Radiogenomics in NF2-Associated Schwannomatosis (Neurofibromatosis Type II): Exploratory Data Analysis.

Our pilot study aimed at exploratory radiogenomic data analysis in patients with NF2-associated schwannomatosis (formerly neurofibromatosis type II) to assume the potential of image biomarkers in this pathology. Fifty-three unrelated patients (37 (69.8%) women, avg. age 30.2 ± 11.2 y.o.) were enrolled in the study. First-order, gray-level co-occurrence matrix (GLCM), gray-level run length matrix (GLRLM), and geometry-based statistics were calculated (3718 features per region of interest). We demonstrated imaging patterns and statistically significant differences in radiomic features potentially related to the genotype and clinical phenotype of the disease. However, the clinical utility of these patterns should be further evaluated. The study was supported by the Russian Science Foundation grant 21-15-00262.

Gamma Knife capsulotomy for correction of obsessive-compulsive symptoms in a patient with schizophrenia: Case report.

The treatment of mental illnesses that are resistant to conservative therapy poses a serious problem. Surgical methods with proven efficacy have been proposed for only a small group of psychiatric diseases, while in practice non-classical clinical situations are seen rather often. A 36-year-old man with a 18-year history of "schizophrenia with a predominant obsessive-compulsive syndrome" was referred to the Burdenko National Medical Research Center of Neurosurgery for consideration of neurosurgical treatment. Based on results of longitudinal independent evaluations of the patient in several specialized clinical centers the disease was considered resistant to medical therapy. Radiosurgical procedure was performed by means of Leksell Gamma Knife Perfexion™ (Elekta AB; Stockholm, Sweden). Ventral portion of the anterior limb of internal capsule was targeted with two 4-mm isocenters on each side, with prescription dose at 50% isodose line of 80 Gy and a maximal dose of 160 Gy. No obvious complications or side effects were noted during 13-month follow-up after radiosurgery. Gradual clinical improvement was observed with 25% reduction of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score at 13 months after treatment. Similarly, the Hospital Anxiety and Depression Scale (HADS) anxiety and depression scores decreased by 24% and 58%, respectively. This is the first published case of radiosurgical treatment of a psychiatric disorder in Russia. It demonstrates the potential efficacy of Gamma Knife capsulotomy for non-classical forms of obsessive-compulsive disorder comorbid with schizophrenia. Nevertheless, definitive conclusions about the reliability of this radiosurgical indication can only be made based on the results of larger studies.

Systematic Clinical Evaluation of a Deep Learning Method for Medical Image Segmentation: Radiosurgery Application.

We systematically evaluate a Deep Learning model in a 3D medical image segmentation task. With our model, we address the flaws of manual segmentation: high inter-rater contouring variability and time consumption of the contouring process. The main extension over the existing evaluations is the careful and detailed analysis that could be further generalized on other medical image segmentation tasks. Firstly, we analyze the changes in the inter-rater detection agreement. We show that the model reduces the number of detection disagreements by [Formula: see text] [Formula: see text]. Secondly, we show that the model improves the inter-rater contouring agreement from [Formula: see text] to [Formula: see text] surface Dice Score [Formula: see text]. Thirdly, we show that the model accelerates the delineation process between [Formula: see text] and [Formula: see text] times [Formula: see text]. Finally, we design the setup of the clinical experiment to either exclude or estimate the evaluation biases; thus, preserving the significance of the results. Besides the clinical evaluation, we also share intuitions and practical ideas for building an efficient DL-based model for 3D medical image segmentation.

Hippocampal Dosimetry and Mnemonic Function Changes After Stereotactic Irradiation of Cavernous Sinus Meningiomas.

