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PDF file - 65K, Top 20 Gene Sets Enriched in MES1 and H28 Cells following DZNep Treatment.

PDF file - 54K, Top 20 Gene Ontologies Modulated by DZNep in MES1 and H28 Cells.

PDF file - 66K, Summary of percentages of mesothelioma or normal mesothelia specimens expressing EZH2 in figure 2D.

DNA methylation, histone modifications, and nucleosomal occupancy collaborate to cause silencing of tumor-related genes in cancer. The development of drugs that target these processes is therefore important for cancer therapy. Inhibitors of DNA methylation and histone deacetylation have been approved by the Food and Drug Administration for treatment of hematologic malignancies. However, drugs that target other mechanisms still need to be developed. Recently, 3-deazaneplanocin A (DZNep) was reported to selectively inhibit trimethylation of lysine 27 on histone H3 (H3K27me3) and lysine 20 on histone H4 (H4K20me3) as well as reactivate silenced genes in cancer cells. This finding opens the door to the pharmacologic inhibition of histone methylation. We therefore wanted to further study the mechanism of action of DZNep in cancer cells. Western blot analysis shows that DZNep globally inhibits histone methylation and is not selective. Two other drugs, sinefungin and adenosine dialdehyde, have similar effects as DZNep on H3K27me3. Intriguingly, chromatin immunoprecipitation of various histone modifications and microarray analysis show that DZNep acts through a different pathway than 5-aza-2′-deoxycytidine, a DNA methyltransferase inhibitor. These observations give us interesting insight into how chromatin structure affects gene expression. We also determined the kinetics of gene activation to understand if the induced changes were somatically heritable. We found that upon removal of DZNep, gene expression is reduced to its original state. This suggests that there is a homeostatic mechanism that returns the histone modifications to their “ground state” after DZNep treatment. Our data show the strong need for further development of histone methylation inhibitors. [Mol Cancer Ther 2009;8(6):1579–88]

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PDF file - 4.4MB, Figure S1 Apoptogenic function and mechanism of LL-37 in LoVo colon cancer cells

Supplementary Data 2 from EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance

Supplementary Tables 1-6 from Inhibition of Histone Lysine Methylation Enhances Cancer–Testis Antigen Expression in Lung Cancer Cells: Implications for Adoptive Immunotherapy of Cancer

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Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) occurs in diverse malignancies, including prostate cancer, breast cancer, and glioblastoma multiforme (GBM). Based on its ability to modulate transcription of key genes implicated in cell cycle control, DNA repair, and cell differentiation, EZH2 is believed to play a crucial role in tissue-specific stem cell maintenance and tumor development. Here, we show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep), or its specific downregulation by short hairpin RNA (shRNA), strongly impairs GBM cancer stem cell (CSC) self-renewal in vitro and tumor-initiating capacity in vivo. Using genome-wide expression analysis of DZNep-treated GBM CSCs, we found the expression of c-myc, recently reported to be essential for GBM CSCs, to be strongly repressed upon EZH2 depletion. Specific shRNA-mediated downregulation of EZH2 in combination with chromatin immunoprecipitation experiments revealed that c-myc is a direct target of EZH2 in GBM CSCs. Taken together, our observations provide evidence that direct transcriptional regulation of c-myc by EZH2 may constitute a novel mechanism underlying GBM CSC maintenance and suggest that EZH2 may be a valuable new therapeutic target for GBM management. [Cancer Res 2009;69(24):9211–8]

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Circadian rhythmicity is associated to clinical variables that play an important role in both schizophrenia (SZ) and substance use disorders (SUD), although the characteristics of the coexistence of these two diagnoses (SZ +) remain mostly unknown. Hence, we studied a sample of 165 male patients divided in three groups each of 55, according to their diagnoses (SZ + , SZ, and SUD), as well as a healthy control (HC; n = 90) group. Alongside with sociodemographic and clinical variables, circadian rhythms were registered through a sleep–wake data structured interview, a circadian typology questionnaire, and distal skin temperature (DST) using the Thermochron iButton every 2 min during 48 h. Analyses showed that SZ + and SZ patients presented a longer sleep (delay in wake-up time) and mostly an intermediate circadian typology, while SUD patients slept less hours, displaying a morning typology. The DST showed the highest daily activation and stability for the SUD group, even when compared with the HC group. The presence of schizophrenia (SZ + and SZ) was related to a DST pattern with a reduced amplitude determined by a wakefulness impairment, which was more pronounced for SZ patients whose sleep period was adequate. The assessment of circadian rhythms in under treatment male patients with SZ should be focused on the diurnal period as a possible marker of either treatment adherence or patient's recovery, irrespective of the presence of a comorbid SUD. Further research with additional objective measures may provide knowledge transferable to therapeutic strategies and could be useful to establish possible endophenotypes in the future.

