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Cancer is a systemic disease encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion, and metastasis. In breast cancer, CAFs not only promote tumor progression but also induce therapeutic resistance. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistance. This review summarizes the current understandings of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. In addition, the effects of other stromal components such as endothelial cells, macrophages, and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to categorize patients into a specific and confirmed subtype for personalized treatment.

In order to obtain a systems‐level understanding of a complex biological system, detailed proteome information is essential. Despite great progress in proteomics technologies, thorough interrogation of the proteome from quantity‐limited biological samples is hampered by inefficiencies during processing. To address these challenges, here we introduce a novel protocol using paramagnetic beads, termed Single‐Pot Solid‐Phase‐enhanced Sample Preparation (SP3). SP3 provides a rapid and unbiased means of proteomic sample preparation in a single tube that facilitates ultrasensitive analysis by outperforming existing protocols in terms of efficiency, scalability, speed, throughput, and flexibility. To illustrate these benefits, characterization of 1,000 HeLa cells and single Drosophila embryos is used to establish that SP3 provides an enhanced platform for profiling proteomes derived from sub‐microgram amounts of material. These data present a first view of developmental stage‐specific proteome dynamics in Drosophila at a single‐embryo resolution, permitting characterization of inter‐individual expression variation. Together, the findings of this work position SP3 as a superior protocol that facilitates exciting new directions in multiple areas of proteomics ranging from developmental biology to clinical applications. Synopsis A new proteomic sample preparation protocol allows fast, efficient and ultra‐sensitive analyses. The method is illustrated by profiling proteomes from sub‐microgram amounts of material, including the first proteome screen of Drosophila development at a single‐embryo resolution. A novel protocol using paramagnetic beads, termed Single‐Pot Solid‐Phase‐enhanced Sample Preparation (SP3) is presented. SP3 enables protein and peptide enrichment, cleanup, digestion, chemical isotope labeling and fractionation in a single tube, without limitations arising from reagent compatibility. SP3 allows unmatched ultra‐sensitive proteome profiling from sub‐microgram amounts of material, as low as 1,000 HeLa cells or a single fly embryo. The first quantitative analysis of early Drosophila development at a single‐embryo resolution reveals dynamic trends in the developmental proteome. Graphical Abstract A new proteomic sample preparation protocol allows fast, efficient and ultra‐sensitive analyses. The method is illustrated by profiling proteomes from sub‐microgram amounts of material, including the first proteome screen of Drosophila development at a single‐embryo resolution.

An improved assay for chromatin accessibility at single-cell resolution in Drosophila melanogaster embryos enables identification of developmental-stage- and cell-lineage-specific patterns of chromatin-level transcriptional regulation. Single-cell ATAC-seq in fly embryos Active gene regulatory elements shape the output of gene transcription and can be mapped across the genome by measuring chromatin accessibility. Eileen Furlong and colleagues apply a technique called ATAC sequencing to profile chromatin accessibility at a single-cell resolution during three stages of Drosophila embryogenesis. They map tissue-specific regulatory elements and show that the chromatin accessibility landscape is sufficient to infer individual cell types and developmental trajectories. A group of cells is found to use regulatory elements of both mesoderm and endoderm, which suggests the existence of a mesendoderm lineage in Drosophila . Understanding how gene regulatory networks control the progressive restriction of cell fates is a long-standing challenge. Recent advances in measuring gene expression in single cells are providing new insights into lineage commitment. However, the regulatory events underlying these changes remain unclear. Here we investigate the dynamics of chromatin regulatory landscapes during embryogenesis at single-cell resolution. Using single-cell combinatorial indexing assay for transposase accessible chromatin with sequencing (sci-ATAC-seq) 1 , we profiled chromatin accessibility in over 20,000 single nuclei from fixed Drosophila melanogaster embryos spanning three landmark embryonic stages: 2–4 h after egg laying (predominantly stage 5 blastoderm nuclei), when each embryo comprises around 6,000 multipotent cells; 6–8 h after egg laying (predominantly stage 10–11), to capture a midpoint in embryonic development when major lineages in the mesoderm and ectoderm are specified; and 10–12 h after egg laying (predominantly stage 13), when each of the embryo’s more than 20,000 cells are undergoing terminal differentiation. Our results show that there is spatial heterogeneity in the accessibility of the regulatory genome before gastrulation, a feature that aligns with future cell fate, and that nuclei can be temporally ordered along developmental trajectories. During mid-embryogenesis, tissue granularity emerges such that individual cell types can be inferred by their chromatin accessibility while maintaining a signature of their germ layer of origin. Analysis of the data reveals overlapping usage of regulatory elements between cells of the endoderm and non-myogenic mesoderm, suggesting a common developmental program that is reminiscent of the mesendoderm lineage in other species 2 , 3 , 4 . We identify 30,075 distal regulatory elements that exhibit tissue-specific accessibility. We validated the germ-layer specificity of a subset of these predicted enhancers in transgenic embryos, achieving an accuracy of 90%. Overall, our results demonstrate the power of shotgun single-cell profiling of embryos to resolve dynamic changes in the chromatin landscape during development, and to uncover the cis -regulatory programs of metazoan germ layers and cell types.

