Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles.

BACKGROUND: p53 is a tumor suppressor and key regulator of glycolysis in cancer cells, however highly mutated in tumors. In ovarian cancer, studies concerning p53 mutations focus on the DNA binding domain since the majority of hotspot mutations affects this region. Yet, mutations in other regions such as the proline rich domain may also affect the protein's expression and activity. The aim of this study is to investigate the effect of various positions of mutations in TP53 gene on glycolysis, apoptosis and transcription of p53 target genes. METHODS: Mutations frequency and their effect on p53 expression were assessed by PCR-SSCP, sequencing and immunohistochemistry on 30 ovarian cancer biopsies. Six tumors were cultured, as well as SK-OV-3, OVCAR-3 and Igrov-1. SK-OV-3 cells were transfected with 2 TP53 mutants. p53 transcriptional activity was assayed by qPCR, apoptosis by flow cytometry and glycolysis by glucose and lactate measurements, with quantification of glycolytic enzymes expression. RESULTS: Our results showed a high frequency of the P72R mutant, associated with p53 overexpression in the ovarian biopsies. However, P72R mutant cells showed similar apoptosis and glycolysis as WT cells. DNA binding domain mutations decreased the transcriptional activity of the protein and increased glucose consumption and lactate production. CONCLUSION: Despite the overexpression of the P72R mutated protein in the biopsies, it showed a similar apoptotic activity and glucose regulation ability as WT p53. Knowing that p53 expression status is used for chemotherapeutic approaches and prognosis in ovarian cancer, the results obtained highlight the importance of locating TP53 mutations.

Disruptions in the left frontoparietal network underlie resting state endophenotypic markers in schizophrenia.

Advances in functional brain imaging have improved the search for potential endophenotypic markers in schizophrenia. Here, we employed independent component analysis (ICA) and dynamic causal modeling (DCM) in resting state fMRI on a sample of 35 schizophrenia patients, 20 first-degree relatives and 35 control subjects. Analysis on ICA-derived networks revealed increased functional connectivity between the left frontoparietal network (FPN) and left temporal and parietal regions in schizophrenia patients (P < 0.001). First-degree relatives shared this hyperconnectivity, in particular in the supramarginal gyrus (SMG; P = 0.008). DCM analysis was employed to further explore underlying effective connectivity. Results showed increased inhibitory connections to the left angular gyrus (AG) in schizophrenia patients from all other nodes of the left FPN (P < 0.001), and in particular from the left SMG (P = 0.001). Relatives also showed a pattern of increased inhibitory connections to the left AG (P = 0.008). Furthermore, the patient group showed increased excitatory connectivity between the left fusiform gyrus and the left SMG (P = 0.002). This connection was negatively correlated to inhibitory afferents to the left AG (P = 0.005) and to the negative symptom score on the PANSS scale (P = 0.001, r = -0.51). Left frontoparietotemporal dysfunction in schizophrenia has been previously associated with a range of abnormalities, including formal thought disorder, working memory dysfunction and sensory hallucinations. Our analysis uncovered new potential endophenotypic markers of schizophrenia and shed light on the organization of the left FPN in patients and their first-degree relatives. Hum Brain Mapp 38:1741-1750, 2017. © 2017 Wiley Periodicals, Inc.

Resting-state functional connectivity of antero-medial prefrontal cortex sub-regions in major depression and relationship to emotional intelligence.