FLA-related conditions are a rare medical occurrence. Despite their rarity, they are considered a public health concern for two reasons: the absence of a regular treatment regimen in the case of central nervous system infections and the fast progression of the symptoms leading to fatal outcomes. A total of 358 articles were retrieved from different databases (91 from PubMed, 26 from NCBI, 138 from Academia, 102 from Science Direct, and one from IJMED). 7 (46.6%) clinical cases came from Egypt, 2 (13.3%) cases of FLA infection came from Nigeria, 3 (20%) cases came from the Gambia, and 1 (6.6%) case was reported from African countries like Algeria, Tunisia, South Africa, and Zambia. Medical conditions caused by free-living amoeba are considered significant public health concerns. These ubiquitous organisms can cause both fatal and debilitating health conditions. Immediate diagnosis of cases and proper hygienic practices are necessary to provide direct medical intervention. They may be the key to reducing the morbidity and mortality rates from FLA-acquired infections. Although several government-led initiatives have been implemented to mitigate a plethora of parasitic diseases, the case of FLA-related conditions in African countries has yet to be realized.

Negative-pressure wound therapy offers many advantages over standard surgical dressings in the treatment of open wounds, including accelerated wound healing, cost savings, and reduced complication rates. Although contraindicated by device manufacturers in malignancy-resected wounds because of hypothesized risk of tumor recurrence, negative-pressure wound therapy is still applied postoperatively because of limited clinical support. The authors performed a systematic review with meta-analysis to compare negative-pressure wound therapy outcomes with those of standard surgical dressings on open wounds, with their null hypothesis stating there would be no outcome differences.A systematic review of the literature on negative-pressure wound therapy and standard surgical dressings on malignancy-resected wounds was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using PubMed, Embase, CINAHL, and Cochrane Central databases. Meta-analysis compared group outcomes, including malignancy recurrence, wound complication, and surgical site infection rates, with a random effects model.A total of 1634 studies were identified and 27 met eligibility criteria, including four randomized controlled trials, four prospective cohort studies, and 19 retrospective reviews. Eighty-one percent of articles ( n = 22) recommended negative-pressure wound therapy in malignancy-resected wounds. Meta-analysis determined that the treatment yielded significantly lower overall surgical site infection ( p = 0.004) and wound complication ( p = 0.01) rates than standard surgical dressings; however, there were no statistically significant differences found for other outcomes between the two groups.This review demonstrates favorable outcomes of negative-pressure wound therapy over standard surgical dressings for malignancy-resected wounds without an increased risk of malignancy recurrence. However, because limited randomized controlled trials (detailing only incisional wounds for limited malignancies and anatomic regions) are available, additional high-power randomized controlled trials are recommended.

Neuronal uptake of ascorbic acid (AA) in humans occurs via the human sodium-dependent vitamin C transporter-2 (hSVCT2). Recent studies show that a significantly lower level of vitamin C is present in the blood of epileptic patients. Consequently, focused studies investigating the involved molecular mechanisms for hSVCT2 regulation are vital to enhance vitamin C body homeostasis. Currently, little is known about the role of valproic acid (VPA), a drug utilized to treat epilepsy and a class I histone deacetylase inhibitor (HDACi), on AA uptake in neuronal systems. Thus, this study aims to examine the effect of VPA on hSVCT2 functional expression in neuronal cells. VPA treatment upregulated the AA uptake and this increased AA uptake was associated with a significant increase in hSVCT2 expression and SLC23A2 promoter activity in SH-SY5Y cells. Knockdown of HDAC2, a predominant isoform in neuronal systems, significantly increased hSVCT2 functional expression. VPA treatment in mice displayed increased mouse (m)SVCT2 protein, mRNA and heterogenous nuclear RNA (hnRNA) expression in the brain. In addition, Yin Yang-1 (YY1), a transcription factor that drives the SLC23A2 promoter activity, protein and mRNA expression levels were markedly upregulated in VPA-treated SH-SY5Y cells and mice brain. Together, our findings suggest that VPA upregulates the functional expression of SVCT2 via HDAC2 and transcriptional mechanism(s).

