Impacts of hot electron diffusion, electron-phonon coupling, and surface atoms on metal surface dynamics revealed by reflection ultrafast electron diffraction.

Metals exhibit nonequilibrium electron and lattice subsystems at transient times following femtosecond laser excitation. In the past four decades, various optical spectroscopy and time-resolved diffraction methods have been used to study electron-phonon coupling and the effects of underlying dynamical processes. Here, we take advantage of the surface specificity of reflection ultrafast electron diffraction (UED) to examine the structural dynamics of photoexcited metal surfaces, which are apparently slower in recovery than predicted by thermal diffusion from the profile of absorbed energy. Fast diffusion of hot electrons is found to critically reduce surface excitation and affect the temporal dependence of the increased atomic motions on not only the ultrashort but also sub-nanosecond times. Whereas the two-temperature model with the accepted physical constants of platinum can reproduce the observed surface lattice dynamics, gold is found to exhibit appreciably larger-than-expected dynamic vibrational amplitudes of surface atoms while keeping the commonly used electron-phonon coupling constant. Such surface behavioral difference at transient times can be understood in the context of the different strengths of binding to surface atoms for the two metals. In addition, with the quantitative agreements between diffraction and theoretical results, we provide convincing evidence that surface structural dynamics can be reliably obtained by reflection UED even in the presence of laser-induced transient electric fields.

PSPC1 Inhibition Synergizes with Poly(ADP-ribose) Polymerase Inhibitors in a Preclinical Model of BRCA-Mutated Breast/Ovarian Cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against BRCA1/2-mutated cancers through synthetic lethality. Unfortunately, most cases ultimately develop acquired resistance. Therefore, enhancing PARP inhibitor sensitivity and preventing resistance in those cells are an unmet clinical need. Here, we investigated the ability of paraspeckle component 1 (PSPC1), as an additional synthetic lethal partner with BRCA1/2, to enhance olaparib sensitivity in preclinical models of BRCA1/2-mutated breast and ovarian cancers. In vitro, the combined olaparib and PSPC1 small interfering RNA (siRNA) exhibited synergistic anti-proliferative activity in BRCA1/2-mutated breast and ovarian cancer cells. The combination therapy also demonstrated synergistic tumor inhibition in a xenograft mouse model. Mechanistically, olaparib monotherapy increased the expressions of p-ATM and DNA-PKcs, suggesting the activation of a DNA repair pathway, whereas combining PSPC1 siRNA with olaparib decreased the expressions of p-ATM and DNA-PKcs again. As such, the combination increased the formation of γH2AX foci, indicating stronger DNA double-strand breaks. Subsequently, these DNA-damaged cells escaped G2/M checkpoint activation, as indicated by the suppression of p-cdc25C (Ser216) and p-cdc2 (Tyr15) after combination treatment. Finally, these cells entered mitosis, which induced increased apoptosis. Thus, this proves that PSPC1 inhibition enhances olaparib sensitivity by targeting DNA damage response in our preclinical model. The combination of olaparib and PSPC1 inhibition merits further clinical investigation to enhance PARP inhibitor efficacy.

Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer.

Epithelial ovarian cancer remains the leading cause of mortality among all gynecologic malignancies owing to recurrence and ultimate development of chemotherapy resistance in the majority of patients. In the chemotherapy-resistant ovarian cancer preclinical model, we investigated whether AZD6738 (an ataxia telangiectasia and Rad3-related (ATR) inhibitor) could synergize with belotecan (a camptothecin analog and topoisomerase I inhibitor). In vitro, both chemotherapy-resistant and chemotherapy-sensitive ovarian cancer cell lines showed synergistic anti-proliferative activity with a combination treatment of belotecan and AZD6738. The combination also demonstrated synergistic tumor inhibition in mice with a chemotherapy-resistant cell line xenograft. Mechanistically, belotecan, a DNA-damaging agent, increased phospho-ATR (pATR) and phospho-Chk1 (pChk1) in consecutive order, indicating the activation of the DNA repair system. This consequently induced G2/M arrest in the cell cycle analysis. However, when AZD6738 was added to belotecan, pATR and pChk1 induced by belotecan alone were suppressed again. A cell cycle analysis in betotecan showed a sub-G1 increase as well as a G2/M decrease, representing the release of G2/M arrest and the induction of apoptosis. In ascites-derived primary cancer cells from both chemotherapy-sensitive and -resistant ovarian cancer patients, this combination was also synergistic, providing further support for our hypothesis. The combined administration of ATR inhibitor and belotecan proved to be synergistic in our preclinical model. This combination warrants further investigation in a clinical trial, with a particular aim of overcoming chemotherapy resistance in ovarian cancer.

