Visual Experience Modulates Spatio-Temporal Dynamics of Circuit Activation

Persistent reduction in sensory drive in early development results in multiple plastic changes of different cortical synapses. How these experience-dependent modifications affect the spatio-temporal dynamics of signal propagation in neocortical circuits is poorly understood. Here we demonstrate that brief visual deprivation significantly affects the propagation of electrical signals in the primary visual cortex. The spatio-temporal spread of circuit activation upon direct stimulation of its input layer (Layer 4) is reduced, as is the activation of L2/3 – the main recipient of the output from L4. Our data suggest that the decrease in spatio-temporal activation of L2/3 depends on reduced L4 output, and is not intrinsically generated within L2/3. The data shown here suggest that changes in the synaptic components of the visual cortical circuit result not only in alteration of local integration of excitatory and inhibitory inputs, but also in a significant decrease in overall circuit activation. Furthermore, our data indicate a differential effect of visual deprivation on L4 and L2/3, suggesting that while feedforward activation of L2/3 is reduced, its activation by long range, within layer inputs is unaltered. Thus, brief visual deprivation induces experience-dependent circuit re-organization by modulating not only circuit excitability, but also the spatio-temporal patterns of cortical activation within and between layers

Amygdala Stimulation Evokes Time-Varying Synaptic Responses in the Gustatory Cortex of Anesthetized Rats

Gustatory stimuli are characterized by a specific hedonic value; they are either palatable or aversive. Hedonic value, along with other psychological dimensions of tastes, is coded in the time-course of gustatory cortex (GC) neural responses and appears to emerge via top-down modulation by the basolateral amygdala (BLA). While the importance of BLA in modulating gustatory cortical function has been well established, the nature of its input onto GC neurons is largely unknown. Somewhat conflicting results from extracellular recordings point to either excitatory or inhibitory effects. Here, we directly test the hypothesis that BLA can evoke time-varying – excitatory and inhibitory – synaptic responses in GC using in vivo intracellular recording techniques in urethane anesthetized rats. Electrical stimulation of BLA evoked a post-synaptic potential (PSP) in GC neurons that resulted from a combination of short and long latency components: an initial monosynaptic, glutamatergic potential followed by a multisynaptic, GABAergic hyperpolarization. As predicted by the dynamic nature of amygdala evoked potentials, trains of five BLA stimuli at rates that mimic physiological firing rates (5–40 Hz) evoke a combination of excitation and inhibition in GC cells. The magnitude of the different components varies depending on the frequency of stimulation, with summation of excitatory and inhibitory inputs reaching its maximum at higher frequencies. These experiments provide the first description of BLA synaptic inputs to GC and reveal that amygdalar afferents can modulate gustatory cortical network activity and its processing of sensory information via time-varying synaptic dynamics

Multimodality treatment of malignant pleural mesothelioma with or without immunotherapy: does it change anything?☆

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Prognostic role of TPL2 in early‑stage non‑small cell lung cancer

Non‑small cell lung cancer (NSCLC) accounts for ~70% of all lung cancer‑associated mortalities worldwide. The serine/threonine protein kinase tumor progression locus 2 [TPL2/MAP3 kinase 8 (MAP3K8)] may impact oncogenic events; however the role of TPL2 in lung carcinogenesis remains unclear. The present study was focused on the potential prognostic role of TPL2 in 101 patients with early‑stage NSCLC. Since TPL2 is a potential target of miR‑21, the association between TPL2 and miR‑21 expression was also examined. TPL2 and miR‑21 mRNA expression was quantified using reverse transcription quantitative polymerase chain reaction (RT‑qPCR). TPL2 protein levels were evaluated by immunohistochemistry (IHC). The present study identified that the mRNA expression of TPL2 was low in 52/101 (51%) cases and high in 49/101 (49%) cases. IHC analysis of TPL2 protein expression often demonstrated identical mRNA results. No statistically significant associations were observed between the mRNA expression of TPL2 and the predominant clinicopathological characteristics of the patients with NSCLC, as well as identifying no association between TPL2 and miR‑21. TPL2 mRNA expression was significantly higher in patients with NSCLC with good prognosis (disease‑free interval P=0.009; overall survival P=0.024), when compared with those of poor prognosis. Focusing on the difference in mRNA expression of TPL2 among the adenocarcinomas in affected patients, TPL2 was more highly expressed in lepidic adenocarcinomas compared with in the other subtypes (P=0.012). The present study is the first examination, to the best of our knowledge, of TPL2 in early‑stage NSCLC in relation to miR‑21, and in different adenocarcinoma subtypes. Future studies must clarify the mechanism by which TPL2 is involved in lung carcinogenesis due to its important translational implications

