Epigenetic Effects and Molecular Mechanisms of Tumorigenesis Induced by Cigarette Smoke: An Overview

Cigarette smoking is one of the major causes of carcinogenesis. Direct genotoxicity induced by cigarette smoke leads to initiation of carcinogenesis. Nongenotoxic (epigenetic) effects of cigarette smoke also act as modulators altering cellular functions. These two effects underlie the mechanisms of tumor promotion and progression. While there is no lack of general reviews on the genotoxic and carcinogenic potentials of cigarette smoke in lung carcinogenesis, updated review on the epigenetic effects and molecular mechanisms of cigarette smoke and carcinogenesis, not limited to lung, is lacking. We are presenting a comprehensive review of recent investigations on cigarette smoke, with special attentions to nicotine, NNK, and PAHs. The current understanding on their molecular mechanisms include (1) receptors, (2) cell cycle regulators, (3) signaling pathways, (4) apoptosis mediators, (5) angiogenic factors, and (6) invasive and metastasis mediators. This review highlighted the complexity biological responses to cigarette smoke components and their involvements in tumorigenesis

Essential Metalloelement Chelates Facilitate Repair of Radiation Injury

Treatment with essential metalloelement (Cu, Fe, Mn, and Zn) chelates or combinations of them before and/or after radiation injury is a useful approach to overcoming radiation injury. No other agents are known to increase survival when they are used to treat after irradiation, in a radiorecovery treatment paradigm. These chelates may be useful in facilitating de novo syntheses of essential metalloelement-dependent enzymes required to repair radiation injury. Reports of radioprotection, which involves treatment before irradiation, with calcium-channel blockers, acyl Melatonin homologs, and substituted anilines, which may serve as chelating agents after biochemical modification in vivo, as well as Curcumin, which is a chelating agent, have been included in this review. These inclusions are intended to suggest additional approaches to combination treatments that may be useful in facilitating radiation recovery. These approaches to radioprotection and radiorecovery offer promise in facilitating recovery from radiation-induced injury experienced by patients undergoing radiotherapy for neoplastic disease and by individuals who experience environmental, occupational, or accidental exposure to ultraviolet, x-ray, or γ-ray radiation. Since there are no existing treatments of radiation-injury intended to facilitate tissue repair, studies of essential metalloelement chelates and combinations of them, as well as combinations of them with existing organic radioprotectants, seem worthwhile

Structures of Darunavir-Resistant HIV‑1 Protease Mutant Reveal Atypical Binding of Darunavir to Wide Open Flaps

The molecular basis for high resistance to clinical inhibitors of HIV-1 protease (PR) was examined for the variant designated PRP51 that was selected for resistance to darunavir (DRV). High resolution crystal structures of PRP51 with the active site D25N mutation revealed a ligand-free form and an inhibitor-bound form showing a unique binding site and orientation for DRV. This inactivating mutation is known to increase the dimer dissociation constant and decrease DRV affinity of PR. The PRP51‑D25N dimers were in the open conformation with widely separated flaps, as reported for other highly resistant variants. PRP51‑D25N dimer bound two DRV molecules and showed larger separation of 8.7 Å between the closest atoms of the two flaps compared with 4.4 Å for the ligand-free structure of this mutant. The ligand-free structure, however, lacked van der Waals contacts between Ile50 and Pro81′ from the other subunit in the dimer, unlike the majority of PR structures. DRV is bound inside the active site cavity; however, the inhibitor is oriented almost perpendicular to its typical position and exhibits only 2 direct hydrogen bond and two water-mediated interactions with atoms of PRP51‑D25N compared with 11 hydrogen bond interactions seen for DRV bound in the typical position in wild-type enzyme. The atypical location of DRV may provide opportunities for design of novel inhibitors targeting the open conformation of PR drug-resistant mutants

Nernst and Seebeck Coefficients of the Cuprate SuperconductorYBa2_2Cu3_3O6.67_{6.67}: A Study of Fermi Surface Reconstruction

The Seebeck and Nernst coefficients $S$ and $\nu$ of the cuprate superconductor YBa$_2$Cu$_3$O$_y$ (YBCO) were measured in a single crystal with doping $p = 0.12$ in magnetic fields up to H = 28 T. Down to T=9 K, $\nu$ becomes independent of field by $H \simeq 30$ T, showing that superconducting fluctuations have become negligible. In this field-induced normal state, $S/T$ and $\nu/T$ are both large and negative in the $T \to 0$ limit, with the magnitude and sign of $S/T$ consistent with the small electron-like Fermi surface pocket detected previously by quantum oscillations and the Hall effect. The change of sign in $S(T)$ at $T \simeq 50$ K is remarkably similar to that observed in La$_{2-x}$Ba$_x$CuO$_4$, La$_{2-x-y}$Nd$_y$Sr$_x$CuO$_4$ and La$_{2-x-y}$Eu$_y$Sr$_x$CuO$_4$, where it is clearly associated with the onset of stripe order. We propose that a similar density-wave mechanism causes the Fermi surface reconstruction in YBCO.Comment: Final version accepted for publication in Phys. Rev. Lett. New title, shorter abstract, minor revision of text and added reference

Lifshitz critical point in the cuprate superconductor YBa2Cu3Oy from high-field Hall effect measurements