Structures of self-assembled n-alkanethiols on gold by reflection high-energy electron diffraction.

The structures of long-chain alkanethiols (C18H37SH) chemisorbed on an Au(111) single crystal were investigated using reflection high-energy electron diffraction (RHEED). The primary structure observed as a major species in the as-deposited films contains gold adatoms below the sulfur headgroups. Between the small ordered domains with the alkyl chains tilting toward six directions are azimuthally disorderly packed regions, with a similar average tilt of 30.2°. In contrast, a significant reduction in the coverage of gold adatoms is found in the thermally-induced phase. This superlattice is shown to contain a mixture of two sulfur arrangements, both of which exhibit a small S-S distance, and the pairing of the aliphatic chains. A microscopic picture is then given for the structural transition. These findings demonstrate how the RHEED technique may be used to resolve structures of nanometer-thick thin films with multiple orders at the interfaces.

The Effects of Aronia melanocarpa 'Viking' Extracts in Attenuating RANKL-Induced Osteoclastic Differentiation by Inhibiting ROS Generation and c-FOS/NFATc1 Signaling.

This study aimed to determine the anti-osteoclastogenic effects of extracts from Aronia melanocarpa 'Viking' (AM) and identify the underlying mechanisms in vitro. Reactive oxygen species (ROS) are signal mediators in osteoclast differentiation. AM extracts inhibited ROS production in RAW 264.7 cells in a dose-dependent manner and exhibited strong radical scavenging activity. The extracts also attenuated the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts. To attain molecular insights, the effect of the extracts on the signaling pathways induced by receptor activator of nuclear factor kappa B ligand (RANKL) were also investigated. RANKL triggers many transcription factors through the activation of mitogen-activated protein kinase (MAPK) and ROS, leading to the induction of osteoclast-specific genes. The extracts significantly suppressed RANKL-induced activation of MAPKs, such as extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38 and consequently led to the downregulation of c-Fos and nuclear factor of activated T cells 1 (NFATc1) protein expression which ultimately suppress the activation of the osteoclast-specific genes, cathepsin K, TRAP, calcitonin receptor and integrin ß3. In conclusion, our findings suggest that AM extracts inhibited RANKL-induced osteoclast differentiation by downregulating ROS generation and inactivating JNK/ERK/p38, nuclear factor kappa B (NF-κB)-mediated c-Fos and NFATc1 signaling pathway.

Therapeutic artifact: Case series.

Artifacts are pervasive in every realm of biological science, and this includes the field of medicine. Unless explicitly recognized by scientific experts, artifacts can be found and may influence research and findings in the medical domain, just as they do in other branches of biological science. Therapeutic artifacts are changes that occur in the body as a result of medical interventions. These artifacts can sometimes pose challenges in forensic investigations, as they may be misinterpreted or mistaken for signs of trauma or foul play. This case series presents three cases illustrating different types of treatment artifacts encountered in forensic medicine. These three cases highlight the importance of considering medical interventions and therapies when interpreting autopsy findings. It is crucial for forensic experts to have a comprehensive understanding of therapeutic artifacts to accurately differentiate them from genuine injuries or pathologies. By recognizing and properly interpreting these artifacts, forensic investigations can be conducted with increased accuracy and ensure that justice is served.

Biosynthesis of JC-La2CoO4 magnetic nanoparticles explored in catalytic and SMMs properties.

We have reported the synthesis of JC-La2CoO4 magnetic nanoparticles from Jatropha Curcas L. leaf extract in aqueous medium and potential application study in catalytic & Single Molecule Magnets (SMMs). Several techniques were used to investigate the structural, morphological, and elemental composition, particle size, optical properties, catalytic and magnetic properties by XRD, FTIR, SEM, EDAX, XPS, UV-visible and squid magnetic measurement. It was found that the crystallite sizes and grain sizes of JC-La2CoO4 NPs were 11.3 ± 1 and 24.1 ± 1 nm respectively and surface morphology of the nanoparticles looks spherical shape with good surface area. The band gap of JC-La2CoO4 was found to be 4.95 eV indicates good semiconductor in nature. XPS studies shows that La and Co present in + 3 and + 2 oxidation state respectively and suggest the composition formula is La2CoO4 with satisfied all the valency of metal ions. The photocatalytic efficiency of La2CoO4 shows good result against methylene blue (MB) compared to other dyes like MO, NO, RhB in presence of sunlight with rate constant 56.73 × 10-3 min-1 and completely degraded within 115 mints. The importance of JC-La2CoO4 has magnetic properties with antiferromagnetic coupling and SMMs properties with nature.

