Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction.

Rationale: The gut and its accessory organ, the liver, are crucial determinants of metabolic homeostasis via the regulation of circulating lipids for cardiovascular health. In response to environmental insults, cells undergo diverse adaptation or pathophysiological processes via stress-responsive eukaryotic initiation factor 2 alpha (eIF2α) kinase signaling and subsequent cellular reprogramming. We noted that patients with inflammatory gut distress display enhanced levels of ribosomal stress-responsive eIF2α kinase, which is notably associated with lipid metabolic process genes. Based on an assumption that eukaryotic ribosomes are a promising stress-responsive module for molecular reprogramming, chemical ribosome-inactivating stressors (RIS) were assessed for their involvement in enterohepatic lipid regulation. Methods: Experimental assessment was based on prediction using the clinical transcriptome and single-cell RNA-sequencing analysis of inflammatory bowel diseases and obesity. The prediction was verified using RIS exposure models of mice, gut organoids, and intestinal cells. The lipidomic profiling was performed to address RIS-induced intracellular fat alterations. Biochemical processes of the mechanisms were evaluated using RT-PCR, western blot analysis, luciferase reporter assays, and confocal microscopy of genetically ablated or chemically inhibited mice, organoids, and cells. Results: Chemical RIS including deoxynivalenol promoted enterohepatic lipid sequestration while lowering blood LDL cholesterol in normal and diet-induced obese mice. Although ribosomal stress caused extensive alterations in cellular lipids and metabolic genes, the cholesterol import-associated pathway was notably modulated. In particular, ribosomal stress enhanced gut levels of the low-density lipoprotein receptor (LDLR) via both transcriptional and post-transcriptional regulation. Subsequently, LDLR facilitated enterohepatic cholesterol accumulation, leading to dyslipidemia in response to ribosomal stress. Moreover, genetic features of stress-responsive LDLR modulators were consistently proven in the inflammation- and obesity-associated gut model. Conclusion: The elucidated ribosome-linked gut lipid regulation provides predictive insights into stress-responsive metabolic rewiring in chronic human diseases as an environmental health prediction.

Security Framework for Network-Based Manufacturing Systems with Personalized Customization: An Industry 4.0 Approach.

Smart manufacturing is pivotal in the context of Industry 4.0, as it integrates advanced technologies like the Internet of Things (IoT) and automation to streamline production processes and improve product quality, paving the way for a competitive industrial landscape. Machines have become network-based through the IoT, where integrated and collaborated manufacturing system responds in real time to meet demand fluctuations for personalized customization. Within the network-based manufacturing system (NBMS), mobile industrial robots (MiRs) are vital in increasing operational efficiency, adaptability, and productivity. However, with the advent of IoT-enabled manufacturing systems, security has become a serious challenge because of the communication of various devices acting as mobile nodes. This paper proposes the framework for a newly personalized customization factory, considering all the advanced technologies and tools used throughout the production process. To encounter the security concern, an IoT-enabled NBMS is selected as the system model to tackle a black hole attack (BHA) using the NTRUEncrypt cryptography and the ad hoc on-demand distance-vector (AODV) routing protocol. NTRUEncrypt performs encryption and decryption while sending and receiving messages. The proposed technique is simulated by network simulator NS-2.35, and its performance is evaluated for different network environments, such as a healthy network, a malicious network, and an NTRUEncrypt-secured network based on different evaluation metrics, including throughput, goodput, end-to-end delay, and packet delivery ratio. The results show that the proposed scheme performs safely in the presence of a malicious node. The implications of this study are beneficial for manufacturing industries looking to embrace IoT-enabled subtractive and additive manufacturing facilitated by mobile industrial robots. Implementation of the proposed scheme ensures operational efficiency, enables personalized customization, and protects confidential data and communication in the manufacturing ecosystem.

