Constituents, Antibacterial Adhesion, Cytotoxic and in Vitro Metastasis Blocking Properties of Salvia fruticosa Essential Oils from Three Palestinian Localities.

Essential oils (EOs) of Salvia fruticosa Mill. gathered from three Palestinian localities were studied to determine their constituents, antibacterial adhesion impact against Klebsiella pneumonia, cytotoxicity, and their function in cancer cell migration. Gas chromatography-mass spectrometry identified the chemical components, while the MTT technique was used to measure the EOs' cytotoxicity against HeLa (cervical) and Caco-2 (colorectal) cancer cells. Antibacterial adhesion was assessed by examining Klebsiella pneumoniae's ability to adhere to Caco-2 cells. Our study found that eucalyptol was present as the main constituent in all S. fruticosa EOs. In addition, K. pneumoniae adhesion and metastasis were reduced after 48 h of application. Salfit's and Hebron's EOs had the most potent cytotoxic effects on Caco-2 and HeLa, with IC50 values in the range of 0.7-1.3 µg/mL. Taking into account the obtained results, it may be concluded that S. fruticosa EOs can serve as potential disinfectant agents for the treatment and prevention of K. pneumoniae-associated illness and cancer.

Exploration of isoxazole analogs: Synthesis, COX inhibition, anticancer screening, 3D multicellular tumor spheroids, and molecular modeling.

In this study, a new series of Isoxazole-carboxamide derivatives were synthesized and characterized via HRMS, 1H-, 13CAPT-NMR, and MicroED. The findings revealed that nearly all of the synthesized derivatives exhibited potent inhibitory activities against both COX enzymes, with IC50 values ranging from 4.1 nM to 3.87 µM. Specifically, MYM1 demonstrated the highest efficacy among the compounds tested against the COX-1, displaying an IC50 value of 4.1 nM. The results showed that 5 compounds possess high COX-2 isozyme inhibitory effects with IC50 value in range 0.24-1.30 µM with COX-2 selectivity indexes (2.51-6.13), among these compounds MYM4 has the lowest IC50 value against COX-2, with selectivity index around 4. Intriguingly, this compound displayed significant antiproliferative effects against CaCo-2, Hep3B, and HeLa cancer cell lines, with IC50 values of 10.22, 4.84, and 1.57 µM, respectively, which was nearly comparable to that of doxorubicin. Compound MYM4 showed low cytotoxic activities on normal cell lines LX-2 and Hek293t with IC50 values 20.01 and 216.97 µM respectively, with safer values than doxorubicin. Furthermore, compound MYM4 was able to induce the apoptosis, suppress the colonization of both HeLa and HepG2 cells. Additionally, the induction of Reactive oxygen species (ROS) production could be the mechanism underlying the apoptotic effect and the cytotoxic activity of the compound. In the 3D multicellular tumor spheroid model, results revealed that MYM4 compound hampered the spheroid formation capacity of Hep3B and HeLa cancer cells. Moreover, the molecular docking of MYM4 compound revealed a high affinity for the COX2 enzyme, with energy scores (S) -7.45 kcal/mol, which were comparable to celecoxib (S) -8.40 kcal/mol. Collectively, these findings position MYM4 as a promising pharmacological candidate as COX inhibitor and anticancer agent.

Green synthesis of fluorescent carbon nanodots from sage leaves for selective anticancer activity on 2D liver cancer cells and 3D multicellular tumor spheroids.

Carbon nanodots, a family of carbon-based nanomaterials, have been synthesized through different methods from various resources, affecting the properties of the resulting product and their application. Herein, carbon nanodots (CNDs) were synthesized with a green and simple hydrothermal method from sage leaves at 200 °C for 6 hours. The obtained CNDs are well dispersed in water with a negative surface charge (ζ-potential = -11 mV) and an average particle size of 3.6 nm. The synthesized CNDs showed concentration-dependent anticancer activity toward liver cancer (Hep3B) cell lines and decreased the viability of the cancer cells to 23% at the highest used concentration (250 µg ml-1 of CNDs). More interestingly, the cytotoxicity of the CNDs was tested in normal liver cell lines (LX2) revealed that the CNDs at all tested concentrations didn't affect their viability including at the highest concentration showing a viability of 86.7%. The cellular uptake mechanisms of CNDs were investigated and they are thought to be through energy-dependent endocytosis and also through passive diffusion. The main mechanisms of endocytosis were lipid and caveolae-mediated endocytosis. In addition, the CNDs have hindered the formation of 3D spheroids from the Hep3B hepatocellular carcinoma cell line. Hence, it would be concluded that the synthesized CNDs from sage are more highly selective to liver cancer cells than normal ones. The CNDs' cancer-killing ability would be referred to as the production of reactive oxygen species.