Malignant pleural mesothelioma and mesothelial hyperplasia: A new molecular tool for the differential diagnosis

Malignant pleural mesothelioma (MPM) is a rare asbestos related cancer, aggressive and unresponsive to therapies. Histological examination of pleural lesions is the gold standard of MPM diagnosis, although it is sometimes hard to discriminate the epithelioid type of MPM from benign mesothelial hyperplasia (MH). This work aims to define a new molecular tool for the differential diagnosis of MPM, using the expression profile of 117 genes deregulated in this tumour. The gene expression analysis was performed by nanoString System on tumour tissues from 36 epithelioid MPM and 17 MH patients, and on 14 mesothelial pleural samples analysed in a blind way. Data analysis included raw nanoString data normalization, unsupervised cluster analysis by Pearson correlation, non-parametric Mann Whitney U-test and molecular classification by the Uncorrelated Shrunken Centroid (USC) Algorithm. The Mann-Whitney U-test found 35 genes upregulated and 31 downregulated in MPM. The unsupervised cluster analysis revealed two clusters, one composed only of MPM and one only of MH samples, thus revealing class-specific gene profiles. The Uncorrelated Shrunken Centroid algorithm identified two classifiers, one including 22 genes and the other 40 genes, able to properly classify all the samples as benign or malignant using gene expression data; both classifiers were also able to correctly determine, in a blind analysis, the diagnostic categories of all the 14 unknown samples. In conclusion we delineated a diagnostic tool combining molecular data (gene expression) and computational analysis (USC algorithm), which can be applied in the clinical practice for the differential diagnosis of MPM

Diaphragm and lung-preserving surgery with hyperthermic chemotherapy for malignant pleural mesothelioma: A 10-year experience

Background: The best surgical treatment for malignant pleural mesothelioma is still under a debate, but recent evidence points toward a less-invasive approach to reduce morbidity and mortality. We reported our 10-year experience of a limited surgical approach associated with hyperthermic intrathoracic chemotherapy (HITHOC). Material and Methods: Between 2005 and 2014, patients with epithelioid or biphasic malignant pleural mesothelioma were treated with lung-diaphragm-pericardium-sparing pleurectomy associated with double-drug HITHOC; at least 3 cycles of adjuvant chemotherapy were then administered. The primary outcome examined was the feasibility of the procedure, whereas secondary outcomes were overall survival and disease-free interval. Results: Among 49 patients, 41 were male. Median age was 68 years (35-76 years). Histology was epithelioid in 43 cases. Pathologic stage I, II, III, and IV occurred in 12, 14, 20, and 3 cases, respectively. No intraoperative complications or postoperative mortality occurred, whereas morbidity rate was 46.9%. Median hospital stay was 8 days (5-45 days). Actuarial median overall survival was 22 months and a 1-, 2-, and 5-year survival accounted for 79.6%, 45.7%, and 9.9%, respectively. Disease-free survival after surgery was 62%, 37.5%, and 18.5% at 1, 2, and 5 years, respectively. Risk factors analysis for overall survival confirmed a significant role for early stages, epithelioid histology, and fibrinogen serum levels. Conclusions: Cytoreductive surgery associated with HITHOC and adjuvant chemotherapy appears feasible and safe, with no mortality and low morbidity. Preserving lung and diaphragmatic function might warrant an acceptable long-term outcome

KRAS and BRAF genotyping of synchronous colorectal carcinomas.

Abstract. v‑Ki‑ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genotyping is required prior to anti‑epidermal growth factor receptor monoclonal antibody therapy administered in cases of metastatic colorectal carcinoma (CRC). Thus, KRAS mutation screening is required for patient management. The present study reported the experience of KRAS/v‑raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational screening on synchronous CRC pairs from 26 patients, which were defined as index lesions (ILs) and concurrent lesions (CLs) on the basis of tumor grade and dimension and their respective lymph node and distant metastases. Overall, KRAS mutations were present in 38.4% of patients, whereas BRAF mutations were present at a frequency of 11.5%. The genotyping of paired synchronous carcinomas indicated that 11 patients (42.3%) exhibited discordant KRAS mutational statuses in terms of the presence of a mutation in only one lesion of the pair or of two different mutations harbored by each lesion. BRAF mutations were present in the synchronous tumors of two cases, whereas in two other cases, only the IL or CL harbored mutant BRAF. Overall, the mutational statuses of distant and lymph node metastases confirm the genetic heterogeneity of synchronous primary tumors. These results highlighted the fact that adequate sampling and comprehensive testing, when feasible, is likely to optimize the decision‑making process for treatment approaches, even in the relatively rare event of multiple synchronous lesions