Polo-like kinase 1 (Plk1) is a serine/threonine kinase involved in the regulation of mitosis and is overexpressed in many tumor types. Inhibition of Plk1 leads to cell cycle arrest, onset of apoptosis, and cell death, thus Plk1 has emerged as an important target for cancer treatment. GSK461364 is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting G2/M cell cycle arrest at low concentrations. However, as is the case for many therapeutic drugs, the risk of developing drug resistance to GSK461364 can present a therapeutic challenge to clinicians. Since the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 is one of the most common mechanisms of drug resistance, we aimed to investigate the effect of ABCB1 on the cellular efficacy of GSK461364. In this study, we observed a significantly reduced activity of GSK461364 in cells overexpressing human ABCB1. We showed that GSK461364 stimulates the ABCB1 ATPase activity and competitively inhibits ABCB1-mediated efflux of calcein-AM in a concentration-dependent manner. Moreover, as a way to assess the impact of ABCB1 on the efficacy of GSK461364, we evaluated the G2/M cell cycle arrest and apoptosis induced by GSK461364. We discovered that, by inhibiting the function of ABCB1, the reduced G2/M cell cycle arrest, apoptosis, and sensitivity to GSK461364 treatment in ABCB1-overexpressing cells can be significantly restored. In conclusion, in order to achieve a better therapeutic outcome, combination therapy of GSK461364 with a modulator of ABCB1 should be further investigated as a potential treatment approach.
This paper proposes a real-time method to carry out the monitoring of factory zone temperatures, humidity and air quality using smart phones. At the same time, the system detects possible flames, and analyzes and monitors electrical load. The monitoring also includes detecting the vibrations of operating machinery in the factory area. The research proposes using ZigBee and Wi-Fi protocol intelligent monitoring system integration within the entire plant framework. The sensors on the factory site deliver messages and real-time sensing data to an integrated embedded systems via the ZigBee protocol. The integrated embedded system is built by the open-source 32-bit ARM (Advanced RISC Machine) core Arduino Due module, where the network control codes are built in for the ARM chipset integrated controller. The intelligent integrated controller is able to instantly provide numerical analysis results according to the received data from the ZigBee sensors. The Android APP and web-based platform are used to show measurement results. The built-up system will transfer these results to a specified cloud device using the TCP/IP protocol. Finally, the Fast Fourier Transform (FFT) approach is used to analyze the power loads in the factory zones. Moreover, Near Field Communication (NFC) technology is used to carry out the actual electricity load experiments using smart phones.
Recently, Event-Related Potential (ERP) has being the most popular method in evaluating brain waves of schizophrenia patients. ERP is one of the electroencephalography (EEG), which is measured the change of brain waves after giving patients certain stimulations instead of resting state. However, with traditional statistical analysis method, both P50 and MMN showed significant difference between controls and patients but not in Gamma band. Gamma band is a 30-50 Hz auditory stimulation which had been suggested may be abnormal in schizophrenia patients. Our data are recruited from 5 schizophrenia patients and 5 controls in National Taiwan University Hospital have been tested with this platform. The results showed that detection rate is 88.24% and we also analyzed the importance of features, including Standard Deviation (SD) and Total Variation (TotalVar) in different stage of wavelet transform. Therefore, this proposed methodology could serve as a valuable clinical decision support for physiologists in evaluating schizophrenia.
Biomedical data analytic system has played an important role in doing the clinical diagnosis for several decades. Today, it is an emerging research area of analyzing these big data to make decision support for physicians. This paper presents a parallelized web-based tool with cloud computing service architecture to analyze the epilepsy. There are many modern analytic functions which are wavelet transform, genetic algorithm (GA), and support vector machine (SVM) cascaded in the system. To demonstrate the effectiveness of the system, it has been verified by two kinds of electroencephalography (EEG) data, which are short term EEG and long term EEG. The results reveal that our approach achieves the total classification accuracy higher than 90%. In addition, the entire training time accelerate about 4.66 times and prediction time is also meet requirements in real time.
Multiclass classification is an important technique to many complex bioinformatics problems. However, their performance is limited by the computation power. Based on the Apache Hadoop design framework, this study proposes a two layer architecture that exploits the inherent parallelism of GA-SVM classification to speed up the work. The performance evaluations on an mRNA benchmark cancer dataset have reduced 86.55% features and raised accuracy from 97.53% to 98.03%. With a user-friendly web interface, the system provides researchers an easy way to investigate the unrevealed secrets in the fast-growing repository of bioinformatics data.
The overexpression of the serine/threonine specific Polo-like kinase 1 (Plk1) has been detected in various types of cancer, and thus has fast become an attractive therapeutic target for cancer therapy. BI 2536 is the first selective inhibitor of Plk1 that inhibits cancer cell proliferation by promoting G2/M cell cycle arrest at nanomolar concentrations. Unfortunately, alike most chemotherapeutic agents, the development of acquired resistance to BI 2536 is prone to present a significant therapeutic challenge. One of the most common mechanisms for acquired resistance in cancer chemotherapy is associated with the overexpression of ATP-binding cassette (ABC) transporters ABCB1, ABCC1 and ABCG2. Here, we discovered that overexpressing of either ABCB1 or ABCG2 is a novel mechanism of acquired resistance to BI 2536 in human cancer cells. Moreover, BI 2536 stimulates the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner, and inhibits the drug substrate transport mediated by these transporters. More significantly, the reduced chemosensitivity and BI 2536-mediated G2/M cell cycle arrest in cancer cells overexpressing either ABCB1 or ABCG2 can be significantly restored in the presence of selective inhibitor or other chemotherapeutic agents that also interact with ABCB1 and ABCG2, such as tyrosine kinase inhibitors nilotinib and lapatinib. Taken together, our findings indicate that in order to circumvent ABCB1 or ABCG2-mediated acquired resistance to BI 2536, a combined regimen of BI 2536 and inhibitors or clinically active drugs that potently inhibit the function of ABC drug transporters, should be considered as a potential treatment strategy in the clinic.
Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. Electroencephalogram (EEG) signals play a critical role in the diagnosis of epilepsy. Multichannel EEGs contain more information than do single-channel EEGs. Automatic detection algorithms for spikes or seizures have traditionally been implemented on single-channel EEG, and algorithms for multichannel EEG are unavailable.
This study aims to investigate the electrical properties of lumbar paraspinal muscles (LPM) of patients with acute lower back pain (LBP) and to study a new approach, namely Electrical Impedance Myography (EIM), for reliable, low-cost, non-invasive, and real-time assessment of muscle-strained acute LBP.
Oral cancers are the 11th most common malignancy reported worldwide, accounting for 3% of all newly diagnosed cancer cases, and one with high mortality ratios among all malignancies. The objective of this study was to study the electrical properties of cancerous tongue tissue (CTT) and normal tongue tissue (NTT). Five tongue cancer patients participated in this study. A disposable probe incorporating four silver electrodes was used to measure the electrical properties of CTT and the surrounding NTT of patients. Measurements were performed at six frequencies: 20 Hz; 50 kHz; 1.3 MHz; 2.5 MHz; 3.7 MHz; and 5 MHz, with the amplitude of the applied voltage limited to 200mV. Four measurement parameters of impedance (Z), phase angle (theta), real part of impedance (R), and imaginary part of impedance (X) of tongue tissue were assessed to see if there was any significant difference in the values obtained in CTT and surrounding NTT. The intraclass correlation coefficient showed that all measurements were reliable. A significant difference (P < 0.05 for the four measurement parameters) was found at 50kHz between CTT and surrounding NTT. It was also found that Z and R of CTT were generally smaller than that of surrounding NTT. In conclusion, bioimpedance at a particular frequency is a potentially promising technique for tongue cancer screening.
Drinking highly arsenic-contaminated groundwater is a likely cause of blackfoot disease in Taiwan, but microorganisms that potentially control arsenic mobility in the subsurface remain unstudied. The objective of this study was to investigate the relevant arsenite-oxidizing and arsenate-reducing microbial community that exists in highly arsenic-contaminated groundwater in Taiwan. We cultured and identified arsenic-transforming bacteria, analyzed arsenic resistance and transformation, and determined the presence of genetic markers for arsenic transformation. In total, 11 arsenic-transforming bacterial strains with different colony morphologies and varying arsenic transformation abilities were isolated, including 10 facultative anaerobic arsenate-reducing bacteria and one strictly aerobic arsenite-oxidizing bacterium. All of the isolates exhibited high levels of arsenic resistance with minimum inhibitory concentrations of arsenic ranging from 2 to 200 mM. Strain AR-11 was able to rapidly oxidize arsenite to arsenate at concentrations relevant to environmental groundwater samples without the addition of any electron donors or acceptors. We provide evidence that arsenic-reduction activity may be conferred by the ars operon(s) that were not amplified by the designed primers currently in use. The 16S rRNA sequence analysis grouped the isolates into the following genera: Pseudomonas, Bacillus, Psychrobacter, Vibrio, Citrobacter, Enterobacter, and Bosea. Among these genera, we present the first report of the genus Psychrobacter being involved in arsenic reduction. Our results further support the hypothesis that bacteria capable of either oxidizing arsenite or reducing arsenate coexist and are ubiquitous in arsenic-contaminated groundwater.
Oral cancers are the 11th most common malignancy reported worldwide, accounting for 3% of all newly diagnosed cancer cases, and one with high mortality ratios among all malignancies. The objectives of this study were therefore to study the electrical properties of cancerous tongue tissue and normal tongue tissue, as well as to investigate a new approach for low-cost, noninvasive, and real-time screening of oral cancer. Twelve tongue cancer patients and twelve healthy subjects participated in this study. A disposable probe with four silver electrodes was used to measure the electrical properties of patients and healthy subjects tongue tissues at six different frequencies, which were 20Hz, 50kHz, 1.3MHz, 2.5MHz, 3.7MHz and 5MHz. The amplitude of the applied voltage was limited to 200mV. Four measurement parameters of impedance, phase angle, real part of impedance, and imaginary part of impedance of tongue were assessed to see if significant difference in values obtained in patients and healthy subjects tongue tissues existed. Intraclass correlation coefficient showed that all measurements had good reliability and validity (ICC>0.95 for all measurements). Significant differences were found at 20Hz (p<0.05-0.001 for the four measurement parameters) and 50kHz (p<0.001 for the four measurement parameters) between patients and healthy subjects tongue tissues. In conclusion, bioimpedance at a particular frequency is a potentially promising technique for tongue cancer screening.
Melanoma is the most serious type of skin cancer with a high potential for metastasis and very low survival rates. The discovery of constitutive activation of the BRAF kinase caused by activating BRAF(V600E) kinase mutation in most melanoma patients led to the discovery of the first potent BRAF(V600E) signaling inhibitor, vemurafenib. Vemurafenib was effective in treating advanced melanoma patients and was proposed for the treatment of other BRAF(V600E) mutant cancers as well. Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF(V600E) mutant cancer cells. It becomes important to identify and evaluate all of the potential mechanisms of cellular resistance to vemurafenib. In this study, we characterized the interactions of vemurafenib with three major ATP-binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2. We found that vemurafenib stimulated the ATPase activity and potently inhibited drug efflux mediated by ABCB1 and ABCG2. Vemurafenib also restored drug sensitivity in ABCG2-overexpressing cells. Moreover, we revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is reduced in BRAF(V600E) mutant A375 cells. Taken together, our findings indicate that ABCG2 confers resistance to vemurafenib in A375 cells, suggesting involvement of this transporter in acquired resistance to vemurafenib. Thus, combination chemotherapy targeting multiple pathways could be an effective therapeutic strategy to overcome acquired resistance to vemurafenib for cancers harboring the BRAF(V600E) mutation.
Ingested fish bone induced intestinal perforations are seldom diagnosed preoperatively due to incomplete patient history taking and difficulties in image evidence identification. Most literature suggests early surgical intervention to prevent sepsis and complications resulting from fish bone migrations. We report the case of a 44-year-old man suffered from acute abdomen induced by a fish bone micro-perforation. The diagnosis was supported by computed tomography (CT) imaging of fish bone lodged in distal ileum and a history of fish ingestion recalled by the patient. Medical treatment was elected to manage the patients condition instead of surgical intervention. The treatment resulted in a complete resolution of abdominal pain on hospital day number 4 without complication. Factors affecting clinical treatment decisions include the nature of micro-perforation, the patients good overall health condition, and the early diagnosis before sepsis signs develop. Micro-perforation means the puncture of intestine wall without CT evidence of free air, purulent peritoneum or abscess. We subsequently reviewed the literature to support our decision to pursue medical instead of surgical intervention.
Sjögrens syndrome (SS) is a chronic inflammatory autoimmune disease that mainly affects tear and salivary glands, whereby SS-patients frequently complain of eye and mouth dryness. Salivary acinar cells of SS-patients display alterations in their cell polarity; which may affect the correct localization and function of proteins involved in regulated exocytosis. Here we determined whether the expression and localization of SNARE proteins (membrane fusion receptors) involved in regulated secretion, such as VAMP8, syntaxin 3 (STX3), STX4 and SNAP-23 were altered in salivary glands (SG) from SS-patients. Additionally, we investigated SNARE proteins function, by evaluating their ability to form SNARE complexes under basal conditions. In SG from SS-patients and control subjects mRNA and proteins levels of SNARE complex components were determined by real-time PCR and Western blotting, respectively. SNARE protein distribution and mucin exocytosis were determined by indirect immunofluorescence. In SS-patients, the expression levels of mRNA and protein for VAMP8, STX4 and STX3 were altered. STX4, STX3, SNAP-23 and VAMP8 relocated from the apical to the basal region of acinar cells. Increased formation of SNARE complexes in a manner independent of external stimuli for secretion was detected. Mucins were detected in the extracellular matrix (ECM). Presence of mucins in the ECM, together with the observed alterations in SNARE protein localization is indicative of ectopic exocytosis. In the context of SS, such aberrantly localized mucins are likely to favor a pro-inflammatory response, which may represent an important initial step in the pathogenesis of this disease.
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