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Although remarkable developments in lung cancer treatments have been made, lung cancer remains the leading cause of cancer mortality worldwide. Epidermal growth factor receptor (EGFR) is occasionally mutated in non-small cell lung cancer and heterogeneity

The lowest-frequency fundamental ν 6 of trifluoroiodomethane (CF 3 I) has never been directly observed and analyzed at high resolution in the gas phase. The ν 6 (e) level interacts with ν 3 (a 1 ) at 286.297 cm -1 via a b -axis Coriolis interaction, which perturbs the rotational structure of both levels. In this work, we report low- J microwave transitions (for J ranging from 0-2) within the ν 6 vibrational level. The l -type doubling observed in our spectrum agreed poorly with the predictions of previously published models of the interacting ν 3 - ν 6 levels, prompting us to refine the model. We performed ab initio anharmonic force-field calculations, which were used to constrain some of the parameters, and which served as a check on some of the floated parameters. We fit a dataset consisting of 3593 transitions, which combined our measurements with previous microwave, millimeter wave, and high-resolution infrared observations. A reasonable set of fit parameters is obtained with ν 6 = 267.28 cm -1 , but we cannot rule out a lower value of ν 6 = 261.5 cm -1 consistent with analyses of the vibrational level structure.

The perovskite quantum dots (QDs) of CsPbX 3 (X = Cl, Br, I) exhibit exceptional photoluminescent properties, but their sensitivity to moisture and heat poses a challenge. This study presents a solvent-free synthesis approach for incorporating CsPbBr 3 perovskite QDs into zeolite A. The introduction of [Cs 8 PbBr 6 ] 4+ perovskite QDs into the zeolite framework resulted in a highly stable configuration, maintaining its initial luminescence properties even after being underwater or exposed to heat. The structure is determined by 3-dimensional single-crystal crystallography. Each octahedral PbBr 6 4- ion is surrounded by Cs + ions and [Cs 8 PbBr 6 ] 4+ perovskite QDs being formed at the 32% of the center of a large cavity. Further, [Na 12 CsBr 8 ] 5+ QDs are formed at the very center of another 46% large cavities by combining Cs + , Na + , and Br - ions. The peak in the emission spectrum of Pb,Br,Cs,Na-A is similar to those of the CsPbBr 3 nanocrystal, Cs 4 PbBr 6 0-dimensional perovskite QDs, and Pb,Br,H,Cs,Na-FAU(X and Y). This work demonstrates that Pb,Br,Cs,Na-A can be produced using a simplified solvent-free synthesis procedure, which exhibits excellent stability against moisture and heat. Moreover, through a straightforward process, various quantum dots (QDs) can be incorporated into zeolite cavities to develop materials with variety photoluminescent properties.

Low-k SiONC thin films with excellent thermal stabilities were deposited using plasma-assisted molecular layer deposition (PA-MLD) with a tetraisocyanatesilane (Si(NCO) 4 ) precursor, N 2 plasma, and phloroglucinol (C 6 H 3 (OH) 3 ). By adjusting the order of the N 2 plasma exposure steps within the PA-MLD process, we successfully developed a deposition technique that allows accurate control of thickness at the Ångström level via self-limiting reactions. The thicknesses of the thin films were measured through spectroscopic ellipsometry (SE). By tuning the N 2 plasma power, we facilitated the formation of -NH 2 sites for phloroglucinol adsorption, achieving a growth per cycle of 0.18 Å cycle -1 with 300 W of N 2 plasma power. Consequently, the thickness of the films increased linearly with each additional cycle. Moreover, the organic linkers within the film formed stable bonds through surface reactions, resulting in a negligible decrease in thickness of approximately -11% even upon exposure to a high annealing temperature of 600 °C. This observation was confirmed by SE, distinguishing the as-prepared film from previously reported low-k films that fail to maintain their thickness under similar conditions. X-ray photoelectron spectroscopy (XPS) and current-voltage (I-V) and capacitance-voltage (C-V) measurement were conducted to evaluate the composition, insulating properties, and dielectric constant according to the deposition and annealing conditions. XPS results revealed that as the plasma power increased from 200 to 300 W, the C/Si ratio increased from 0.37 to 0.67, decreasing the dielectric constant from 3.46 to 3.12. Furthermore, there was no significant difference in the composition before and after annealing, and the hysteresis decreased from 0.58 to 0.19 V owing to defect healing, while maintaining the leakage current density, breakdown field, and dielectric constant. The low dielectric constant, accurate thickness control, and excellent thermal stability of this MLD SiONC thin film enable its application as an interlayer dielectric in back-end-of-line process., (© 2024 IOP Publishing Ltd.)

Nonadiabatic interaction of adsorbate nuclear motion with the continuum of electronic states is known to affect the dynamics of chemical reactions at metal surfaces. A large body of work has probed the fundamental mechanisms of such interactions for atomic and diatomic molecules at surfaces. In polyatomic molecules, the possibility of mode-specific damping of vibrational motion due to the effects of electronic friction raises the question of whether such interactions could profoundly affect the outcome of chemistry at surfaces by selectively removing energy from a particular intramolecular adsorbate mode. However, to date, there have not been any fundamental experiments demonstrating nonadiabatic electron-vibration coupling in a polyatomic molecule at a surface. In this work, we scatter excited metastable formaldehyde and formaldehyde-d 2 from a low work function surface and detect ejected exoelectrons that accompany molecular relaxation. The exoelectron ejection efficiency exhibits a strong dependence on the vibrational mode that is excited: out-of-plane bending excitation (ν 4 ) leads to significantly more exoelectrons than does CO stretching excitation (ν 2 ). The results provide clear evidence for mode-specific energy transfer from vibration to surface electrons.