Preclinical Platform Using a Triple-negative Breast Cancer Syngeneic Murine Model to Evaluate Immune Checkpoint Inhibitors.

BACKGROUND/AIM: To evaluate the feasibility of syngeneic mouse models of breast cancer by analyzing the efficacy of immune checkpoint inhibitors (ICIs) and potential predictive biomarkers. MATERIALS AND METHODS: To establish the murine triple-negative breast cancer (TNBC) models, JC, 4T1, EMT6, and E0771 cells were subcutaneously implanted into female syngeneic mice. When the tumor reached 50-100 mm3, each mouse model was divided into a treatment (using a murine PD-1 antibody) and a no-treatment control group. The treatment group was further divided into the responder and non-responder groups. Potential predictive biomarkers were evaluated by analyzing serum cytokines, peripheral blood T cells and tumor infiltrating immune cells. RESULTS: The EMT6 model showed the highest tumor response rate (54%, 6/11) of the syngeneic models: 4T1 (45%, 5/11), JC (40%, 4/10), or E0771 (23%, 3/13). Early changes in tumor size at 7 days post-PD-1 inhibitor treatment predicted the final efficacy of the PD-1 inhibitor. Peripheral blood CD8+ and CD4+ T cells with or without Ki67 expression at 7 days post-PD-1 inhibitor treatment were higher in the finally designated responder group than in the non-responder group. At the time of sacrifice, analyses of tumor infiltrating lymphocytes consistently supported these results. We also demonstrated that retro-orbital blood sampling procedures (baseline, 7 days post-treatment, time of sacrifice) were safe for serum cytokine analyses, suggesting that our preclinical platform may be used for biomarker research using serum cytokines. CONCLUSION: Our syngeneic mouse model of TNBC is a feasible preclinical platform to evaluate ICI efficacy combined with other drugs and predictive biomarkers in the screening process of immune-oncology drug development.

Combined PI3K Inhibitor and Eribulin Enhances Anti-Tumor Activity in Preclinical Models of Paclitaxel-Resistant, PIK3CA-Mutated Endometrial Cancer.

Endometrial cancer stands as the predominant gynecological malignancy in developed nations. For advanced or recurrent disease, paclitaxel-based chemotherapy is the standard front-line therapy. However, paclitaxel resistance eternally develops. Based on the high prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a phosphatidylinositol 3-kinase (PI3K) inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. We generated paclitaxel-resistant cell lines from PIK3CA-mutated endometrial cancer cell lines by gradually increasing the concentration of paclitaxel in cell cultures. We observed that the PI3K/AKT and epithelial-mesenchymal transition (EMT) pathways in paclitaxel-resistant cells were significantly upregulated compared with those in parental cells. Then, we demonstrated that the combination of alpelisib (a PI3K inhibitor) and eribulin more effectively suppressed the cellular growth of paclitaxel-resistant cells in in vitro and in vivo xenograft models. Mechanistically, we demonstrated that the effect of the combination could be enhanced by inhibiting both the PI3K/AKT and EMT pathways. Therefore, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation.

Targeting PEG10 as a novel therapeutic approach to overcome CDK4/6 inhibitor resistance in breast cancer.

