CDKN1C (encoding tumor suppressor p57(KIP2)) is a cyclin-dependent kinase (CDK) inhibitor whose family members are often transcriptionally downregulated in human cancer via promoter DNA methylation. ...In this study, we show that CDKN1C is repressed in breast cancer cells mainly through histone modifications. In particular, we show that CDKN1C is targeted by histone methyltransferase EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3), and can be strongly activated by inhibition of EZH2 in synergy with histone deacetylase inhibitor. Consistent with the overexpression of EZH2 in a variety of human cancers including breast cancer, CDKN1C in these cancers is downregulated, and breast tumors expressing low levels of CDKN1C are associated with a poor prognosis. We further show that assessing both EZH2 and CDKN1C expression levels as a measurement of EZH2 pathway activity provides a more predictive power of disease outcome than that achieved with EZH2 or CDKN1C alone. Taken together, our study reveals a novel epigenetic mechanism governing CDKN1C repression in breast cancer. Importantly, as a newly identified EZH2 target with prognostic value, it has implications in patient stratification for cancer therapeutic targeting EZH2-mediated gene repression.
Here, we focus on molecular biomarkers derived from transcriptomic studies to summarize the recent advances in our understanding of the mechanisms associated with differential prognosis and treatment ...outcome in breast cancer.
Breast cancer is certainly immunogenic; yet it has been historically resistant to immunotherapy. In the past few years, refined immunotherapeutic manipulations have been shown to be effective in a significant proportion of cancer patients. For example, drugs targeting the PD-1 immune checkpoint have been proven to be an effective therapeutic approach in several solid tumors including melanoma and lung cancer. Very recently, the activity of such therapeutics has also been demonstrated in breast cancer patients. Pari passu with the development of novel immune modulators, the transcriptomic analysis of human tumors unveiled unexpected and paradoxical relationships between cancer cells and immune cells.
This review examines our understanding of the molecular pathways associated with intratumoral immune response, which represents a critical step for the implementation of stratification strategies toward the development of personalized immunotherapy of breast cancer.
Historically, play behavior has been difficult to define. This likely stems from the number of different species, types of play, and context under which it occurs. In 2016, the Chicago Zoological ...Society – Brookfield Zoo hosted the Psychonomic Society leading edge workshop on the evolutionary and psychological significance of play. Sixteen experts attended from the diverse fields of African ethnology, animal behavior, animal science, animal welfare, cognitive psychology, cognitive zoology, comparative psychology, cultural anthropology, developmental psychology, educational psychology, ethology, neuroscience, primatology, and zoology. Approximately half of the participants studied human play and the other half studied non-human play. Before the workshop, participants were asked to send in either their personal definition of play or the one that they cite in peer-reviewed literature. Definitions were then reviewed to determine characteristics of play inclusive of all disciplines. The goal of the current study was not to do a literature review on play behavior, but to come up with a list of characteristics across all forms of play that could be used as a common terminology moving forward. Hopefully the results of this workshop and the current article will help to increase cross-disciplinary research in the field of play.
Immunotherapy efficacy data on appendiceal cancer from clinical trials does not exist, due to appendiceal cancer incidence of 0.97 per 100,000. The goal of this study was to preclinically explore the ...application of immunotherapy in treating appendiceal cancer in a personalized organoid model.
Patient tumor organoids (PTO) were fabricated using unsorted tumor cells with and without enrichment with patient-matched immune components derived from peripheral blood leukocytes, spleen, or lymph nodes immune-enhanced PTOs (iPTO). Organoids were cultured for 7 days, followed by treatment with immunotherapy (pembrolizumab, ipilimumab, nivolumab), and assessed for treatment efficacy.