A Comprehensive Study on Cyber Attacks in Communication Networks in Water Purification and Distribution Plants: Challenges, Vulnerabilities, and Future Prospects.

In recent years, the Internet of Things (IoT) has had a big impact on both industry and academia. Its profound impact is particularly felt in the industrial sector, where the Industrial Internet of Things (IIoT), also known as Industry 4.0, is revolutionizing manufacturing and production through the fusion of cutting-edge technologies and network-embedded sensing devices. The IIoT revolutionizes several industries, including crucial ones such as oil and gas, water purification and distribution, energy, and chemicals, by integrating information technology (IT) with industrial control and automation systems. Water, a vital resource for life, is a symbol of the advancement of technology, yet knowledge of potential cyberattacks and their catastrophic effects on water treatment facilities is still insufficient. Even seemingly insignificant errors can have serious consequences, such as aberrant pH values or fluctuations in the concentration of hydrochloric acid (HCI) in water, which can result in fatalities or serious diseases. The water purification and distribution industry has been the target of numerous hostile cyber security attacks, some of which have been identified, revealed, and documented in this paper. Our goal is to understand the range of security threats that are present in this industry. Through the lens of IIoT, the survey provides a technical investigation that covers attack models, actual cases of cyber intrusions in the water sector, a range of security difficulties encountered, and preventative security solutions. We also explore upcoming perspectives, illuminating the predicted advancements and orientations in this dynamic subject. For industrial practitioners and aspiring scholars alike, our work is a useful, enlightening, and current resource. We want to promote a thorough grasp of the cybersecurity landscape in the water industry by combining key insights and igniting group efforts toward a safe and dependable digital future.

High-Speed Network DDoS Attack Detection: A Survey.

Having a large number of device connections provides attackers with multiple ways to attack a network. This situation can lead to distributed denial-of-service (DDoS) attacks, which can cause fiscal harm and corrupt data. Thus, irregularity detection in traffic data is crucial in detecting malicious behavior in a network, which is essential for network security and the integrity of modern Cyber-Physical Systems (CPS). Nevertheless, studies have shown that current techniques are ineffective at detecting DDoS attacks on networks, especially in the case of high-speed networks (HSN), as detecting attacks on the latter is very complex due to their fast packet processing. This review aims to study and compare different approaches to detecting DDoS attacks, using machine learning (ML) techniques such as k-means, K-Nearest Neighbors (KNN), and Naive Bayes (NB) used in intrusion detection systems (IDSs) and flow-based IDSs, and expresses data paths for packet filtering for HSN performance. This review highlights the high-speed network accuracy evaluation factors, provides a detailed DDoS attack taxonomy, and classifies detection techniques. Moreover, the existing literature is inspected through a qualitative analysis, with respect to the factors extracted from the presented taxonomy of irregular traffic pattern detection. Different research directions are suggested to support researchers in identifying and designing the optimal solution by highlighting the issues and challenges of DDoS attacks on high-speed networks.

Caveolin-1-ACE2 axis modulates xenobiotic metabolism-linked chemoresistance in ovarian clear cell carcinoma.

Among epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) remains markedly resistant to platinum-based chemotherapy, leading to poor clinical outcomes. In response to xenobiotic insults, caveolar platforms play crucial roles in modulating stress signaling responses in cancer cells. It has been hypothesized that caveolin-1 (Cav-1), a main component of the lipid raft, may regulate the response to platinum-based treatment in OCCC. The clinical transcriptomic evaluation demonstrated that high Cav-1 expression was positively associated with a favorable prognosis in patients with ovarian cancer. Cav-1 overexpression enhanced sensitivity to cisplatin (CDDP) treatment, whereas Cav-1 deficiency promoted chemoresistance in OCCC cells. Mechanistically, although Cav-1 counteracted angiotensin-converting enzyme 2 (ACE2) expression, ACE2 positively facilitated resistance to CDDP in OCCC cells. Furthermore, ACE2 restricted aryl hydrocarbon receptor expression and subsequent transcription of drug-metabolizing enzymes. Of note, ACE2 positively regulated the expression of the platinum-clearing enzyme CYP3A4. These findings suggest that the Cav-1-ACE2 axis modulates xenobiotic metabolism-linked chemoresistance in OCCC, predicting potential roles for the stress sentinel networks in oncogenic processes.