Gundelia tournefortii inhibits hepatocellular carcinoma progression by lowering gene expression of the cell cycle and hepatocyte proliferation in immunodeficient mice.

Gundelia (G.) tournefortii has antibacterial, anti-inflammatory, and hypolipemic effects. We evaluated the anticancer effect of G. tournefortii in an hepatocellular carcinoma (HCC) mouse model of an HCC cell line (Hep3B) injected into NOD.CB17-Prkdc-SCID/NCrHsD male mice. Tumorigenicity was assessed by tumor size, histology, serum α-fetoprotein (αFP), and glypican 3 (GPC3). HCC-related gene expression of the cell cycle (Cyclin-dependent kinase inhibitor 2A (CDNK2A)), proliferation (MKI67), and platelet-derived growth factor receptor α (PDGFA) were measured. HCC cell cycle alterations, apoptosis, and antioxidant markers in serum and liver following treatment with G. tournefortii were determined. Signaling pathways of liver p53 and phosphorylated PI3K, AKT, and mTOR were also evaluated. Results indicate a significant increase in tumor size in HCC animals associated with elevated αFP, GPC3, and MKI67. Tumor markers of p53 and phosphorylated AKT/PI3K/mTOR signaling pathway were diminished, with less proliferating cells and reduced PDGFRA gene expression following G. tournefortii infection. H&E staining showed a remarkable reduction in inflammatory lesions in HCC mice treated with G. tournefortii. This result was in line with a significant delay in the G2/M phase of HCC-primary hepatocytes by 1.39- to 2.4-fold and reduced HCC necrosis associated with inhibited CDNK2A gene expression. Antioxidant activity was significantly lower in the HCC mice than in the control group. Moreover, G. tournefortii inhibited the HCC formation of 3D MCTS spheroids. G. tournefortii treatment markedly restored antioxidant levels and displayed anticancer and antiproliferative effects and could be a promising cancer therapy.

Anticancer Activity of Thiophene Carboxamide Derivatives as CA-4 Biomimetics: Synthesis, Biological Potency, 3D Spheroid Model, and Molecular Dynamics Simulation.

The present study aimed to synthesize thiophene carboxamide derivatives, which are considered biomimetics of the anticancer medication Combretastatin A-4 (CA-4), and compare the similarity in the polar surface area (PSA) between the novel series and CA-4. Our results showed that the PSA of the most synthesized structures was biomimetic to CA-4, and similar chemical and biological properties were observed against Hep3B cancer cell line. Among the synthesized series 2b and 2e compounds were the most active molecules on Hep3B (IC50 = 5.46 and 12.58 µM, respectively). The 3D results revealed that both 2b and 2e structures confuse the surface of Hep3B cancer cell lines' spheroid formation and force these cells to aggregate into a globular-shaped spheroid. The 2b and 2e showed a comparable interaction pattern to that observed for CA-4 and colchicine within the tubulin-colchicine-binding pocket. The thiophene ring, due to holding a high aromaticity character, participated critically in that observed interaction profile and showed additional advanced interactions over CA-4. The 2b and 2e tubulin complexes showed optimal dynamics trajectories within a time scale of 100 ns at 300 K temperature, which asserts their high stability and compactness. Together, these findings revealed the biomimetic role of 2b and 2e compounds in CA-4 in preventing cancer progression.

Information-Theoretic Properties of Auditory Sequences Dynamically Influence Expectation and Memory.

A basic function of cognition is to detect regularities in sensory input to facilitate the prediction and recognition of future events. It has been proposed that these implicit expectations arise from an internal predictive coding model, based on knowledge acquired through processes such as statistical learning, but it is unclear how different types of statistical information affect listeners' memory for auditory stimuli. We used a combination of behavioral and computational methods to investigate memory for non-linguistic auditory sequences. Participants repeatedly heard tone sequences varying systematically in their information-theoretic properties. Expectedness ratings of tones were collected during three listening sessions, and a recognition memory test was given after each session. Information-theoretic measures of sequential predictability significantly influenced listeners' expectedness ratings, and variations in these properties had a significant impact on memory performance. Predictable sequences yielded increasingly better memory performance with increasing exposure. Computational simulations using a probabilistic model of auditory expectation suggest that listeners dynamically formed a new, and increasingly accurate, implicit cognitive model of the information-theoretic structure of the sequences throughout the experimental session.

