ABSTRACT
The oscillation frequencies observed in Sun-like stars are susceptible to being shifted by magnetic activity effects. The measured shifts depend on a complex relationship involving the mode ...type, the field strength, and spatial distribution of activity, as well as the inclination angle of the star. Evidence of these shifts is also present in frequency separation ratios that are often used when inferring global properties of stars in order to avoid surface effects. However, one assumption when using frequency ratios for this purpose is that there are no near-surface perturbations that are non-spherically symmetric. In this work, we studied the impact on inferred stellar properties when using frequency ratios that are influenced by non-homogeneous activity distributions. We generate several sets of artificial oscillation frequencies with various amounts of shift and determine stellar properties using two separate pipelines. We find that for asteroseismic observations of Sun-like targets we can expect magnetic activity to affect mode frequencies that will bias the results from stellar modelling analysis. Although for most stellar properties this offset should be small, typically less than 0.5 per cent in mass, estimates of age and central hydrogen content can have an error of up to 5 per cent and 3 per cent, respectively. We expect a larger frequency shift and therefore larger bias for more active stars. We also warn that for stars with very high or low inclination angles, the response of modes to activity is more easily observable in the separation ratios and hence will incur a larger bias.
Late Recurrence Following Early Breast Cancer Thomas, Alexandra; Parsons, Heather A; Smith, Karen Lisa
Journal of clinical oncology,
05/2022, Letnik:
40, Številka:
13
Journal Article
Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if ...modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are associated with increased number and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.
Background
Metaplastic breast cancer (MBC) is a rare disease subtype characterized by an aggressive clinical course. MBC is commonly triple negative (TN), although hormone receptor (HR) positive and ...human epidermal growth receptor 2 (HER2) positive cases do occur. Previous studies have reported similar outcomes for MBC with regard to HR status. Less is known about outcomes for HER2 positive MBC.
Materials and Methods
Surveillance, Epidemiology, and End Results Program data were used to identify women diagnosed 2010–2014 with MBC or invasive ductal carcinoma (IDC). Kaplan‐Meier curves estimated overall survival (OS) and multivariate Cox models were fitted. For survival analyses, only first cancers were included, and 2014 diagnoses were excluded to allow for sufficient follow‐up.
Results
Our MBC sample included 1,516 women. Relative to women with IDC, women with MBC were more likely to be older (63 vs. 61 years), black (16.0% vs. 11.1%), and present with stage III disease (15.6% vs. 10.8%). HER2 positive and HER2 negative/HR positive MBC tumors represented 5.2% and 23.0% of cases. For MBC overall, 3‐year OS was greatest for women with HER2 positive MBC (91.8%), relative to women with TN (75.4%) and HER2 negative/HR positive MBC (77.1%). This difference was more pronounced for stage III MBC, for which 3‐year OS was 92.9%, 47.1%, and 42.2% for women with HER2 positive, TN, and HER2 negative/HR positive MBC, respectively. A multivariate Cox model of MBC demonstrated that HER2 positive tumors (relative to TN) were associated with improved survival (hazard ratio = 0.32, 95% confidence interval CI 0.13–0.79). In a second Cox model of exclusively HER2 positive tumors, OS did not differ between MBC and IDC disease subtypes (hazard ratio = 1.16, 95% CI 0.48–2.81).
Conclusion
In this contemporary, population‐based study of women with MBC, HER2 but not HR status was associated with improved survival. Survival was similar between HER2 positive MBC and HER2 positive IDC. This suggests HER2 positive MBC is responsive to HER2‐directed therapy, a finding that may offer insights for additional therapeutic approaches to MBC.
Implications for Practice
This population‐based study reports recent outcomes, by receptor status, for women with metaplastic breast cancer. Survival in metaplastic breast cancer is not impacted by hormone receptor status. To the authors' knowledge, this is the first report indicating that women with human epidermal growth receptor 2 (HER2) positive metaplastic breast cancer have survival superior to women with HER2 negative metaplastic breast cancer and survival similar to women with HER2 positive invasive ductal carcinoma. This information can be used for counseling patients diagnosed with metaplastic breast cancer. Further understanding of HER2 positive metaplastic breast cancer could offer insights for the development of therapeutic approaches to metaplastic breast cancer more broadly.
