Enhanced Missing Proteins Detection in NCI60 Cell Lines Using an Integrative Search Engine Approach.

The Human Proteome Project (HPP) aims deciphering the complete map of the human proteome. In the past few years, significant efforts of the HPP teams have been dedicated to the experimental detection of the missing proteins, which lack reliable mass spectrometry evidence of their existence. In this endeavor, an in depth analysis of shotgun experiments might represent a valuable resource to select a biological matrix in design validation experiments. In this work, we used all the proteomic experiments from the NCI60 cell lines and applied an integrative approach based on the results obtained from Comet, Mascot, OMSSA, and X!Tandem. This workflow benefits from the complementarity of these search engines to increase the proteome coverage. Five missing proteins C-HPP guidelines compliant were identified, although further validation is needed. Moreover, 165 missing proteins were detected with only one unique peptide, and their functional analysis supported their participation in cellular pathways as was also proposed in other studies. Finally, we performed a combined analysis of the gene expression levels and the proteomic identifications from the common cell lines between the NCI60 and the CCLE project to suggest alternatives for further validation of missing protein observations.

Development and Performance Evaluation of a Clinical Predictive Model to Estimate the Risk of Red Blood Cell Requirements in Brain Tumor Surgery.

BACKGROUND: The identification of factors associated with perioperative red blood cell (RBC) transfusion provides an opportunity to optimize the patient and surgical plan, and to guide perioperative crossmatch and RBC orders. We examined the association among potential bleeding risk factors and RBC requirements to develop a novel predictive model for RBC transfusion in patients undergoing brain tumor surgery. METHODS: This retrospective study included 696 adults who underwent brain tumor surgery between 2008 and 2018. Multivariable logistic regression with backward stepwise selection for predictor selection was used during modeling. Model performance was evaluated using area under the receiver operating characteristic curve, and calibration was evaluated with Hosmer-Lemeshow goodness-of-fit χ 2 -estimate. RESULTS: Preoperative hemoglobin level was inversely associated with the probability of RBC transfusion (odds ratio [OR]: 0.50; 95% confidence interval [CI]: 0.39-0.63; P <0.001). The need for RBC transfusion was also greater in patients who had a previous craniotomy (OR: 2.71; 95% CI: 1.32-5.57; P =0.007) and in those with larger brain tumor volume (OR: 1.01; 95% CI: 1.00-1.02; P =0.009). The relationship between number of planned craniotomy sites and RBC transfusion was not statistically significant (OR: 2.11; 95% CI: 0.61-7.32; P =0.238). A predictive model for RBC requirements was built using these 4 variables. The area under the receiver operating characteristic curve was 0.79 (95% CI: 0.70-0.87; P <0.001) showing acceptable calibration for predicting RBC transfusion requirements. CONCLUSIONS: RBC requirements in patients undergoing brain tumor surgery can be estimated with acceptable accuracy using a predictive model based on readily available preoperative clinical variables. This predictive model could help to optimize both individual patients and surgical plans, and to guide perioperative crossmatch orders.

Computational classifiers for predicting the short-term course of Multiple sclerosis.

BACKGROUND: The aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS). METHODS: We obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center. RESULTS: We found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end-points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later. CONCLUSIONS: The usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability.

The semantic organization of the animal category: evidence from semantic verbal fluency and network theory.

Semantic memory is the subsystem of human memory that stores knowledge of concepts or meanings, as opposed to life-specific experiences. How humans organize semantic information remains poorly understood. In an effort to better understand this issue, we conducted a verbal fluency experiment on 200 participants with the aim of inferring and representing the conceptual storage structure of the natural category of animals as a network. This was done by formulating a statistical framework for co-occurring concepts that aims to infer significant concept-concept associations and represent them as a graph. The resulting network was analyzed and enriched by means of a missing links recovery criterion based on modularity. Both network models were compared to a thresholded co-occurrence approach. They were evaluated using a random subset of verbal fluency tests and comparing the network outcomes (linked pairs are clustering transitions and disconnected pairs are switching transitions) to the outcomes of two expert human raters. Results show that the network models proposed in this study overcome a thresholded co-occurrence approach, and their outcomes are in high agreement with human evaluations. Finally, the interplay between conceptual structure and retrieval mechanisms is discussed.

Vestibular Impairment in Hemifacial Spasm Syndrome: A Case Report.