Low-power wide-area network technologies allow sending sensor information through long distances with low data rates. Long Range (LoRa) is one of these technologies, which is less susceptible to noise and interference. This technology operates in unlicensed bands, increasing the chances of having interfering devices in the communication link. The issue of LoRa jamming with external interference and the effect of such interference in radio range has not been addressed in the literature. Therefore, tests measured packet loss, received signal strength, and signal-to-noise ratio with one end node located kilometers away from a gateway. Data were measured with and without external interference, to establish system robustness. This article computes an empirical model of the immunity region, where the level of interference does not affect LoRa communication. Results show that LoRa devices required interference levels up to 14 dBm to have total packet losses. These results are relevant for implementing LoRa systems, motivating researches to perform site surveys of interference and to account for range reduction in network design.

There are several types of gamma radiation detectors, which have different characteristics depending on its use. We designed and instrumented a gamma detector for low energies of a small and portable size to obtain spectrum from radioactive sources and from that analyze each spectrum. This instrument basically consists of a scintillator crystal coupled to a SiPM this in turn coupled to a PCB card designed with capacitors and resistors for a better signal, a voltage source of 29 volts. For signal acquisition the system must be connected to an oscilloscope this in turn is controlled by a script developed in Python. For the calibration radioactive isotopes with the same dimensions were used, caesium-137 (Cs-137), cobalto-60 (Co-60), sodium-22 (Na-22) and manganese-54 (Mn-54) as gamma ray emission.

Aim: Although a relationship between circadian disruption and development of several psychiatric disorders, such as major depressive disorder (MDD) and substance use disorder (SUD), has been observed, knowledge on this area is scarce yet. Therefore, this study aims to analyze the circadian functioning and quality of life (QOL) in SUD patients with and without comorbid MDD, two highly prevalent clinical entities with difficult therapeutic management.Methods: One hundred sixty-three male patients under treatment, 81 with SUD and 82 with SUD comorbid major depressive disorder (SUD + MDD), were evaluated. For the circadian functioning assessment, we calculated Social Jet Lag (SJL) and used the reduced Morningness–Eveningness Questionnaire (rMEQ) and the Pittsburgh Sleep Quality Index (PSQI). QOL was measured using the shortened version of the World Health Organization's Quality of Life Questionnaire (WHOQOL-BREF). We collected sociodemographic and clinical variables to evaluate their possible influence on the circadian functioning. Intergroup differences among the variables were examined by different analyses of covariance (ANCOVA and MANCOVA). The possible relationships of quantitative clinical variables with rMEQ, PSQI, and WHOQOL-BREF were explored using bivariate correlation analysis.Results: Lower SJL appears in the SUD + MDD group compared with SUD. The intermediate-type was more prevalent in the SUD group, while a higher percentage of morning-type patients was found in the SUD + MDD. Sleep quality (including latency and daytime dysfunction) was worse for SUD + MDD patients than for SUD even after controlling age and age of SUD onset variables. Last, QOL was poorer in patients with SUD + MDD and, for them, psychological health had a negative relationship with SJL and severity of depression.Conclusions: Our data support and extend previous findings indicating that SUD + MDD is associated with worse clinical characteristics, more sleep problems, and poorer QOL than SUD patients. These results underline the importance of a precise assessment of these measurements in future studies conducted in SUD patients with/without MDD comorbidity that could be considered from a therapeutic point of view.