INTRODUCTION: It is believed that hippocampal exposure plays a major role in the development of memory disorders after cranial irradiation. This effect is evident in whole-brain irradiation and is less certain in local irradiation of intracranial targets. The present study aims to clarify the dosimetric features and dynamics of memory functions after local irradiation of the hippocampus when treating cavernous sinus meningiomas. METHODS: The study included 28 patients (24 females and 4 males) with cavernous sinus meningiomas diagnosed according to typical clinical and radiological findings. The mean age was 52 years (30-65 years). Stereotactic radiotherapy in standard fractionation regimen (54 Gy total dose) was the primary treatment in all patients. Patients underwent memory testing (ability to reproduce and recognize) using a previously developed and validated methodology at standard time points: before the start of radiotherapy, at the end of the course, and 6 and 12 months after treatment. Hippocampal dose, dynamics of memory function, and their possible relationship were evaluated. RESULTS: In total, 28 cavernous sinus meningiomas (15 left-sided and 13 right-sided) were treated. The mean target volume was 24.0 ccm (8.2 ccm to 53.8 ccm). Twelve months after radiotherapy, there was an increase in the median total number of recognition errors from 6.5 [4;11] to 9.5 [5;12], p=0.025, the median number of "old-similar" errors from 2 [1;3.25] to 3 [1.75;5], p=0.021, and the median number of "similar-old" errors from 3 [1;5] to 5.5 [3;7], p<0.001. The number of reproduction errors did not increase. A moderate correlation (p = 0.03, correlation coefficient = 0.41) was found between the dose to 10% of the ipsilateral hippocampus and the total number of reproduction errors at the end of the course. No other significant correlations were found at the end of radiotherapy and six and 12 months after it. CONCLUSION: Thus, even partial lateralized exposure of the hippocampus during irradiation of the cavernous sinus meningiomas affects its function in the form of specific pattern separation type disturbances, which are detected as early as 12 months after the impact. The hippocampus in this treatment should be considered as a critical structure whose sensitivity to irradiation requires additional assessment.

Pilocytic Astrocytoma Enlargement Following Irradiation: Relapse or Pseudoprogression?

Pilocytic astrocytomas are the most common gliomas (World Health Organization (WHO) grade 1) in children. According to many authors, stereotactic irradiation (radiotherapy and radiosurgery) is an effective method that provides a prolonged, recurrence-free survival in patients who have had partial tumor removal or in patients with an unresectable tumor. We present a case of a patient with midbrain pilocytic astrocytoma that enlarged considerably in the first six months after irradiation and then diminished in size during the next six months without any antitumor treatment. The clinical and radiological follow-up data for this patient, the surgery results for similar patients, and the data from other authors led us to the conclusion that early tumor volume enlargement after irradiation is usually pseudoprogression.

Successful CyberKnife Irradiation of 1000 cc Hemicranial Meningioma: 6-year Follow-up.

Meningiomas are common benign tumors with accepted treatment approaches and usually don't challenge healthcare specialists. We present a case of a huge unresectable hemicranial meningioma, which was successfully treated with hypofractionated irradiation. A male patient, sixty-two years of age, suffered for over 12 years from headaches, facial deformity, right eye displacement, right eye movement restriction, right-sided ptosis, and facial hypoesthesia. MRI and CT studies revealed an extended hemicranial meningioma. Prior to irradiation, the patient underwent four operations. Eventually, the tumor was irradiated with the CyberKnife in August 2009. Tumor volume composed 1085 cc. The mean dose of 35.3 Gy was delivered in 7 fractions (31.5 Gy at 72% isodose line comprising 95% of tumor volume). The patient was followed during six years and experienced only mild (Grade 1-2 CTCAE) acute skin and mucosa reactions. During the follow-up period, we observed target volume shrinkage for 17% (for 26% after excluding hyperostosis) and regression of intracranial hypertension signs. Due to the extreme volume and complex shape of the tumor, spreading along the surface of the hemisphere as well as an optic nerve involvement, the case presented would not be generally considered suitable for irradiation, especially for hypofractionation. We regard this clinical situation not as a treatment recommendation, but as a demonstration of the underestimated possibilities of hypofractionation regimen and CyberKnife system, both of which are limited with our habit of conventional treatments.

ATP synthesis without R210 of subunit a in the Escherichia coli ATP synthase.

Interactions between subunit a and oligomeric subunit c are essential for the coupling of proton translocation to rotary motion in the ATP synthase. A pair of previously described mutants, R210Q/Q252R and P204T/R210Q/Q252R [L.P. Hatch, G.B. Cox and S.M. Howitt, The essential arginine residue at position 210 in the a subunit of the Escherichia coli ATP synthase can be transferred to position 252 with partial retention of activity, J. Biol. Chem. 270 (1995) 29407-29412] has been constructed and further analyzed. These mutants, in which the essential arginine of subunit a, R210, was switched with a conserved glutamine residue, Q252, are shown here to be capable of both ATP synthesis by oxidative phosphorylation, and ATP-driven proton translocation. In addition, lysine can replace the arginine at position 252 with partial retention of both activities. The pH dependence of ATP-driven proton translocation was determined after purification of mutant enzymes, and reconstitution into liposomes. Proton translocation by the lysine mutant, and to a lesser extent the arginine mutant, dropped off sharply above pH 7.5, consistent with the requirement for a positive charge during function. Finally, the rates of ATP synthesis and of ATP-driven proton translocation were completely inhibited by treatment with DCCD (N,N'-dicyclohexylcarbodiimide), while rates of ATP hydrolysis by the mutants were not significantly affected, indicating that DCCD modification disrupts the F(1)-F(o) interface. The results suggest that minimal requirements for proton translocation by the ATP synthase include a positive charge in subunit a and a weak interface between subunit a and oligomeric subunit c.