Objective: To investigate molecular and functional consequences of additional exposures to iodine- or gadolinium-based contrast agents within 24 hours from the initial intravenous administration of iodine-based contrast agents through an animal study., Materials and Methods: Fifty-six Sprague-Dawley male rats were equally divided into eight groups: negative control, positive control (PC) with single-dose administration of CT contrast agent, and additional administration of either CT or MR contrast agents 2, 4, or 24 hours from initial CT contrast agent injection. A 12 µL/g of iodinated contrast agent or a 0.47 µL/g of gadolinium-based contrast agent were injected into the tail vein. Serum levels of blood urea nitrogen, creatinine, cystatin C (Cys C), and malondialdehyde (MDA) were measured. mRNA and protein levels of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated., Results: Levels of serum creatinine (SCr) were significantly higher in repeated CT contrast agent injection groups than in PC (0.21 ± 0.02 mg/dL for PC; 0.40 ± 0.02, 0.34 ± 0.03, and 0.41 ± 0.10 mg/dL for 2-, 4-, and 24-hour interval groups, respectively; P < 0.001). There was no significant difference in the average Cys C and MDA levels between PC and repeated CT contrast agent injection groups (Cys C, P = 0.256-0.362; MDA, P > 0.99). Additional doses of MR contrast agent did not make significant changes compared to PC in SCr ( P > 0.99), Cys C ( P = 0.262), and MDA ( P = 0.139-0.771) levels. mRNA and protein levels of KIM-1 and NGAL were not significantly different among additional CT or MR contrast agent groups ( P > 0.05)., Conclusion: A sufficient time interval, probably more than 24 hours, between repeated contrast-enhanced CT examinations may be necessary to avoid deterioration in renal function. However, conducting contrast-enhanced MRI on the same day as contrast-enhanced CT may not induce clinically significant kidney injury., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Although the use of iodinated contrast agents is sometimes unavoidable for accurate diagnosis, contrast-induced acute kidney injury (CI-AKI) is a possible complication of its administration. The pathogenesis of CI-AKI has not been fully elucidated, but oxidative stress is thought to be a major factor. Sestrin2 plays an important role in cellular and mitochondrial homeostasis by regulating oxidative stress. In this study, we aimed to investigate whether recombinant adenovirus containing sestrin2 (RS) can attenuate CI-AKI by reducing oxidative stress in a CI-AKI mice model. Our results showed that RS decreases oxidative stress, pro-inflammatory cytokines (TNF-α, IL-1α, IL-1β and IL-6) and apoptosis (Bax/Bcl2 and cleaved caspase-3) in the CI-AKI model. Additionally, RS alleviated mitochondrial damage, as evidenced by morphological changes, are restored ATP synthesis. Furthermore, RS administration resulted in a decrease in mitochondrial fission marker (Drp1) that was increased in the CI-AKI model, while the mitochondrial fusion marker (Mfn2) increased, indicating a restoration of mitochondrial dynamics. Decreased relative blood volume, as evaluated on computed tomography (CT), significantly increased compared to the CI-AKI group after RS administration. Finally, renal injury markers such as Kim-1, Ngal, IL-18 also decreased and kidney function was preserved with RS. These results suggested that RS can mitigate the deterioration of renal function in CI-AKI model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The formation of two-electron chemical bonds requires the alignment of spins. Hence, it is well established for gas-phase reactions that changing a molecule's electronic spin state can dramatically alter its reactivity. For reactions occurring at surfaces, which are of great interest during, among other processes, heterogeneous catalysis, there is an absence of definitive state-to-state experiments capable of observing spin conservation and therefore the role of electronic spin in surface chemistry remains controversial. Here we use an incoming/outgoing correlation ion imaging technique to perform scattering experiments for O( 3 P) and O( 1 D) atoms colliding with a graphite surface, in which the initial spin-state distribution is controlled and the final spin states determined. We demonstrate that O( 1 D) is more reactive with graphite than O( 3 P). We also identify electronically nonadiabatic pathways whereby incident O( 1 D) is quenched to O( 3 P), which departs from the surface. With the help of molecular dynamics simulations carried out on high-dimensional machine-learning-assisted first-principles potential energy surfaces, we obtain a mechanistic understanding for this system: spin-forbidden transitions do occur, but with low probabilities., (© 2023. The Author(s).)

We employ time-slice and velocity map ion imaging methods to explore the quantum-state resolved dynamics in thermal N 2 O decomposition on Pd(110). We observe two reaction channels: a thermal channel that is ascribed to N 2 products initially trapped at surface defects and a hyperthermal channel involving a direct release of N 2 to the gas phase from N 2 O adsorbed on bridge sites oriented along the [001] azimuth. The hyperthermal N 2 is highly rotationally excited up to J = 52 ( v ″ = 0) with a large average translational energy of 0.62 eV. Between 35 and 79% of the estimated barrier energy (1.5 eV) released upon dissociation of the transition state (TS) is taken up by the desorbed hyperthermal N 2 . The observed attributes of the hyperthermal channel are interpreted by post-transition-state classical trajectories on a density functional theory-based high-dimensional potential energy surface. The energy disposal pattern is rationalized by the sudden vector projection model, which attributes to unique features of the TS. Applying detailed balance, we predict that in the reverse Eley-Rideal reaction, both N 2 translational and rotational excitation promote N 2 O formation.

Inhibition of translation initiation has emerging implications for the development of mechanism-based anticancer therapeutics. Phosphorylation of eIF2α is recognized as a key target that regulates the translation initiation cascade. Based on the bioisosteric replacement of urea-derived eIF2α phosphorylation activator 1, a novel series of N-aryl-N'-[4-(aryloxy)cyclohexyl]squaramide derivatives was designed and synthesized; their effects on the activation of eIF2α phosphorylation was assessed systematically. A brief structure-activity relationship analysis was established by stepwise structural optimization of the squaramide series. Subsequently, the antiproliferative activities of the selected analogues were determined in human leukemia K562 cells. We then identified 10 potent eIF2α phosphorylation activators with considerable anticancer activity. The most promising analogues 19 and 40 possessed higher cancer cell selectivity (SI = 6.16 and 4.83, respectively) than parent 1 (SI = 2.20). Finally, protein expression analysis revealed that compounds 19 and 40 induced eIF2α phosphorylation and its downstream effectors ATF4 and CHOP., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

There is wide interest in developing accurate theories for predicting rates of chemical reactions that occur at metal surfaces, especially for applications in industrial catalysis. Conventional methods contain many approximations that lack experimental validation. In practice, there are few reactions where sufficiently accurate experimental data exist to even allow meaningful comparisons to theory. Here, we present experimentally derived thermal rate constants for hydrogen atom recombination on platinum single-crystal surfaces, which are accurate enough to test established theoretical approximations. A quantum rate model is also presented, making possible a direct evaluation of the accuracy of commonly used approximations to adsorbate entropy. We find that neglecting the wave nature of adsorbed hydrogen atoms and their electronic spin degeneracy leads to a 10× to 1000× overestimation of the rate constant for temperatures relevant to heterogeneous catalysis. These quantum effects are also found to be important for nanoparticle catalysts.

Animal cloning has been popularized for more than two decades, since the birth of Dolly the Sheep 25 years ago in 1996. There has been an apparent waning of interest in cloning, evident by a reduced number of reports. Over 1500 dogs, representing approximately 20% of the American Kennel Club's recognized breeds, have now been cloned, making the dog (Canis familiaris) one of the most successfully cloned mammals. Dogs have a unique relationship with humans, dating to prehistory, and a high degree of genome homology to humans. A number of phenotypic variations, rarely recorded in natural reproduction have been observed in in these more than 1000 clones. These observations differ between donors and their clones, and between clones from the same donor, indicating a non-genetic effect. These differences cannot be fully explained by current understandings but point to epigenetic and cellular reprograming effects of somatic cell nuclear transfer. Notably, some phenotypic variations have been reversed through further cloning. Here we summarize these observations and elaborate on the cloning procedure., (© 2022. The Author(s).)

We report chirality detection of structural isomers in a gas phase mixture using nanosecond photoelectron circular dichroism (PECD). Combining pulsed molecular beams with high-resolution resonance enhanced multi-photon ionization (REMPI) allows specific isolated transitions belonging to distinct components in the mixture to be targeted.