摘要
背景。化生性乳腺癌 (MBC) 是一种以侵袭性临床病程为特征的罕见疾病亚型。MBC 通常呈三阴性 (TN), 但会发生激素受体 (HR) 阳性和人类表皮生长受体 2 (HER2) 阳性病例。既往研究已报告了 MBC 在 HR 状态方面的相似预后。对 HER2 阳性 MBC 的预后知之较少。
材料和方法。使用监测、流行病学和最终结果项目数据识别在 2010 至 2014 年期间诊断出 MBC 或浸润性导管癌 (IDC) 的女性。采用 Kaplan‐Meier 曲线估算总生存率 (OS), 并拟合多变量 Cox 模型。对于生存率分析, 仅将先发癌症包括在内, 并排除了 2014 年的诊断以便进行充分随访。
结果。我们的 MBC 样本包括 1 516 名女性。与 IDC 女性相比, MBC 女性更可能如下所述：年龄较大（63 岁 vs. 61 岁）、黑色人种 (16.0% vs. 11.1%) 以及患有 III 期疾病 (15.6% vs. 10.8%)。HER2 阳性和 HER2 阴性/HR 阳性 MBC 肿瘤占病例的 5.2% 和 23.0%。对于 MBC 总体, 相对于 TN (75.4%) 和 HER2 阴性/HR 阳性 MBC (77.1%) 女性, HER2 阳性 MBC 女性的 3 年 OS 最高 (91.8%)。对于 III 期 MBC, 此差异更为明显, 其中 HER2 阳性、TN 以及 HER2 阴性/HR 阳性 MBC 女性的 3 年 OS 分别为 92.9%、47.1% 和 42.2%。MBC 的多变量 Cox 模型表明, HER2 阳性肿瘤（相对于 TN）与生存率改善有关风险比=0.32, 95% 置信区间（CI）0.13‐0.79。在另一个仅针对 HER2 阳性肿瘤的 Cox 模型中, OS 在 MBC 与 IDC 疾病亚型之间无差异（风险比=1.16, 95% CI 0.48‐2.81）。
结论。在 MBC 女性的本项同期人群研究中, HER2 状态（而非 HR 状态）与生存率改善有关。HER2 阳性 MBC 与 HER2 阳性 IDC 的生存率相似。这表明 HER2 阳性 MBC 对 HER2 导向治疗有反应, 这一发现可为其他 MBC 治疗方法提供见解。
对临床实践的启示：本项人群研究按受体状态报告了化生性乳腺癌女性的近期预后。化生性乳腺癌的生存率不受激素受体状态的影响。据作者所知, 这是第一份指出人类表皮生长受体 2 (HER2) 阳性化生性乳腺癌女性的生存率高于 HER2 阴性化生性乳腺癌女性, 而与 HER2 阳性浸润性导管癌女性生存率相似的报告。这些信息可用于为诊断出化生性乳腺癌的患者提供建议。对 HER2 阳性化生性乳腺癌的进一步了解可更为广泛地为化生性乳腺癌的治疗方法开发提供见解
Metaplastic breast cancer (MBC) is a rare subtype of breast cancer that is generally associated with poor outcomes. This article reports outcomes by receptor status for a large group of women with metaplastic breast cancer.