A 52-year-old man presented with left hemifacial spasm (HFS). A magnetic resonance imaging scan showed compression of the left facial nerve at the cerebellopontine angle by a dolichoectatic basilar artery. The neurotological evaluation showed an otolithic deficit, with canalicular preservation and normal hearing. The deficit improved after surgical decompression. No previous report has described the impairment of vestibular function in patients presenting with HFS.

Primary central nervous system lymphoma and 5-aminolevulinic acid.

BACKGROUND: Despite surgical resection of primary central nervous system lymphomas (PCNSL) having been always discouraged, recent evidence supports that it might improve prognosis in this patient population. Five- aminolevulinic acid-derived fluorescence is widely used for the resection of malignant gliomas, but its role in PCNSL surgery remains unclear. CASE DESCRIPTION: We present two patients with a solitary solid intraparenchymal mass. As high-grade glioma leaded the list of differential diagnosis (other possibilities were metastasis, abscess, and PCNSL), a five- aminolevulinic acid-guided complete resection (with strong fluorescence in both cases) was done. Surgery was uneventfully carried on with complete resection until five-aminolevulinic acid-induced fluorescence was no longer evident. After surgery, patients have no neurological deficits and had good recovery. Pathological examination revealed that both tumors were PCNSL. Adjuvant radiotherapy and chemotherapy were started. After 1 year of follow-up, patients have good evolution and have no recurrences. CONCLUSION: These cases add to the growing literature which shows that surgery might play an important role in the management of PCNSL with an accessible and single lesion. Five-aminolevulinic acid could also be a useful tool to achieve complete resection and improve prognosis in this group of patients.

Clinical Profile and Results Obtained in Patients Treated by Auditory Brainstem Implants. / Perfil clínico y resultados obtenidos en los pacientes tratados mediante implante auditivo del tronco del encéfalo.

INTRODUCTION: Cochlear implants have been able to treat some types of hearing loss, but those related to cochlear nerve impairment made it necessary to find new ways to manage these deficits; leading to auditory brainstem implants (ABI). AIM: Our objective is to present the clinical profile of patients treated through an ABI and the results obtained from 1997 to 2017. MATERIAL AND METHODS: On the one hand, patients with statoacoustic nerve tumours (VIIIcranial nerve) were selected, and on the other hand, patients withoutVIII tumours with congenital malformations of the inner ear. Before and after the placement of the ABI, hearing was assessed through tonal audiometry, from which the PTA (Pure Tone Average) and the CAP (Categories of Auditory Performance) scale were obtained. RESULTS: A total of 20 patients undergoing ABI surgery were included. Eight were of tumour cause (40%) and 12 non-tumour (60%). In 15 subjects (75%) a suboccipital approach was performed and in 5 (25%) translabyrinthine. The mean of active electrodes before the implantation of Cochlear® (Nucleus ABI24) was 13/21 (61.90%) versus 8.5/12 (70.83%) of the Med-el® (ABI Med-el). An improvement in the mean PTA of 118.49dB was found against 46.55dB at 2years. On the CAP scale, values of1 were obtained in the preimplantation and of 2.57 (1-5) in the 2-year revision. CONCLUSION: The ABI is a safe option, and with good hearing results when the indication is made correctly.

Brain pathways of verbal working memory: a lesion-function correlation study.

Working memory relies on information processing by several well-identified gray matter regions. However, the white matter regions and pathways involved in this cognitive process remain unknown. An attractive and underexplored approach to study white matter connectivity in cognitive functions is through the use of non-aprioristic models, which specifically search disrupted white matter pathways. For this purpose, we used voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 54 multiple sclerosis patients with their performance on a verbal working memory task. With this approach, we have identified critical white matter regions involved in verbal working memory in humans. They are located in the cingulum, parieto-frontal pathways and thalamo-cortical projections, with a left-sided predominance, as well as the right cerebellar white matter. Our study provides direct evidence on the white matter pathways subserving verbal working memory in the human brain.

Mapping the brain pathways of declarative verbal memory: Evidence from white matter lesions in the living human brain.

