Although chemotherapy, targeted therapy and endocrine therapy decrease rate of disease recurrence in most breast cancer patients, many patients exhibit acquired resistance. Hyperactivation of the PI3K/AKT/mTOR pathway is associated with drug resistance and cancer progression. Currently, a number of drugs targeting PI3K/AKT/mTOR are being investigated in clinical trials by combining them with standard therapies to overcome acquired resistance in breast cancer. In this review, we summarize the critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3K/AKT/mTOR inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer.

The skeletonized elephant trunk procedure is an effective way of closing the residual false lumen of the descending aorta and might contribute to better long-term outcomes for both acute and chronic type A aortic dissection.

Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancers without effective targeted therapies. Mifepristone (MIF), a drug regularly used for abortion, has been reported to have anti-tumor activity in multiple hormone-dependent cancers, including luminal type breast cancers. In this study, we showed that MIF suppressed tumor growth of the TNBC cell lines and patient-derived xenografts in NOD-SCID mice. Furthermore, MIF reduced the TNBC cancer stem cell (CSC) population through down-regulating KLF5 expression, a stem cell transcription factor over-expressed in basal type TNBC and promoting cell proliferation, survival and stemness. Interestingly, MIF suppresses the expression of KLF5 through inducing the expression of miR-153. Consistently, miR-153 decreases CSC and miR-153 inhibitor rescued MIF-induced down-regulation of the KLF5 protein level and CSC ratio. Taken together, our findings suggest that MIF inhibits basal TNBC via the miR-153/KLF5 axis and MIF may be used for the treatment of TNBC.

Calcium plays a central role in regulating signal transduction pathways. Calcineurin B-like proteins (CBLs), which harbor a crucial region consisting of EF hands that capture Ca2+, interact in a specific manner with CBL-interacting protein kinases (CIPKs). This two gene families or their interacting-complex widely respond to various environment stimuli and development processes. The genome-wide annotation and specific expression patterns of CBLs and CIPKs, however, in grapevine remain unclear. In the present study, eight CBL and 20 CIPK genes were identified in grapevine genome, and divided into four and five subfamilies, respectively, based on phylogenetic analysis, and validated by gene structure and the distribution of conserved protein motifs. Four (50%) out of eight VvCBLs and eight (40%) out of 20 VvCIPKs were found to be derived from tandem duplication, and five (25%) out of 20 VvCIPKs were derived from segmental duplication, indicating that the expansion of grapevine CBL and CIPK gene families were mainly contributed by gene duplication, and all duplication events between VvCIPK genes only detected in intron poor clade. Estimating of synonymous and non-synonymous substitution rates of both gene families suggested that VvCBL genes seems more conserved than VvCIPK genes, and were derived by positive selection pressure, whereas VvCIPK genes were mainly derived by purifying selection pressure. Expressional analyses of VvCBL and VvCIPK genes based on microarray and qRT-PCR data performed diverse expression patterns of VvCBLs and VvCIPKs in response to both various abiotic stimuli and at different development stages. Furthermore, the co-expression analysis of grapevine CBLs and CIPKs suggested that CBL-CIPK complex seems to be more responsive to abiotic stimuli than during different development stages. VvCBLs may play an important and special role in regulating low temperature stress. The protein interaction analysis suggested divergent mechanisms might exist between Arabidopsis and grapevine. Our results will facilitate the future functional characterization of individual VvCBLs and VvCIPKs.

Cancer is the most common cause of human death worldwide. Conventional anticancer therapies, including chemotherapy and radiation, are associated with severe side effects and toxicities as well as low specificity. Peptides are rapidly being developed as potential anticancer agents that specifically target cancer cells and are less toxic to normal tissues, thus making them a better alternative for the prevention and management of cancer. Recent research has focused on anticancer peptides from natural animal sources, such as terrestrial mammals, marine animals, amphibians, and animal venoms. However, the mode of action by which bioactive peptides inhibit the proliferation of cancer cells remains unclear. In this review, we present the animal sources from which bioactive peptides with anticancer activity are derived and discuss multiple proposed mechanisms by which these peptides exert cytotoxic effects against cancer cells.

No abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, which begins with isolated steatosis and advances to nonalcoholic steatohepatitis (NASH), steatofibrosis, and cirrhosis. The pathways involved in disease progression are not understood. Loss-of-function mutations in Wnt coreceptor LDL receptor-related protein 6 (LRP6) underlie early-onset atherosclerosis, metabolic risk factors, and NAFLD in humans by unknown mechanisms. We generated mice with the human disease-associated LRP6(R611C) mutation and phenotypically characterized their liver. Homozygote LRP6(R611C) (LRP6(mut/mut)) mice exhibited both steatohepatitis and steatofibrosis. These traits were associated with increased activity of the noncanonical Wnt/Ras homolog family member A, Rho-associated protein kinase 2, and PKC-α/-μ pathways. Accordingly, there was increased TGF-β1 activity, coupled with enhanced expression of smooth muscle α-actin and vimentin that colocalized with albumin in LRP6(mut/mut) mouse liver. LRP6 knockdown reprogramed HepG2 cells to express both these markers, linking impaired Wnt signaling with hepatocyte transdifferentiation. The causal link between altered Wnt signaling and NASH was established by normalization of the disease pathways and rescue of the liver traits by Wnt3a administration to LRP6(mut/mut) mice. Thus, this study identifies diverse disease pathways that underlie a spectrum of NASH-related liver diseases and are linked by a single human genetic variant. LRP6 and noncanonical Wnt pathways are important potential therapeutic targets against NASH.

Abstract1-Methylcyclopropene (1-MCP) is an inhibitor of ethylene perception that is widely used to maintain the quality of several climacteric fruits during storage. A large body of literature now exists on the effects of 1-MCP on climacteric fruit ripening for different species and environmental conditions, presenting an opportunity to use meta-analysis to systematically dissect these effects. We classified 44 ripening indicators of climacteric fruits into five categories: physiology and biochemistry, quality, enzyme activity, color, and volatiles. Meta-analysis showed that 1-MCP treatment reduced 20 of the 44 indicators by a minimum of 22% and increased 6 indicators by at least 20%. These effects were associated with positive effects on delaying ripening and maintaining quality. Of the seven moderating variables, species, 1-MCP concentration, storage temperature and time had substantial impacts on the responses of fruit to 1-MCP treatment. Fruits from different species varied in their responses to 1-MCP, with the most pronounced responses observed in rosaceous fruits, especially apple, European pear fruits, and tropical fruits. The effect of gaseous 1-MCP was optimal at 1 μl/l, with a treatment time of 12–24 h, when the storage temperature was 0 °C for temperate fruits or 20 °C for tropical fruits, and when the shelf temperature was 20 °C, reflecting the majority of experimental approaches. These findings will help improve the efficacy of 1-MCP application during the storage of climacteric fruits, reduce fruit quality losses and increase commercial value.