.03-2.49). CONCLUSION: The results of this study suggest that the combination of resistance training and multinutritional supplementation may be more effective at improving muscle mass and walking speed than an intervention only based on resistance training.

Spin pumping by parametrically excited exchange magnons.

We experimentally show that exchange magnons can be detected by using a combination of spin pumping and the inverse spin-Hall effect proving its wavelength integrating capability down to the submicrometer scale. The magnons were injected in a ferrite yttrium iron garnet film by parametric pumping and the inverse spin-Hall effect voltage was detected in an attached Pt layer. The role of the density, wavelength, and spatial localization of the magnons for the spin pumping efficiency is revealed.

Spin Seebeck insulator.

Thermoelectric generation is an essential function in future energy-saving technologies. However, it has so far been an exclusive feature of electric conductors, a situation which limits its application; conduction electrons are often problematic in the thermal design of devices. Here we report electric voltage generation from heat flowing in an insulator. We reveal that, despite the absence of conduction electrons, the magnetic insulator LaY(2)Fe(5)O(12) can convert a heat flow into a spin voltage. Attached Pt films can then transform this spin voltage into an electric voltage as a result of the inverse spin Hall effect. The experimental results require us to introduce a thermally activated interface spin exchange between LaY(2)Fe(5)O(12) and Pt. Our findings extend the range of potential materials for thermoelectric applications and provide a crucial piece of information for understanding the physics of the spin Seebeck effect.

Transmission of electrical signals by spin-wave interconversion in a magnetic insulator.

The energy bandgap of an insulator is large enough to prevent electron excitation and electrical conduction. But in addition to charge, an electron also has spin, and the collective motion of spin can propagate-and so transfer a signal-in some insulators. This motion is called a spin wave and is usually excited using magnetic fields. Here we show that a spin wave in an insulator can be generated and detected using spin-Hall effects, which enable the direct conversion of an electric signal into a spin wave, and its subsequent transmission through (and recovery from) an insulator over macroscopic distances. First, we show evidence for the transfer of spin angular momentum between an insulator magnet Y(3)Fe(5)O(12) and a platinum film. This transfer allows direct conversion of an electric current in the platinum film to a spin wave in the Y(3)Fe(5)O(12) via spin-Hall effects. Second, making use of the transfer in a Pt/Y(3)Fe(5)O(12)/Pt system, we demonstrate that an electric current in one metal film induces voltage in the other, far distant, metal film. Specifically, the applied electric current is converted into spin angular momentum owing to the spin-Hall effect in the first platinum film; the angular momentum is then carried by a spin wave in the insulating Y(3)Fe(5)O(12) layer; at the distant platinum film, the spin angular momentum of the spin wave is converted back to an electric voltage. This effect can be switched on and off using a magnetic field. Weak spin damping in Y(3)Fe(5)O(12) is responsible for its transparency for the transmission of spin angular momentum. This hybrid electrical transmission method potentially offers a means of innovative signal delivery in electrical circuits and devices.

Growth pattern in the muscular layer reflects the biological behaviour of colorectal cancer.

OBJECTIVE: To determine the clinical value of evaluating the cancer morphology in muscularis propria (MP) for colorectal cancer (CRC) patients. METHOD: A total of 994 patients with advanced CRC were reviewed in terms of two distinctive growth patterns in the MP: (i) horizontal spread between the circular and longitudinal muscle layers (H-spread) and (ii) 'streaming' spread between the muscle bundles of the circular muscle layer (S-spread). RESULTS: The incidence of H-spread (n = 153) and S-spread (n = 150) showed a positive correlation with tumour-node-metastasis (TNM) stage and both exerted a negative impact on postoperative survival. Adverse morphology in the MP (H-spread and/or S-spread) was consistent with a high grade of vascular invasion and budding in the extramural layer, as also with unfavourable fibrotic stromas in the reactive fibrous zone; the 5-year survival rate in patients with such features was 64.2%, which was lower than that in those without (86.5%, P < 0.0001). Multivariate analysis demonstrated that adverse morphology was an independent prognostic determinant, along with T- and N -stage. As the mode of H-spread, perineural invasion in the myenteric plexus was found to be predominant over lymphatic spread on the basis of S100 and CD34 immunostaining, but neural cell adhesion molecule expression, whether on cancer cells or on neural cells, was not significant for this growth pattern. CONCLUSION: A particular group of CRCs ingeniously utilizes the thin space between muscle fascicles for development in the MP. Although the biological mechanism remains unknown, this distinctive growth pattern could be a useful indicator to identify CRC patients at high risk of recurrence.