Correction: Frequent Mobile Electronic Medical Records Users Respond More Quickly to Emergency Department Consultation Requests: Retrospective Quantitative Study.

[This corrects the article DOI: 10.2196/14487.].

Antibiotic-disrupted ribosome biogenesis facilitates tumor chemokine superinduction.

Upon exposure to internal or external stressors, ribosomes stand sentinel via modulation of ribosome assembly and protein translation. Ribosome-dependent cellular dysfunctions have been associated with pathophysiological processes during inflammation and tumorigenesis. In the present study, ribosome biogenesis was assessed to determine its effects on tumor chemokines, potentially contributing to cancer cell malignant features. In particular, ribosome biogenesis inhibition by antibiotic actinomycin D (ActD) enhanced the expression of chemokines in intestinal cancer cells under endoplasmic reticulum stress that governs multiple pro-tumoral reprogramming. Mechanistically, ribosome biogenesis inhibition superinduced proinflammatory chemokines via transcriptional and post-transcriptional regulation. Moreover, ribosomal stress-responsive p53 and its target macrophage inhibitory cytokine 1 (MIC-1) mediated chemokine superinduction by activating TGF-ß-activated kinase 1 (TAK-1) and nuclear factor-kappa B (NF-κB) in intestinal cancer cells. Cancer cell-based regulation of chemokine induction via MIC-1 signaling was verified using clinical transcriptome datasets. Clinical tumor tissue-derived MIC-1 was a positive regulator of chemokines and genes involved in the ribosome biogenesis pathway, supporting the in vitro assessments. Moreover, MIC-1-correlated chemokine expressions predicted poor prognoses in patients with colorectal cancer. Ribosome-based chemokine regulation via MIC-1 signaling would provide novel insights into translational interventions against malignant inflammatory insults.

TRIB2 Stimulates Cancer Stem-Like Properties through Activating the AKT-GSK3ß-ß-Catenin Signaling Axis.

Tribbles homolog 2 (TRIB2) is implicated in tumorigenesis and drug resistance in various types of cancers. However, the role of TRIB2 in the regulation of tumorigenesis and drug resistance of cancer stem cells (CSCs) is still elusive. In the present study, we showed increased expression of TRIB2 in spheroid-forming and aldehyde dehydrogenase-positive CSC populations of A2780 epithelial ovarian cancer cells. Short hairpin RNA-mediated silencing of TRIB2 expression attenuates the spheroid-forming, migratory, tumorigenic, and drug-resistant properties of A2780 cells, whereas overexpression of TRIB2 increases the CSC-like characteristics. TRIB2 overexpression induced GSK3ß inactivation by augmenting AKT-dependent phosphorylation of GSK3ß at Ser9, followed by increasing ß-catenin level via reducing the GSK3ß-mediated phosphorylation of ß-catenin. Treatment of TRIB2-ovexpressed A2780 cells with the phosphoinositide-3-kinase inhibitor LY294002 abrogated TRIB2-stimulated proliferation, migration, drug resistance of A2780 cells. These results suggest a critical role for TRIB2 in the regulation of CSC-like properties by increasing the stability of ß-catenin protein via the AKT-GSK3ß-dependent pathways.

Moisture Computing-Based Internet of Vehicles (IoV) Architecture for Smart Cities.

