Design and Synthesis of Novel 2-Acetamido, 6-Carboxamide Substituted Benzothiazoles as Potential BRAFV600E Inhibitors - In vitro Evaluation of their Antiproliferative Activity.

The oncogenic BRAFV600E kinase leads to abnormal activation of the MAPK signaling pathway and thus, uncontrolled cellular proliferation and cancer development. Based on our previous virtual screening studies which issued 2-acetamido-1,3 benzothiazole-6-carboxamide scaffold as active pharmacophore displaying selectivity against the mutated BRAF, eleven new substituted benzothiazole derivatives were designed and synthesized by coupling of 2-acetamidobenzo[d]thiazole-6-carboxylic acid with the appropriate amines in an effort to provide even more efficient inhibitors and tackle drug resistance often developed during cancer treatment. All derived compounds bore the benzothiazole scaffold substituted at position-2 by an acetamido moiety and at position-6 by a carboxamide functionality, the NH moiety of which was further linked through an alkylene linker to a sulfonamido (or amino) aryl (or alkyl) functionality or a phenylene linker to a sulfonamido aromatic (or non-aromatic) terminal pharmacophore in the order -C H -NHSO -R or reversely -C H -SO N(H)-R.

BRAF paradox breakers PLX8394, PLX7904 are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 and shown by detailed pathway analysis.

PLX7904 and PLX8394 are novel BRAFV600E inhibitors-BRAFi that are designed to evade the paradoxical MAPK activation, a trait for the name "paradox breakers"-PB. Current FDA approved inhibitors (Vemurafenib, Dabrafenib, Encorafenib) although improved progression-free survival of mtBRAF melanoma patients suffer from this treatment related side effect. mtBRAF Colorectal Cancer (CRC) is resistant to the approved BRAF inhibitors, although combinatorial treatment co-targeting BRAF and EGFR/MEK is offering a promising prospect.

Noxa upregulation and 5-gene apoptotic biomarker panel in colorectal cancer.

Background: NOXA and MCL1 are involved in the intrinsic pathway of apoptosis, where Noxa selectively binds to MCL1 and prevents it from inhibiting apoptosis. Both factors are considered as potential tumour biomarkers, while MCL1 has attracted interest as target in cancer. The purpose of this study was to investigate the expression of NOXA and MCL1 in 160 CRC tumour samples, to investigate their significance, also in combination with IAPs, DR5 expression and KRAS gene mutations in CRC.

Brain source localization of MMN and P300 ERPs in mild cognitive impairment and Alzheimer's disease: a high-density EEG approach.

Alzheimer's disease is the most common neurodegenerative disease of Western societies, suggesting the need for early diagnosis, even in preclinical stages. In this vein, the localization of neuronal generators of event-related potential (ERP) components, that is, the mismatch negativity and the P300, based on high-density electroencephalogram data, was explored as a means to enhance their sensitivity as markers of preclinical Alzheimer's disease (AD). A 2-tone oddball experiment was conducted, involving 21 healthy elderly, 21 mild cognitive impairment, and 21 mild AD patients, while high-density electroencephalogram data were recorded.

Death receptor 5 (DR5) and a 5-gene apoptotic biomarker panel with significant differential diagnostic potential in colorectal cancer.

High expression of Inhibitor of apoptosis proteins (IAPs) has been related to colorectal cancer (CRC) progression, resistance to treatment and poor prognosis. TRAIL (TNF-related apoptosis-inducing ligand) through its receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) can selectively induce cancer cell apoptosis. The mRNA expression of DR4, DR5, c-IAP1, c-IAP2, XIAP and BIRC5/Survivin genes was examined in 100 paired (cancerous-normal) colorectal tissue specimens by real-time PCR, 50 of which were KRAS wild-type and 50 KRAS-mutant.

Age-induced differences in brain neural activation elicited by visual emotional stimuli: A high-density EEG study.

Identifying the brain sources of neural activation during processing of emotional information remains a very challenging task. In this work, we investigated the response to different emotional stimuli and the effect of age on the neuronal activation. Two negative emotion conditions, i.

Cognitive MMN and P300 in mild cognitive impairment and Alzheimer's disease: A high density EEG-3D vector field tomography approach.

Precise preclinical detection of dementia for effective treatment and stage monitoring is of great importance. Miscellaneous types of biomarkers, e.g.

Gender effect in human brain responses to bottom-up and top-down attention using the EEG 3D-Vector Field Tomography.

The effect of gender in rapidly allocating attention to objects, features or locations, as reflected in brain activity, is examined in this study. A visual-attention task, consisting of bottom-up (visual pop-out) and top-down (visual search) conditions during stimuli of four triangles, i.e.

Phase-amplitude cross-frequency coupling in EEG-derived cortical time series upon an auditory perception task.

Recent evidence suggests that cross-frequency coupling (CFC) plays an essential role in multi-scale communication across the brain. The amplitude of the high frequency oscillations, responsible for local activity, is modulated by the phase of the lower frequency activity, in a task and region-relevant way. In this paper, we examine this phase-amplitude coupling in a two-tone oddball paradigm for the low frequency bands (delta, theta, alpha, and beta) and determine the most prominent CFCs.

Brain source localization of MMN, P300 and N400: aging and gender differences.

The localization of neuronal generators during an ERP study, using a high-density electroencephalogram (HD-EEG) equipment was made on three Evoked Related Potential (ERP) components, i.e., the Mismatch Negativity (MMN), the P300 and the N400.

Electroencephalogram and Alzheimer's disease: clinical and research approaches.