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells.

Glioblastoma is characterised by invasive growth and a high degree of radioresistance. Survivin, a regulator of chromosome segregation, is highly expressed and known to induce radioresistance in human gliomas. In this study, we examined the effect of survivin suppression on radiosensitivity in malignant glioma cells, while focusing on centrosome aberration and chromosome instability (CIN). We suppressed survivin by small interfering RNA transfection, and examined the radiosensitivity using a clonogenic assay and a trypan blue exclusion assay in U251MG (p53 mutant) and D54MG (p53 wild type) cells. To assess the CIN status, we determined the number of centrosomes using an immunofluorescence analysis, and the centromeric copy number by fluorescence in situ hybridisation. As a result, the radiosensitisation differed regarding the p53 status as U251MG cells quickly developed extreme centrosome amplification (=CIN) and enhanced the radiosensitivity, while centrosome amplification and radiosensitivity increased more gradually in D54MG cells. TUNEL assay showed that survivin inhibition did not lead to apoptosis after irradiation. This cell death was accompanied by an increased degree of aneuploidy, suggesting mitotic cell death. Therefore, survivin inhibition may be an attractive therapeutic target to overcome the radioresistance while, in addition, proper attention to CIN (centrosome number) is considered important for improving radiosensitivity in human glioma.

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene.

Neuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase beta/zeta (RPTPbeta), we postulated that simultaneous binding of MAGI proteins to RPTPbeta and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPbeta. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPbeta for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n= approximately 1400). PTPRZ1, which codes for RPTPbeta, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P=0.0003; gene-wide P=0.0064; hypothesis-wide P=0.026). The data provide evidence for a role of PTPRZ1, and for RPTPbeta signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPbeta in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia.

p16 Gene transfer increases cell killing with abnormal nucleation after ionising radiation in glioma cells.

It is well established that cells synchronised at the G1-S phase are highly radiosensitive. In this study, p16-null human glioma cell lines were induced into G1 cell cycle arrest by adenovirus-mediated p16 gene transfer, and examined for radiation-induced cell killing. Clonogenic analysis and trypan blue extraction test showed that the p16 gene transfer enhanced radiation-induced cell killing in p16-null glioma cell lines. TUNEL assays and pulse-field gel electrophoresis confirmed that the radiation-induced cell killing of p16-transfected cells could be caused by a nonapoptotic mechanism. Gimsa staining demonstrated that irradiation alone or Ax-mock infection plus irradiation results in a slight increase in the frequency of cells with abnormal nucleus, compared to unirradiated uninfected or Ax-mock infected cells. However, Ax-hp16 or Ax-hp21 infection alone modestly increased the frequency of cells with abnormal nucleus (especially bi- and multinucleation), and 4-Gy irradiation of Ax-hp16 or Ax-hp21 infected cells substantially enhanced this frequency. These results suggest that there exists some unknown interaction between radiation and p16 in cytoplasm/membranes, which decreases cytokinesis and promotes abnormal nucleation. Thus, p16 expression prevented radiation-induced apoptosis by promoting abnormal nucleation, thereby leading to another mode of cell death.

Detection of a pineoblastoma with large central cyst in a young child.

THE PATIENT: We present the very rare case of a pineoblastoma with large central cyst in a 7-year-old boy who presented with a short history of gradually worsening headache and upward gaze palsy. IMAGING INVESTIGATIONS: On CT and MRI studies, it was seen as a peripherally calcified, irregularly shaped mass with heterogeneous low signal intensity on T1-weighted images and ringed enhancement after gadolinium administration; there was homogeneous high signal intensity on T1-weighted images. DISCUSSION: We discuss differential diagnosis for several types of cystic tumors in the pineal region, including pineoblastomas.