BACKGROUND: Major depressive disorder has been associated with abnormal resting-state functional connectivity (FC), especially in cognitive processing and emotional regulation networks. Although studies have found abnormal FC in regions of the default mode network (DMN), no study has investigated the FC of specific regions within the anterior DMN based on cytoarchitectonic subdivisions of the antero-medial pre-frontal cortex (PFC). Studies from different areas in the field have shown regions within the anterior DMN to be involved in emotional intelligence. Although abnormalities in this region have been observed in depression, the relationship between the ventromedial PFC (vmPFC) function and emotional intelligence has yet to be investigated in depressed individuals. METHODS: Twenty-one medication-free, non-treatment resistant, depressed patients and 21 healthy controls underwent a resting state functional magnetic resonance imaging session. The participants also completed an ability-based measure of emotional intelligence: the Mayer-Salovey-Caruso Emotional Intelligence Test. FC maps of Brodmann areas (BA) 25, 10 m, 10r, and 10p were created and compared between the two groups. RESULTS: Mixed-effects analyses showed that the more anterior seeds encompassed larger areas of the DMN. Compared to healthy controls, depressed patients had significantly lower connectivity between BA10p and the right insula and between BA25 and the perigenual anterior cingulate cortex. Exploratory analyses showed an association between vmPFC connectivity and emotional intelligence. CONCLUSIONS: These results suggest that individuals with depression have reduced FC between antero-medial PFC regions and regions involved in emotional regulation compared to control subjects. Moreover, vmPFC functional connectivity appears linked to emotional intelligence.

Distinct hierarchical alterations of intrinsic neural timescales account for different manifestations of psychosis.

Hierarchical perceptual-inference models of psychosis may provide a holistic framework for understanding psychosis in schizophrenia including heterogeneity in clinical presentations. Particularly, hypothesized alterations at distinct levels of the perceptual-inference hierarchy may explain why hallucinations and delusions tend to cluster together yet sometimes manifest in isolation. To test this, we used a recently developed resting-state fMRI measure of intrinsic neural timescale (INT), which reflects the time window of neural integration and captures hierarchical brain gradients. In analyses examining extended sensory hierarchies that we first validated, we found distinct hierarchical INT alterations for hallucinations versus delusions in the auditory and somatosensory systems, thus providing support for hierarchical perceptual-inference models of psychosis. Simulations using a large-scale biophysical model suggested local elevations of excitation-inhibition ratio at different hierarchical levels as a potential mechanism. More generally, our work highlights the robustness and utility of INT for studying hierarchical processes relevant to basic and clinical neuroscience.

On the role of the anterior prefrontal cortex in cognitive 'branching': An fMRI study.

The most anterior portion of prefrontal cortex (aPFC), more specifically Brodman Area 10 (BA10), has been implicated in 'branching operations', or the ability to perform tasks related to one goal, while keeping in working memory information related to a secondary goal. Such findings have been based on fMRI recordings under complex behavioral paradigms that compare 'branching' tasks with tasks where one goal is pursued at a time, but are limited by their complete reliance on verbal working memory and by small sample sizes. Here, we test the specificity of BA 10 to branching in similar behavioral paradigms but with a larger sample and in two different conditions involving verbal and visual working memory respectively. We find that BA 10 and other frontal and parietal brain areas are activated in all tasks, with an extent and level of significance increasing with the complexity of the task. We conclude that the activation of BA 10 is not specific to branching as previously hypothesized, but is related to the level of complexity of working memory performance. For further insight into the specific role of anterior portions of the frontal cortex we highlight the importance of simple control tasks with gradual and incremental increase in complexity.

A multicenter, phase II study of the RAF-kinase inhibitor sorafenib in patients with advanced renal cell carcinoma.

The treatment of advanced renal cell carcinoma (RCC) has advanced significantly over the last two decades. This multicenter study was designed with the primary objective to evaluate the efficacy and safety of sorafenib as first-line treatment in patients with advanced or metastatic RCC in the Middle East, who were considered to be ineligible for other approved first-line therapies. A total of 75 eligible patients from 8 centers in the Middle East were included in this study. The patients comprised 48 men and 27 women, with a median age of 52 years (range, 19-78 years). A total of 50 patients had clear cell carcinoma, 17 had papillary carcinoma and 8 had other pathological subtypes. At enrollment, 55 of the 75 patients had undergone previous nephrectomy. A total of 67 patients presented with metastatic disease, while 8 patients had regional residual lesions or local recurrence. The patients were treated with 400 mg oral sorafenib twice daily on a continuous basis as a single agent. Treatment was discontinued upon disease progression, prohibitive toxicity, surgical complications, loss to follow-up, or refusal to continue therapy. The median treatment duration was 21 weeks (range, 1-137 weeks). Sorafenib was tolerated by the majority of the patients. Grade 3/4 hand-foot syndrome occurred in 17 patients; diarrhea, elevated liver enzymes and fatigue were observed in 3 patients each; and grade 3/4 vomiting, hypertension and anemia, in 1 patient each. Of the 75 patients included in this study, 60 were evaluable for response. One patient achieved a complete response for 91 weeks and 6 patients exhibited a partial response (median duration of 23 weeks) with an overall response rate of 11.7%. Disease stabilization occurred in 37 patients (61.7%). Thus, disease control was achieved in 44 of the 60 patientrs (73%). At a median follow-up period of 53.5 weeks (range, 8.5-192 weeks), an intention-to-treat analysis demonstrated a median time-to-disease progression of 25.7 weeks, with a median overall survival of 54.8 weeks. In conclusion, sorafenib was found to be tolerable and effective as first-line therapy in patients with advanced RCC.

