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Breast cancer (BC) currently ranks second in the global cancer incidence rate. Hypoxia is a common phenomenon in BC. Under hypoxic conditions, cells in the tumor microenvironment (TME) secrete numerous extracellular vesicles (EVs) to achieve intercellular communication and alter the metabolism of primary and metastatic tumors that shape the TME. In addition, emerging studies have indicated that hypoxia can promote resistance to tumor treatment. Engineered EVs are expected to become carriers for cancer treatment due to their high biocompatibility, low immunogenicity, high drug delivery efficiency, and ease of modification. In this review, we summarize the mechanisms of EVs in the primary TME and distant metastasis of BC under hypoxic conditions. Additionally, we highlight the potential applications of engineered EVs in mitigating the malignant phenotypes of BC cells under hypoxia. Key points: • Breast cancer, which has the second highest incidence rate of cancer in the world, has a 5-year survival rate as high as 90% without metastasis. However, once metastasis occurs, the rate decreases to 10%. • Hypoxia is a significant feature of BC and impacts its TME composition, metabolic characteristics, metastasis capacity, and therapeutic resistance. • Under hypoxia, the above biological processes rely mainly on the participation of EVs. • Engineered EVs have significant potential to address the aforementioned clinical issues. [ABSTRACT FROM AUTHOR]

Stratigraphic data from salt marshes provide accurate reconstructions of Holocene relative sea-level (RSL) change and necessary constraints to models of glacial isostatic adjustment (GIA), which is the dominant cause of Late-Holocene RSL rise along the U.S. mid-Atlantic coast. Here, we produce a new Mid- to Late-Holocene RSL record from a salt marsh bordering Great Bay in southern New Jersey using basal peats. We use a multi-proxy approach (foraminifera and geochemistry) to identify the indicative meaning of the basal peats and produce sea-level index points (SLIPs) that include a vertical uncertainty for tidal range change and sediment compaction and a temporal uncertainty based on high precision Accelerator Mass Spectrometry radiocarbon dating of salt-marsh plant macrofossils. The 14 basal SLIPs range from 1211 ± 56 years BP to 4414 ± 112 years BP, which we combine with published RSL data from southern New Jersey and use with a spatiotemporal statistical model to show that RSL rose 8.6 m at an average rate of 1.7 ± 0.1 mm/year (1σ) from 5000 years BP to present. We compare the RSL changes with an ensemble of 1D (laterally homogenous) and site-specific 3D (laterally heterogeneous) GIA models, which tend to overestimate the magnitude of RSL rise over the last 5000 years. The continued discrepancy between RSL data and GIA models highlights the importance of using a wide array of ice model and viscosity model parameters to more precisely fit site-specific RSL data along the U.S. mid-Atlantic coast. [ABSTRACT FROM AUTHOR]

Analyses of glacial isostatic adjustment (GIA) and deglacial relative sea‐level (RSL) change in the Russian Arctic deliver important insights into the Earth's viscosity structure and the deglaciation history of the Eurasian ice sheet complex. Here, we validate the 1D GIA models ICE‐6G_C (VM5a) and ICE‐7G_NA (VM7) and select new 3D GIA models in the Russian Arctic against a quality‐controlled deglacial RSL database of >500 sea‐level data points from 24 regions. Both 1D models correspond to the RSL data along the southern coast of the Barents Sea and Franz Josef Land from ∼11 ka BP to present but show notable misfits (>50 m at 10 ka BP) with the White Sea data. We find 3D model predictions of deglacial RSL resolve most of the misfits with the observed data for the White Sea while retaining comparable fits in other regions of the Russian Arctic. Our results further reveal: (a) RSL in the western Russian Arctic is sensitive to elastic lithosphere with lateral thickness variation and 3D viscosity structure in the upper mantle; and (b) RSL in the whole Russian Arctic is less sensitive to 3D viscosity structure in the lower mantle compared to the upper mantle. The 3D models reveal a compromise in the upper mantle between the background viscosity and scaling factor to best fit the RSL data, which needs to be considered in future 3D GIA studies. Plain Language Summary: The western Russian Arctic was partially covered by the Eurasian ice sheet complex during the Last Glacial Maximum (∼26 ka BP) and is a focus area for understanding the response of the solid Earth to ice loading and unloading events, known as glacial isostatic adjustment (GIA). We use a database containing standardized relative sea‐level (RSL) data to validate one‐dimensional (1D; laterally homogeneous) GIA models and test new three‐dimensional (3D; laterally heterogeneous) GIA models. We find that 1D models fit the RSL data along the southern coast of Barents Sea and Franz‐Josef‐Land but show significant misfits with the RSL data in the White Sea region. We find the optimal 3D model improves the fit around the White Sea region while retaining good fits achieved by 1D models. Our results reveal deglacial RSL changes are (a) sensitive to laterally varying lithosphere and viscosity structure in the upper mantle in the western Russian Arctic; and (b) insensitive to viscosity structure in the lower mantle compared to the upper mantle in the Russian Artic. Furthermore, we notice that 3D GIA models with different background 1D viscosities and lateral viscosity variations can provide similar fit with the RSL data. Key Points: We validate 1D GIA models ICE‐6G_C (VM5a) and ICE‐7G_NA (VM7) and test new 3D GIA models with a deglacial RSL database in the Russian ArcticThe optimal 3D model retains the good fits achieved by 1D models and considerably improves the fits where 1D models show notable misfitsThe 3D models reveal a moderate compromise in the upper mantle between the background viscosity and scaling factor to best fit the RSL data [ABSTRACT FROM AUTHOR]