The dysregulation of glycolysis regardless of oxygen availability is one of the major characteristics of cancer cells. While the drug resistance of ovarian cancer cells has been extensively studied, the molecular mechanism of anticancer drug resistance under low-glucose conditions remains unknown. In this study, we investigated the pathway mediating drug resistance under low-glucose conditions by examining the relationship between embryonic lethal abnormal vision Drosophila homolog-like (ELAVL) protein and glycolysis-related enzymes. Ovarian cancer cells resistant to 2.5 nM paclitaxel were exposed to low-glucose media for 2 weeks, and the expression levels of ELAVL2, ELAVL4, glycolytic enzymes, and drug resistance-related proteins were elevated to levels comparable to those in cells resistant to 100 nM paclitaxel. Gene silencing of ELAVL2/4 using small interfering RNA prevented the upregulation of glycolysis-related enzymes, reduced lactate production, and sensitized 2.5 nM paclitaxel-resistant ovarian cancer cells to anticancer agents under hypoglycemic conditions. Furthermore, pharmacological inhibition of glycolytic enzymes with 2-deoxyglucose, a specific inhibitor of glycolysis, triggered caspase-dependent apoptosis, reduced lactate generation, and blocked the expression of drug resistance-related proteins under low-glucose conditions. These results suggest that the level of ELAVL2/4 is responsible for the development of chemoresistance through activation of the glycolysis pathway under glucose deprivation conditions., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The abnormal expression of tropomyosin receptor kinase (Trk) serves an important role in the promotion of cancer progression. Homeobox C6 (HOXC6) and A disintegrin and metalloproteinase domain‑containing 8 (ADAM8) are associated with the invasiveness of cancer cells. However, the exact relationship between these molecules and their downstream signaling pathways in chemoresistant colon cancer cells are largely unknown. Therefore, the current study investigated the association between TrkB/C with HOXC6 and ADAM8 in the induction of drug‑resistant colon cancer cell metastasis. The results demonstrated that chemoresistant colon cancer cells exhibited upregulated TrkB/C, HOXC6 and ADAM8 expression. Additionally, but also chemoresistant colon cancer cells demonstrated higher migratory activities compared with parent colon cancer cells. The pharmacological inhibition of TrkB/C activity reduced the phosphorylation of mitogen‑activated protein kinase kinase/ERK and subsequently suppressed HOXC6 and ADAM8 expression. In addition, gene silencing of HOXC6 inhibited ADAM8 and MMP activity, and inhibited the migration and invasion of drug‑resistant cancer cells. However, the targeted downregulation of ADAM8 using small interfering RNA failed to suppress TrkB/C‑associated ERK‑mediated HOXC6 signaling activity. Furthermore, pre‑treatment with ADAM10‑ and ADAM17‑specific inhibitors had no effect on attenuating the invasiveness of chemoresistant colon cancer cells. The results indicated that TrkB/C‑mediated ERK activation serves an important role in the metastasis of drug‑resistant colon cancer cells through the regulation of HOXC6/ADAM8 activity.

In cancer, resistance to chemotherapy is one of the main reasons for therapeutic failure. Cells that survive after treatment with anticancer drugs undergo various changes, including in cell metabolism. In this study, we investigated the effects of AKT-mediated miR-125b-5p alteration on metabolic changes and examined how these molecules enhance migration and induce drug resistance in colon cancer cells. AKT1 and AKT3 activation in drug-resistant colon cancer cells caused aberrant downregulation of miR-125b-5p, leading to GLUT5 expression. Targeted inhibition of AKT1 and AKT3 restored miR-125b-5p expression and prevented glycolysis- and lipogenesis-related enzyme activation. In addition, restoring the level of miR-125b-5p by transfection with the mimic sequence not only significantly blocked the production of lactate and intracellular fatty acids but also suppressed the migration and invasion of chemoresistant colon cancer cells. GLUT5 silencing with small interfering RNA attenuated mesenchymal marker expression and migratory activity in drug-resistant colon cancer cells. Additionally, treatment with 2,5-anhydro-d-mannitol resensitized chemoresistant cancer cells to oxaliplatin and 5-fluorouracil. In conclusion, our findings suggest that changes in miR-125b-5p and GLUT5 expression after chemotherapy can serve as a new marker to indicate metabolic change-induced migration and drug resistance development., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Photoelectron circular dichroism (PECD) is a highly sensitive enantiospecific spectroscopy for studying chiral molecules in the gas phase using either single-photon ionization or multiphoton ionization. In the short pulse limit investigated with femtosecond lasers, resonance-enhanced multiphoton ionization (REMPI) is rather instantaneous and typically occurs simultaneously via more than one vibrational or electronic intermediate state due to limited frequency resolution. In contrast, vibrational resolution in the REMPI spectrum can be achieved using nanosecond lasers. In this work, we follow the high-resolution approach using a tunable narrow-band nanosecond laser to measure REMPI-PECD through distinct vibrational levels in the intermediate 3s and 3p Rydberg states of fenchone. We observe the PECD to be essentially independent of the vibrational level. This behaviour of the chiral sensitivity may pave the way for enantiomer specific molecular identification in multi-component mixtures: one can specifically excite a sharp, vibrationally resolved transition of a distinct molecule to distinguish different chiral species in mixtures.

CD248, also called endosialin or tumor endothelial marker-1, is markedly upregulated in almost all cancers, including colon cancers. Changes in microRNA profiles are one of the direct causes of cancer development and progression. In this study, we investigated whether a change in CD248 expression in colon cancer cells could induce drug resistance after chemotherapy, and we explored the relationship between miR-125b-5p levels and CD248 expression in Toll-like receptor (TLR)-modified chemoresistant colon cancer cells. TLR2/6 and TLR5 upregulation in drug-resistant colon cancer cells contributed to miR-125b-5p downregulation and specificity protein 1 (Sp1)-mediated CD248 upregulation via nuclear factor-kappa B (NF-κB) activation. Exposure to specific TLR2/6 or TLR5 ligands enhanced the expression of mesenchymal markers as well as the migratory activity of oxaliplatin- or 5-fluorouracil-resistant colon cancer cells. The transfection of a synthetic miR-125b-5p mimic into chemoresistant cells prevented Sp1 and CD248 activation and significantly impaired invasive activity. Furthermore, Sp1 or CD248 gene silencing as well as miR-125b-5p overexpression markedly reversed drug resistance and inhibited epithelial-mesenchymal transition in colon cancer cells. Taken together, these results suggest that changes in miR-125b-5p levels play an important role in Sp1-mediated CD248 expression and the development of drug resistance in TLR-mutated colon cancer cells., (© 2019 Wiley Periodicals, Inc.)

The 193-nm photolysis of CH 2 CHCN illustrates the capability of chirped-pulse Fourier transform millimeter-wave spectroscopy to characterize transition states. We investigate the HCN, HNC photofragments in highly excited vibrational states using both frequency and intensity information. Measured relative intensities of J = 1-0 rotational transition lines yield vibrational-level population distributions (VPD). These VPDs encode the properties of the parent molecule transition state at which the fragment molecule was born. A Poisson distribution formalism, based on the generalized Franck-Condon principle, is proposed as a framework for extracting information about the transition-state structure from the observed VPD. We employ the isotopologue CH 2 CDCN to disentangle the unimolecular 3-center DCN elimination mechanism from other pathways to HCN. Our experimental results reveal a previously unknown transition state that we tentatively associate with the HCN eliminated via a secondary, bimolecular reaction., Competing Interests: The authors declare no competing interest.

