Mechanism of action and resistant profile of anti-HIV-1 coumarin derivatives

Dicamphanoyl khellactone (DCK) is a coumarin derivative that can potently inhibit HIV-1 replication. DCK does not inhibit RNA-dependent DNA synthesis. However, an HIV reverse transcriptase (RT) inhibitor-resistant strain, HIV-1/RTMDR1, is resistant to DCK. Thus, it is possible that HIV-1 RT is the target of DCK. To test this possibility, DCK-resistant viruses were selected in the presence of DCK. Our results indicate that a single amino acid mutation, E138K in HIV-1 RT, is sufficient to confer DCK resistance. Interestingly, a DCK derivative, 3'R,4'R-Di-O-(-)-camphanoyl-2-ethyl-2',2'-dimethyldihydropyrano[2,3-f]chromo ne (DCP8), is effective against HIV-1/RTMDR1. However, the DCK-escape virus carrying the E138K mutation remains resistant to DCP8. Since DCK did not inhibit the RNA-dependent DNA polymerase activity of HIV-1 RT when using poly-rA or poly-rC as template, we evaluated the effect of DCK on the DNA-dependent DNA polymerase activity of HIV-1 RT. Our results indicate that DCK can inhibit the DNA-dependent DNA polymerase activity of HIV-1 RT. In conclusion, DCK is a unique HIV-1 RT inhibitor that inhibits the DNA-dependent DNA polymerase activity. In contrast, DCK did not significantly affect the RNA-dependent DNA polymerase activity when poly-rA or poly-rC was used as templates. An E138K mutation in the non-nucleoside RT inhibitors (NNRTIs) binding pocket of HIV-1 RT confers resistance to DCK and its chromone derivative, DCP8

Stemness and chemoresistance in epithelial ovarian carcinoma cells under shear stress

One of greatest challenges to the successful treatment of cancer is drug resistance. An exciting approach is the eradication of cancer stem cells (CSCs). However, little is known about key signals regulating the formation and expansion of CSCs. Moreover, lack of a reliable predictive preclinical model has been a major obstacle to discover new cancer drugs and predict their clinical activity. Here, in ovarian cancer, a highly chemoresistant tumor that is rapidly fatal, we provide the first evidence demonstrating the causal involvement of mechanical stimulus in the CSC phenotype using a customizable microfluidic platform and three-dimensional spheroids, which most closely mimic tumor behavior. We found that ovarian cancer cells significantly acquired the expression of epithelial-to-mesenchymal transition and CSC markers and a remarkable chemoresistance to clinically relevant doses of frontline chemotherapeutic drugs cisplatin and paclitaxel when grown under fluid shear stress, which corroborates with the physiological attainable levels in the malignant ascites, but not under static condition. Furthermore, we uncovered a new link of microRNA-199a-3p, phosphatidylinositol 3-kinase/Akt, and multidrug transporter activation in shear stress-induced CSC enrichment. Our findings shed new light on the significance of hydrodynamics in cancer progression, emphasizing the need of a flow-informed framework in the development of therapeutics

Health-related quality of life in pediatric patients with leukemia in Singapore: a cross-sectional pilot study