Recently, the concept of combining 'things' on the Internet to provide various services has gained tremendous momentum. Such a concept has also impacted the automotive industry, giving rise to the Internet of Vehicles (IoV). IoV enables Internet connectivity and communication between smart vehicles and other devices on the network. Shifting the computing towards the edge of the network reduces communication delays and provides various services instantly. However, both distributed (i.e., edge computing) and central computing (i.e., cloud computing) architectures suffer from several inherent issues, such as high latency, high infrastructure cost, and performance degradation. We propose a novel concept of computation, which we call moisture computing (MC) to be deployed slightly away from the edge of the network but below the cloud infrastructure. The MC-based IoV architecture can be used to assist smart vehicles in collaborating to solve traffic monitoring, road safety, and management issues. Moreover, the MC can be used to dispatch emergency and roadside assistance in case of incidents and accidents. In contrast to the cloud which covers a broader area, the MC provides smart vehicles with critical information with fewer delays. We argue that the MC can help reduce infrastructure costs efficiently since it requires a medium-scale data center with moderate resources to cover a wider area compared to small-scale data centers in edge computing and large-scale data centers in cloud computing. We performed mathematical analyses to demonstrate that the MC reduces network delays and enhances the response time in contrast to the edge and cloud infrastructure. Moreover, we present a simulation-based implementation to evaluate the computational performance of the MC. Our simulation results show that the total processing time (computation delay and communication delay) is optimized, and delays are minimized in the MC as apposed to the traditional approaches.

Frequent Mobile Electronic Medical Records Users Respond More Quickly to Emergency Department Consultation Requests: Retrospective Quantitative Study.

BACKGROUND: Specialty consultation is a critical aspect of emergency department (ED) practice, and a delay in providing consultation might have a significant clinical effect and worsen ED overcrowding. Although mobile electronic medical records (EMR) are being increasingly used and are known to improve the workflow of health care providers, limited studies have evaluated their effectiveness in real-life clinical scenarios. OBJECTIVE: For this study, we aimed to determine the association between response duration to an ED specialty consultation request and the frequency of mobile EMR use. METHODS: This retrospective study was conducted in an academic ED in Seoul, South Korea. We analyzed EMR and mobile EMR data from May 2018 to December 2018. Timestamps of ED consultation requests were retrieved from a PC-based EMR, and the response interval was calculated. Doctors' log frequencies were obtained from the mobile EMR, and we merged data using doctors' deidentification numbers. Pearson's product-moment correlation was performed to identify this association. The primary outcome was the relationship between the frequency of mobile EMR usage and the time interval from ED request to consultation completion by specialty doctors. The secondary outcome was the relationship between the frequency of specialty doctors' mobile EMR usage and the response time to consultation requests. RESULTS: A total of 25,454 consultations requests were made for 15,555 patients, and 252 specialty doctors provided ED specialty consultations. Of the 742 doctors who used the mobile EMR, 208 doctors used it for the specialty consultation process. After excluding the cases lacking essential information, 21,885 consultations with 208 doctors were included for analysis. According to the mobile EMR usage pattern, the average usage frequency of all users was 13.3 logs/day, and the average duration of the completion of the specialty consultation was 51.7 minutes. There was a significant inverse relationship between the frequency of mobile EMR usage and time interval from ED request to consultation completion by specialty doctors (coefficient=-0.19; 95% CI -0.32 to -0.06; P=.005). Secondary analysis with the response time was done. There was also a significant inverse relationship between the frequency of specialty doctors' mobile EMR usage and the response time to consultation requests (coefficient=-0.18; 95% CI -0.30 to -0.04; P=.009). CONCLUSIONS: Our findings suggest that frequent mobile EMR usage is associated with quicker response time to ED consultation requests.

The Efficacy of Body Mass Index and Total Body Fat Percent in Diagnosis Obesity according to Menopausal Status.

