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Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.

Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.

We investigate the flow of brine-enriched shelf water from Storfjorden (Svalbard) into Fram Strait and onto the western Svalbard Shelf using a regional set-up of NEMO-SHELF, a 3-D numerical ocean circulation model. The model is set up with realistic bathymetry, atmospheric forcing, open boundary conditions and tides. The model has 3 km horizontal resolution and 50 vertical levels in the sh-coordinate system which is specially designed to resolve bottom boundary layer processes. In a series of modelling experiments we focus on the influence of tides on the propagation of the dense water plume by comparing results from tidal and non-tidal model runs. Comparisons of non-tidal to tidal simulations reveal a hotspot of tidally induced horizontal diffusion leading to the lateral dispersion of the plume at the southernmost headland of Spitsbergen which is in close proximity to the plume path. As a result the lighter fractions in the diluted upper layer of the plume are drawn into the shallow coastal current that carries Storfjorden water onto the western Svalbard Shelf, while the dense bottom layer continues to sink down the slope. This bifurcation of the plume into a diluted shelf branch and a dense downslope branch is enhanced by tidally induced shear dispersion at the headland. Tidal effects at the headland are shown to cause a net reduction in the downslope flux of Storfjorden water into the deep Fram Strait. This finding contrasts previous results from observations of a dense plume on a different shelf without abrupt topography.

We investigate the flow of brine-enriched shelf water from Storfjorden (Svalbard) into Fram Strait and onto the western Svalbard Shelf using a regional set-up of NEMO-SHELF, a 3-D numerical ocean circulation model. The model is set up with realistic bathymetry, atmospheric forcing, open boundary conditions and tides. The model has 3 km horizontal resolution and 50 vertical levels in the sh-coordinate system which is specially designed to resolve bottom boundary layer processes. In a series of modelling experiments we focus on the influence of tides on the propagation of the dense water plume by comparing results from tidal and non-tidal model runs. Comparisons of non-tidal to tidal simulations reveal a hotspot of tidally induced horizontal diffusion leading to the lateral dispersion of the plume at the southernmost headland of Spitsbergen which is in close proximity to the plume path. As a result the lighter fractions in the diluted upper layer of the plume are drawn into the shallow coastal current that carries Storfjorden water onto the western Svalbard Shelf, while the dense bottom layer continues to sink down the slope. This bifurcation of the plume into a diluted shelf branch and a dense downslope branch is enhanced by tidally induced shear dispersion at the headland. Tidal effects at the headland are shown to cause a net reduction in the downslope flux of Storfjorden water into the deep Fram Strait. This finding contrasts previous results from observations of a dense plume on a different shelf without abrupt topography.

Dense water overflow off continental shelves (cascading) is one of the contributing processes of shelf-deep ocean exchange, and of topical interest to climate studies and nutrient fluxes. Dense water originating from cooling, evaporation, freezing and salinization on a shallow shelf spills over the shelf edge and may develop as near-bottom gravity current or an intermediate-depth intrusion. It is difficult to observe in nature due to its intermittent character. This paper provides an extensive inventory of observed cases of water cascades around the World Ocean, summarises their locations and individual properties, and provides statistics of the identified cases. The search for cascading was carried out using oceanographic databases and a literature review. This study identified 61 confirmed cases world-wide, including 25 cases in the Arctic seas, 12 at mid-latitudes, seven in sub-tropical and tropical regions, and 17 off the Antarctic shelves. Eighteen cascades had not been reported before. We analyze a set of numerical parameters of dense water cascades, allowing us to quantify, compare and contrast the properties of water cascades. The overall average density contrast between the confirmed cascades and ambient water is 0.37 (kg/m3); it can be as much as 2 (kg/m3) on some Arctic shelves. Frequently initiated by strong cooling at the surface, cascades often remain colder through the descent, thus supplying the deep ocean with colder and fresher water. In non-dimensional variables, the data from all climate zones fit well to a unique curve, which represents a relationship between a cascade’s internal structure and the parameters describing its forcing. On average, the down-slope volumetric flux provided by dense water cascades is estimated as 0.05 to 0.08 Sv per 100 km of shelf edge.