Heterogeneity in sarcoma cell lines reveals enhanced motility of tetraploid versus diploid cells.

Soft tissue sarcomas with complex genomics are very heterogeneous tumors lacking simple prognosis markers or targeted therapies. Overexpression of a subset of mitotic genes from a signature called CINSARC is of bad prognosis, but the significance of this signature remains elusive. Here we precisely measure the cell cycle and mitosis duration of sarcoma cell lines and we found that the mitotic gene products overexpression does not reflect variation in the time spent during mitosis or G2/M. We also found that the CINSARC cell lines, we studied, are composed of a mixture of aneuploid, diploid, and tetraploid cells that are highly motile in vitro. After sorting diploid and tetraploid cells, we showed that the tetraploid cell clones do not possess a proliferative advantage, but are strikingly more motile and invasive than their diploid counterparts. This is correlated with higher levels of mitotic proteins overexpression. Owing that mitotic proteins are almost systematically degraded at the end of mitosis, we propose that it is the abnormal activity of the mitotic proteins during interphase that boosts the sarcoma cells migratory properties by affecting their cytoskeleton. To test this hypothesis, we designed a screen for mitotic or cytoskeleton protein inhibitors affecting the sarcoma cell migration potential independently of cytotoxic activities. We found that inhibition of several mitotic kinases drastically impairs the CINSARC cell invasive and migratory properties. This finding could provide a handle by which to selectively inhibit the most invasive cells.

Unsupervised analysis of polyphonic music by sparse coding.

We investigate a data-driven approach to the analysis and transcription of polyphonic music, using a probabilistic model which is able to find sparse linear decompositions of a sequence of short-term Fourier spectra. The resulting system represents each input spectrum as a weighted sum of a small number of "atomic" spectra chosen from a larger dictionary; this dictionary is, in turn, learned from the data in such a way as to represent the given training set in an (information theoretically) efficient way. When exposed to examples of polyphonic music, most of the dictionary elements take on the spectral characteristics of individual notes in the music, so that the sparse decomposition can be used to identify the notes in a polyphonic mixture. Our approach differs from other methods of polyphonic analysis based on spectral decomposition by combining all of the following: (a) a formulation in terms of an explicitly given probabilistic model, in which the process estimating which notes are present corresponds naturally with the inference of latent variables in the model; (b) a particularly simple generative model, motivated by very general considerations about efficient coding, that makes very few assumptions about the musical origins of the signals being processed; and (c) the ability to learn a dictionary of atomic spectra (most of which converge to harmonic spectral profiles associated with specific notes) from polyphonic examples alone-no separate training on monophonic examples is required.

Cancer incidence among Australian nuclear industry workers.

To assess whether workers at Lucas Heights Science and Technology Centre (LHSTC) had different levels of cancer incidence from the New South Wales (NSW) population in Australia. A retrospective cohort study was undertaken at LHSTC. Data on 7,076 workers employed between 1957-98 were abstracted from personnel, dosimetry, and medical files. An inception cohort was defined which included 4,523 workers in employment between 1972-96 to examine cancer incidence. Cancer registrations in the inception cohort were identified to 1996 through electronic linkage of records with the NSW and the Australian national registers of cancer incidence. All-cancer incidence in workers at LHSTC was 15% below the NSW rates [SIR=0.85; 95% CI=(0.75, 0.95)]. Of 37 specific cancers and groups of cancers examined, statistically significant excesses relative to NSW rates were observed only for pleural cancer incidence [SIR=17.71; 95%=(7.96, 39.43)], and for incidence of cancer of the small intestine [SIR=4.34; 95% CI=(1.40, 13.46)]. This study gives little evidence of an increased risk of cancers associated with radiation exposure in a cohort of nuclear workers in Australia. The observed increase in the risk of cancer of the pleura was probably due to unmeasured exposures, given the lack of an established association with radiation exposure, and the strong link to asbestos exposure. Findings for cancers of the small intestine were based on small numbers and were likely to be due to chance.

TP53 drives invasion through expression of its Δ133p53ß variant.

TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53ß promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53ß increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53ß is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53ß depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53ß induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression.

Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart.