BACKGROUND: Breast cancer is the global leading cancer burden in women and the hormone receptor-positive (HR+) subtype is a major part of breast cancer. Though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are highly effective therapy for HR+ subtype, acquired resistance is inevitable in most cases. Herein, we investigated the paternally expressed gene 10 (PEG10)-associated mechanism of acquired resistance to CDK4/6 inhibitors. METHODS: Palbociclib-resistant cells were generated by exposing human HR+ breast cancer cell lines to palbociclib for 7-9 months. In vitro mechanistic study and in vivo xenograft assay were performed. For clinical relevance, public mRNA microarray data sets of early breast cancer were analyzed and PEG10 immunohistochemical staining was performed using pre-CDK4/6 inhibitor tumor samples. RESULTS: We observed that PEG10 was significantly upregulated in palbociclib-resistant cells. Ectopic overexpression of PEG10 in parental cells caused CDK4/6 inhibitor resistance and enhanced epithelial-mesenchymal transition (EMT). On the contrary, PEG10-targeting siRNA or antisense oligonucleotides (ASOs) combined with palbociclib synergistically inhibited proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice and suppressed EMT as well. The mechanistic study confirmed that high PEG10 expression suppressed p21, a natural CDK inhibitor, and SIAH1, a post-translational degrader of ZEB1, augmenting CDK4/6 inhibitor resistance. Then PEG10 siRNA combined with palbociclib suppressed cell cycle progression and EMT via activating p21 and SIAH1, respectively. Consequently, combined PEG10 inhibition and palbociclib overcame CDK4/6 inhibitor resistance. Furthermore, high PEG10 expression was significantly associated with a shorter recurrence-free survival (RFS) based on public mRNA expression data. In pre-CDK4/6 inhibitor treatment tissues, PEG10 positivity by IHC also showed a trend toward a shorter progression-free survival (PFS) with CDK4/6 inhibitor. These results support clinical relevance of PEG10 as a therapeutic target. CONCLUSIONS: We demonstrated a novel PEG10-associated mechanism of CDK4/6 inhibitor resistance. We propose PEG10 as a promising therapeutic target for overcoming PEG10-associated resistance to CDK4/6 inhibitors.

Tuning the semimetallic charge transport in the Weyl semimetal candidate Eu2Ir2O7(111) epitaxial thin film with an all-in-all-out spin structure.

We report the stoichiometric epitaxial growth of the Eu2Ir2O7(111) thin film on YSZ substrate by a two-step solid phase epitaxy (SPE) method. An optimized post-annealing environment of the SPE was superior over the conventional air annealing procedure to get rid of the typical impurity phase, Eu2O3. The thickness-dependent structural study on Eu2Ir2O7(111) thin films suggests a systematic control of Ir/Eu stoichiometry in our films, which is otherwise difficult to achieve. In addition, the low-temperature electrical resistivity studies strongly support the claim. The power-law dependence analysis of the resistivity data exhibits a power exponent of 0.52 in 50 nm sample suggesting possible disorder-driven semimetallic charge transport in the 3D Weyl semimetallic (WSM) candidate Eu2Ir2O7. In addition, the all-in-all-out/all-out-all-in antiferromagnetic domains of Ir4+sublattice is verified using the field cooled magnetoresistance measurements at 2 K. Hall resistivity analysis indicate semimetallic hole carrier type dominance near the Fermi level up to the measured temperature range of 2-120 K. Altogether, our study reveals the ground state of stoichiometric Eu2Ir2O7(111) thin film, with an indirect tuning of the off-stoichiometry using thickness of the samples, which is of interest in the search of the predicted 3D WSM phase.

Single Molecule Magnets of Co2 and Co2La MOFs Synthesized by New Schiff Base Ligand N,N'-bis(o-Vanillinidene) Ethylenediamine (o-VEDH2).

Schiff base ligand N,N'-bis(o-vanillinidene) ethylenediamine (o-VEDH2) has been employed to synthesize new [CoIICoIV(o-VED)(OAc)2(µ2-OAc)(OMe)]•MeOH (1) and [ Co 2 IV (o-VED)2(en)2(NCCH3)(OCH3)][La(NO3)6]( NO 3 - )•2MeOH•MeCN•H2O (2) metal-organic frameworks (MOFs) that have interesting single molecule magnets (SMMs) property. The synthesized complexes are characterized by single crystal X-ray diffraction, fourier transform infrared spectroscopy (FTIR), UV-visible spectroscopy, and squid magnetic measurement. Single crystal X-ray data show that both complexes crystallize in the monoclinic crystal system with P21/c(14) and P21/n(14) space groups and generate unique MOF-like structures. Overall, both the metal centers of 1 form octahedral geometry with a butterfly core structure. Variable temperature (T) and field (H) solid-state direct-current (dc) and alternative current (ac) magnetic susceptibility measurements were performed on both the complexes over 1.8 to 300 K, which exhibited a ground state spins (S) of 4 and 5 of complexes 1 and 2, respectively. The AC out-phase and in-phase properties of complexes show SMMs. Other properties such as optical, sensing, and DNA-binding interactions were also investigated by the complexes. Complexes 1 and 2 have energy band gaps of 3.7 and 3.03 eV indicating semiconductor properties. Simultaneously, complex 1 was found to sense H2O2 with a rate constant (k) = 1.59 × 10-4 s-1, whereas complex 2 was found to bind with calf-thymus-DNA by intercalation mode with binding constant (K b ) of 1.22 × 105 M-1.