OBJECTIVES: Body mass index (BMI) is commonly used in epidemiological study or clinical center. However, it is not exactly correlated with body fat composition and does not reflect sex, age, or race. The aim of this article is to evaluate the validity of BMI standards relative to total body fat (TBF) and to estimate new BMI criteria that correspond to TBF for obesity, especially for Asian postmenopausal women. METHODS: A total 3,936 patients were included in this cross-sectional study, including 1,565 premenopausal and 2,371 postmenopausal women. At the time of visit, demographic data were collected. We demonstrated the validity of BMI cut-point of 25 kg/m2 by using area under the curve (AUC), and presented the empirical optimal BMI cut-point by using Youden's index and overall accuracy in both premenopausal and postmenopausal women. RESULTS: BMI-defined obesity (≥ 25 kg/m2) represents high AUC values (> 0.9) for each TBF. In premenopausal women, TBF ≥ 38% and corresponding BMI value was 29.45 kg/m2 indicated the highest both Youden's index and overall accuracy. In comparison, postmenopausal women who were TBF ≥ 38% showed the highest Youden's index and overall accuracy, and corresponding BMI value was 26.45 kg/m2. CONCLUSIONS: We proposed new BMI criteria for obesity by using TBF reference. With application of bioelectrical impedance analysis, the diagnosis of obesity using BMI criteria may differ between premenopausal and postmenopausal women.

Risk factors related to the recurrence of endometrioma in patients with long-term postoperative medical therapy.

OBJECTIVES: The purpose of this study was to identify clinical risk factors for the recurrence of ovarian endometrioma after ovarian cystectomy in Korean women with long-term postoperative medical therapy. MATERIAL AND METHODS: A total of 134 patients who were surgically treated for endometriotic cysts at Pusan National University Hospital were included in this retrospective study. All patients received long-term postoperative medical treatment for at least 12 months after the first-line conservative surgery. Several epidemiologic variables were analyzed as possible risk factors for recurrence. Endometrioma recurrence was considered when a cystic mass was observed on transvaginal or transrectal sonography. Statistical analysis was performed using independent t-tests for parametric continuous variables. RESULTS: The mean follow-up period for the 134 patients was 56.5 ± 14.3 months (range, 36-120 months) and the mean duration of the medical therapy was 17.9 ± 17.3 months (range, 12-120 months). The overall recurrence rate was 35/134 (26.12%). Our univariate analysis showed statistically significant differences between the recurrent and non-recurrent groups in terms of weight (P = 0.013), body mass index (P = 0.007), age at the time of surgery (P = 0.013), the diameter of the largest cyst (P = 0.001), the presence of dysmenorrhea (P < 0.0001), and postoperative pregnancy (P = 0.016). Multivariate analysis showed that body mass index (OR 1.153, 95% CI 1.003-1.326, P = 0.046), age at the time of surgery (OR 0.924, 95% CI 0.860-0.992, P = 0.029), and presence of dysmenorrhea (OR 12.226, 95% CI 3.543-42.188, P < 0.0001) were significantly correlated with the recurrence of endometrioma. CONCLUSIONS: We found that patients with dysmenorrhea after surgery, and a younger age of the patient at the time of surgery were the highest risk factors associated with the recurrence of endometrioma, despite long-term postoperative medication.

TRRAP stimulates the tumorigenic potential of ovarian cancer stem cells.

Ovarian cancer is the most fatal gynecological malignancy in women and identification of new therapeutic targets is essential for the continued development of therapy for ovarian cancer. TRRAP (transformation/transcription domain-associated protein) is an adaptor protein and a component of histone acetyltransferase complex. The present study was undertaken to investigate the roles played by TRRAP in the proliferation and tumorigenicity of ovarian cancer stem cells. TRRAP expression was found to be up-regulated in the sphere cultures of A2780 ovarian cancer cells. Knockdown of TRRAP significantly decreased cell proliferation and the number of A2780 spheroids. In addition, TRRAP knockdown induced cell cycle arrest and increased apoptotic percentages of A2780 sphere cells. Notably, the mRNA levels of stemness-associated markers, that is, OCT4, SOX2, and NANOG, were suppressed in TRRAP-silenced A2780 sphere cells. In addition, TRRAP overexpression increased the mRNA level of NANOG and the transcriptional activity of NANOG promoter in these cells. Furthermore, TRRAP knockdown significantly reduced tumor growth in a murine xenograft transplantation model. Taken together, the findings of the present study suggest that TRRAP plays an important role in the regulation of the proliferation and stemness of ovarian cancer stem cells. [BMB Reports 2018; 51(10): 515-520].