There has been a paradigm shift in health service delivery to a more holistic approach, which considers Quality of Life (QoL) and overall functioning. Health-Related Quality of Life (HRQoL) is a multidimensional construct that encompasses physical functioning as well as psychosocial aspects of emotional and social functioning. This study explored factors related to HRQoL in Asian pediatric patients with leukemia in Singapore. The available variables included: age, treatment duration, household income, gender, ethnicity, religion, diagnosis, and phase of treatment. It is hypothesized that the relationships will be significant. In the current study, there were 60 patients (60% males) with leukemia; their ages ranged from 1 to 21 years (Mean = 8.03, Standard Deviation = 4.55). The hypothesis was partially supported. Age had a significant positive relationship with physical functioning, r(60) = 0.28, p < 0.05, physical health, r(60) = 0.28, p < 0.05, and the total HRQoL score, r(60) = 0.29, p < 0.05. Treatment duration had a positive relationship with school functioning, r(60) = 0.28, p < 0.05. All other correlations were statistically non-significant. The effects of the available psychosocial variables of gender, ethnicity, and religion were examined on scores from the Pediatric Quality of Life Inventory (PedsQL). Ethnicity had a significant effect on social functioning, U = 292.00, p < 0.05, r = 0.3 (medium effect size). Specifically, Chinese (Median = 85.00, n = 33) had significantly higher scores on social functioning than others (Median = 70.00, n = 27). The remaining comparisons were statistically non-significant. The current findings added to QoL research, and provided an impetus for more research in the area of HRQoL for children with leukemia in Singapore

Structure and dynamics of Rh surfaces

Lattice relaxations, surface phonon spectra, surface energies, and work functions are calculated for Rh(100) and Rh(110) surfaces using density-functional theory and the full-potential linearized augmented plane wave method. Both, the local-density approximation and the generalized gradient approximation to the exchange-correlation functional are considered. The force constants are obtained from the directly calculated atomic forces, and the temperature dependence of the surface relaxation is evaluated by minimizing the free energy of the system. The anharmonicity of the atomic vibrations is taken into account within the quasiharmonic approximation. The importance of contributions from different phonons to the surface relaxation is analyzed.Comment: 9 pages, 7 figures, scheduled to appear in Phys. Rev. B, Feb. 15 (1998). Other related publications can be found at http://www.rz-berlin.mpg.de/th/paper.htm

Human papillomavirus 16 E6 induces FoxM1B in oral keratinocytes through GRHL2

High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPVoral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development

Multipole interaction between atoms and their photonic environment

Macroscopic field quantization is presented for a nondispersive photonic dielectric environment, both in the absence and presence of guest atoms. Starting with a minimal-coupling Lagrangian, a careful look at functional derivatives shows how to obtain Maxwell's equations before and after choosing a suitable gauge. A Hamiltonian is derived with a multipolar interaction between the guest atoms and the electromagnetic field. Canonical variables and fields are determined and in particular the field canonically conjugate to the vector potential is identified by functional differentiation as minus the full displacement field. An important result is that inside the dielectric a dipole couples to a field that is neither the (transverse) electric nor the macroscopic displacement field. The dielectric function is different from the bulk dielectric function at the position of the dipole, so that local-field effects must be taken into account.Comment: 17 pages, to be published in Physical Review

Indication, Safety and Clinical Impact of Cardiovascular Magnetic Resonance: A Pilot Run of the First National CMR Registry for Malaysia

Background: Cardiovascular magnetic resonance (CMR) is a rapidly emerging noninvasive imaging technique providing high resolution images without any application of radiation. It has broad range of clinical applications and is increasingly been used in clinical practice in Malaysia. A national CMR Registry is needed to assess its practice in Malaysia. Objective: To evaluate indications, safety and impact on patient management of CMR in Sarawak Heart Centre. Materials Methods: A pilot run of CMR Registry in single centre with consecutive patients who underwent clinical CMR from January-June 2015. Retrospective data collection from CMR database and case notes. Results: A total of 169 patients underwent clinical CMR, with 20 did not complete scan; 25% due to claustrophobia. 94% of patients received gadolinium-based contrast agent. Most important indications were viability assessment (54.4%), cardiomyopathy (28.2%), and risk stratification in suspected coronary artery disease (CAD) (4.7%). 6.7% of patients underwent stress MR (adenosine or dobutamine). Severe complications only occurred in 0.7% of the cases (anaphylactic reaction secondary to contrast agent). No mortality during/due to CMR. There was direct impact of CMR on the clinical management by confirming suspected diagnosis (59.1%), excluding suspected diagnosis (21.5%), providing additional information for suspected diagnosis which is confirmed or excluded (18.1%) and providing unsuspected completely new diagnosis (1.3%). Invasive coronary angiogram was avoided and diagnosis were excluded in all patients referred for risk stratification of suspected coronary artery disease. Invasive therapeutic procedures such as PCI, CABG, valve surgerywere triggered in 49.6 % of patients after CMR was done, regardless of indication. Out of 81 patients who underwent CMR for viability study, 76.5% were planned for revascularisation (CABG or PCI) with the restwere planned for optimalmedical therapy only after the CMR. Conclusions: The top indications of CMR in Sarawak are viability assessment, cardiomyopathy and risk stratification in suspected CAD, which differs from the EuroCMR registry results. This demonstrated the importance of establishing a national multicentre CMR registry in Malaysia, and subsequently substudy on specific conditions. With appropriate medical personnel training and patient selection, CMR is safe and has strong impact on clinical management