Efficient photon upconversion at low light intensities promises major advances in technologies spanning solar energy harvesting to deep-tissue biophotonics. Here, we discover the critical mechanisms that enable near-infrared dye antennas to significantly enhance performance in lanthanide-doped upconverting nanoparticle (UCNP) systems, and leverage these findings to design dye–UCNP hybrids with a 33,000-fold increase in brightness and a 100-fold increase in efficiency over bare UCNPs. We show that increasing the lanthanide content in the UCNPs shifts the primary energy donor from the dye singlet to its triplet, and the resultant triplet states then mediate energy transfer into the nanocrystals. Time-gated phosphorescence, density functional theory, singlet lifetimes and triplet-quenching experiments support these findings. This interplay between the excited-state populations in organic antennas and the composition of UCNPs presents new design rules that overcome the limitations of previous upconverting materials, enabling performances now relevant for photovoltaics, biophotonics and infrared detection.

Regulatory interactions buffer development against genetic and environmental perturbations, but adaptation requires phenotypes to change. We investigated the relationship between robustness and evolvability within the gene regulatory network underlying development of the larval skeleton in the sea urchin Strongylocentrotus purpuratus. We find extensive variation in gene expression in this network throughout development in a natural population, some of which has a heritable genetic basis. Switch-like regulatory interactions predominate during early development, buffer expression variation, and may promote the accumulation of cryptic genetic variation affecting early stages. Regulatory interactions during later development are typically more sensitive (linear), allowing variation in expression to affect downstream target genes. Variation in skeletal morphology is associated primarily with expression variation of a few, primarily structural, genes at terminal positions within the network. These results indicate that the position and properties of gene interactions within a network can have important evolutionary consequences independent of their immediate regulatory role.

Triple negative breast cancer (TNBC) is associated with high pathological complete remission (pCR) rate in neoadjuvant treatment (NAT). TNBC patients who achieve pCR have superior outcome than those without pCR. A meta-analysis was done to evaluate whether integrating novel approaches into NAT can improve the pCR rate in TNBC. Medical subject heading terms (Breast Neoplasm) and key words (triple negative OR estrogen receptor (ER) negative OR HER2 negative) AND (primary systemic OR neoadjuvant OR preoperative) were used to select eligible studies. Experimental arm in each study was considered as the testing regimen, and control arm was defined as the standard regimen in this meta-analysis. A total of 11 studies with 14 paired regimens were included in the final analysis. Aggregate pCR rate was 37.3% and 44.6% in the standard and testing group, respectively. Novel approaches in the testing regimen significantly improved the pCR rate in NAT of TNBC patients compared with the standard regimen, with an odds ratio (OR) of 1.34 (95% confidence interval (CI) 1.11-1.62, P = 0.002). Considering specific regimens, we demonstrated the pCR rate to be much higher in the carboplatin-containing (OR = 1.80, 95% CI 1.39-2.32, P<0.001) or bevacizumab-containing regimens (OR = 1.36, 95% CI 1.11-1.66, P = 0.003) than in the control regimens. The addition of carboplatin in NAT had a pCR rate as high as 51.2% in TNBC patients, with an absolute pCR difference of 13.8% as compared with control regimens. No significant heterogeneity was identified among studies evaluating the addition of carboplatin or bevacizumab efficacy in NAT. This meta-analysis indicates that these novel NAT regimens have achieved a significant pCR improvement in TNBC patients, especially among patients treated with carboplatin-containing or bevacizumab-containing regimen. This can help us design appropriate trials in the adjuvant setting and guide clinical practice.

Cellular senescence and the senescence-associated secretory phenotype (SASP) are implicated in aging and age-related disease, and SASP-related inflammation is thought to contribute to tissue dysfunction in aging and diseased animals. However, whether and how SASP factors influence the regenerative capacity of tissues remains unclear. Here, using intestinal organoids as a model of tissue regeneration, we show that SASP factors released by senescent fibroblasts deregulate stem cell activity and differentiation and ultimately impair crypt formation. We identify the secreted N-terminal domain of Ptk7 as a key component of the SASP that activates non-canonical Wnt / Ca 2+ signaling through FZD7 in intestinal stem cells (ISCs). Changes in cytosolic [Ca 2+ ] elicited by Ptk7 promote nuclear translocation of YAP and induce expression of YAP/TEAD target genes, impairing symmetry breaking and stem cell differentiation. Our study discovers secreted Ptk7 as a factor released by senescent cells and provides insight into the mechanism by which cellular senescence contributes to tissue dysfunction in aging and disease. Cellular senescence and associated secretory phenotype (SASP) are thought to contribute to aging and tissue dysfunction, though it is unclear how SASP impacts regeneration. Here the authors show that SASP factors impair regeneration, and that Ptk7 is a key secreted protein mediating that dysregulation.

In this cohesive, dramatic, and highly readable book, the author establishes a roadmap for the diagnosis and psychotherapeutic treatment of psychotic disorders based on finding, understanding and reordering of unbearable affect. He provides concrete clinical advice, vivid examples, and crisp jargon-free descriptions of theoretical concepts and clinical techniques. Most of all, he demonstrates that it is possible for psychotic patients to take control of their conditions, rebuild family relationships, and establish themselves in the viable productive lives that they have long despaired of achieving.