Between September 2019 and May 2021, 26 patients were enrolled in the study. Successful testing was conducted in 19 of 26 (73.1%) patients, with 13 of 19 (68.4%) and 6 of 19 (31.6%) patients having low-grade appendiceal (LGA) and high-grade appendiceal (HGA) primaries, respectively. Immunotherapy response, with increased expression of granzyme B and cleaved caspase 3 and decreased expression of CK20 and ATP activity, was exhibited in 4 of 19 (21.1%) pembrolizumab-treated and 2 of 19 (10.5%) nivolumab-treated iPTOs. Post-immunotherapy cellular viability, in responding HGA organoids to pembrolizumab, decreased to less than 15% (
< 0.05). LGA iPTO treatment responses were observed in pembrolizumab and nivolumab, with an 8%-47.4% (
< 0.05) viability compared with controls. Ipilimumab showed no efficacy in the examined cohort.
Immunotherapy shows measurable efficacy in appendiceal cancer organoids. Information derived from immunocompetent organoids may be applied in selecting patients for clinical trial enrollment in rare diseases where preclinical models of disease are lacking.
The goal of the current study was to create reference intervals and values for several common and one potential novel physiological indicators of animal welfare for four species of cetaceans. The ...subjects included 189 bottlenose dolphins (Tursiops truncatus), 27 Indo-Pacific bottlenose dolphins (Tursiops aduncus), eight Pacific white-sided dolphins (Lagenorhynchus obliquidens), and 13 beluga whales (Delphinapterus leucas) at Alliance of Marine Mammal Parks and Aquariums and/or Association of Zoos and Aquariums accredited facilities. During two sampling time periods between July and November of 2018 and between January and April of 2019, fecal samples were collected weekly for five weeks from all animals. Samples were processed and analyzed using enzyme immunoassay for fecal cortisol, aldosterone, and dehydroepiandrosterone (DHEA) metabolites. Linear mixed models were used to examine demographic and time factors impacting hormone metabolite concentrations. Age, sex, and time of year were all significant predictors for some of the models (p < 0.01). An iOS mobile application ZooPhysioTrak was created for easy access to species-specific reference intervals and values accounting for significant predictors. For facilities without access to this application, additional reference intervals and values were constructed without accounting for significant predictors. Information gained from this study and the use of the application can provide reference intervals and values to make informed management decisions for cetaceans in zoological facilities.
We present results of weak lensing cluster counts obtained from 11-degree2 Subaru/SuprimeCam data. Although the area is much smaller than previous work dealing with weak lensing peak statistics, the ...number density of galaxies usable for weak lensing analysis is about twice as large. The higher galaxy number density reduces the noise in the weak lensing mass maps, and thus increases the signal-to-noise ratio (S/N) of peaks of the lensing signal due to massive clusters. This enables us to construct a weak lensing selected cluster sample by adopting a high threshold S/N, such that the contamination rate due to false signals is small. We find six peaks with S/N > 5. For all the peaks, previously identified clusters of galaxies are matched within a separation of 1′, demonstrating good correspondence between the peaks and clusters of galaxies. We evaluate the statistical error in the weak lensing cluster counts using mock weak lensing data generated from full-sky ray-tracing simulations, and find N
peak = 6 ± 3.1 in an effective area of 9.0 degree2. We compare the measured weak lensing cluster counts with the theoretical model prediction based on halo models and place the constraint on the Ω
m
–σ8 plane which is found to be consistent with currently standard ΛCDM models. It is demonstrated that the weak lensing cluster counts can place a unique constraint on the σ8–c
0 plane, where c
0 is the normalization of the dark matter halo mass–concentration relationship. Finally we discuss prospects for ongoing/future wide field optical galaxy surveys.
Abstract
We present high signal-to-noise galaxy–galaxy lensing measurements of the Baryon Oscillation Spectroscopic Survey constant mass (CMASS) sample using 250 deg2 of weak-lensing data from ...Canada–France–Hawaii Telescope Lensing Survey and Canada–France–Hawaii Telescope Stripe 82 Survey. We compare this signal with predictions from mock catalogues trained to match observables including the stellar mass function and the projected and two-dimensional clustering of CMASS. We show that the clustering of CMASS, together with standard models of the galaxy–halo connection, robustly predicts a lensing signal that is 20–40 per cent larger than observed. Detailed tests show that our results are robust to a variety of systematic effects. Lowering the value of
$S_{\rm 8}=\sigma _{\rm 8} \sqrt{\Omega _{\rm m}/0.3}$
compared to Planck Collaboration XIII reconciles the lensing with clustering. However, given the scale of our measurement (r < 10 h
−1 Mpc), other effects may also be at play and need to be taken into consideration. We explore the impact of baryon physics, assembly bias, massive neutrinos and modifications to general relativity on ΔΣ and show that several of these effects may be non-negligible given the precision of our measurement. Disentangling cosmological effects from the details of the galaxy–halo connection, the effect of baryons, and massive neutrinos, is the next challenge facing joint lensing and clustering analyses. This is especially true in the context of large galaxy samples from Baryon Acoustic Oscillation surveys with precise measurements but complex selection functions.
BACKGROUND: Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How ...these signatures relate to one another in biological and prognostic contexts remains to be clarified. RESULTS: To investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes. CONCLUSIONS: These findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.
In gene expression profiling studies, including single-cell RNAsequencing (scRNA-seq) analyses, the identification and characterization of co-expressed genes provides critical information on cell ...identity and function. Gene co-expression clustering in scRNA-seq data presents certain challenges. We show that commonly used methods for single-cell data are not capable of identifying co-expressed genes accurately, and produce results that substantially limit biological expectations of co-expressed genes. Herein, we present single-cell Latent-variable Model (scLM), a gene co-clustering algorithm tailored to single-cell data that performs well at detecting gene clusters with significant biologic context. Importantly, scLM can simultaneously cluster multiple single-cell datasets, i.e., consensus clustering, enabling users to leverage single-cell data from multiple sources for novel comparative analysis. scLM takes raw count data as input and preserves biological variation without being influenced by batch effects from multiple datasets. Results from both simulation data and experimental data demonstrate that scLM outperforms the existing methods with considerably improved accuracy. To illustrate the biological insights of scLM, we apply it to our in-house and public experimental scRNA-seq datasets. scLM identifies novel functional gene modules and refines cell states, which facilitates mechanism discovery and understanding of complex biosystems such as cancers. A user-friendly R package with all the key features of the scLM method is available at https://github.com/QSong-github/scLM.
Tumor-infiltrating leukocytes can either limit cancer growth or facilitate its spread. Diagnostic strategies that comprehensively assess the functional complexity of tumor immune infiltrates could ...have wide-reaching clinical value. In previous work we identified distinct immune gene signatures in breast tumors that reflect the relative abundance of infiltrating immune cells and exhibited significant associations with patient outcomes. Here we hypothesized that immune gene signatures agnostic to tumor type can be identified by de novo discovery of gene clusters enriched for immunological functions and possessing internal correlation structure conserved across solid tumors from different anatomic sites.
We assembled microarray expression datasets encompassing 5,295 tumors of the breast, colon, lung, ovarian and prostate. Unsupervised clustering methods were used to determine number and composition of gene clusters within each dataset. Immune-enriched gene clusters (signatures) identified by gene ontology enrichment were analyzed for internal correlation structure and conservation across tumors then compared against expression profiles of: 1) flow-sorted leukocytes from peripheral blood and 2) >300 cancer cell lines from solid and hematologic cancers. Cox regression analysis was used to identify signatures with significant associations with clinical outcome.
We identified nine distinct immune-enriched gene signatures conserved across all five tumor types. The signatures differentiated specific leukocyte lineages with moderate discernment overall, and naturally organized into six discrete groups indicative of admixed lineages. Moreover, seven of the signatures exhibit minimal and uncorrelated expression in cancer cell lines, suggesting that these signatures derive predominantly from infiltrating immune cells. All nine immune signatures achieved statistically significant associations with patient prognosis (p<0.05) in one or more tumor types with greatest significance observed in breast and skin cancers. Several signatures indicative of myeloid lineages exhibited poor outcome associations that were most apparent in brain and colon cancers.
These findings suggest that tumor infiltrating immune cells can be differentiated by immune-specific gene expression patterns that quantify the relative abundance of multiple immune infiltrates across a range of solid tumor types. That these markers of immune involvement are significantly associated with patient prognosis in diverse cancers suggests their clinical utility as pan-cancer markers of tumor behavior and immune responsiveness.
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