This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ET(A)-Rs/ET(B)-Rs, at the coronary endothelium (CE) and cardiomyocyte (CM) sites. It is carried out in normal and normotensive rats with streptozotocin-induced diabetes mellitus receiving different treatment modalities. Normal rats were divided into two groups, namely a placebo (N) and a losartan-treated (NL), and diabetic rats into four groups receiving placebo (D), insulin-treated (DI), losartan-treated (DL), and insulin/losartan-treated (DIL) respectively. Binding kinetics of ET-1 to ET(A)-Rs/ET(B)-Rs on CE and CMs were assessed in the above groups to try to explain the effect of therapeutic doses of an angiotensin II receptor subtype-1 blocker on the dynamics of this ligand and its receptor in insulin supplemented diabetic animals. Each group was divided into two subgroups: CHAPS-untreated and CHAPS-treated rat hearts perfused with [125I]ET-1 to respectively estimate ET-1 binding affinity (tau = 1/k-n) to its receptor subtype(s) on CE and CMs using mathematical modeling describing a 1:1 reversible binding stoichiometry. Heart perfusion results revealed that insulin treatment significantly decreased tau on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in tau value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized tau on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ET(A)-R density in all diabetic groups. However, significant decrease in ET(B)-R density was observed in all groups compared to the normal, and was reconfirmed by immunohistochemical analysis. In conclusion, coadministration of insulin and losartan in nonhypertensive animals suffering from diabetes type 1 may offer new cardiac protection benefits by improving coronary blood flow and cardiomyocyte contractility through modulating ET-1 receptor subtypes density and affinity at CE and CM sites.

Mortality rates among nuclear industry workers at Lucas Heights Science and Technology Centre.

OBJECTIVES: To assess whether workers at Lucas Heights Science and Technology Centre (LHSTC) have different levels of mortality from the New South Wales (NSW) and Australian populations. METHODS: A retrospective cohort study was undertaken at LHSTC. Data on 7,076 workers employed between 1957-98 were abstracted from personnel, dosimetry, and medical files. Deaths registrations in the cohort were identified to 1998 through electronic linkage of records with NSW and national registers of cancer incidence and mortality. Two inception cohorts were defined as including 4,717 and 3,543 workers in employment between 1972-98 and 1980-98, to examine cancer mortality and all-cause mortality respectively. RESULTS: All-cause mortality was 31% lower than the national rates; all-cancer mortality was 19% below the NSW rate. Of 37 specific cancers and groups of cancers examined, statistically significant excesses relative to NSW rates were observed only for pleural cancer mortality (SMR = 21.11; 95% Cl 8.79-50.72). CONCLUSIONS: The observed increase in the risk of cancer of the pleura was probably due to unmeasured exposures, given the lack of an established association with radiation exposure and the strong link to asbestos exposure.

Rhus coriaria (sumac) extract reduces migration capacity of uterus cervix cancer cells

Abstract Uterus cervix cancer is one of the most common malignant gynecological tumors in women globally. Its standard treatment includes radiotherapy and chemotherapy are considered highly toxic, expensive and exhaustive for patients. Medicinal plants became increasingly a better and a safer alternative therapeutic approach. Rhus coriaria L., Anacardiaceae, is a medicinal plant whose anti-cancer effect has been explored in few cancer types including breast and colorectal cancer. However, its effect on uterus cervix cancer is still unknown. In this study, we showed that non-cytotoxic concentrations of R. coriaria reduces uterus cervix cell migration capacity. We have also found that R. coriaria has a growth inhibitory effect on cervical cancer cells in a time- and a concentration-dependent manner. We have carried out a phytochemical compound analysis of R. coriaria extract using liquid chromatography-mass spectrometry method in order to identify bioactive compounds in R. coriaria extract that could potentially induce its anti-cancer effects. Our results are promising to involve R. coriaria as a therapeutic drug candidate for uterus cervix cancer.

FDTD simulation of electromagnetic wave scattering from retina cells.

Finite Difference Time Domain (FDTD) method was developed to model changes in the light scattering properties of retinal photoreceptors resulting from the functional response of living retina to external light stimulation. Physiological processes such as membrane hyper-polarization and conformation changes of rhodopsin in the photoreceptors outer segment (OS) were simulated by varying the optical properties of the cell organelles. The FDTD code was validated by comparing the results from a 2D simulation of light scattering from an infinite cylinder to the Mie analytical solution for the same geometry. Results from the FDTD simulations show that hyper-polarization of the outer cell membrane is the least likely cause for the observed increase in light scattering in photoreceptors. Other computational data suggests that the experimentally observed changes in reflectivity are most likely related to cell dynamics and to cell volume changes.