Comorbidity of substance use disorders (SUD) and severe mental illness (SMI) is highly frequent in patients, the most common diagnoses being schizophrenia (SZ), bipolar disorder (BD) and major depressive disorder (MDD). Since comorbidity has its own clinical features, and neurocognitive functioning is not always similar to psychiatric symptoms the present study explores the cognitive performance of patients with dual disorders. A neuropsychological battery of tests was used to assess 120 under treatment male patients, 40 for each group considered (SZ + SUD, BD + SUD and MDD + SUD) who were mainly polyconsumers. Significant differences (with premorbid IQ as a covariate) were found among the groups, with SZ + SUD having a worse performance in attention, verbal learning, short term memory and recognition. The consideration of a global Z score for performance evidenced an impaired neurocognitive pattern for SZ + SUD compared with BD + SUD and MDD + SUD. According to norms, all patients showed difficulties in verbal learning, short-term memory and recognition. Our research indicated that the neurocognitive functioning of dual disorder patients was influenced by the comorbid SMI, with SZ + SUD presenting major difficulties. Future studies should thoroughly explore the role of such difficulties as indicators or endophenotypes for dual schizophrenia disorders, and their usefulness for prevention and treatment.

Premorbid functioning has been related with several clinical features and prognosis of schizophrenia spectrum disorders. Comorbidity with substance use is highly prevalent and usually hinders clinical improvement in this kind of psychiatric disorders. This systematic review analyzes the differences in the premorbid functioning of subjects with a schizophrenia spectrum disorder with substance use (SSD+, dual psychosis) or without it (SSD-). A systematic review (PRISMA guidelines), including search in electronic databases (MEDLINE, Web of Science, and Cochrane Library), was performed. 118 published works were considered of which only 20 met our inclusion criteria. Although there is a great variability in methodologies, diagnoses included, and substances used, studies using the Premorbid Functioning Scale to assess the academic and/or social domains found that SSD+ subjects had a poorer academic but better social premorbid functioning than those with SSD-. Current evidence is not conclusive, so additional studies are required to integrate intervening factors in order to clarify the clinical implications of premorbid functioning to improve the course and therapeutic response of patients.

Dual disorders (substance use and mental illness comorbidity) are a condition that has been strongly associated with severe symptomatology and clinical complications. The study of circadian characteristics in patients with Severe Mental Illness or Substance Use Disorder (SUD) has shown that such variables are related with mood symptoms and worse recovery. In absence of studies about circadian characteristics in patients with dual disorders we examined a sample of 114 male participants with SUD and comorbid Schizophrenia (SZ+; n = 38), Bipolar Disorder (BD+; n = 36) and Major Depressive Disorder (MDD+; n = 40). The possible differences in the sample of patients according to their psychiatric diagnosis, circadian functioning with recordings of distal skin temperature during 48 h (Thermochron iButton®), circadian typology and sleep-wake schedules were explored. MDD+ patients were more morning-type, while SZ+ and BD+ had an intermediate-type; the morning-type was more frequent among participants under inpatient SUD treatment. SZ+ patients had the highest amount of sleeping hours, lowest arousal and highest drowsiness followed by BD+ and MDD+, respectively. These observed differences suggest that treatment for patients with dual disorders could include chronobiological strategies to help them synchronize patterns with the day-light cycle, since morning-type is associated with better outcomes and recovery.

Objetivos: El presente trabajo explora la influencia del trastorno mental comórbido en el funcionamiento rítmico circadiano de pacientes en fase de tratamiento de deshabituación. La ritmicidad circadiana se ha asociado, tanto en pacientes con Trastorno por Uso de Sustancias (TUS) como en trastornos mentales graves, con la severidad sintomatológica clínica y la recuperación, pero la investigación con pacientes duales es muy escasa. Material y métodos: Se seleccionaron 114 pacientes duales varones distribuidos en tres grupos según el diagnóstico comórbido: esquizofrenia (SZ+; N=38), trastorno bipolar (TB+; N=36) y trastorno depresivo mayor (TDM+; N=40). El funcionamiento circadiano se evaluó con registros de los horarios de sueño-vigilia, la tipología circadiana (matutina, intermedia y vespertina) y la temperatura cutánea durante 48 horas (Thermochron iButton®). Resultados y conclusiones: Los pacientes SZ+ mostraron mayor cantidad de horas de sueño nocturno con un horario más tardío de despertar respecto a aquellos con diagnóstico TB+ y TDM+ (F(2,112)=7.84; p 3,23; p