Amniotic fluid index, single deepest pocket and transvaginal cervical length: Parameter of predictive delivery latency in preterm premature rupture of membranes.

OBJECTIVE: Prediction of delivery latency complicated with preterm premature rupture of membrane (PPROM) is crucial for reducing maternal and neonatal complications. Therefore, we investigated the correlations between latency period and cut-off values of ultrasonographic parameters, ultimately predicting delivery latency. MATERIALS AND METHODS: The retrospective study was performed on 121 PPROM patients enrolled between March 2010 and July 2015. Parameters including amniotic fluid index (AFI), single deepest pocket (SDP) and transvaginal cervical length (TVCL) were measured in 99 singleton pregnancies with PPROM. Latency was defined as the period from sonographic measurements to delivery day. The parameters were analyzed independently by Wilcoxon rank sum test and Fisher's exact test. Cut-off values were determined using a receiver operating characteristic (ROC) curve. RESULTS: In delivery latency within 3 days, AFI and SDP were decreased with significantly shorter TVCL. AFI and SDP had the highest sensitivity (82.2%) and SDP combined with TVCL showed the highest specificity (75.9%) in area under curve (AUC) value. The predicted median latency period was less than 2 days within the cutoff value of parameter (AFI ≤ 7.72, SDP ≤ 3.2 and TVCL ≤ 1.69). CONCLUSION: AFI and SDP combined with TVCL could be useful predictive parameters of the latency interval from PPROM to delivery.

Development and Validation of a Multidisciplinary Mobile Care System for Patients With Advanced Gastrointestinal Cancer: Interventional Observation Study.

BACKGROUND: Mobile health apps have emerged as supportive tools in the management of advanced cancers. However, only a few apps have self-monitoring features, and they are not standardized and validated. OBJECTIVE: This study aimed to develop and validate a multidisciplinary mobile care system with self-monitoring features that can be useful for patients with advanced gastrointestinal cancer. METHODS: The development of the multidisciplinary mobile health management system was divided into 3 steps. First, the service scope was set up, and the measurement tools were standardized. Second, the service flow of the mobile care system was organized. Third, the mobile app (Life Manager) was developed. The app was developed to achieve 3 major clinical goals: support for quality of life, nutrition, and rehabilitation. Three main functional themes were developed to achieve clinical goals: a to-do list, health education, and in-app chat. Thirteen clinically oriented measures were included: the modified Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events questionnaire, Scored Patient-Generated Subjective Global Assessment (PG-SGA), distress, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, International Physical Activity Questionnaire-Short Form, Low anterior resection syndrome score, satisfaction rate, etc. To validate the system, a prospective observational study was conducted. Patients with gastric cancer or colon cancer undergoing chemotherapy were recruited. We followed the subjects for 12 weeks, and selected clinical measures were taken online and offline. RESULTS: After the development process, a multidisciplinary app, the Life Manager, was launched. For evaluation, 203 patients were recruited for the study, of whom 101 (49.8%) had gastric cancer, and 102 (50.2%) were receiving palliative care. Most patients were in their fifties (35.5%), and 128 (63.1%) were male. Overall, 176 subjects (86.7%) completed the study. Among subjects who dropped out, the most common reason was the change of patient's clinical condition (51.9%). During the study period, subjects received multiple health education sessions. For the gastric cancer group, the "general gastric cancer education" was most frequently viewed (322 times), and for the colon cancer group, the "warming-up exercise" was most viewed (340 times). Of 13 measurements taken from subjects, 9 were taken offline (response rate: 52.0% to 90.1%), and 3 were taken online (response rate: 17.6% to 57.4%). The overall satisfaction rate among subjects was favorable and ranged from 3.93 (SD 0.88) to 4.01 (SD 0.87) on the 5-point Likert scale. CONCLUSIONS: A multidisciplinary mobile care system for patients with advanced gastrointestinal cancer was developed with clinically oriented measures. A prospective study was performed for its evaluation, which showed favorable satisfaction.