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by cognitive deficits, problems in activities of daily living, and behavioral disturbances. Electroencephalogram (EEG) has been demonstrated as a reliable tool in dementia research and diagnosis. The application of EEG in AD has a wide range of interest.

Tumor heterogeneity revealed by KRAS, BRAF, and PIK3CA pyrosequencing: KRAS and PIK3CA intratumor mutation profile differences and their therapeutic implications.

Current clinical problems in colorectal cancer (CRC) diagnostics and therapeutics include the disease complexity, tumor heterogeneity, and resistance to targeted therapeutics. In the present study, we examined 171 CRC adenocarcinomas from Greek patients undergoing surgery for CRC to determine the frequency of KRAS, BRAF, and PIK3CA point mutations from different areas of tumors in heterogeneous specimens. Ninety two out of 171 (53.

Epigenetic regulation of miR-21 in colorectal cancer: ITGB4 as a novel miR-21 target and a three-gene network (miR-21-ITGΒ4-PDCD4) as predictor of metastatic tumor potential.

Previous studies have uncovered several transcription factors that determine biological alterations in tumor cells to execute the invasion-metastasis cascade, including the epithelial-mesenchymal transition (EMT). We sought to investigate the role of miR-21 in colorectal cancer regulation. For this purpose, miR-21 expression was quantified in a panel of colorectal cancer cell lines and clinical specimens.

EZH2 is regulated by ERK/AKT and targets integrin alpha2 gene to control Epithelial-Mesenchymal Transition and anoikis in colon cancer cells.

Epithelial-Mesenchymal Transition is a good example of cell plasticity. In tumorigenesis, this process has been associated with metastasis. Overexpression of EZH2 has been detected in most malignant human tumors, including colorectal carcinomas.

A molecular signature for oncogenic BRAF in human colon cancer cells is revealed by microarray analysis.

Sporadic colorectal cancer develops through a number of functional mutations. Key events are mutually exclusive mutations in BRAF or RAS oncogenes. Signatures for BRAF oncogene have been revealed in melanoma.

Enhanced Sign Language Recognition Using Weighted Intrinsic-Mode Entropy and Signer's Level of Deafness.

Sign language (SL) forms an important communication canal for the deaf. In this paper, enhanced SL recognition, by relating the individual way of signing with the signer's level of deafness (LoD) through a novel hybrid adaptive weighting (HAW) process applied to surface electromyogram and 3-D accelerometer data, is proposed. Using a LoD-driven genetic algorithm, HAW optimally weights the intrinsic modes of the acquired signals, preparing them for sample entropy (SampEn) estimation that follows.

Using sample entropy for automated sign language recognition on sEMG and accelerometer data.

Communication using sign language (SL) provides alternative means for information transmission among the deaf. Automated gesture recognition involved in SL, however, could further expand this communication channel to the world of hearers. In this study, data from five-channel surface electromyogram and three-dimensional accelerometer from signers' dominant hand were subjected to a feature extraction process.

TRAIL receptor upregulation and the implication of KRAS/BRAF mutations in human colon cancer tumors.

TRAIL raises hopes as a promising anti-tumor agent due to its selectivity toward cancer cells. Higher expression of its pro-death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) attenuates higher sensitivity to TRAIL-induced apoptosis, and represents a marker for better cancer prognosis and treatment. Since receptor availability can be analogous to ligand efficacy, we performed RT-PCR analysis of DR4 and DR5 in 51 colon cancer biopsy specimens and respective normal mucosa, while 11 of these tumors were determined immunohistochemically for protein expression.

Sign language recognition using intrinsic-mode sample entropy on sEMG and accelerometer data.

Sign language forms a communication channel among the deaf; however, automated gesture recognition could further expand their communication with the hearers. In this work, data from five-channel surface electromyogram and 3-D accelerometer from the signer's dominant hand were analyzed using intrinsic-mode entropy (IMEn) for the automated recognition of Greek sign language (GSL) isolated signs. Discriminant analysis was used to identify the effective scales of the intrinsic-mode functions and the window length for the calculation of the IMEn that contributes to the efficient classification of the GSL signs.

Intrinsic mode entropy: an enhanced classification means for automated Greek Sign Language gesture recognition.

Sign language forms a communication channel among the deaf; however, automated gesture recognition could further expand their communication with the hearers. In this work, data from three-dimensional accelerometer and five-channel surface electromyogram of the user's dominant forearm are analyzed using intrinsic mode entropy (IMEn) for the automated recognition of Greek Sign Language (GSL) gestures. IMEn was estimated for various window lengths and evaluated by the Mahalanobis distance criterion.

Evaluation of surface EMG features for the recognition of American Sign Language gestures.

In this work, analysis of the surface electromyogram (sEMG) signal is proposed for the recognition of American sign language (ASL) gestures. To this purpose, sixteen features are extracted from the sEMG signal acquired from the user's forearm, and evaluated by the Mahalanobis distance criterion. Discriminant analysis is used to reduce the number of features used in the classification of the signed ASL gestures.

Mutation analysis of 24 known cancer genes in the NCI-60 cell line set.

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported.

A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.

Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents.

Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults.

The protein kinase gene family is the most frequently mutated in human cancer. Previous work has documented activating mutations in the KIT receptor tyrosine kinase in testicular germ-cell tumors (TGCT). To investigate further the potential role of mutated protein kinases in the development of TGCT and to characterize the prevalence and patterns of point mutations in these tumors, we have sequenced the coding exons and splice junctions of the annotated protein kinase family of 518 genes in a series of seven seminomas and six nonseminomas.

Somatic mutations of the protein kinase gene family in human lung cancer.

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines.