Explore the vast range of titles available.

Although synergy is a pillar of modern pharmacology, toxicology, and medicine, there is no consensus on its definition despite its nearly one hundred-year history. Moreover, methods for statistical determination of synergy that account for variation of response to treatment are underdeveloped and if exist are reduced to the traditional t-test, but do not comply with the normal distribution assumption. We offer statistical models for estimation of synergy using an established definition of Bliss drugs' independence. Although Bliss definition is well-known, it remains a theoretical concept and has never been applied for statistical determination of synergy with various forms of treatment outcome. We rigorously and consistently extend the Bliss definition to detect statistically significant synergy under various designs: (1) in vitro, when the outcome of a cell culture experiment with replicates is the proportion of surviving cells for a single dose or multiple doses, (2) dose-response methodology, (3) in vivo studies in organisms, when the outcome is a longitudinal measurement such as tumor volume, and (4) clinical studies, when the outcome of treatment is measured by survival. For each design, we developed a specific statistical model and demonstrated how to test for independence, synergy, and antagonism, and compute the associated p-value.

Precision oncology seeks to integrate multiple layers of data from a patient's cancer to effectively tailor therapy. Conventional chemotherapies are sometimes effective but accompanied by adverse events, warranting the identification of a biomarker of chemosensitivity. Identify an mRNA biomarker that predicts chemosensitivity across solid tumor subtypes. We performed a pan-solid tumor analysis integrating gene expression and drug sensitivity profiles from 3 cancer cell line datasets to identify transcripts correlated with sensitivity to a panel of chemotherapeutics. We then tested the ability of an mRNA biomarker to predictive clinical outcomes in cohorts of patients with breast, lung, or ovarian cancer. Expression levels of several mRNA transcripts were significantly correlated with sensitivity or resistance chemotherapeutics in cancer cell line datasets. The only mRNA transcript significantly correlated with sensitization to multiple classes of DNA-damaging chemotherapeutics in all 3 cell line datasets was encoded by Schlafen Family Member 11 (SLFN11). Analyses of multiple breast, lung, and ovarian cancer patient cohorts treated with chemotherapy confirmed SLFN11 mRNA expression as a predictive biomarker of longer overall survival and improved tumor response. Tumor SLFN11 mRNA expression is a biomarker of sensitivity to an array of DNA-damaging chemotherapeutics across solid tumor subtypes.

Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD8 + and CD4 + T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, ( R )- 9b , recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive. Immune checkpoint blockade is showing promise in cancer immune therapy, but many solid tumours are resistant. Authors here identify a pathway in T cells that leads to increased activity of C-terminal Src kinase, a negative regulator of T cell activity, thus disabling tumour infiltrating T cells and causing immune therapy resistance.

Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) is a tyrosine kinase that was discovered in 1994. It is a member of a family of nonreceptor tyrosine kinases that also includes Brk (PTK6) and Frk. Compared with other tyrosine kinases, there is relatively little information about the structure, function, and regulation of SRMS. In this review, we summarize the current state of knowledge regarding SRMS, including recent results aimed at identifying downstream signaling partners. We also present a structural model for the enzyme and discuss the potential involvement of SRMS in cancer cell signaling.

Choanoflagellates are the closest known relatives of metazoans. To discover potential molecular mechanisms underlying the evolution of metazoan multicellularity, we sequenced and analysed the genome of the unicellular choanoflagellate Monosiga brevicollis . The genome contains approximately 9,200 intron-rich genes, including a number that encode cell adhesion and signalling protein domains that are otherwise restricted to metazoans. Here we show that the physical linkages among protein domains often differ between M. brevicollis and metazoans, suggesting that abundant domain shuffling followed the separation of the choanoflagellate and metazoan lineages. The completion of the M. brevicollis genome allows us to reconstruct with increasing resolution the genomic changes that accompanied the origin of metazoans. A key protozoan genome The genome sequence of the marine choanoflagellate Monosiga brevicollis has now been determined. Choanoflagellates are a mainly sessile group of protozoa resembling the 'feeding cells' of sponges, and are considered to be the closest living unicellular relatives of multicellular animals. Comparison of the M. brevicollis sequence with metazoan genomes suggests that the last unicellular ancestor of animals had intron-rich genes, some encoding protein domains characteristically associated with cell adhesion and the extracellular matrix in animals. This organism is strictly unicellular, but other choanoflagellates form colonies and may provide clues as to the origin of cell signalling and other systems in early metazoans.