Intracellular reactive oxygen species (ROS) play an important role in the proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). HSPCs are difficult to be expanded ex vivo while maintaining their stemness when they are exposed to oxidative damage after being released from the bone marrow. There have been efforts to overcome this limitation by using various cytokine cocktails and antioxidants. In this study, we investigated the effects of echinochrome A (Ech A)-a well-established and non-toxic antioxidant-on the ex vivo expansion of HSPCs by analyzing a CD34 + cell population and their biological functions. We observed that Ech A-induced suppression of ROS generation and p38-MAPK/JNK phosphorylation causes increased expansion of CD34 + cells. Moreover, p38-MAPK/JNK inhibitors SB203580 and SP600125 promoted ex vivo expansion of CD34 + cells. We also demonstrated that the activation of Lyn kinase and p110δ is a novel mechanism for Ech A to enhance ex vivo expansion of CD34 + cells. Ech A upregulated phospho-Src, phospho-Lyn, and p110δ expression. Furthermore, the Ech A-induced ex vivo expansion of CD34 + cells was inhibited by pretreatment with the Src family inhibitor PP1 and p110δ inhibitor CAL-101; PP1 blocked p110δ upregulation and PI3K/Akt activation, whereas CAL-101 and PI3K/Akt pathway inhibitor LY294002 did not block Src/Lyn activation. These results suggest that Ech A initially induces Src/Lyn activation, upregulates p110δ expression, and finally activates the PI3K/Akt pathway. CD34 + cells expanded in the presence of Ech A produced equal or more hematopoietic colony-forming cells than unexpanded CD34 + cells. In conclusion, Ech A promotes the ex vivo expansion of CD34 + cells through Src/Lyn-mediated p110δ expression, suppression of ROS generation, and p38-MAPK/JNK activation. Hence, Ech A is a potential candidate modality for the ex vivo, and possibly in vivo, expansion of CD34 + cells.

The dream of theoretical surface chemistry is to predict the outcome of reactions in order to find the ideal catalyst for a certain application. Having a working ab initio theory in hand would not only enable these predictions but also provide insights into the mechanisms of surface reactions. The development of theoretical models can be assisted by experimental studies providing benchmark data. Though for some reactions a quantitative agreement between experimental observations and theoretical calculations has been achieved, theoretical surface chemistry is in general still far away from gaining predictive power. Here we review recent experimental developments towards the understanding of surface reactions. It is demonstrated how quantum-state resolved scattering experiments on reactive and nonreactive systems can be used to test front-running theoretical approaches. Two challenges for describing dynamics at surfaces are addressed: nonadiabaticity in diatomic molecule surface scattering and the increasing system size when observing and describing the dynamics of polyatomic molecules at surfaces. Finally recent experimental studies on reactive systems are presented. It is shown how elementary steps in a complex surface reaction can be revealed experimentally.

Death-associated protein kinase 1 (DAPK1) expression induced by diverse death stimuli mediates apoptotic activity in various cancers, including ovarian cancer. In addition, mutual interaction between the tumor suppressor p53 and DAPK1 influences survival and death in several cancer cell lines. However, the exact role and connection of DAPK1 and p53 family proteins (p53, p63, and p73) in drug-resistant ovarian cancer cells have not been studied previously. In this study, we investigated whether DAPK1 induction by gliotoxin derived from marine fungus regulates the level of transcriptionally active p63 (TAp63) to promote apoptosis in an autophagy-dependent manner. Pre-exposure of paclitaxel-resistant ovarian cancer cells to gliotoxin inhibited the expression of multidrug resistant-associated proteins (MDR1 and MRP1-3), disrupted the mitochondrial membrane potential, and induced caspase-dependent apoptosis through autophagy induction after subsequent treatment with paclitaxel. Gene silencing of DAPK1 prevented TAp63-mediated downregulation of MDR1 and MRP1-3 and autophagic cell death after sequential treatment with gliotoxin and then paclitaxel. However, pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, had no effect on the levels of DAPK1 and TAp63 or on the inhibition of MDR1 and MRP1-3. These results suggest that DAPK1-mediated TAp63 upregulation is one of the critical pathways that induce apoptosis in chemoresistant cancer cells.

CD97 shows a strong relationship with metastasis and poor clinical outcome in various tumors, including ovarian cancer. The expression of CD97 in metastatic ovarian cancer cells was higher than that in primary ovarian cancer cells. Mature miRNAs are frequently de-regulated in cancer and incorporated into a specific mRNA, leading to post-transcriptional silencing. In this study, we investigated whether the miR-503-5p targeting of the CD97 3'-untranslated region (3'-UTR) contributes to ovarian cancer metastasis as well as the underlying mechanism regulating cancer progression. In LPS-stimulated or paclitaxel-resistant ovarian cancer cells, stimulation with recombinant human CD55 (rhCD55) of CD97 in ovarian cancer cells activated NF-κB-dependent miR-503-5p down-regulation and the JAK2/STAT3 pathway, consequently promoting the migratory and invasive capacity. Furthermore, restoration of miR-503-5p by transfection with mimics or NF-κB inhibitor efficiently blocked CD97 expression and the downstream JAK2/STAT3 signaling pathway. Target inhibition of JAK with siRNA also impaired colony formation and metastasis of LPS-stimulated and paclitaxel-resistant ovarian cancer cells. Taken together, these results suggest that high CD97 expression, which is controlled through the NF-κB/miR-503-5p signaling pathway, plays an important role in the invasive activity of metastatic and drug-resistant ovarian cancer cells by activating the JAK2/STAT3 pathway., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

We report experimental results on the state-to-state vibrational relaxation of CO(v = 17) in collisions with Ag(111) at incidence translational energies between 0.27 eV and 0.57 eV. These together with previous results provide a comprehensive set of data on two molecules (CO and NO)-one open and one closed shell-and two metals (Ag and Au). In all four cases, the incidence vibrational energy has been varied over several eV. We find a unifying relation between the probability of vibrational relaxation and the energetics of electron transfer from the metal to the molecule. This argues strongly that electronic friction based theories are not capable of explaining these data.

Metformin and pioglitazone are two commonly prescribed oral hypoglycemic agents for diabetes. Recent evidence suggests that these drugs may contribute to bladder cancer. This study investigated molecular mechanism underlying effects of metformin and pioglitazone in bladder epithelial carcinogenesis in type 2 diabetes. The cells derived from human bladder epithelial cells (HBlEpCs) were treated with metformin or pioglitazone with high glucose and insulin. Cell viability and proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and a bromodeoxyuridine incorporation assay, respectively, while cell cycle regulatory factors and oncogene expression were analyzed using western blotting. Metformin or pioglitazone suppressed cell viability concentration and time dependently, which was reversed by exposure to high glucose with or without insulin. Prolonged exposure to high glucose and insulin enhanced cyclin D, cyclin-dependent kinase 4 (Cdk4), and Cdk2 expression and suppressed cyclin-dependent kinase inhibitors p21 and p15/16 in HBlEpC cotreated with pioglitazone and metformin. Levels of tumor suppressor proteins p53 and cav-1 were downregulated while those of the oncogenic protein as c-Myc were upregulated under high glucose and insulin supplementation in HBlEpC cotreated with pioglitazone and metformin. Prolonged exposure to high glucose with or without insulin downregulated B cell lymphoma 2-associated X (Bax) and failed to enhance the expression of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) in drug-treated cells. These results suggest that hyperglycemic and insulinemic conditions promote cell cycle progression and oncogenic signaling in drug-treated bladder epithelial cells and uncontrolled hyperglycemia and hyperinsulinemia are probably greater cancer risk factors than diabetes drugs.