Relative sea-level (RSL) records from far-field regions distal from ice sheets remain poorly understood, particularly in the early Holocene. Here, we extended the Holocene RSL data from Singapore by producing early Holocene sea-level index points (SLIPs) and limiting dates from a new ~40 m sediment core. We merged new and published RSL data to construct a standardized Singapore RSL database consisting of 88 SLIPs and limiting data. In the early Holocene, RSL rose rapidly from −21.0 to −0.7 m from ~9500 to 7000 cal. yrs. BP. Thereafter, the rate of RSL rise decelerated, reaching a mid-Holocene highstand of 4.0 ± 4.5 m at 5100 cal. yrs. BP, before falling to its present level. There is no evidence of any inflections in RSL when the full uncertainty of SLIPs is considered. When combined with other standardized data from the Malay-Thai Peninsula, our results also show substantial misfits between regional RSL reconstructions and glacial isostatic adjustment (GIA) model predictions in the rate of early Holocene RSL rise, the timing of the mid-Holocene highstand and the nature of late-Holocene RSL fall towards the present. It is presently unknown whether these misfits are caused by regional processes, such as subsidence of the continental shelf, or inaccurate parameters used in the GIA model. [ABSTRACT FROM AUTHOR]

We quantify GIA prediction uncertainties of 250 1D and 3D glacial isostatic adjustment (GIA) models through comparisons with deglacial relative sea‐level (RSL) data from North America and rate of vertical land motion (U̇) and gravity rate of change (Ġ) from GNSS and GRACE data, respectively. Spatially, the size of the RSL uncertainties varies across North America with the largest from Hudson Bay and near previous ice margins along the northern Atlantic and Pacific coasts, which suggests 3D viscosity structure in the lower mantle and laterally varying lithospheric thickness. Temporally, RSL uncertainties decrease from the Last Glacial Maximum to present except for west of Hudson Bay and the northeastern Pacific coast. The uncertainties of both these regions increase from 30 to 45 m between 15 and 11 ka BP, which may be due to the rapid decrease of surface loading at that time. Present‐day U̇ and Ġ uncertainties are largest in southwestern Hudson Bay with magnitudes of 2.4 mm/year and 0.4 μGal/year, mainly due to the 3D viscosity structure in the lower mantle. Key Points: We predict the GIA signal with uncertainties of RSL and present‐day U̇ and Ġ in North America that are associated with 3D structuresGIA‐predicted RSL uncertainties are largest around Hudson Bay and near former ice margins along northern Atlantic and Pacific coastsThe maximum uncertainties of present‐day U̇ and Ġ are centered in southwestern Hudson Bay and near former ice margins [ABSTRACT FROM AUTHOR]