The Internet of things (IoT) has quickly been introduced into wireless networks and systems, opening several possibilities in terms of connectivity. IoT arises from the vast need to monitor, manage, and configure “things” remotely. Different industrial or residential applications can use IoT to obtain or send data, such as remote control of alarms, water meters, simple traffic, and light points. This research project focuses on the IoT implementation of devices LoRa that uses the LoRaWAN protocol. LoRaWAN is a network infrastructure that could be applied to monitor different variables in environments where IoT wireless technology is implemented. The current project involves designing a LoRaWAN network to support IoT in transporting school routes in Barranquilla’s southwest. The project incorporates a prototype that allows the vehicle monitoring, geographical location in real-time, percentage of the occupation, arrivals, and departures times, among other variables. Implementing this technology in the chosen sector will benefit families that require the school transport service because they will monitor the operation of the service provided. This paper details the devices and technology to be implemented in the final prototype, specifying their topology, application, technical specification, operating characteristics, and their configuration and work logic under different scenarios. For the development of the project, the guidelines defined in each of the Top-Down network design methodology phases are applied. Finally, two essential aspects are shown, such as analyzing the results obtained in the tests and the future work to be carried out based on the research.

This work provides some criteria that allow network administrators to measure the impact of different network configurations have on voice, data, and video applications quality of service offered to the different users. For that, this project implemented tests to measure parameters such as packet loss, delay and jitter using static routing, different packet scheduling algorithms (Custom Queuing, Priority Queuing, and Weighted First Queuing), different services (voice, data, and video), and connection speeds using Cisco 2800 Routers and D-ITG traffic generator in conjunction with the Network Time Protocol synchronizer. A comparative analysis of sensitive parameters for Quality of Service was conducted to describe network behavior for each service. The implemented services presented performances according to quality requirements, reported in the literature. Specifically, the data service presented delay and jitter within the levels considered acceptable for this application and zero packet loss. For its part, the video service presented levels of delay and jitter according to the quality requirements for streaming. Finally, the voice service presented the best configuration performance with the Priority Queuing algorithm, for all measured service quality parameters.

Low Power Wide Area Networks provide long-range, energy-efficient communication. LoRaWAN fulfills all these characteristics employing the Chirp Spread Spectrum modulation technique. Thus, the technology shows an important alternative for the Internet of Things, and different studies created simulation models of LoRaWAN. Nonetheless, LoRa communication systems operate in free bands with modulation frequencies of 400 and 900 MHz. Therefore, directly simulating the system in these passband frequencies requires higher memory and processing resources compared to simulating a baseband system. This paper details a technique to study LoRa communications, by employing the Complex Envelope method. The method describes the transfer function of the communication system using an equivalent baseband representation. Results of bit error rate for different transmission parameters agree with other models in the literature, showing the validity of our approach.

Many surgeons are reluctant to discontinue prophylactic antibiotics after 24 hours in tissue expander breast reconstruction (TEBR) because of fear of increased risk of surgical site infection (SSI). Currently, there is no consensus regarding antibiotic prophylaxis duration in TEBR. In addition, there remains a lack of research investigating microorganisms involved in SSI across various perioperative antibiotic protocols. The purpose of this study was to examine how 2 different prophylactic antibiotic regimens impacted the bacterial profiles of SSI and rate of implant loss after TEBR.A single-institution retrospective review of immediate TEBRs between 2001 and 2018 was performed. Surgical site infections requiring hospitalization before stage 2 were included. Highly virulent organisms were defined as ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species). Implant loss was defined as removal of tissue expander without immediate replacement.Of 660 TEBRs, 85 (12.9%) developed an SSI requiring hospitalization before stage 2. Fifty-six (65.9%) received less than 24 hours of perioperative intravenous antibiotics and oral antibiotics after discharge (group 1), and 29 (34.1%) received less than 24 hours of intravenous antibiotics only (group 2). There was no significant difference in demographics, preoperative chemotherapy/radiation, acellular dermal matrix usage, or treatment of SSI between groups. In group 1, 64% (n = 36) developed culture positive SSIs, compared with 83% (n = 24) in group 2 (P = 0.076). Staphylococcus aureus was the most common bacteria in both groups. Group 2 demonstrated a significantly increased incidence of gram-positive organisms (46.4% vs 72.4%, P = 0.022) and S. aureus (21.4% vs 55.2%, P = 0.002). However, there was no significant difference in overall highly virulent (P = 0.168), gram-negative (P = 0.416), or total isolated organisms (P = 0.192). Implant loss between groups 1 and 2 (62.5% vs 62.1%, P = 0.969) respectively, was nearly identical.Our study demonstrates that, despite differences in bacterial profiles between 2 antibiotic protocols, prolonged postoperative antibiotic use did not protect against overall highly virulent infections or implant loss. Antibiotic stewardship guidelines against the overuse of prolonged prophylactic regimens should be considered. Further analysis regarding timing of SSIs and antibiotic treatment is warranted.