Understanding the contribution of the brain white matter pathways to declarative verbal memory processes has been hindered by the lack of an adequate model in humans. An attractive and underexplored approach to study white matter region functionality in the living human brain is through the use of non-aprioristic models which specifically search disrupted white matter pathways. For this purpose, we employed voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 46 multiple sclerosis patients with their performance on declarative verbal memory storage and retrieval. White matter correlating with storage was in the temporal lobe-particularly lateral to the hippocampus and in the anterior temporal stem-, in the thalamic region and in the anterior limb of the internal capsule, all on the left hemisphere, and also in the right anterior temporal stem. The same volumes were relevant for retrieval, but to them were added temporo-parieto-frontal paramedian bundles, particularly the cingulum and the fronto-occipital fasciculus. These 3D maps indicate the white matter regions most critically involved in declarative verbal memory in humans.

Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic Acid-guided surgery.

BACKGROUND: There is evidence in the literature supporting that fluorescent tissue signal in fluorescence-guided surgery extends farther than tissue highlighted in gadolinium in T1 sequence magnetic resonance imaging (MRI), which is the standard to quantify the extent of resection. OBJECTIVE: To study whether the presence of residual fluorescent tissue after surgery carries a different prognosis for glioblastoma (GBM) cases with complete resection confirmed by MRI. METHODS: A retrospective review in our center found 118 consecutive patients with high-grade gliomas operated on with the use of fluorescence-guided surgery with 5-aminolevulinic acid. Within that series, the 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. We studied the influence of residual fluorescence in the surgical field on overall survival and neurological complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale, O-methylguanine methyltransferase methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy. RESULTS: The median overall survival was 27.0 months (confidence interval = 22.4-31.6) in patients with nonresidual fluorescence (n = 25) and 17.5 months (confidence interval = 12.5-22.5) for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in the multivariate analysis with all covariables, hazard ratio = 2.5 (P = .041). The neurological complication rate was 18.5% in patients with nonresidual fluorescence and 8% for the group with residual fluorescence (P = .267). CONCLUSION: GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue.

Perfil clínico y resultados obtenidos en los pacientes tratados mediante implante auditivo del tronco del encéfalo / Clinical Profile and Results Obtained in Patients Treated by Auditory Brainstem Implants

INTRODUCCIÓN: Los implantes cocleares han paliado algunas hipoacusias, pero las relacionadas con alteraciones del nervio coclear obligaron a buscar nuevas formas de tratamiento, dando lugar a los implantes auditivos del tronco cerebral (IATC). OBJETIVOS: Exponer el perfil clínico de los pacientes tratados mediante un IATC y los resultados entre los años 1997 y 2017. MATERIAL Y MÉTODOS: Se seleccionaron por un lado pacientes con tumores del nervio estatoacústico (VIII par craneal) y por otro lado pacientes sin tumores del VIII con malformaciones congénitas del oído interno. Previa y posteriormente a la colocación del IATC se evaluó la audición a través de audiometría tonal liminar, de la que se obtuvo el umbral tonal medio (UTM) y de la escala de rendimiento auditivo Categories Auditory Performance (CAP). RESULTADOS: Se incluyeron un total de 20 pacientes sometidos a una cirugía de IATC. Ocho de los casos fueron de causa tumoral (40%) y 12 no tumorales (60%). En 15 sujetos (75%) se realizó abordaje suboccipital y en 5 (25%) translaberíntico. La media de electrodos activos al inicio en los implantes de la casa comercial Cochlear® (Nucleus ABI24), la cual tiene un total de 21 electrodos, fue de 13 (61,90%) frente a 8,5 (70,83%) de los 12 electrodos que presenta el implante de la casa Med-el® (ABI Med-el). Se comprobó una mejora en el UTM medio de 118,49dB basal frente a 46,55 dB a los 2 años. En la escala CAP se parte en todos los casos de un valor de1, y en la revisión a los 2 años, de 2,57 (1-5). CONCLUSIÓN: Concluimos que el IATC es una opción segura y con buenos resultados auditivos cuando la indicación se hace de manera correcta