Host-Guest Complexation of [60]Fullerenes and Porphyrins Enabled by “Click Chemistry”

Herein the synthesis, characterization, and organization of a first-generation dendritic fulleropyrrolidine bearing two pending porphyrins are reported. Both the dendron and the fullerene derivatives were synthesized by Cu(I) -catalyzed alkyne-azide cycloaddition (CuAAC). The electron-donor-acceptor conjugate possesses a shape that allows the formation of supramolecular complexes by encapsulation of C60 within the jaws of the two porphyrins of another molecule. The interactions between the two photoactive units (i.e., C60 and Zn-porphyrin) were confirmed by cyclic voltammetry as well as by steady-state and time-resolved spectroscopy. For example, a shift of about 85 mV was found for the first reduction of C60 in the electron-donor-acceptor conjugate compared with the parent molecules, which indicates that C60 is included in the jaws of the porphyrin. The fulleropyrrolidine compound exhibits a rich polymorphism, which was corroborated by AFM and SEM. In particular, it was found to form supramolecular fibrils when deposited on substrates. The morphology of the fibrils suggests that they are formed by several rows of fullerene-porphyrin complexes

Thirty-Day Clinical Outcome of Primary Percutaneous Intervention Versus Fibrinolysis Followed by Coronary Angiography in ST-Segment Elevation Myocardial Infarction

Background: Primary percutaneous coronary intervention (PCI)is the preferred reperfusion strategy in patients with ST-segment elevation myocardial infarction (STEMI). However, timely PCI cannot be offered to many patients. Objective: The purpose of this study was to compare the 30-day clinical outcome of primary PCI strategy and fibrinolysis followed by coronary angiography strategy in STEMI patients. Methods: This was a prospective, observational, single center study. All patients admitted for STEMI from 1 January 2016 to 30 November 2016 were screened for the study. Patients were divided into 2 reperfusion strategies: primary PCI or fibrinolysis followed by coronary angiography. Primary outcome was composite of all-cause mortality at 30 days. Results: A total of 178 patients were identified: 33 (18.5%) underwent primary PCI and 145 (81.5%) underwent fibrinolysis first. The median door-to-balloon time in the primary PCI group was 161.0 minutes (IQR 84.5). The median time from fibrinolysis-to-arrival at catheterization lab was 1738 minutes (IQR 901). The median total ischaemic time was 369 min (IQR 524) and 210 (IQR 247) for the primary PCI and fibrinolysis first group respectively (p=0.002). Kaplan-Meier survival analysis for 30-day all-cause mortality was 24.2% vs 9.7% respectively in primary PCI and fibrinolysis group p=0.018). Multivariate Linear Regression showed that Killip Class and LVEF were independent predictors of 30-day all-cause mortality. Reperfusion strategy was not associated with 30-day all-cause mortality (p=0.216). Conclusions: The clinical outcome of primary PCI strategy in STEMI is not better than fibrinolysis followed by coronary angiography strategy when timely PCI cannot be performed