A functionally inactive, cold-stabilized form of the Escherichia coli F1Fo ATP synthase.

An unusual effect of temperature on the ATPase activity of E. coli F1Fo ATP synthase has been investigated. The rate of ATP hydrolysis by the isolated enzyme, previously kept on ice, showed a lag phase when measured at 15 degrees C, but not at 37 degrees C. A pre-incubation of the enzyme at room temperature for 5 min completely eliminated the lag phase, and resulted in a higher steady-state rate. Similar results were obtained using the isolated enzyme after incorporation into liposomes. The initial rates of ATP-dependent proton translocation, as measured by 9-amino-6-chloro-2-methoxyacridine (ACMA) fluorescence quenching, at 15 degrees C also varied according to the pre-incubation temperature. The relationship between this temperature-dependent pattern of enzyme activity, termed thermohysteresis, and pre-incubation with other agents was examined. Pre-incubation of membrane vesicles with azide and Mg2+, without exogenous ADP, resulted in almost complete inhibition of the initial rate of ATPase when assayed at 10 degrees C, but had little effect at 37 degrees C. Rates of ATP synthesis following this pre-incubation were not affected at any temperature. Azide inhibition of ATP hydrolysis by the isolated enzyme was reduced when an ATP-regenerating system was used. A gradual reactivation of azide-blocked enzyme was slowed down by the presence of phosphate in the reaction medium. The well-known Mg2+ inhibition of ATP hydrolysis was shown to be greatly enhanced at 15 degrees C relative to at 37 degrees C. The results suggest that thermohysteresis is a consequence of an inactive form of the enzyme that is stabilized by the binding of inhibitory Mg-ADP.

Ultrafast purification and reconstitution of His-tagged cysteine-less Escherichia coli F1Fo ATP synthase.

His-tagged cysteine-less F1Fo ATP synthase from Escherichia coli was purified using Ni-NTA affinity chromatography. During the purification procedure the loss of total ATPase activity did not exceed 50%, and the extent of purification was about 80-fold. The purified enzyme was essentially free of other proteins, was highly active in ATP hydrolysis (75 units/mg at pH 8 and 37 degrees C), and was sensitive to N,N'-dicyclohexylcarbodiimide (70%). Incorporation of F1Fo into soybean liposomes yielded well-coupled and highly active proteoliposomes. The entire procedure, from the disruption of cells by French press to the preparation of proteoliposomes, took only about 8 h. Some improvements in procedures for the estimation of rates of both ATP hydrolysis and ATP-dependent 9-amino-6-chloro-2-methoxyacridine (ACMA) fluorescence quenching are described.

Functional transitions of F0F1-ATPase mediated by the inhibitory peptide IF1 in yeast coupled submitochondrial particles.

The mechanism of inhibition of yeast F(0)F(1)-ATPase by its naturally occurring protein inhibitor (IF1) was investigated in submitochondrial particles by studying the IF1-mediated ATPase inhibition in the presence and absence of a protonmotive force. In the presence of protonmotive force, IF1 added during net NTP hydrolysis almost completely inhibited NTPase activity. At moderate IF1 concentration, subsequent uncoupler addition unexpectedly caused a burst of NTP hydrolysis. We propose that the protonmotive force induces the conversion of IF1-inhibited F(0)F(1)-ATPase into a new form having a lower affinity for IF1. This form remains inactive for ATP hydrolysis after IF1 release. Uncoupling simultaneously releases ATP hydrolysis and converts the latent form of IF1-free F(0)F(1)-ATPase back to the active form. The relationship between the different steps of the catalytic cycle, the mechanism of inhibition by IF1 and the interconversion process is discussed.