Background Epithelial-mesenchymal transition (EMT) is a dynamic process that contributes to breast cancer progression, metastasis, and therapy resistance. EMT also influences the tumor immune microenvironment, shaping immune cell infiltration and function. Although the immunological features of fully epithelial or fully mesenchymal tumor states have been characterized, the immune landscape associated with intermediate or partial EMT states remains poorly understood. Methods To examine the relationship between EMT progression and immune cell composition and function, we established five single-cell–derived clonal populations from the triple-negative 4T1 mouse mammary tumor cell line, representing a spectrum of EMT phenotypes, and analyzed tumors derived from these clones using single-cell RNA sequencing. Results Tumors derived from these clones retained their relative EMT states in vivo, and EMT progression was associated with a graded reduction in tumor immunogenicity, accompanied by alterations in immune cell composition and function. Along the EMT spectrum, tumor cells exhibited progressive downregulation of major histocompatibility complex (MHC) class I and II gene expression, along with decreased infiltration of cytotoxic CD8+ T cells and reduced expression of key effector and trafficking genes ( Gzmb ,  Ccr5 ,  Cxcr6 ). B cell composition also shifted, with decreased frequencies of IgG1-producing plasma cells and an enrichment of regulatory-like B cells. Natural killer (NK) cells similarly demonstrated progressive functional suppression, marked by reduced expression of cytotoxic molecules and the downregulation of specific effector pathways. Conclusions These findings reveal that EMT is associated with immune cell recruitment and function in a graded manner, providing a rationale for integrating EMT phenotyping into therapeutic strategies to overcome immune resistance in breast cancer.

Many breast cancers exhibit a degree of dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from hormone dependence in estrogen receptor-positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17beta-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.

Creolimax fragrantissima is a member of the ichthyosporean clade, the earliest branching holozoan lineage. The kinome of Creolimax is markedly reduced as compared to those of metazoans. In particular, Creolimax possesses a single non-receptor tyrosine kinase: CfrSrc, the homolog of c-Src kinase. CfrSrc is an active tyrosine kinase, and it is expressed throughout the lifecycle of Creolimax . In animal cells, the regulatory mechanism for Src involves tyrosine phosphorylation at a C-terminal site by Csk kinase. The lack of Csk in Creolimax suggests that a different mode of negative regulation must exist for CfrSrc. We demonstrate that CfrPTP-3, one of the 7 tyrosine-specific phosphatases (PTPs) in Creolimax , suppresses CfrSrc activity in vitro and in vivo . Transcript levels of CfrPTP-3 and two other PTPs are significantly higher than that of CfrSrc in the motile amoeboid and sessile multinucleate stages of the Creolimax life cycle. Thus, in the context of a highly reduced kinome, a pre-existing PTP may have been co-opted for the role of Src regulation. Creolimax represents a unique model system to study the adaptation of tyrosine kinase signaling and regulatory mechanisms.

Estrogen receptor alpha (ER)-positive breast cancer is commonly treated with endocrine therapies, including antiestrogens that bind and inhibit ER activity, and aromatase inhibitors that suppress estrogen biosynthesis to inhibit estrogen-dependent ER activity. Paradoxically, treatment with estrogens such as 17b-estradiol can also be effective against ER+ breast cancer. Despite the known efficacy of estrogen therapy, the lack of a predictive biomarker of response and understanding of the mechanism of action have contributed to its limited clinical use. Herein, we demonstrate that ER overexpression confers resistance to estrogen deprivation through ER activation in human ER+ breast cancer cells and xenografts grown in mice. However, ER overexpression and the associated high levels of ER transcriptional activation converted 17b-estradiol from a growth-promoter to a growth-suppressor, offering a targetable therapeutic vulnerability and a potential means of identifying patients likely to benefit from estrogen therapy. Since ER+ breast cancer cells and tumors ultimately developed resistance to continuous estrogen deprivation or continuous 17b-estradiol treatment, we tested schedules of alternating treatments. Oscillation of ER activity through cycling of 17b-estradiol and estrogen deprivation provided long-term control of patient-derived xenografts, offering a novel endocrine-only strategy to manage ER+ breast cancer.

Changing ocean conditions in higher latitude ecosystems and the potential impact on marine fish underscores the need for baseline information on their biology and growth. Here we present length weight regression (LWR) results of 12 species of fish from coastal, estuarine and lagoon waters of the eastern Bering, Chukchi, and Beaufort seas: Myoxocephalus scorpioides (Fabricius, 1780); Myoxocephalus quadricornis (Linnaeus, 1758); Myoxocephalus scorpius (Linnaeus, 1758); Gymnocanthus tricuspis (Reinhardt, 1830); Lumpenus fabricii Reinhardt, 1836; Lumpenus sagitta Wilimovsky, 1956; Osmerus dentex Steindachner et Kner, 1870; Hypomesus olidus (Pallas, 1814); Mallotus villosus (Müller, 1776); Liopsetta glacialis (Pallas, 1776); Pungitius pungitius (Linnaeus, 1758); Diaphus theta Eigenmann et Eigenmann, 1890. Of the species examined, four were in the family Cottidae, three in Osmeridae, two in Stichaeidae, and one each in Gasterosteidae, Myctophidae, and Pleuronectidae. Results showed the LWR coefficient b was significantly >3 for all cottids (sculpins) and osmerids (smelts), indicating positive allometric growth. One species ( L. fabricii ) in Stichaeidae had a b significantly >3, with the other species ( L. sagitta ) being significantly <3. The one species in Gasterosteidae (stickleback, P. pungitius ) and Myctophidae (lanternfish, D. theta ) also showed significantly <3, indicating negative allometric growth. Of the species examined, this is the first reporting of LWR results for Arctic sculpin ( M. scorpioides ).