Metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and ...endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b+Gr1+ myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention.
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► CXCL1/2 mediate breast cancer metastasis through myeloid cell recruitment ► CXCL1/2 promote breast cancer cell survival through myeloid-cell-derived S100A8/9 ► Chemotherapeutic agents induce TNF-α to hyperactivate the CXCL1/2–S100A8/9 axis ► Blocking CXCL1 signaling improves chemotherapy efficacy and diminishes metastasis
A paracrine cascade that triggers the production of survival factors by surrounding stromal cells, enabling the survival of metastatic cancer cells, is also elicited by chemotherapeutic agents and is central to chemoresistance. Blocking this chemokine axis may improve the efficacy of chemotherapy and reduce metastatic burden in breast cancer.
The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for ...the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain.
The synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation asserts that the induction of synaptic potentiation creates only the potential for a lasting change ...in synaptic efficacy, but not the commitment to such a change. Other neural activity, before or after induction, can also determine whether persistent change occurs. Recent findings, leading us to revise the original hypothesis, indicate that the induction of a local, synapse-specific 'tagged' state and the expression of long-term potentiation are dissociable. Additional observations suggest that there are major differences in the mechanisms of functional and structural plasticity. These advances call for a revised theory that incorporates the specific molecular and structural processes involved. Addressing the physiological relevance of previous in vitro findings, new behavioural studies have experimentally translated the hypothesis to learning and the consolidation of newly formed memories.
Functional diversity of the highly polymorphic human leukocyte antigen class I (HLA-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele ...advantage hypothesis dictates that an HLA-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes
. However, the effect of sequence divergence between HLA-I alleles-a quantifiable measure of HLA-I evolution-on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient's genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex-peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.
CD8
T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific ...HLA-I genotype influences response to anti-programmed cell death protein 1 or anti-cytotoxic T lymphocyte-associated protein 4 is currently unknown. We determined the HLA-I genotype of 1535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci ("A," "B," and "C") improved overall survival after ICB compared with patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed different elements that may impair CD8
T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.
We review here for the first time, the literature on control of ice nucleation in cryopreservation. Water and aqueous solutions have a tendency to undercool before ice nucleation occurs. Control of ...ice nucleation has been recognised as a critical step in the cryopreservation of embryos and oocytes but is largely ignored for other cell types. We review the processes of ice nucleation and crystal growth in the solution around cells and tissues during cryopreservation with an emphasis on non IVF applications. The extent of undercooling that is encountered during the cooling of various cryocontainers is defined and the methods that have been employed to control the nucleation of ice are examined. The effects of controlled ice nucleation on the structure of the sample and the outcome of cryopreservation of a range of cell types and tissues are presented and the physical events which define the cellular response are discussed.
Nucleation of ice is the most significant uncontrolled variable in conventional cryopreservation leading to sample to sample variation in cell recovery, viability and function and should be controlled to allow standardisation of cryopreservation protocols for cells for biobanking, cell based assays or clinical application. This intervention allows a way of increasing viability of cells and reducing variability between samples and should be included as standard operating procedures are developed.
Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and ...other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.
Bones and Bodies is a highly accessible account of the
establishment of the scientific discipline of biological
anthropology. Alan G Morris takes us back over the past century of
anthropological ...discovery in South Africa and uncovers the stories
of individual scientists and researchers who played a significant
role in shaping perceptions of how peoples of southern Africa, both
ancient and modern, came to be viewed and categorised both in the
public imagination and the scientific literature. Morris reveals
how much of the earlier anthropological studies were tainted with
the tarred brush of race science. He evaluates the works of famous
anthropologists and archaeologists such as Raymond Dart, Thomas
Dreyer, Matthew Drennan and Robert Broom, and demonstrates through
a wide array of sources how they described their fossil discoveries
through the prism of racist interpretation. Morris also shows how
modern anthropology tried to rid itself of the stigma of these
early racist accounts. In the 1960s and 1970s, Ronald Singer and
Phillip Tobias introduced modern methods into the discipline that
disputed much of what the public believed about race and human
evolution. In an age in which the authority of experts and
empirical science is increasingly being questioned, this book shows
the battle facing modern anthropology to acknowledge its racial
past but also how its study of human variation remains an important
field of enquiry at institutions of higher learning.
Bones and Bodies is a highly accessible account of the
establishment of the scientific discipline of biological
anthropology. Alan G Morris takes us back over the past century of
anthropological discovery in South Africa and uncovers the stories
of individual scientists and researchers who played a significant
role in shaping perceptions of how peoples of southern Africa, both
ancient and modern, came to be viewed and categorised both in the
public imagination and the scientific literature. Morris reveals
how much of the earlier anthropological studies were tainted with
the tarred brush of race science, evaluating the works of famous
anthropologists and archaeologists such as Raymond Dart, Thomas
Dreyer, Matthew Drennan and Robert Broom. Morris also considers how
modern anthropology tried to rid itself of the stigma of these
early racist accounts. In the 1960s and 1970s, Ronald Singer and
Phillip Tobias introduced modern methods into the discipline that
disputed much of what the public wished to believe about race and
human evolution. Bones and Bodies shows the battle facing
modern anthropology to acknowledge its racial past but also how its
study of human variation remains an important field of enquiry at
institutions of higher learning.
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