Treatment with celecoxib and bortezomib as single chemotherapeutic agents reduces the viability and proliferation of colorectal cancer cells. The use of these agents in combination with other chemotherapeutic agents is usually associated with adverse effects. In the present study, a combination of celecoxib and bortezomib was investigated for potential synergistic effects in colon cancer cells. The sequential exposure to celecoxib with bortezomib synergistically induced apoptotic death in human colon cancer cells compared with groups treated with a single drug or other drug combinations. c-Jun N-terminal kinase/p38-mitogen-activated protein kinase-induced endoplasmic reticulum (ER) stress through serial exposure to celecoxib and bortezomib may have induced the intracellular Ca 2+ release, leading to the generation of autophagosomes in p53-expressing HCT-116 cells. Targeted inhibition of p53 activity or ER stress or treatment with the Ca 2+ -chelating agent BAPTA-AM suppressed the ER stress-mediated Ca 2+ release and apoptosis. Although p53 -/- HCT-116 cells were less sensitive to sequential treatment with celecoxib and bortezomib, co-localization of autophagosomes was detected in the absence of CCAAT-enhancer-binding protein homologous protein expression. Treatment of p53 -/- HCT-116 cells with BAPTA-AM did not inhibit apoptosis following serial treatment with celecoxib and bortezomib. These results suggest that the order of drug administration is important in treating cancer and that the sequential treatment with celecoxib and bortezomib enhances the ER stress-mediated autophagy-associated cell death of colon cancer cells, regardless of p53 expression.

Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is inevitable change of age‑related macular degeneration (AMD). Smoking is a major risk factor for the development of EMT in several diseases, including lung cancer. Cigarette smoke‑induced stress promotes the production of epidermal growth factor (EGF) in RPE cells. However, the underlying signaling pathways induced by aberrant EGF receptor (EGFR) expression in cigarette smoke-exposed RPE cells remain largely unknown. In the present study, the morphological transformation and production of EMT-associated cytokines were investigated to analyze the effect of smoking on the retina. Furthermore, EGF‑treated or cigarette smoke‑exposed RPE cells, as well as the downstream targets of EGFR, were investigated to identify the key molecules involved in EMT of cigarette smoke‑stimulated RPE cells via immunoblotting. Exposure of RPE cells to cigarette smoke extract (CSE) induced secretion of VEGF and TGF‑β1, and increased the expression of EMT markers. CSE‑mediated focal adhesion kinase (FAK) activation resulted in the phosphorylation and activation of spleen associated tyrosine kinase (Syk)/Src proto‑oncogene, non‑receptor tyrosine kinase (Src), leading to migration and invasion of RPE cells. Knockdown of FAK or pharmacological inhibition of Syk/Src abrogated CSE‑mediated VEGF and TGF‑β1 production and blocked the phosphorylation of Smad2/3 in CSE‑stimulated RPE cells. Erlotinib (an EGFR inhibitor) suppressed EGF and CSE‑mediated switch from an epithelial to mesenchymal phenotype. Baicalein, an inhi-bitor of 12/15‑lipooxygenase, also efficiently suppressed CSE‑induced EMT processes by inhibiting EGFR‑associated downstream signaling transduction. The results identified a novel signaling pathway mediated by EGFR in CSE‑activated RPE cells, and suggest baicalein as a potential new therapeutic drug for CSE‑associated retinopathy.

The activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is critical for the induction of epithelial-mesenchymal transition (EMT) by growth factors, including insulin-like growth factor 1 (IGF-1). The activation of intracellular lipogenesis provides proliferative and survival signals for cancer cells. In this study, we investigated the connection between lipogenesis-related EMT processes and IGF-1-mediated PI3K p110 isoform activation in primary (SW480 cells) and metastatic (SW620) colon carcinoma cells. We also examined the underlying signaling pathway that promotes fatty acid synthesis in IGF-1-activated colon cancer cells. IGF-1 stimulation upregulated the expression of lipogenic enzymes as well as the activation of Nardilysin (N-arginine dibasic convertase, NRD1) and its downstream targets, a disintegrin and metalloproteases 10 (ADAM10) and ADAM17. The upregulation of the Lyn/Syk-mediated PI3K p110δ isoform in SW480 cells and the Lyn-dependent PI3K p110α isoform in SW620 cells triggered fatty acid production and cell motility in IGF-1-activated colon cancer cells. Pharmacological inhibition with A66 (PI3K p110α specific inhibitor) and CAL-101 (PI3K p110δ specific inhibitor) efficiently inhibited EMT in colon cancer cells by blocking the NRD1/ADAM family protein signaling pathway. Gene silencing of NRD1 and ADAM family proteins attenuated the generation of intracellular fatty acid and the migratory activity of colon cancer cells. Our results suggest that the different isoforms of the PI3K p110 subunit could be therapeutic targets for primary and metastatic colon cancer and that regulation of the NRD1/ADAM signaling pathway controls lipogenesis-mediated EMT in IGF-1-stimulated colon cancer cells.

Ampelopsin (Amp) is bioactive natural product and exerts anti-cancer effects against several cancer types. The present study investigated the anti-colon cancer activity of Amp and explored its mechanism of action. The treatment of colon cancer cells with Amp resulted in the dose- and time-dependent induction of apoptosis via the activation of endoplasmic reticulum (ER) stress, 5' adenosine monophosphate-activated protein kinase (AMPK), and c-Jun N-terminal protein kinase (JNK)/p38 mitogen-activated protein kinases (MAPKs). Salubrinal, an ER stress inhibitor, prevented the upregulation of ER stress-associated proteins, including phosphorylated protein kinase RNA-like ER kinase, phosphorylated eukaryotic translation initiation factor 2α, glucose-regulated protein 78, and CCAAT/enhancer-binding protein homologous protein, as well as suppressing AMPK activation and the MAPK signaling pathway. Knockdown of AMPK by RNA interference failed to block ER stress. Additionally, SP600125 (a JNK inhibitor) and SB203580 (a p38-MAPK inhibitor) effectively inhibited apoptosis and attenuated the expression of X-linked IAP-associated factor 1 (XAF1) and apoptotic Bcl-2 family proteins (BCL2 antagonist/killer 1 and BCL2-associated X protein) in Amp-treated colon cancer cells. Furthermore, reactive oxygen species (ROS)-mediated ER stress/AMPK apoptotic signaling pathway in Amp-treated colon cancer cells were markedly inhibited by treatment with N-acetyl-L-cysteine, a ROS scavenger. These results demonstrate that treatment with Amp induces the apoptotic death of colon cancer cells through ER stress-initiated AMPK/MAPK/XAF1 signaling. These results also provide experimental information for developing Amp as therapeutic drug against colon cancer.

Toll-like receptor (TLR)-mediated signaling induces cell migration or invasion in several tumors and various stages of cancer. Interactions of mesothelin, a 40-kDa cell surface glycoprotein, with cancer antigen 125 (CA125) is associated with drug resistance, metastasis, and poor clinical outcome of ovarian cancer patients. In this study, we examined the role of TLR5 and TLR7 in the metastasis of ovarian cancer through the induction of mesothelin/CA125 expression and investigated its underlying mechanism. TLR5 agonist (flagellin) and TLR7 agonist (imiquimod) upregulated mesenchymal phenotypes and produced epithelial-mesenchymal transition (EMT)-related cytokines in the SKOV3 cells; however, TLR7 expressing CaOV3 cells had no response to the specific ligand, imiquimod, for enhancing its EMT processes. Stimulation of the SKOV3 cells with flagellin or imiquimod activated Wiskott-Aldrich syndrome protein verprolin-homologous 3 (WAVE3) and mesothelin/CA125, whereas it suppressed the expression of TAp63. Moreover, knockdown of TLR5 or TLR7 in SKOV3 cells profoundly impaired the TLR5- or TLR7-intiated downstream signaling pathway. Loss of WAVE3 in SKOV3 cells led to the inhibition of invasion, suppression of mesenchymal characteristics, prevention of OCT4/SOX2 secretion, and attenuation of mesothelin/CA125 expression after stimulation with flagellin or imiquimod. Although the disruption of mesothelin decreased the migratory activity of the TLR5/7-activated SKOV3 cells, knockdown of mesothelin failed to reduce the expression of mesenchymal markers, OCT4, and SOX2. In addition, targeting OCT4 or SOX2 with siRNA had no effect on the expression of mesothelin and the suppression of transcriptionally active p63 (TAp63) in the TLR5/7-stimulated SKOV3 cells. Our results suggest that TLR5/7-mediated WAVE3 activation not only controls the mesothelin-related EMT processes but also modulates OCT4/SOX2-mediated mesenchymal marker expression. Taken together, both TLR5 and TLR7 expression are critical for the TLR5/7-induced metastasis of ovarian cancer and the inhibition of WAVE3 might be a new therapeutic target to control ovarian cancer metastasis.