Green synthesis of copper nanoparticles from an extract of Jatropha curcas leaves: characterization, optical properties, CT-DNA binding and photocatalytic activity.

The green synthesis of copper nanoparticles (CuNPs) using a leaf extract from Jatropha curcas (JC) has been documented in our present research work. The existence of flavonoids, tannins, glycosides, and alkaloids was confirmed by the phytochemical analysis of the plant extract and these chemicals can be used as reducing, stabilizing and capping agents. After six months, the JC-CuNPs were found to be stable without any evidence of agglomeration. The JC-CuNPs were characterised by XRD, FT-IR, SEM, TEM and UV-vis spectrophotometry. The average particle and crystal sizes of the JC-CuNPs were found to be 10 ± 1 and 12 ± 1 nm, respectively. The SPR peaks were found at 266 and 337 nm, measured using electronic spectroscopy, and the calculated optical band gap was found to be 3.6 eV at 337 nm, indicating the semiconductor behaviour of the JC-CuNPs. JC-CuNPs have potential photocatalytic activity against methylene blue (MB) compared with other dyes in the presence of sunlight and the rate constant (k) value is 2.30 × 10-4 s-1. The JC-CuNPs also have a binding property with CT-DNA through an intercalation mode and the binding constant (K b) is 1.024 × 102 M-1.

New Dual-Functional and Reusable Bimetallic Y2ZnO4 Nanocatalyst for Organic Transformation under Microwave/Green Conditions.

A novel bimetallic and reusable Y2ZnO4 nanocatalyst was synthesized by a simple coprecipitation method. The prepared nanocatalyst exhibited dual catalytic activity and was characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), energy-dispersive X-ray spectroscopy (EDX), and scanning electron microscopy (SEM). The average crystallite and grain sizes were found to be 17 ± 1 and 10 ± 2 nm, respectively. On the one hand, the catalytic activity of the nanocatalyst was studied for the Knoevenagel condensation reaction of aromatic aldehydes with active methylene compounds, such as ethyl cyanoacetate and malononitrile, under microwave irradiation and solvent-free conditions. On the other hand, the nanoparticles also showed faster photocatalytic activity against methyl orange (MO) compared to other dyes. The nanocatalyst was easily recoverable by a simple filtration method and was recycled without any significant loss of catalytic activity. The advantages of this nanocatalyst were a simple workup procedure, high reaction yields, solvent-free conditions, reusability, and a short reaction time under green reaction conditions.

Synthesis of Two Mononuclear Schiff Base Metal (M = Fe, Cu) Complexes: MOF Structure, Dye Degradation, H2O2 Sensing, and DNA Binding Property.

O-Vanillin and ethylenediamine were used for the synthesis of N,N'-bis(O-vanillinidene)ethylenediamine (O-VEDH2) Schiff base ligand, which was characterized by UV-visible and 1H NMR spectroscopy. The Schiff base ligand O-VEDH2 has been employed to synthesize novel [C18H22FeN2O6]NO3 (1) and C18H16CuN2O5 (2) complexes by the simple slow evaporation method. The single crystals were characterized by X-ray crystallography, as well as Fourier-transform infrared and UV-visible spectroscopy techniques. Complexes 1 and 2 crystallize in monoclinic and orthorhombic space groups with P121/n1 (14) and Pnma (62) point groups, respectively, and both show metal-organic frameworks like structures. Complexes 1 and 2 have optical band gaps of 4.1 and 2.9 eV, respectively, indicating their semiconducting properties. The dye degradation activity and H2O2 sensing of the complexes 1 and 2 were determined in different conditions. The photocatalytic test was performed in the presence of sunlight, methylene blue (MB), and complexes 1 and 2. An interesting result was obtained that complex 2 has degradation ability against MB and the rate constant (K) is 5.46 × 10-5 s-1, whereas complex 1 has H2O2 sensing properties. Both complexes are bound to Calf-thymus DNA by intercalation binding mode, and binding constants (K b) of complexes 1 and 2 are 3.77 × 103 and 1.49 × 104 M-1, respectively.