3%, 64.5%, 48.5%, and 23.7% in patients with 0, 1, 2, and 3 points, respectively, with a median BCSS of 72, 52, 35, and 16 months, respectively (P  less then  0.001). The multivariate prognostic analysis showed that the risk score staging system was an independent prognostic factor associated with BCSS. Patients with a higher risk score had a lower BCSS. Sensitivity analyses replicated similar findings after stratification according to tumor stage, nodal stage, the sites of distant metastasis, and the number of distant metastasis. In conclusion, our risk score staging system shows promise for the prognostic stratification of de novo stage IV breast cancer.Migration and invasion are key properties of metastatic cancer cells. These properties can be acquired through intrinsic reprogramming processes such as epithelial-mesenchymal transition. In this study, we discovered an alternative "migration-by-tethering" mechanism through which cancer cells gain the momentum to migrate by adhering to mesenchymal stem cells or osteoblasts. This tethering is mediated by both heterotypic adherens junctions and gap junctions, and leads to a unique cellular protrusion supported by cofilin-coated actin filaments. Inhibition of gap junctions or depletion of cofilin reduces migration-by-tethering. We observed evidence of these protrusions in bone segments harboring experimental and spontaneous bone metastasis in animal models. These data exemplify how cancer cells may acquire migratory ability without intrinsic reprogramming. Furthermore, given the important roles of osteogenic cells in early-stage bone colonization, our observations raise the possibility that migration-by-tethering may drive the relocation of disseminated tumor cells between different niches in the bone microenvironment.Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.Replication stress entails the improper progression of DNA replication. In cancer cells, including breast cancer cells, an important cause of replication stress is oncogene activation. Importantly, tumors with high levels of replication stress may have different clinical behavior, and high levels of replication stress appear to be a vulnerability of cancer cells, which may be therapeutically targeted by novel molecularly targeted agents. Unfortunately, data on replication stress is largely based on experimental models. Further investigation of replication stress in clinical samples is required to optimally implement novel therapeutics. To uncover the relation between oncogene expression, replication stress, and clinical features of breast cancer subgroups, we immunohistochemically analyzed the expression of a panel of oncogenes (Cyclin E, c-Myc, and Cdc25A,) and markers of replication stress (phospho-Ser33-RPA32 and γ-H2AX) in breast tumor tissues prior to treatment (n = 384). Triple-negative breast cancers (TNBCs) exhibited the highest levels of phospho-Ser33-RPA32 (P  less then  0.001 for all tests) and γ-H2AX (P  less then  0.05 for all tests). Moreover, expression levels of Cyclin E (P  less then  0.001 for all tests) and c-Myc (P  less then  0.001 for all tests) were highest in TNBCs. Expression of Cyclin E positively correlated with phospho-RPA32 (Spearman correlation r = 0.37, P  less then  0.001) and γ-H2AX (Spearman correlation r = 0.63, P  less then  0.001). Combined, these data indicate that, among breast cancers, replication stress is predominantly observed in TNBCs, and is associated with expression levels of Cyclin E. These results indicate that Cyclin E overexpression may be used as a biomarker for patient selection in the clinical evaluation of drugs that target the DNA replication stress response.The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology.  https://www.selleckchem.com/products/sd-208.html  These are divided into three basic competencies Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http//journals.sagepub.com/doi/10.1177/2374289517715040.1.The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http//journals.sagepub.com/doi/10.1177/2374289517715040.1.Although many examples of simulated and real microgravity demonstrating their profound effect on biological systems are described in literature, few reports deal with hypergravity and vibration effects, the levels of which are severely increased during the launch preceding the desired microgravity period. Here, we used planarians, flatworms that can regenerate any body part in a few days. Planarians are an ideal model to study the impact of launch-related hypergravity and vibration during a regenerative process in a "whole animal" context. Therefore, planarians were subjected to 8.5 minutes of 4 g hypergravity (i.e. a human-rated launch level) in the Large Diameter Centrifuge (LDC) and/or to vibrations (20-2000 Hz, 11.3 Grms) simulating the conditions of a standard rocket launch. The transcriptional levels of genes (erg-1, runt-1, fos, jnk, and yki) related with the early stress response were quantified through qPCR. The results show that early response genes are severely deregulated after static and dynamic loads but more so after a combined exposure of dynamic (vibration) and static (hypergravity) loads, more closely simulating real launch exposure profiles.