Electronically nonadiabatic dynamics can be important in collisions of molecules at surfaces; for example, when vibrational degrees of freedom of molecules are coupled to electron-hole-pair (EHP) excitation of a metal. Such dynamics have been inferred from a host of observations involving multiquantum relaxation of NO molecules scattered from metal surfaces. Electron transfer forming transient NO - is thought to be essential to the nonadiabatic coupling. The question remains: is this behavior usual? Here, we present final vibrational state distributions resulting from the scattering of CO(v i = 17) from Au(111), which exhibits significantly less vibrational relaxation than NO(v i = 16). We explain this observation in terms of the lower electron affinity of CO compared to NO, a result that is consistent with the formation of a transient CO - ion being important to CO vibrational relaxation.

The conversion of translational to rotational motion often plays a major role in the trapping of small molecules at surfaces, a crucial first step for a wide variety chemical processes that occur at gas-surface interfaces. However, to date most quantum-state resolved surface scattering experiments have been performed on diatomic molecules, and little detailed information is available about how the structure of nonlinear polyatomic molecules influences the mechanisms for energy exchange with surfaces. In the current work, we employ a new rotationally resolved 1 + 1' resonance-enhanced multiphoton ionization (REMPI) scheme to measure the rotational distribution in formaldehyde molecules directly scattered from the Au(111) surface at incidence kinetic energies in the range 0.3-1.2 eV. The results indicate a pronounced propensity to excite a-axis rotation (twirling) rather than b- or c-axis rotation (tumbling or cartwheeling), and are consistent with a rotational rainbow scattering model. Classical trajectory calculations suggest that the effect arises-to zeroth order-from the three-dimensional shape of the molecule (steric effects). Analysis suggests that the high degree of rotational excitation has a substantial influence on the trapping probability of formaldehyde at incidence translational energies above 0.5 eV.

Nonreactive surface scattering of atoms, molecules and clusters can be almost universally described by two mechanisms: trapping-desorption and direct-scattering. A hard cube model with an attractive square well provides a zeroth order description of the branching ratio between these two mechanisms as a function of the incidence energy. However, the trapping process is likely to be enhanced by excitation of internal degrees of freedom during the collision. In this molecular beam surface scattering study, we characterize formaldehyde/Au(111) scattering using angle resolved time-of-flight techniques. The two mechanisms are found to compete in the range of the investigated normal incidence energies between 0.1 and 1.3 eV. Whereas at low incidence energies trapping-desorption dominates, direct-scattering becomes more likely at incidence energies above 0.37 eV. This incidence energy is slightly higher than the desorption energy which is found to be 0.32 ± 0.03 eV by temperature programmed desorption techniques. A simple hard cube model underestimates the observed trapping probabilities indicating the importance of trapping induced by excitation of internal molecular degrees of freedom.

Cluster of differentiation (CD) 44 and epidermal growth factor (EGF) are closely involved in cellular migration and have been used as stem cell markers. Although the hyaluronan (HA)‑binding CD44 is responsible for enhanced cellular motility, the mechanism underlying its actions in various cell types and clinical conditions have yet to be elucidated. In the present study, the multikinase inhibitor sorafenib was used to investigate the diverse effects of EGF stimulation on epithelial‑mesenchymal transition (EMT) in ovarian cancer cells using immunoblotting and reverse transcription‑polymerase chain reaction. In addition, the association between EGF and CD44/HA signaling pathways in the control of mesenchymal phenotype was determined by gene silencing with small interfering RNA transfection. EGF stimulation of ovarian cancer cells increased cellular migration, mesenchymal transition, CD44 expression and the activation of matrix metalloproteinase (MMP)‑2 and MMP‑9. Sorafenib effectively suppressed the loss of epithelial characteristics in EGF‑treated SK‑OV‑3 ovarian cancer cells, via targeting the mitogen‑activated protein kinase (MAPK)/extracellular signal‑regulated kinase (ERK) pathway. Although treatment of Caov‑3 ovarian cancer cells with sorafenib blocked the expression of mesenchymal phenotypes following EGF stimulation, EGF‑activated Caov‑3 cells exhibited reduced MAPK/ERK signaling. Furthermore, EGF‑activated Caov‑3 cells increased the expression of hyaluronan synthase 2 and HA‑CD44 ligation in EGF‑exposed Caov‑3 cells, which resulted in the activation of the Ras/Raf/MEK signaling pathway, amplification of migratory activity and the expression of mesenchymal markers, including N‑cadherin and vimentin. Furthermore, silencing EGFR in SK‑OV‑3 cells and CD44 in Caov‑3 cells suppressed their migratory activity, through inhibition of the MAPK/ERK pathway. The present results suggested that EGF‑mediated signaling may regulate metastasis and invasion of ovarian cancer cells, in a cancer cell type‑dependent manner.

The intermediate state dependence of photoelectron circular dichroism (PECD) in resonance-enhanced multi-photon ionization of fenchone in the gas phase is experimentally studied. By scanning the excitation wavelength from 359 to 431 nm, we simultaneously excite up to three electronically distinct resonances. In the PECD experiment performed with a broadband femtosecond laser, their respective contributions to the photoelectron spectrum can be resolved. High-resolution spectroscopy allows us to identify two of the resonances as belonging to the B- and C-bands, which involve excitation to states with 3s and 3p Rydberg character, respectively. We observe a sign change in the PECD signal, depending on which electronic state is used as an intermediate, and are able to identify two differently behaving contributions within the C-band. Scanning the laser wavelength reveals a decrease of PECD magnitude with increasing photoelectron energy for the 3s state. Combining the results of high-resolution spectroscopy and femtosecond experiment, the adiabatic ionization potential of fenchone is determined to be IP a Fen =(8.49±0.06) eV.

Epstein-Barr virus (EBV) infection is closely related to carcinogenesis of various cancers, and is also associated with the development of drug resistance in cancer stem cells. However, in EBV-positive cancer cells, the mechanistic details of the downstream signaling and the connection of PI3K with the NF-κB pathway for development of drug resistance remain controversial. Diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM) cells infected by EBV display drug resistance-related proteins (MDR1, MRP1 and MRP2) and stem cell markers (OCT4 and SOX2). EBV-infected HT (HT/EBV) and H929 (H929/EBV) cells activated p110δ expression, but downregulated the expression of p110α and p110β. A combination of CAL-101, a p110δ-specific inhibitor, with bortezomib treatment of HT/EBV cells synergistically suppressed proliferation, reduced levels of drug resistance-related proteins, activated caspase cleavage and recovered expression of p110α/p110β. Additionally, co-treatment with CAL-101 and bortezomib attenuated the expression of OCT4 and SOX2 via inhibition of activated NF-κB. Co-treatment with CAL-101 and bortezomib also attenuated drug resistance and NF-κB activity of EBV-infected H929 cells. Our results provide supportive evidence for the clinical application of CAL-101 and bortezomib to treat EBV-infected hematologic cancer.