Background and importance Medication overdose headache (MOH) is a secondary headache disorder occurring on 15 or more days per month developing as a consequence of regular overdose of headache medication for more than 3 months. The prevalence of MOH is approximately 1–2% and is higher in women than in men. Many medications used to treat headaches have the potential for causing MOH. Currently, MOH secondary to triptans is increasing and leads to MOH sooner than with other medications. Anxiety and depression may be risk factors for the evolution of migraine into MOH. Aim and objectives To determine the prevalence of patients treated with triptans at risk of MOH (regular intake for ≥10 days/month for >3 months) and the profile in our health area; to identify and communicate to the prescribers those patients with overuse of triptans; and to inform all clinicians about MOH: aetiology, clinical features, diagnosis and treatment. Material and methods We analysed the dispensation records of all patients treated with triptans over 3 months (June 2019–September 2019). Data collected were sex, age, monthly intake frequency and co-medication. We alerted prescribers by email, including management and de-prescription recommendations for MOH. We posted content about MOH in our blog. Results The prevalence of patients treated with triptans was 0.50%; 47 of 538 patients taking triptans (8.7%) were at risk of MOH. Their median age was 55 years and most were women (79%). Median monthly intake was 16 doses (10–48). Thirty patients (64%) had prescriptions for anxiety and/or depression and 13 patients (28%) had preventive therapy prescriptions for headache. Twenty-nine prescribers were notified by email. Dispensation record history, co-medication, MOH management guide and patient education leaflets were attached. Conclusion and relevance MOH is a common problem in clinical practice that needs to be properly managed to increase the likelihood of successful chronic daily headache treatment. The results obtained in our population were similar to published studies, both in prevalence and in patient profile. However, the MOH rate was still lacking as it needs a clinician diagnosis. In 6 months we will collect information about the evolution of these patients, and we expect that our intervention will lead to treatment optimisation, better use of triptans and headache relief. References and/or acknowledgements No conflict of interest.

Health-related quality of life (HRQoL) assessment has interest as an indicator of degree of affectation and prognosis in mental disorders. HRQoL is impaired in both Substance Use Disorder (SUD) and Major Depressive Disorder (MDD), two conditions highly prevalent, although less studied when both are coexisting (SUD + MDD). Hence, we decided to explore HRQoL with the SF-36 survey in a sample of 123 SUD and 114 SUD + MDD patients (51 symptomatic and 63 asymptomatic of depressive symptoms) under treatment. We performed analyses to examine HRQoL among groups, and its predictive value at 3-, 6- and 12-month follow-ups through regression models. Patients with SUD + MDD had worse HRQoL than SUD patients and population norms. For Mental Health, Vitality, and General Health dimensions, lower scores were observed for SUD + MDD regardless the presence/absence of depressive symptoms. For Physical Functioning and Health Change, depressive symptomatology and not the comorbidity of SUD + MDD diagnoses explained HRQoL limitations. At 3-, 6- and 12-month follow-ups we observed two predictors of relapses, General Health for asymptomatic SUD + MDD, and Physical Functioning for SUD. Improving HRQoL in SUD + MDD may be targeted during patient’s treatment; future studies should explore the influence of HRQoL on patient’s prognosis taking into account the presence/absence of depressive symptomatology.