INTRODUCTION: Cochlear implants have been able to treat some types of hearing loss, but those related to cochlear nerve impairment made it necessary to find new ways to manage these deficits; leading to auditory brainstem implants (ABI). AIM: Our objective is to present the clinical profile of patients treated through an ABI and the results obtained from 1997 to 2017. MATERIAL AND METHODS: On the one hand, patients with statoacoustic nerve tumours (VIII cranial nerve) were selected, and on the other hand, patients withoutVIII tumours with congenital malformations of the inner ear. Before and after the placement of the ABI, hearing was assessed through tonal audiometry, from which the PTA (Pure Tone Average) and the CAP (Categories of Auditory Performance) scale were obtained. RESULTS: A total of 20 patients undergoing ABI surgery were included. Eight were of tumour cause (40%) and 12 non-tumour (60%). In 15 subjects (75%) a suboccipital approach was performed and in 5 (25%) translabyrinthine. The mean of active electrodes before the implantation of Cochlear® (Nucleus ABI24) was 13/21 (61.90%) versus 8.5/12 (70.83%) of the Med-el® (ABI Med-el). An improvement in the mean PTA of 118.49 dB was found against 46.55dB at 2 years. On the CAP scale, values of1 were obtained in the preimplantation and of 2.57 (1-5) in the 2-year revision. CONCLUSION: The ABI is a safe option, and with good hearing results when the indication is made correctly

Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway.

BACKGROUND: The biological basis of gray matter (GM) atrophy in multiple sclerosis is not well understood, but GM damage seems to be the most critical factor leading to permanent disability. OBJECTIVE: To assess to what extent white matter (WM) lesions contribute to regional GM atrophy in multiple sclerosis. DESIGN: Because optic pathway GM atrophy and optic radiation lesions, rather than being related to each other, could be independent results of the disease, we applied a nonaprioristic WM method to analyze the interrelationships of both phenomena. On a voxel-by-voxel basis, we correlated T1 magnetic resonance imaging-derived lesion probability maps of the entire brain with atrophy of the lateral geniculate nuclei and calcarine/pericalcarine cortices. SETTING: Multiple sclerosis center, University of Navarra, Pamplona, Spain. PATIENTS: Sixty-one patients with multiple sclerosis. MAIN OUTCOME MEASURE: Mapping of WM regions contributing to GM atrophy in the optic pathway. RESULTS: Patients with multiple sclerosis had lateral geniculate nucleus atrophy, which correlated with the presence of lesions specifically in the optic radiations but not in the rest of the brain. Optic pathway lesions explained up to 28% of the change of variance in lateral geniculate nucleus atrophy. Patients also had occipital cortex atrophy, which did not correlate with lesions in the optic radiations or any other WM region. CONCLUSIONS: Focal WM damage is associated with upstream GM atrophy, suggesting that retrograde damage of the perikarya from axonal injury in multiple sclerosis plaques is one of the significant factors in the genesis of GM atrophy, although other neurodegenerative processes are probably at work as well.

Fractal dimension analysis of grey matter in multiple sclerosis.

The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of a complex object. Among other applications, FD has been used to identify abnormalities of the human brain in conventional magnetic resonance imaging (MRI), including white matter abnormalities in patients with Multiple Sclerosis (MS). Extensive grey matter (GM) pathology has been recently identified in MS and it appears to be a key factor in long-term disability. The aim of the present work was to assess whether FD measurement of GM in T1 MRI sequences can identify GM abnormalities in patients with MS in the early phase of the disease. A voxel-based morphometry approach optimized for MS was used to obtain the segmented brain, where we later calculated the three-dimensional FD of the GM in MS patients and healthy controls. We found that patients with MS had a significant increase in the FD of the GM compared to controls. Such differences were present even in patients with short disease durations, including patients with first attacks of MS. In addition, the FD of the GM correlated with T1 and T2 lesion load, but not with GM atrophy or disability. The FD abnormalities of the GM here detected differed from the previously published FD of the white matter in MS, suggesting that different pathological processes were taking place in each structure. These results indicate that GM morphology is abnormal in patients with MS and that this alteration appears early in the course of the disease.

Temporal lobectomy in acute complicated herpes simplex encephalitis: technical case report.

