Contrasting internally and externally generated Atlantic Multidecadal Variability and the role for AMOC in CMIP6 historical simulations.

Atlantic multidecadal variability (AMV) has long been thought to be an expression of low-frequency variability in the Atlantic Meridional Overturning Circulation (AMOC). However, alternative hypotheses have been forwarded, including that AMV is primarily externally forced. Here, we review the current state of play by assessing historical simulations made for the sixth coupled model intercomparison project (CMIP6). Overall, the importance of external forcing is sensitive to the type of AMV index used, due to the importance of globally coherent externally forced signals in the models. There are also significant contrasts between the processes that drive internally and externally forced AMV, but these processes can be isolated by exploring the multivariate expression of AMV. Specifically, internal variability in CMIP6 models is consistent with an important role of ocean circulation and AMOC and the externally forced AMV is largely a surface-flux forced mechanism with little role for the ocean. Overall, the internal multivariate fingerprint of AMV is similar to the observed, but the externally forced fingerprint appears inconsistent with observations. Therefore, climate models still suggest a key role for ocean dynamics, and specifically AMOC, in observed AMV. Nevertheless, models remain deficient in a number of areas, and a stronger role for externally forced dynamical changes cannot be ruled out. This article is part of a discussion meeting issue 'Atlantic overturning: new observations and challenges'.

Systems Biology Analysis of Temporal Dynamics That Govern Endothelial Response to Cyclic Stretch.

Endothelial cells in vivo are subjected to a wide array of mechanical stimuli, such as cyclic stretch. Notably, a 10% stretch is associated with an atheroprotective endothelial phenotype, while a 20% stretch is associated with an atheroprone endothelial phenotype. Here, a systems biology-based approach is used to present a comprehensive overview of the functional responses and molecular regulatory networks that characterize the transition from an atheroprotective to an atheroprone phenotype in response to cyclic stretch. Using primary human umbilical vein endothelial cells (HUVECs), we determined the role of the equibiaxial cyclic stretch in vitro, with changes to the radius of the magnitudes of 10% and 20%, which are representative of physiological and pathological strain, respectively. Following the transcriptome analysis of next-generation sequencing data, we identified four key endothelial responses to pathological cyclic stretch: cell cycle regulation, inflammatory response, fatty acid metabolism, and mTOR signaling, driven by a regulatory network of eight transcription factors. Our study highlights the dynamic regulation of several key stretch-sensitive endothelial functions relevant to the induction of an atheroprone versus an atheroprotective phenotype and lays the foundation for further investigation into the mechanisms governing vascular pathology. This study has significant implications for the development of treatment modalities for vascular disease.

Nerve growth factor receptor (NGFR): a potential marker for specific molecular subtypes of breast cancer.

AIMS: Nerve growth factor receptor (NGFR) is a transmembrane receptor for the neurotrophin family. It acts either as tumour suppressor or oncogene depending on cellular context. Its role in breast cancers remained conflicting, possibly due to the heterogeneity of breast cancer subtypes. METHODS: In this study, we have analysed NGFR expression in 602 cases of breast cancers by immunohistochemistry. Its expression was correlated with biomarker expression and different breast cancer subtypes. RESULTS: NGFR expression was found to be positively correlated with basal markers, including Ki67, Cytokeratin (CK5/6), CK14, p63, c-kit and Epidermal growth factor receptor (EGFR) , but negatively with hormonal receptors. Among different molecular subtypes, it was negatively associated with luminal A, but positively with luminal B, and basal-like breast cancer BLBC subtypes. When comparing NGFR with other basal markers in BLBC, though less sensitive, its specificity was comparable to or better than other basal markers. For luminal B cancers, NGFR showed a high specificity which was also comparable to or better than the defining markers (estrogen receptor (ER), progesterone receptor (PR), Human epidermal growth receptor 2 (HER2) and Ki-67) for the subtype. CONCLUSIONS: Overall, these findings suggested that NGFR expression could be indicative for the BLBCs or luminal B subtypes. It may represent a potential adjunct marker for these two subtypes.

αB-crystallin is a useful marker for triple negative and basal breast cancers.

AIMS: Basal-like breast cancers (BLBCs), a breast cancer subtype with triple-negative status, pose significant problems in clinical management because of their aggressive behaviour. Recently, an association between αΒ-crystallin expression and BLBCs has been suggested, and we therefore investigated whether αΒ-crystallin could be a putative marker allowing BLBCs to be identified more accurately. METHODS AND RESULTS: We evaluated the expression of αB-crystallin and other biomarkers in 395 cases of breast carcinoma by immunohistochemistry, analysed the correlation of their expression with different breast cancer subtypes, and compared their sensitivity as well as specificity in identifying BLBCs. αΒ-crystallin expression was found to be correlated positively with basal markers and histological subtypes associated with BLBCs. A significant positive correlation of αΒ-crystallin expression was also found with triple-negative breast cancers (TNBC) (C = 0.409, P < 0.001) and BLBCs (C = 0.393, P < 0.001). Comparing αΒ-crystallin with other basal markers, only αΒ-crystallin demonstrated both high sensitivity (48.6%) and specificity (93.8%) as a TNBC marker. All other markers showed either a lower sensitivity of <40% or a lower specificity of <90%. αΒ-crystallin also demonstrated a high specificity (92.9%) and an even higher sensitivity (56.5%) for BLBCs. CONCLUSIONS: The findings indicated that αB-crystallin was a highly sensitive and specific marker for TNBCs and BLBCs.