As temperature increases with depth and the creep resistance of rock decreases exponentially, a high-viscosity sub-lithospheric layer, just beneath the 'elastic' lithosphere is expected to exist. Depending on the temperature profile, a low-viscosity asthenosphere may also exist if the temperature deeper down gets high enough. Since the temperature profile is expected to change laterally – especially from below the oceans to cratonic areas underneath continents, rock properties of the lithosphere, high-viscosity sub-lithosphere and low-viscosity asthenosphere are expected to change laterally. Our aim is to constrain sub-lithospheric properties (depth, thickness and viscosity), lateral lithospheric thickness variations and asthenospheric properties using observed GIA data. A Coupled Laplace-Finite Element Method is used to compute gravitationally self-consistent sea level with time-dependent coastline and rotational feedback in addition to changes in deformation, gravity and the state of stress. We start with the VM5a-ICE-6G_C model combination and then modify the lithospheric, sub-lithospheric and asthenospheric properties (including lateral thickness variation) while keeping the mantle viscosities the same as VM5a. Through this study, we confirm that the sub-lithospheric and asthenospheric properties can significantly affect the predicted global relative sea level (RSL), present-day gravity rate-of-change (g-dot) and uplift rate (u-dot) in Laurentia and Fennoscandia. In addition, incorporating the elastic lithosphere with lateral thickness variation, sub-lithosphere and asthenosphere can improve the fit to global RSL, but the predicted peak values of g-dot and u-dot in Laurentia may decrease slightly but not significant enough to affect the fit to the observed data. Our results prefer an elastic lithosphere that has maximum thickness of 140 km under continental cratons but reduces to 60 km underneath the oceans. The results preferred depth of the asthenospheric bottom is around 190–200 km with asthenospheric viscosity around 1020Pa s. Finally, we show that the best laterally heterogeneous mantle model we found in previous publication when combined with the lithosphere with lateral thickness variaion gives the best fit to global RSL and peak g-dot and u-dot in Laurentia simultaneously. [ABSTRACT FROM AUTHOR]

Most models of glacial isostatic adjustment (GIA) assume that the Earth is laterally homogeneous. However, seismic and geological observations clearly show that the Earth's mantle is laterally heterogeneous. Previous studies of GIA with lateral heterogeneity mostly focused on its effect or sensitivity on GIA predictions, and it is not clear to what extent can lateral heterogeneity solve the misfits between GIA predictions and observations. Our aim is to search for the best 3-D viscosity models that can simultaneously fit the global relative sea level data, the peak uplift rates (u-dot from the Global Navigation Satellite System) and peak gravity-rate-of-change (g-dot from the Gravity Recovery And Climate Experiment satellite mission) in Laurentia and Fennoscandia. However, the search is dependent on the ice and viscosity model inputs—the latter depends on the background viscosity and the seismic tomography models used. In this paper, the ICE-6G_C ice model, with Bunge and Grand's seismic tomography model and background viscosity models close to VM5 will be assumed. A coupled Laplace-finite element method is used to compute gravitationally self-consistent sea level change with time-dependent coastlines and rotational feedback in addition to changes in deformation, gravity and the state of stress. Several laterally heterogeneous models are found to fit the global sea level data better than laterally homogeneous models. Two of these laterally heterogeneous models also fit the observed peak g-dot and u-dot rates in Laurentia simultaneously. However, even with the introduction of lateral heterogeneity, no model that is able to fit the present-day g-dot and uplift rate data in Fennoscandia has been found. Therefore, either the ice history of ICE-6G_C in Fennoscandia and Barents Sea needs some modifications or the sublithospheric property/non-thermal effect underneath northern Europe must be different from that underneath Laurentia. [ABSTRACT FROM AUTHOR]