Escalator: An Autonomous Scheduling Scheme for Convergecast in TSCH.

Time Slotted Channel Hopping (TSCH) is widely used in the industrial wireless sensor networks due to its high reliability and energy efficiency. Various timeslot and channel scheduling schemes have been proposed for achieving high reliability and energy efficiency for TSCH networks. Recently proposed autonomous scheduling schemes provide flexible timeslot scheduling based on the routing topology, but do not take into account the network traffic and packet forwarding delays. In this paper, we propose an autonomous scheduling scheme for convergecast in TSCH networks with RPL as a routing protocol, named Escalator. Escalator generates a consecutive timeslot schedule along the packet forwarding path to minimize the packet transmission delay. The schedule is generated autonomously by utilizing only the local routing topology information without any additional signaling with other nodes. The generated schedule is guaranteed to be conflict-free, in that all nodes in the network could transmit packets to the sink in every slotframe cycle. We implement Escalator and evaluate its performance with existing autonomous scheduling schemes through a testbed and simulation. Experimental results show that the proposed Escalator has lower end-to-end delay and higher packet delivery ratio compared to the existing schemes regardless of the network topology.

An Algorithm for Timely Transmission of Solicitation Messages in RPL for Energy-Efficient Node Mobility.

The IPv6 Routing Protocol for Low Power and Lossy Networks (RPL) was proposed for various applications of IPv6 low power wireless networks. While RPL supports various routing metrics and is designed to be suitable for wireless sensor network environments, it does not consider the mobility of nodes. Therefore, there is a need for a method that is energy efficient and that provides stable and reliable data transmission by considering the mobility of nodes in RPL networks. This paper proposes an algorithm to support node mobility in RPL in an energy-efficient manner and describes its operating principle based on different scenarios. The proposed algorithm supports the mobility of nodes by dynamically adjusting the transmission interval of the messages that request the route based on the speed and direction of the motion of mobile nodes, as well as the costs between neighboring nodes. The performance of the proposed algorithm and previous algorithms for supporting node mobility were examined experimentally. From the experiment, it was observed that the proposed algorithm requires fewer messages per unit time for selecting a new parent node following the movement of a mobile node. Since fewer messages are used to select a parent node, the energy consumption is also less than that of previous algorithms.

NSAID-activated gene 1 mediates pro-inflammatory signaling activation and paclitaxel chemoresistance in type I human epithelial ovarian cancer stem-like cells.

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in developed countries. Chronic endogenous sterile pro-inflammatory responses are strongly linked to EOC progression and chemoresistance to anti-cancer therapeutics. In the present study, the activity of epithelial NF-κB, a key pro-inflammatory transcription factor, was enhanced with the progress of EOC. This result was mechanistically linked with an increased expression of NSAID-Activated Gene 1 (NAG-1) in MyD88-positive type I EOC stem-like cells, compared with that in MyD88-negative type II EOC cells. Elevated NAG-1 as a potent biomarker of poor prognosis in the ovarian cancer was positively associated with the levels of NF-κB activation, chemokines and stemness markers in type I EOC cells. In terms of signal transduction, NAG-1-activated SMAD-linked and non-canonical TGFß-activated kinase 1 (TAK-1)-activated pathways contributed to NF-κB activation and the subsequent induction of some chemokines and cancer stemness markers. In addition to effects on NF-κB-dependent gene regulation, NAG-1 was involved in expression of EGF receptor and subsequent activation of EGF receptor-linked signaling. The present study also provided evidences for links between NAG-1-linked signaling and chemoresistance in ovarian cancer cells. NAG-1 and pro-inflammatory NF-κB were positively associated with resistance to paclitaxel in MyD88-positive type I EOC cells. Mechanistically, this chemoresistance occurred due to enhanced activation of the SMAD-4- and non-SMAD-TAK-1-linked pathways. All of the present data suggested NAG-1 protein as a crucial mediator of EOC progression and resistance to the standard first-line chemotherapy against EOC, particularly in MyD88-positive ovarian cancer stem-like cells.

Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer.

Hypoxia and NOTCH signaling have been reported to be associated with the self-renewal and drug resistance of cancer stem cells (CSCs). However, the molecular mechanisms by which hypoxia and NOTCH signaling stimulate the self-renewal and drug resistance of ovarian CSCs are poorly understood. In the present study, we identified SOX2 as a key transcription factor for CSC-like characteristics in the downstream of hypoxia-induced NOTCH signaling in epithelial ovarian cancer cells. Hypoxic treatment or overexpression of intracellular domain of NOTCH1 (NICD1) in ovarian cancer cells increased sphere formation, drug resistance, and expression of CSC-associated genes such as SOX2, ALDH, and ABC transporters. Hypoxic treatment increased the expression of NICD1, and hypoxic treatment or NICD1 overexpression increased SOX2 promoter activity, which was inhibited by deletion of HIF-1 or CSL binding sites. Furthermore, DAPT treatment decreased the effect of hypoxic treatment, and SOX2 knockdown decreased the effect of hypoxic treatment and NICD overexpression on sphere formation and drug resistance in established ovarian cancer cell lines and primary ovarian cancer cells. These results suggest that hypoxia-NOTCH1-SOX2 signaling axis is important for activation of ovarian CSCs, which may provide a novel opportunity for developing therapeutics to eradicate CSCs in ovarian cancer patients.

Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells.

Cancer stem cells are a subpopulation of cancer cells characterized by self-renewal ability, tumorigenesis and drug resistance. The aim of this study was to investigate the role of HMGA1, a chromatin remodeling factor abundantly expressed in many different cancers, in the regulation of cancer stem cells in ovarian cancer. Spheroid-forming cancer stem cells were isolated from A2780, SKOV3 and PA1 ovarian cancer cells by three-dimensional spheroid culture. Elevated expression of HMGA1 was observed in spheroid cells along with increased expression of stemness-related genes, such as SOX2, KLF4, ALDH, ABCB1 and ABCG2. Furthermore, spheroid A2780 cells, compared with adherent cells, showed higher resistance to chemotherapeutic agents such as paclitaxel and doxorubicin. HMGA1 knockdown in spheroid cells reduced the proliferative advantage and spheroid-forming efficiency of the cells and the expression of stemness-related genes. HMGA1 overexpression in adherent A2780 cells increased cancer stem cell properties, including proliferation, spheroid-forming efficiency and the expression of stemness-related genes. In addition, HMGA1 regulated ABCG2 promoter activity through HMGA1-binding sites. Knockdown of HMGA1 in spheroid cells reduced resistance to chemotherapeutic agents, whereas the overexpression of HMGA1 in adherent ovarian cancer cells increased resistance to chemotherapeutic agents in vitro. Furthermore, HMGA1-overexpressing A2780 cells showed a significant survival advantage after chemotherapeutic agent treatment in a xenograft tumorigenicity assay. Together, our results provide novel insights regarding the critical role of HMGA1 in the regulation of the cancer stem cell characteristics of ovarian cancer cells, thus suggesting that HMGA1 may be an important target in the development of therapeutics for ovarian cancer patients.