A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin ( 1) and variecolactone ( 2) was identified in Aspergillus aculeatus ATCC 16872. Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues ( 5- 7). Analysis of the compounds' anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities, 5 was associated with significantly reduced toxic side effects in cancer-bearing mice, indicating its potentially broader therapeutic window. Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.

ObjectiveDetection and quantification of RNA synthesis in cells is a widely used technique for monitoring cell viability, health, and metabolic rate.After exposure to environmental stimuli, both the internal reference gene and target gene would be degraded. As a result, it is imperative to consider the accurate capture of nascent RNA and the detection of transcriptional levels of RNA following environmental stimulation. This study aims to create a Click Chemistry method that utilizes its property to capture nascent RNA from total RNA that was stimulated by the environment. MethodsThe new RNA was labeled with 5-ethyluridine (5-EU) instead of uracil, and the azido-biotin medium ligand was connected to the magnetic sphere using a combination of “Click Chemistry” and magnetic bead screening. Then the new RNA was captured and the transcription rate of 16S rRNA was detected by fluorescence molecular beacon (M.B.) and quantitative reverse transcription PCR (qRT-PCR). ResultsThe bacterial nascent RNA captured by “Click Chemistry” screening can be used as a reverse transcription template to form cDNA. Combined with the fluorescent molecular beacon M.B.1, the synthesis rate of rRNA at 37℃ is 1.2 times higher than that at 15℃. The 16S rRNA gene and cspI gene can be detected by fluorescent quantitative PCR,it was found that the measured relative gene expression changes were significantly enhanced at 25℃ and 16℃ when analyzed with nascent RNA rather than total RNA, enabling accurate detection of RNA transcription rates. ConclusionCompared to other article reported experimental methods that utilize screening magnetic columns, the technical scheme employed in this study is more suitable for bacteria, and the operation steps are simple and easy to implement, making it an effective RNA capture method for researchers.

Upon his untimely death, Michal Boym (1612-1659) left behind an enormous written legacy; covering a diverse range of interests in fields such as Chinese linguistics, cartography, botany, zoology, philosophy and medicine. This article attempts to examine Boym's De indiciis morborum ex linguae coloribus & affectionibus (The signs of disease on the tongue, colors and affections), a translation of a previously unidentified Chinese text. The text specifically deals with the subject of tongue diagnosis, in relation to contagious diseases that were still raging in the 17th century China. Arriving to China at the end of the Ming Dynasty (1368-1644), Boym was able to personally witness the early development of tongue examination as an independent specialty; he recognized its significance and tried to incorporate it into his ultimately unfinished Chinese medical corpus. Boym's work eventually facilitated the assimilation of tongue observation in European medicine during the 19th century.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
Adenocarcinoma of Lung/genetics* ; Carcinoma, Non-Small-Cell Lung/genetics* ; Carcinoma, Squamous Cell/genetics* ; Genetic Heterogeneity ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lung Neoplasms/genetics* ; Polymorphism, Single Nucleotide

Fixed-dose combinations development requires pharmacokinetic drugdrug interaction (DDI) studies between active ingredients. For some drugs, pharmacokinetic properties such as long half-life or delayed distribution, make it difficult to conduct such clinical trials and to estimate the exact magnitude of DDI. In this study, the conventional (non-compartmental analysis and bioequivalence [BE]) and modelbased analyses were compared for their performance to evaluate DDI using amlodipine as an example. Raw data without DDI or simulated data using pharmacokinetic models were compared to the data obtained after concomitant administration.Regardless of the methodology, all the results fell within the classical BE limit. It was shown that the model-based approach may be valid as the conventional approach and reduce the possibility of DDI overestimation. Several advantages (i.e., quantitative changes in parameters and precision of confidence interval) of the model-based approach were demonstrated, and possible application methods were proposed. Therefore, it is expected that the model-based analysis is appropriately utilized according to the situation and purpose.

The Asian Society of Gynecologic Oncology International Workshop 2018 on gynecologic oncology was held in the Ajou University Hospital, Suwon, Korea on the 24th to 25th August 2018. The workshop was an opportunity for Asian doctors to discuss the latest findings of gynecologic cancer, including cervical, ovarian, and endometrial cancers, as well as the future of fertility-sparing treatments, minimally invasive/radical/debulking surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Clinical guidelines and position statement of Asian countries were presented by experts. Asian clinical trials for gynecologic cancers were reviewed and experts emphasized the point that original Asian study is beneficial for Asian patients. In Junior session, young gynecologic oncologists presented their latest research on gynecologic cancers.
Antineoplastic Agents ; Asian Continental Ancestry Group ; Drug Therapy ; Education ; Endometrial Neoplasms ; Female ; Gyeonggi-do ; Humans ; Immunotherapy ; Korea ; Ovarian Neoplasms ; Radiotherapy ; Uterine Cervical Neoplasms

BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic, debilitating disease affecting millions of adults worldwide. With improved knowledge on PAH and better management, long-term survival in patients has significantly increased in the past 20 years. Bosentan is a nonselective, dual endothelin receptor antagonist used in the treatment of PAH. While the drug has already been established to improve exercise capacity and patient survival globally, no study has investigated its clinical effectiveness and safety among Filipino patients yet. A post marketing study was conducted to determine the efficacy and safety of bosentan (125 mg administered twice daily) among adult Filipino patients with PAH. METHODS: A non-randomized, non-comparative, open-label trial was conducted involving adult patients at a tertiary government hospital in Metro Manila. Study duration was from March to September 2012. Primary end points of the study were patients' response to efficacy and safety. RESULTS: A total of 14 patients were enrolled in the study and 13 included in the analysis. Mean age of the participants was 34 ± 11.54 years. Remarkable changes were observed for 6WMD and small improvements noted for Borg dyspnea index and CPET. There was no difference between baseline and 12th week WHO functional classification. FEVl /FVC, MVV, RV /TLC and sRaw showed modest improvement; there was a notable difference in the systolic PAP vs baseline; PVR, PVRI, SVR and SVRI demonstrated the largest changes via cardiac catherization and iloprost. Four patients experienced at least one serious adverse event, with one reported as suspected unexpected serious adverse reaction. Out of 13 patients, 1 O (76.9%) considered bosentan as effective while 11 (84.6%) considered it safe. CONCLUSION Bosentan improved exercise capacity, pulmonary function and cardiopulmonary hemodynamics among study participants. The drug is generally well-tolerated and effective. Bosentan is among the useful options for treatment of adult Filipino patients with PAH.

Objectives: This scoping review aimed to support a landscape analysis to identify lessons learned about intersectoral collaborations (ISCs) by describing their existing models in the context of dengue, malaria and yellow fever. Methods: A scoping review following the methodology of Joanna Briggs Institute was performed using the following inclusion criteria: studies involving humans; studies discussing intersectoral collaborations, malaria/dengue/yellow fever, and prevention or control at any level; and studies in countries endemic for the aforementioned diseases. Studies were screened using Covidence, while data were extracted using NVivo. Results: Of the 7,535 records retrieved, 69 were included in the qualitative analysis. Most ISCs were initiated by multilateral organizations and ministries of health, and none by communities. Strategies included advocacy, health education, research, public health measures, resource mobilization, service delivery and training; mostly employed on a community level. Monitoring and evaluation were mostly formative, ongoing, and participatory. Gaps included administrative and policy barriers, resource shortages, and inadequate research and training. Conclusions Multiple models of ISC exist in the literature. There is a need to develop a comprehensive framework for an effective and sustainable multisectoral approach for the prevention and control of VBDs ensuring adequate resources, active stakeholders, and strategies that span the entire socio-ecological spectrum.
Dengue ; Disease Vectors ; Intersectoral Collaboration ; Malaria ; Vector Borne Diseases

Anesthesia for a patient with a large mediastinal mass is a challenge for anesthesiologists, given the risk of airway collapse and hemodynamic compromise. Moreover, there are very few reports on the anesthetic management of non-intubated video-assisted thoracoscopic surgery (VATS). Thus, in the following case report, we provide an account of the successful anesthetic management and excisional biopsy of a large anterior mediastinal mass (measuring 13 × 10 cm) utilizing non-intubated VATS. The patient was kept awake, maintaining consciousness and spontaneous respiration throughout the procedure, in order to prevent devastating airway collapse and pain control and cough prevention were achieved by thoracic epidural analgesia and lidocaine nebulization.
Analgesia, Epidural ; Anesthesia ; Anesthesia, Epidural* ; Biopsy* ; Consciousness ; Cough ; Hemodynamics ; Humans ; Lidocaine ; Respiration ; Thoracic Surgery, Video-Assisted

PURPOSE: Although combining aromatase inhibitors (AI) with gonadotropin-releasing hormone agonists (GnRHa) is becoming more common, it is still not clear if GnRHa is as effective as bilateral salpingo-oophorectomy (BSO). MATERIALS AND METHODS: We retrospectively analyzed data of 66 premenopausal patients with hormone receptor– positive, human epidermal growth factor receptor 2–negative recurrent and metastatic breast cancer who had been treated with AIs in combination with GnRHa or BSO between 2002 and 2015. RESULTS: The median patient age was 44 years. Overall, 24 (36%) received BSO and 42 (64%) received GnRHa. The clinical benefit rate was higher in the BSO group than in the GnRHa group (88% vs. 69%, p=0.092). Median progression-free survival (PFS) was longer in the BSO group, although statistical significance was not reached (17.2 months vs. 13.3 months, p=0.245). When propensity score matching was performed, the median PFS was 17.2 months for the BSO group and 8.2 months for the GnRHa group (p=0.137). Multivariate analyses revealed that the luminal B subtype (hazard ratio, 1.67; 95% confidence interval [CI], 1.08 to 2.60; p=0.022) and later-line treatment (≥ third line vs. first line; hazard ratio, 3.24; 95% CI, 1.59 to 6.59; p=0.001) were independent predictive factors for a shorter PFS. Incomplete ovarian suppression was observed in a subset of GnRHa-treated patients whose disease showed progression, with E2 levels higher than 21 pg/mL. CONCLUSION: Both BSO and GnRHa were found to be effective in our AI-treated premenopausal metastatic breast cancer patient cohort. However, further studies in larger populations are needed to determine if BSO is superior to GnRHa.
Aromatase Inhibitors* ; Aromatase* ; Breast Neoplasms* ; Breast* ; Cohort Studies ; Disease-Free Survival ; Female ; Gonadotropin-Releasing Hormone* ; Humans ; Multivariate Analysis ; Ovariectomy ; Phenobarbital ; Premenopause ; Propensity Score ; Receptor, Epidermal Growth Factor ; Retrospective Studies