Dense water overflow off continental shelves (cascading) is one of the contributing processes of shelf-deep ocean exchange, and of topical interest to climate studies and nutrient fluxes. Dense water originating from cooling, evaporation, freezing and salinization on a shallow shelf spills over the shelf edge and may develop as near-bottom gravity current or an intermediate-depth intrusion. It is difficult to observe in nature due to its intermittent character. This paper provides an extensive inventory of observed cases of water cascades around the World Ocean, summarises their locations and individual properties, and provides statistics of the identified cases. The search for cascading was carried out using oceanographic databases and a literature review. This study identified 61 confirmed cases world-wide, including 25 cases in the Arctic seas, 12 at mid-latitudes, seven in sub-tropical and tropical regions, and 17 off the Antarctic shelves. Eighteen cascades had not been reported before. We analyze a set of numerical parameters of dense water cascades, allowing us to quantify, compare and contrast the properties of water cascades. The overall average density contrast between the confirmed cascades and ambient water is 0.37 (kg/m3); it can be as much as 2 (kg/m3) on some Arctic shelves. Frequently initiated by strong cooling at the surface, cascades often remain colder through the descent, thus supplying the deep ocean with colder and fresher water. In non-dimensional variables, the data from all climate zones fit well to a unique curve, which represents a relationship between a cascade’s internal structure and the parameters describing its forcing. On average, the down-slope volumetric flux provided by dense water cascades is estimated as 0.05 to 0.08 Sv per 100 km of shelf edge.

Cascading is a specific type of buoyancy-driven current in which dense water formed by cooling, evaporation, or freezing in the surface layer over the continental shelf descends down the continental slope to a greater depth. We have identified, by world-wide trawling and analysis of raw databases, several distinct mechanisms of preconditioning for cascades. We have validated, where possible, existing theories and developed simple models, which allow estimation of the parameters for preconditioning, initiating, and down-slope fluxes as well as evolution of the temperature contrasts during cascading events. Compliance or noncompliance of observations with these simple and easy-to-use models has been related to the stage of cascade development and to local factors. Estimates of observed down-slope transport rates in case studies accord with theory, which is thereby substantially validated. Typical values of cascading transport rates were in the range 0.5–1.6 m2s−1. We hazard a very approximate global estimate of order 105 km3yr−1 or average 3 Sv based on our findings and previous studies.

Observed density sections through dense-water pools or lenses on sloping topography typically have an asymmetric structure. One side of the dense lens usually is bounded by isopycnals that slope steeply down to the seabed while, on the other side, the slope of isopycnals is more gentle. A common situation is for the steepest-sloping isopycnals to be on the upslope side of a lens (which is termed the “head-up” state), but the reverse is occasionally true (which is called the “head-down” state). Here a 1½-layer reduced-gravity model, which resolves the bottom boundary layer to provide physical insight into the three-dimensional evolution of these alternative forms, is used. It is found that the head-up state arises when the thickness of the central core of a lens exceeds about two Ekman depth scales, and the head-down state arises when the converse is true. The speed of along- and cross-slope motion of the central, thick core of a dense lens is also investigated, and the results from an ensemble of runs with the three-dimensional reduced-gravity model are found to accord suprisingly well with some approximations derived from bulk dynamics. From a practical point of view, the results concerning the shape of isopycnals bounding dense lenses on slopes can provide valuable information from which to infer important aspects of the underlying dynamics.

Cascading is a specific type of buoyancy-driven current in which dense water formed by cooling, evaporation, or freezing in the surface layer over the continental shelf descends down the continental slope to a greater depth. We have identified, by world-wide trawling and analysis of raw databases, several distinct mechanisms of preconditioning for cascades. We have validated, where possible, existing theories and developed simple models, which allow estimation of the parameters for preconditioning, initiating, and down-slope fluxes as well as evolution of the temperature contrasts during cascading events. Compliance or noncompliance of observations with these simple and easy-to-use models has been related to the stage of cascade development and to local factors. Estimates of observed down-slope transport rates in case studies accord with theory, which is thereby substantially validated. Typical values of cascading transport rates were in the range 0.5–1.6 m2s−1. We hazard a very approximate global estimate of order 105 km3yr−1 or average 3 Sv based on our findings and previous studies.

Observed density sections through dense-water pools or lenses on sloping topography typically have an asymmetric structure. One side of the dense lens usually is bounded by isopycnals that slope steeply down to the seabed while, on the other side, the slope of isopycnals is more gentle. A common situation is for the steepest-sloping isopycnals to be on the upslope side of a lens (which is termed the “head-up” state), but the reverse is occasionally true (which is called the “head-down” state). Here a 1½-layer reduced-gravity model, which resolves the bottom boundary layer to provide physical insight into the three-dimensional evolution of these alternative forms, is used. It is found that the head-up state arises when the thickness of the central core of a lens exceeds about two Ekman depth scales, and the head-down state arises when the converse is true. The speed of along- and cross-slope motion of the central, thick core of a dense lens is also investigated, and the results from an ensemble of runs with the three-dimensional reduced-gravity model are found to accord suprisingly well with some approximations derived from bulk dynamics. From a practical point of view, the results concerning the shape of isopycnals bounding dense lenses on slopes can provide valuable information from which to infer important aspects of the underlying dynamics.