The Hall coefficient R_H of the cuprate superconductor YBa2Cu3Oy was measured in magnetic fields up to 60 T for a hole concentration p from 0.078 to 0.152, in the underdoped regime. In fields large enough to suppress superconductivity, R_H(T) is seen to go from positive at high temperature to negative at low temperature, for p > 0.08. This change of sign is attributed to the emergence of an electron pocket in the Fermi surface at low temperature. At p < 0.08, the normal-state R_H(T) remains positive at all temperatures, increasing monotonically as T \to 0. We attribute the change of behaviour across p = 0.08 to a Lifshitz transition, namely a change in Fermi-surface topology occurring at a critical concentration p_L = 0.08, where the electron pocket vanishes. The loss of the high-mobility electron pocket across p_L coincides with a ten-fold drop in the conductivity at low temperature, revealed in measurements of the electrical resistivity $\rho$ at high fields, showing that the so-called metal-insulator crossover of cuprates is in fact driven by a Lifshitz transition. It also coincides with a jump in the in-plane anisotropy of $\rho$, showing that without its electron pocket the Fermi surface must have strong two-fold in-plane anisotropy. These findings are consistent with a Fermi-surface reconstruction caused by a unidirectional spin-density wave or stripe order.Comment: 16 pages, 13 figures, see associated Viewpoint: M. Vojta, Physics 4, 12 (2011

Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix.

Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome

Sleep During Pregnancy: The nuMoM2b Pregnancy and Sleep Duration and Continuity Study

Study Objectives: To characterize sleep duration, timing and continuity measures in pregnancy and their association with key demographic variables. Methods: Multisite prospective cohort study. Women enrolled in the nuMoM2b study (nulliparous women with a singleton gestation) were recruited at the second study visit (16-21 weeks of gestation) to participate in the Sleep Duration and Continuity substudy. Women <18 years of age or with pregestational diabetes or chronic hypertension were excluded from participation. Women wore a wrist activity monitor and completed a sleep log for 7 consecutive days. Time in bed, sleep duration, fragmentation index, sleep efficiency, wake after sleep onset, and sleep midpoint were averaged across valid primary sleep periods for each participant. Results: Valid data were available from 782 women with mean age of 27.3 (5.5) years. Median sleep duration was 7.4 hours. Approximately 27.9% of women had a sleep duration of 9 hours. In multivariable models including age, race/ethnicity, body mass index, insurance status, and recent smoking history, sleep duration was significantly associated with race/ethnicity and insurance status, while time in bed was only associated with insurance status. Sleep continuity measures and sleep midpoint were significantly associated with all covariates in the model, with the exception of age for fragmentation index and smoking for wake after sleep onset. Conclusions: Our results demonstrate the relationship between sleep and important demographic characteristics during pregnancy

Persistent Tissue Kinetics and Redistribution of Nanoparticles, Quantum Dot 705, in Mice: ICP-MS Quantitative Assessment

Background: Quantum dots (QDs) are autofluorescent semiconductor nanocrystals that can be used for in vivo biomedical imaging. However, we know little about their in vivo disposition and health consequences. Objectives: We assessed the tissue disposition and pharmacokinetics of QD705 in mice. Methods: We determined quantitatively the blood and tissue kinetics of QD705 in mice after single intravenous (iv) injection at the dose of 40 pmol for up to 28 days. Inductively coupled plasma–mass spectrometry (ICP-MS) measurement of cadmium was the primary method of quantification of QD705. Fluorescence light microscopy revealed the localization of QD705 in tissues. Results: Plasma half-life of QD705 in mice was short (18.5 hr), but ICP-MS analyses revealed QD705 persisted and even continued to increase in the spleen, liver, and kidney 28 days after an iv dose. Considerable time-dependent redistribution from body mass to liver and kidney was apparent between 1 and 28 days postdosing. The recoveries at both time points were near 100%; all QD705s reside in the body. Neither fecal nor urinary excretion of QD705 was detected appreciably in 28 days postdosing. Fluorescence microscopy demonstrated deposition of QD705 in the liver, spleen, and kidneys. Conclusion: Judging from the continued increase in the liver (29–42% of the administered dose), kidney (1.5–9.2%), and spleen (4.8–5.2%) between 1 and 28 days without any appreciable excretion, QD705 has a very long half-life, potentially weeks or even months, in the body and its health consequences deserve serious consideration

Large dispersive interaction between a CMOS double quantum dot and microwave photons

We report a large coupling rate, $g_0/(2\pi)=183$ MHz, between the charge state of a double quantum dot in a CMOS split-gate silicon nanowire transistor and microwave photons in a lumped-element resonator formed by hybrid integration with a superconducting inductor. We enhance the coupling by exploiting the large interdot lever arm of an asymmetric split-gate device, $\alpha=0.72$, and by inductively coupling to the resonator to increase its impedance, $Z_\text{r}=560$ $\Omega$. In the dispersive regime, the large coupling strength at the DQD hybridisation point produces a frequency shift comparable to the resonator linewidth, the optimal setting for maximum state visibility. We exploit this regime to demonstrate rapid gate-based readout of the charge degree of freedom, with an SNR of 3.3 in 50 ns. In the resonant regime, the fast charge decoherence rate precludes reaching the strong coupling regime, but we show a clear route to spin-photon circuit quantum electrodynamics using hybrid CMOS systems.Comment: 9 pages, 7 figure