Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition.

Invasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. There is a paucity of options for TNBC treatment, which highlights the need for additional innovative treatment approaches. NIH-III mice were injected in the abdominal mammary fat pad with luciferase-expressing derivative of the human TNBC cell line, MDA-MB-231 cells. Animals were gavage-fed with nitrofen at the doses of 1, 3 or 6 mg/kg/alternate days. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity (cLogP of nearly 5) and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which lack the nitro group and/or have replaced the diaryl ether linker with a diarylamine that could allow modulation of polarity. In vitro anti-invasiveness activity of nitrofen analogues were evaluated by quantitative determination of invasion of MDA-MB-231-Luciferase cells through Matrigel using a Boyden chamber. Our in vivo data show that nitrofen efficiently blocks TNBC tumor metastasis. In vitro data suggest that this is not due to cytotoxicity, but rather is due to impairment of invasive capacity of the cells. Further, using an in vitro model of EMT, we show that nitrofen interferes with the process of EMT and promotes mesenchymal to epithelial transformation. In addition, we show that three of the nitrofen analogues significantly reduced invasive potential of TNBC cells, which may, at least partially, be attributed to the analogues' ability to promote mesenchymal to epithelial-like transformation of TNBC cells. Our study shows that nitrofen, and more importantly its analogues, are significantly effective in limiting the invasive potential of TNBC cell lines with minimal cytotoxic effect. Further, we demonstrate that nitrofen its analogues, are very effective in reversing mesenchymal phenotype to a more epithelial-like phenotype. This may be significant for the treatment of patients with mesenchymal-TNBC tumor subtype who are well known to exhibit high resistance to chemotherapy.

Evolving tides aggravate nuisance flooding along the U.S. coastline.

Nuisance flooding (NF) is defined as minor, nondestructive flooding that causes substantial, accumulating socioeconomic impacts to coastal communities. While sea-level rise is the main driver for the observed increase in NF events in the United States, we show here that secular changes in tides also contribute. An analysis of 40 tidal gauge records from U.S. coasts finds that, at 18 locations, NF increased due to tidal amplification, while decreases in tidal range suppressed NF at 11 locations. Estuaries show the largest changes in NF attributable to tide changes, and these can often be traced to anthropogenic alterations. Limited long-term measurements from estuaries suggest that the effects of evolving tides are more widespread than the locations considered here. The total number of NF days caused by tidal changes has increased at an exponential rate since 1950, adding ~27% to the total number of NF events observed in 2019 across locations with tidal amplification.

Changing Tides: The Role of Natural and Anthropogenic Factors.

Tides are changing worldwide at rates not explained by astronomical forcing. Rather, the observed evolution of tides and other long waves, such as storm surges, is influenced by shelf processes and changes to the roughness, depth, width, and length of embayments, estuaries, and tidal rivers. In this review, we focus on processes in estuaries and tidal rivers, because that is where the largest changes to tidal properties are occurring. Recent literature shows that changes in tidal amplitude have been ubiquitous worldwide over the past century, often in response to wetland reclamation, channel dredging, and other environmental changes. While tidal amplitude changes are sometimes slight (<1%) or even negative, we identify two types of systems that are particularly prone to tidal amplification: (a) shallow, strongly damped systems, in which a small increase in depth produces a large decrease in effective friction, and (b) systems in which wave reflection and resonance are strongly influenced by changes to depth, friction, and convergence. The largest changes in amplitude occur inland, some distance from the coast, and can sometimes be measured in meters. Tide changes are a leading indicator that the dynamics of storm surges and river flood waves have also changed and are often associated with shifts in sediment transport, salinity intrusion, and ecosystem properties. Therefore, the dynamics of tidal evolution have major implications for coastal management, particularly for systems that are sensitive to changes in geometry induced by sea-level rise and anthropogenic development.

Coupling of sea level and tidal range changes, with implications for future water levels.

Are perturbations to ocean tides correlated with changing sea-level and climate, and how will this affect high water levels? Here, we survey 152 tide gauges in the Pacific Ocean and South China Sea and statistically evaluate how the sum of the four largest tidal constituents, a proxy for the highest astronomical tide (HAT), changes over seasonal and interannual time scales. We find that the variability in HAT is significantly correlated with sea-level variability; approximately 35% of stations exhibit a greater than ±50 mm tidal change per meter sea-level fluctuation. Focusing on a subset of three stations with long records, probability density function (PDF) analyses of the 95% percentile exceedance of total sea level (TSL) show long-term changes of this high-water metric. At Hong Kong, the increase in tides significantly amplifies the risk caused by sea-level rise. Regions of tidal decrease and/or amplification highlight the non-linear response to sea-level variations, with the potential to amplify or mitigate against the increased flood risk caused by sea-level rise. Overall, our analysis suggests that in many regions, local flood level determinations should consider the joint effects of non-stationary tides and mean sea level (MSL) at multiple time scales.

Absolute stereochemistry assignment of N-phosphorylimine-derived aza-Diels-Alder adducts with TDDFT CD calculations.

N-phosphorylimines undergo Lewis acid-catalyzed Diels-Alder reactions with Danishefsky's diene. Application of the chiral catalyst zinc(II)-(S)-BINOL results in good-to-low asymmetric induction but poor chemical conversion. However, the absolute stereochemistry of novel aza-Diels-Alder cycloadducts, such as diethyl 4-oxo-2-phenyl-3,4-dihydropyridin-1(2H)-ylphosphonate, can be determined using circular dichroism (CD). Comparison between experimental and TDDFT-calculated CD spectrum shows that use of the (S)-catalyst results in predominant formation of the (6R) cycloadducts.