OBJECTIVE: Herpes virus encephalitis is a rare, life-threatening complication of therapy in patients with brain tumors. A surgical therapeutic approach may be needed because the infection can be resistant to acyclovir in immunocompromised patients, and complications and long-term sequelae are frequent. CLINICAL PRESENTATION: We present the case of a right-handed, 6-year-old girl with a brainstem tumor who had herpes virus encephalitis with refractory seizures while on immunosuppressive treatment. The virus was resistant to acyclovir but responded to gancyclovir. The patient developed local refractory brain edema with right uncal herniation. INTERVENTION: To reduce the intracranial pressure, internal decompressive craniotomy was performed, which consisted of a right temporal lobectomy that allowed us to remove the focal necrotic-hemorrhagic tissue, decrease inflammation, and avoid subsequent chronic gliotic scarring. Clinical improvement was clear with prompt recovery and acute control of seizures. The only remaining deficits were mild memory and attention impairments. Seizures did not recur in the next 6 months. CONCLUSION: Antiviral resistance should be suspected in immunocompromised patients with herpes virus encephalitis if there is no early response to acyclovir. If uncal herniation of the nondominant temporal lobe develops, temporal lobectomy, as an internal decompressive procedure, can be lifesaving. Lobectomy stopped the acute refractory seizures and can be considered a good approach to prevent later epilepsy, with only mild residual cognitive deficits.

HLA-DR2 and white matter lesion distribution in MS.

Human leukocyte antigen DR2 (HLA-DR2) is a well-established genetic risk factor for multiple sclerosis (MS). However, it is still unknown whether this factor is associated with a specific disease phenotype, and in particular, to a regional distribution of white matter (WM) lesion phenotype on magnetic resonance imaging (MRI). On a voxel-by-voxel basis, we analyzed the T1 and T2 MRI-derived lesion maps of 50 patients with MS in order to determine the possible influence of HLA-DR2 genotype on the lesional MRI pattern at early stages of the disease. HLA-DR2 was present in 15 (30%) patients of our cohort. They displayed similar WM lesion distribution as the subjects without this factor. Thus, lesion distribution in MS seems to be independent of the DR2 genotype.

Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS.

OBJECTIVES: To assess the association between the thickness of the retinal nerve fiber layer (RNFL), assessed by optical coherence tomography (OCT), retinal periphlebitis (RP), and multiple sclerosis (MS) disease activity. METHODS: We studied a prospective cohort of 61 patients and 29 matched controls for 2 years, performing a neurologic assessment every 3 months and an ophthalmologic evaluation, including OCT scans, every 6 months. Baseline MRI studies were also carried out from which brain volume and lesion load were assessed. RESULTS: We found that the RNFL thickness in patients with MS was thinner than in controls, particularly in the temporal quadrant (p = 0.004). Although RNFL atrophy was greater in patients who also had optic neuritis (p = 0.002), it also augmented in MS patients who did not have optic neuritis compared with controls (p = 0.014). RNFL atrophy was correlated with greater disability (r = -0.348, p = 0.001) and longer disease duration (r = -0.301, p = 0.003). Furthermore, baseline temporal quadrant RNFL atrophy was associated with the presence of new relapses and changes in the Expanded Disability Status Scale by the end of the study (p < 0.05 in all cases). Indeed, RNFL thickness was correlated with white matter volume (r = 0.291, p = 0.005) and gray matter volume (r = 0.239, p = 0.021). The presence of RP was a risk factor for having new relapses in the next 2 years (odds ratio = 1.52, p = 0.02), and patients with RP had larger gadolinium-enhancing lesions volume (p = 0.003). CONCLUSION: Retinal nerve fiber layer atrophy and the presence of retinal periphlebitis are associated with disease activity, suggesting that retinal evaluation can be used as biomarkers of multiple sclerosis activity.

Fractal dimension and white matter changes in multiple sclerosis.

The brain white matter (WM) in multiple sclerosis (MS) suffers visible and non-visible (normal-appearing WM (NAWM)) changes in conventional magnetic resonance (MR) images. The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of a complex object. Our aim was to assess the usefulness of FD analysis in the measurement of WM abnormalities in conventional MR images in patients with MS, particularly to detect NAWM changes. First, we took on a voxel-based morphometry approach optimized for MS to obtain the segmented brain. Then, the FD of the whole grey-white matter interface (WM border) and skeletonized WM was calculated in patients with MS and healthy controls. To assess the FD of the NAWM, we focused our analysis on single sections without lesions at the centrum semiovale level. We found that patients with MS had a significant decrease in the FD of the entire brain WM compared with healthy controls. Such a decrease of the FD was detected not only on MR image sections with MS lesions but also on single sections with NAWM. Taken together, the results showed that FD identifies changes in the brain of patients with MS, including in NAWM, even at an early phase of the disease. Thus, FD might become a useful marker of diffuse damage of the central nervous system in MS.