The mid-Holocene sea-level highstand refers to higher-than-present relative sea levels (RSLs) in far-field regions between 7000 and 4000 years ago because of equatorial ocean syphoning and continental levering. But the timing, magnitude, and spatial variability of the highstand are uncertain and the highstand parameterization in Glacial Isostatic Adjustment (GIA) modelling is understudied. Here, we use the RSL records of Southeast Asia to investigate the sensitivity of the mid-Holocene highstand properties to Earth and ice model parameters, including lithospheric thickness, mantle viscosity (both 1D and 3D), and deglaciation history of Antarctica and global ice sheets. We found that the Earth model variation only affects the magnitude of the mid-Holocene highstand unless extraordinary low upper mantle viscosity is used. The timing of the highstand moves towards present and there is an absence of the highstand if upper mantle viscosity is < 4.0 × 1019 Pa s or ≤ 1.0 × 1019 Pa s, respectively. Ice model variation changes both the timing and magnitude of the mid-Holocene highstand. Delaying the ice-equivalent sea level will shift the timing of the highstand later and result in a lower highstand magnitude. We produced a mid-Holocene highstand "treasure map" that considers topography change and accommodation space to guide future RSL data collection efforts in Southeast Asia. The highstand "treasure map" indicates that the northeast and central west coast of Malay-Thai Peninsula, east coast of Sumatra, north coast of Java, and southwest coast of Borneo are very likely (90% probability) to preserve mid-Holocene highstand evidence. • We investigate the sensitivity of the mid-Holocene sea-level highstand to Earth and ice model parameters of Glacial Isostatic Adjustment models. • Earth model variation only affects the magnitude of the highstand unless extraordinarily low upper mantle viscosity is used, while ice model variation changes both the timing and magnitude of the highstand. • The highstand along the coasts of inner Sundaland, including west and east coasts of Malay-Thai Peninsula, east coast of Sumatra, and west coast of Borneo, are sensitive to upper (1D) and lower (both 1D and 3D) mantle viscosities. • The coastlines that are very likely (90% probability) to have the mid-Holocene highstand preservation are northeast and central west coast of Malay-Thai Peninsula, east coast of Sumatra, north coast of Java, and southwest coast of Borneo. [ABSTRACT FROM AUTHOR]

Holocene relative sea-level (RSL) data from far-field islands in the mid-Pacific have been used to validate the ice-melting histories of glacial isostatic adjustment (GIA) models. However, a lack of quality control in the reconstruction of RSL hinders the understanding of regional variability that can constrain ice-equivalent sea-level changes. Here, we present a standardised database of Holocene RSL data from five regions in the mid-Pacific (Cook Islands, Tuamotu Islands, Christmas (Kiritimati) Island, Gilbert Islands and Fiji). We categorised the data as high or low quality based on the susceptibility of samples to age and/or elevation errors. Of the 614 data points that were reviewed, 25% were rejected and 100 sea-level index points (SLIPs) were reinterpreted as limiting data. The new database consists of 141 SLIPs and 262 marine and 56 terrestrial limiting data points reconstructed from a variety of sea-level indicators (e.g., coral microatolls, mangrove peat, beachrock, and beach ridges), of which 71% provide high-quality constraints on RSL. The early to mid Holocene RSL evolution in the Cook Islands, Gilbert Islands and Fiji are poorly constrained due to a lack of high-quality SLIPs and limiting data during this period. The Tuamotu Islands provided the only record of early to mid Holocene evolution of RSL, indicating rapid RSL rise from between −22.9 m and −15.2 m at ∼9.0 ka to between −0.2 m and 0.5 m by ∼6.5 ka, at rates as high as 9.8 ± 5.1 mm/a, with a slowdown in the rate of RSL rise sometime between ∼8.2 ka and ∼6 ka. The Christmas (Kiritimati) Island record indicates stable RSL within ∼1.5 m of present-day levels over the past ∼6.6 ka. In the late Holocene, the Cook Islands record suggests a gradual fall in RSL over the past ∼2.9 ka at rates below 0.1 ± 4.3 mm/a. SLIPs at Fiji also indicate a slight fall in RSL at rates of less than 0.5 ± ∼4.4 mm/a at ∼4 ka, following which RSL fell from above 0.9 m at ∼3 ka to between −0.3 m and 0.6 m by ∼2.5– ∼2.1 ka. We highlight the importance of standardisation and quality control to critically evaluate the processes controlling RSL and validate GIA models. Indeed, the new standardised database has implications for the timing of the mid- Holocene highstand, which has been used to support the ICE-4G and ICE-7G_NA models. Due to the poor constraints of data in the mid-Pacific islands, particularly in the early Holocene, there remains no unique solution for a global ice-melting history. [ABSTRACT FROM AUTHOR]