The expression of different toll-like receptors (TLRs) on tumor cells has been associated with disease aggressiveness, treatment resistance, and poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered critical for cancer cell survival and proliferation. Thus, we investigated the effect of TLR-stimulated PI3K activation on the epithelial-to-mesenchymal transition (EMT) of primary (Caov-3) and metastatic (SK‑OV‑3) epithelial ovarian cancer cell lines in this study. TLR engagement with various ligands promoted the expression of class IA PI3K (p110α, p110β, and p110δ) and increased the expression of mesenchymal markers (N-cadherin, Slug, Vimentin, Snail, α-SMA, and TCF) in SK‑OV‑3 cells. The migratory activity and secretion of EMT-related cytokines of SK‑OV‑3 were significantly higher compared to those of Caov-3 after activation with TLR agonist. Although the invasive capacity and production of EMT-related cytokines of LPS-stimulated SK‑OV‑3 cells were significantly suppressed by all pharmacological inhibitors of the p110 isoform, the Syk/Src-dependent p110β isoform prominently attenuated migration activity. In contrast, the production of IL-10 and galectin-1 was mainly affected by the p110δ isoform. Gene silencing of TLR4 and galectin-1 with siRNA decreased the expression of matrix metalloproteinase-2 (MMP2) and MMP9 and reduced mesenchymal markers in LPS-treated SK‑OV‑3 cells. This study demonstrated that TLR-mediated PI3K activation modulated the invasion and metastasis of ovarian cancer through the production of galectin-1, suggesting that inhibition of the p110 isoform is a promising therapeutic approach against metastatic ovarian cancer.

The extracellular signals induced by vascular endothelial growth factor (VEGF) are implicated in choroidal neovascularization (CNV) and thus, are associated with vision-limiting complications in the human retina. Vandetanib is an oral anticancer drug that selectively inhibits the activities of VEGF receptor and epidermal growth factor receptor tyrosine kinase; however, the effects of vandetanib on VEGF in retinal pigment epithelial (RPE) cells have not yet been studied. In the present study, a combined treatment of vandetanib and a disintegrin and metalloproteinase (ADAM) protein inhibitors were used to assess the regulation of Epstein-Barr virus (EBV)-infected ARPE19 cells (ARPE19/EBV) migration as a model of CNV. Vandetanib suppressed the expression of the mesenchymal markers ADAM10 and ADAM17 in ARPE19/EBV cells, and also upregulated epithelial cell markers of the RPE cells, E-cadherin and N-cadherin. The migratory activity of ARPE19/EBV induced by VEGF was efficiently blocked by vandetanib. Furthermore, co-treatment with vandetanib and an ADAM10 inhibitor (GI254023X) or ADAM17 inhibitor (Marimastat) synergistically prevented migration and the expression of vimentin, Snail and α-smooth muscle actin by regulating extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. These results suggest that a combination treatment of vandetanib and ADAM inhibitors may be developed as a novel therapeutic regimen to control retina neovascular disease.

Aim: To investigate the molecular mechanisms by which long-term exposure to cigarette smoke extract (CSE) contributes to ovarian cancer metastasis., Materials and Methods: Western blot analysis for diverse p110 isoforms of phosphoinositide 3-kinase (PI3K)-related signaling pathway and epithelial-mesenchymal transition (EMT) markers was performed to analyze the underlying mechanisms. Migratory activity of CSE-exposed ovarian cancer cells was determined by transendothelial migration and invasion assay., Results: After exposure to CSE for four weeks, CaOV3 (primary) and SKOV3 (metastatic) ovarian cancer cells showed enhanced mesenchymal characteristics and produced EMT-related cytokines [intwerleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and transforming growth factor-beta 1 (TGF-β1)]. CSE exposure activated the Src-p110δ-p21 protein-activated kinase 1 (PAK1) in CaOV3 cells and the Lyn-p110β-Rho-associated kinases 1/2 (ROCK1/2) in SKOV3 cells, which led to the stimulation of LIM kinase 1 (LIMK1) phosphorylation and TGF-β1 release. LIMK1 knockdown efficiently blocked the migratory activity and suppressed the mesenchymal phenotypes of CSE-treated ovarian cancer cells. Reactive oxygen species (ROS) initiated the CSE-mediated EMT processes in ovarian cancer cells., Conclusion: Characterization of the p110 isotypes of PI3K is critical for regulating cancer metastasis; LIMK1 could be a common therapeutic target of ovarian cancer metastasis., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cancer cell resistance to chemotherapy is associated with a poor prognosis. The compound 2-deoxy-D-glucose (2-DG) enhances the effect of chemotherapy against cancer cells lines in vitro and in vivo. However, its effect on the epithelial to mesenchymal transition (EMT) in drug-resistant cancer cells has not been fully elucidated. In this study, we investigated whether treatment of 5-fluorouracil or oxaliplatin-resistant colorectal cancer (CRC) cells with 2-DG suppressed their migratory activity and enhanced their susceptibility to chemotherapy. Chemoresistant CRC cells stably expressed drug resistance-related proteins (MDR1, MRP1, MRP2, and MRP3) and showed mesenchymal characteristics and a migratory phenotype. 2-DG treatment attenuated glycolysis-related enzyme expression, invasion activity, and EMT-related cytokine secretion in drug-resistant CRC cells. In addition, 2-DG inhibited the activation of a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17. Gene silencing of ADAM10 and ADAM17 with small interfering RNA downregulated mesenchymal properties, reduced EMT-associated cytokine secretion, and rendered chemoresistant cells susceptible to anticancer drug treatment. Collectively, these findings suggest that increased glycolytic metabolism in drug-resistant cells has an effect on both migratory activity and cell viability through the activation of ADAM10 and ADAM17.

Toll-like receptor 4 (TLR4) activation is a key contributor to the carcinogenesis of colon cancer. Overexpression of galectin-1 (Gal-1) also correlates with increased invasive activity of colorectal cancer. Lactate production is a critical predictive factor of risk of metastasis, but the functional relationship between intracellular lactate and Gal-1 expression in TLR4-activated colon cancer remains unknown. In this study, we investigated the underlying mechanism and role of Gal-1 in metastasis and invasion of colorectal cancer (CRC) cells after TLR4 stimulation. Exposure to the TLR4 ligand lipopolysaccharide (LPS) increased expression of Gal-1, induced EMT-related cytokines, triggered the activation of glycolysis-related enzymes, and promoted lactate production. Gene silencing of TLR4 and Gal-1 in CRC cells inhibited lactate-mediated epithelial-mesenchymal transition (EMT) after TLR4 stimulation. Gal-1-mediated activation of a disintegrin and metalloproteinase 10 (ADAM10) and ADAM 17 increased the invasion activity and expression of mesenchymal characteristics in LPS-activated CRC cells. Conversely, inhibition of ADAM10 or ADAM17 effectively blocked the generation of lactate and the migration capacity of LPS-treated CRC cells. Thus, the TLR4/Gal-1 signaling pathway regulates lactate-mediated EMT processes through the activation of ADAM10 and ADAM17 in CRC cells.