Gemcitabine plus carboplatin combination therapy as second-line treatment in patients with relapsed breast cancer.

This study was designed to determine the safety and efficacy of the combination therapy of gemcitabine plus carboplatin when used as a second-line treatment in patients with metastatic breast cancer (MBC). From February 2002 to May 2003, 30 previously treated patients with adenocarcinoma of the breast received gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin to an area under the curve (AUC) of 5 on day 1. The carboplatin dose was changed to an AUC of 4.5 because of toxicity, with cycles repeated every 3 weeks. Among 30 patients enrolled, 25 were assessable for response rate (RR). There was no complete response; 9 patients (30%) had partial response, for an overall RR of 30%. The median time to progression for the study group was 20.47 weeks (range, 8-46 weeks). Treatment-related toxicities included grade 3/4 neutropenia in 50% of patients (20% of whom had febrile neutropenia), grade 3/4 anemia in 26.6% of patients, and grade 3/4 thrombocytopenia in 30%. Eleven patients (36.67%) had grade 1 alopecia, and 1 patient (3.33%) had grade 2 alopecia. Moderate nausea was observed in 8 patients (26.67%), and vomiting occurred in 7 patients. Four patients had asthenia and 3 (10%) experienced stomatitis. Three patients discontinued treatment because of hematologic toxicity (thrombocytopenia) and 2 patients are still receiving treatment. Carboplatin plus gemcitabine is an active combination for patients with MBC despite significant but manageable hematologic toxicity.

Regional cerebral blood flow changes associated with focal electrically administered seizure therapy (FEAST).

INTRODUCTION: Use of electroconvulsive therapy (ECT) is limited by cognitive disturbance. Focal electrically-administered seizure therapy (FEAST) is designed to initiate focal seizures in the prefrontal cortex. To date, no studies have documented the effects of FEAST on regional cerebral blood flow (rCBF). METHODS: A 72 year old depressed man underwent three single photon emission computed tomography (SPECT) scans to capture the onset and resolution of seizures triggered with right unilateral FEAST. We used Bioimage Suite for within-subject statistical analyses of perfusion differences ictally and post-ictally compared with the baseline scan. RESULTS: Early ictal increases in regional cerebral blood flow (rCBF) were limited to the right prefrontal cortex. Post-ictally, perfusion was reduced in bilateral frontal and occipital cortices and increased in left motor and precuneus cortex. CONCLUSION: FEAST appears to triggers focal onsets of seizure activity in the right prefrontal cortex with subsequent generalization. Future studies are needed on a larger sample.

Cortical contributions to saccadic suppression.

The stability of visual perception is partly maintained by saccadic suppression: the selective reduction of visual sensitivity that accompanies rapid eye movements. The neural mechanisms responsible for this reduced perisaccadic visibility remain unknown, but the Lateral Geniculate Nucleus (LGN) has been proposed as a likely site. Our data show, however, that the saccadic suppression of a target flashed in the right visual hemifield increased with an increase in background luminance in the left visual hemifield. Because each LGN only receives retinal input from a single hemifield, this hemifield interaction cannot be explained solely on the basis of neural mechanisms operating in the LGN. Instead, this suggests that saccadic suppression must involve processing in higher level cortical areas that have access to a considerable part of the ipsilateral hemifield.