Glycogen synthase kinase-3β (GSK-3β) in cancer cells is a critical regulatory component of both cellular metabolism and epithelial-mesenchymal transition (EMT) processes via regulation of the β-catenin/E-cadherin and phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Lipogenesis of cancer cells also plays a critical role in survival and metastasis. We investigated the role of GSK-3β-mediated intracellular fatty acid synthesis to control EMT in TLR4-activated colorectal cancer cells and the underlying regulatory mechanism. Engagement of TLR4 with lipopolysaccharide (LPS) in colon cancer cells promoted the induction of phosphorylated GSK-3β and related lipogenic enzymes as well as the expression of CD74, CD44 and macrophage inhibitory factor (MIF), but decreased expression of transcriptionally active p63 (TAp63). In addition, targeted inhibition of GSK-3β using SB216763 was accompanied by decreased intracellular fatty acid synthesis and blockage of CD74 and CD44 expression, whereas it reversed the level of TAp63. Although TAp63 overexpression had no effect on the expression of CD74 and CD44 in LPS-treated colon cancer cells, GSK-3β-dependent fatty acid synthesis and invasive activity were significantly suppressed. Notably, inhibition of CD44 or CD74 by siRNA not only attenuated de novo lipogenesis and migratory activity but also restored the expression of TAp63 in LPS-activated colon cancer cells. These results suggest that TAp63-mediated GSK-3β activation induced by TLR4 stimulation triggers migration and invasion of colon cancer cells through the regulation of lipid synthesis and GSK-3β-mediated CD74/CD44 expression could be a target to control fatty acid-related EMT process through the modulation of TAp63 expression.

The formaldehyde molecule is an important model system for understanding dynamical processes in small polyatomic molecules. However, prior to this work, there have been no reports of a resonance-enhanced multiphoton ionization (REMPI) detection scheme for formaldehyde suitable for rovibrationally state-selective detection in molecular beam scattering experiments. Previously reported tunable REMPI schemes are either non-rotationally resolved, involve multiple resonant steps, or involve many-photon ionization steps. In the current work, we present a new 1 + 1' REMPI scheme for formaldehyde. The first photon is tunable and provides rotational resolution via the vibronically allowed à (1)A2 ← X[combining tilde] (1)A1 transition. Molecules are then directly ionized from the à state by one photon of 157 nm. The results indicate that the ionization cross section from the 4(1) vibrational level of the à state is independent of the rotational level used as intermediate, to within experimental uncertainty. The 1 + 1' REMPI intensities are therefore directly proportional to the à ← X[combining tilde] absorption intensities and can be used for quantitative measurement of X[combining tilde]-state population distributions.

Berberine exhibits antiproliferative or cytotoxic effects against various cancers. ROS and wild-type p53 play a critical role in berberine-induced cytotoxic effects. In this study, we investigated the correlation between XAF1 and functional p53 in EBV-transformed B cells or cancerous B cells after treatment with berberine. Berberine decreased cell viability and induced apoptosis through a mitochondria-dependent pathway in EBV-transformed B cells and cancerous B cells, but not in normal peripheral blood mononuclear cells. Activated p53 and its downstream targets XAF1 and GADD45α interacted with PUMA, Bax, and Bim in mitochondria after treatment with berberine. Blocking phosphorylation of p38/JNK MAPK and treatment with PFT-α, a selective p53 inhibitor, effectively prevented apoptosis and the upregulation of phosphorylated p53, XAF1, and GADD45α. NAC, a ROS scavenger, also suppressed berberine-induced mitochondria disruption and the whole apoptotic process via restoration of p53-related proteins and proapoptotic Bcl-2 family proteins. Taken together, our results suggest that ROS generation might be a predisposing event in berberine-induced mitochondrial apoptosis in EBV-transformed B cells through the upregulation of XAF1 and GADD45α expression by MAPK and functional p53.

Objective: To explore whether memantine, an N-methyl-D-aspartate receptor antagonist, exerts a neuroprotective effect against apoptosis of spiral ganglion cells (SGCs) induced by gentamicin., Study Design: An animal experiment., Setting: Dong-A University College of Medicine, Busan, Korea., Subjects and Methods: Gentamicin was injected into the left cochleae of guinea pigs to induce apoptosis of SGCs; the contralateral cochleae served as controls. Memantine was intraperitoneally injected 12 hours and 1 hour prior to gentamicin injection. At 1 week after gentamicin and/or memantine injection, the cochleae were removed and stained with hematoxylin and eosin to evaluate morphologic changes and apoptosis. Western blotting was performed to measure FasL expression and the extent of caspase activation in SGCs., Results: SGC numbers remained stable after memantine treatment. Western blotting showed that FasL expression and activation of caspases 3, 8, and 9 were reduced in SGCs after memantine treatment., Conclusion: Memantine attenuated the gentamicin-induced apoptosis of SGCs in guinea pigs. Moreover, memantine may affect Fas-FasL signaling in the receptor-mediated apoptotic pathway and caspase activation involved in the receptor-mediated and mitochondrial apoptotic pathways., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Since its invention in 2006, the broadband chirped pulse Fourier transform spectrometer has transformed the field of microwave spectroscopy. The technique enables the collection of a ≥10 GHz bandwidth spectrum in a single shot of the spectrometer, which allows broadband, high-resolution microwave spectra to be acquired several orders of magnitude faster than what was previously possible. We discuss the advantages and challenges associated with the technique and look back on the first ten years of chirped pulse Fourier transform spectroscopy. In addition to enabling faster-than-ever structure determination of increasingly complex species, the technique has given rise to an assortment of entirely new classes of experiments, ranging from chiral sensing by three-wave mixing to microwave detection of multichannel reaction kinetics. However, this is only the beginning. Future generations of microwave experiments will make increasingly creative use of frequency-agile pulse sequences for the coherent manipulation and interrogation of molecular dynamics.

Formaldehyde is the smallest stable organic molecule containing the carbonyl functional group and is commonly considered to be a prototype for the study of high-resolution spectroscopy of polyatomic molecules. The a-axis Coriolis interaction between the near-degenerate ν4 and ν6 (out-of-plane and in-plane wagging modes, respectively) of the ground electronic state has received extensive attention and is thoroughly understood. In the first excited singlet Ã (1)A2 electronic state, the analogous Coriolis interaction does not occur, because the à state suffers from a pseudo-Jahn-Teller distortion, which causes a double-well potential energy structure in the q4 (') out-of-plane coordinate, and which dramatically reduces the effective ν4 (') frequency. The ν4 (') frequency is reduced by such a great extent in the à state that it is the 3ν4 (') overtone which is near degenerate with ν6 ('). In the current work, we report the precise ν6 (') fundamental frequency in the à state, and we determine the strength of the a-axis Coriolis interaction between 3ν4 (') and ν6 ('). We also provide a rotational analysis of the ν4 (')+ν6 (') combination band, which interacts with 3ν4 (') via an additional c-axis Coriolis perturbation, and which allows us to provide a complete deperturbed fit to the 3ν4 (') rotational structure. Knowledge of the Coriolis interaction strengths among the lowest-lying levels in the à state will aid the interpretation of the spectroscopy and dynamics of many higher-lying band structures, which are perturbed by analogous interactions.