Colorectal cancer (CRC) is the second deadliest cancer in the US due to its propensity to metastasize. Stromal cells and especially cancer-associated fibroblasts (CAF) play a critical biophysical ...role in cancer progression, but the precise pro-metastatic mechanisms are not clear. Activin A, a TGF-β family member, is a strong pro-metastatic cytokine in the context of CRC. Here, we assessed the link between biophysical forces and pro-metastatic signaling by testing the hypothesis that CAF-generated mechanical forces lead to activin A release and associated downstream effects. Consistent with our hypothesis, we first determined that stromal activin A secretion increased with increasing substrate stiffness. Then we found that stromally-secreted activin A induced ligand-dependent CRC epithelial cell migration and epithelial to mesenchymal transition (EMT). In addition, serum activin A levels are significantly increased in metastatic (stage IV) CRC patients (1.558 ng/ml versus 0.4179 ng/ml, p < 0.05). We propose that increased tumor microenvironment stiffness leads to stromal cell-mediated TGF-β family signaling relying on the induction and utilization of activin A signaling.
Abberent protein-protein interactions potentiate many diseases and one example is the toxic, self-assembly of α-Synuclein in the dopaminergic neurons of patients with Parkinson's disease; therefore, ...a potential therapeutic strategy is the small molecule modulation of α-Synuclein aggregation. In this work, we develop an Oligopyridylamide based 2-dimensional Fragment-Assisted Structure-based Technique to identify antagonists of α-Synuclein aggregation. The technique utilizes a fragment-based screening of an extensive array of non-proteinogenic side chains in Oligopyridylamides, leading to the identification of NS132 as an antagonist of the multiple facets of α-Synuclein aggregation. We further identify a more cell permeable analog (NS163) without sacrificing activity. Oligopyridylamides rescue α-Synuclein aggregation mediated Parkinson's disease phenotypes in dopaminergic neurons in early and post disease Caenorhabditis elegans models. We forsee tremendous potential in our technique to identify lead therapeutics for Parkinson's disease and other diseases as it is expandable to other oligoamide scaffolds and a larger array of side chains.
Triple negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. Although TNBC is not defined by specific therapeutic targets, a subset of ...patients have tumors that overexpress cyclins. High cyclin D/E expression catalyzes CDK4/2 activity. In turn, CDK4/2 can non-canonically phosphorylate Smad3, a key TGFβ signaling intermediate, and this phosphorylation has been associated with the shift from tumor-suppressive to oncogenic TGFβ pathway action in breast oncogenesis. Additionally, CDK-mediated Smad3 phosphorylation facilitates an interaction between Smad3 and Pin1, a cis-trans isomerase that is also overexpressed in aggressive breast cancers. Treatment with CYC065, a CDK2/9 inhibitor, decreased non-canonical Smad3 phosphorylation and inhibited the Pin1-Smad3 interaction. We hypothesized that the interaction of Pin1 and Smad3, facilitated by CDK-mediated Smad3 phosphorylation, promotes TNBC cell aggressiveness. Inhibition of the Pin1-Smad3 interaction in TNBC cell lines, through depletion of Pin1 or CYC065 treatment, resulted in decreased cell migration/invasion and impeded the EMT program. Inhibition of CDK-mediated phosphorylation of Smad3 by mutagenesis also decreased cell migration, underscoring the importance of non-canonical CDK2 phosphorylation of Smad3 to enable cell motility. Pin1 depletion restored Smad3 protein levels and tumor-suppressive activity, suggesting that the Pin1-Smad3 interaction has a negative impact on canonical Smad3 action. Collectively, the data show that the Pin1-Smad3 interaction, facilitated by CDK-mediated Smad3 phosphorylation, is associated with oncogenic TGFβ signaling and breast cancer progression. Inhibition of this interaction with CYC065 treatment may provide an important therapeutic option for TNBC patients.
Coding, Braiding, Transmission: On the Aesthetic Life of Dark Sousveillance" is a critical analysis of Tamar Clarke-Brown and Isaac Kariuki's 2017 digital startup and collaborative performance ...installation entitled Coding: Braiding: Transmission. In this speculative work of art, the gesture of braiding hair codes encrypted messages, staging the possibility of black women's furtive communication in the wake of mass surveillance. The argument emphasizes the fugitive possibilities advanced by Clarke-Brown and Kariuki's experimental formal strategy-identifying Coding: Braiding: Transmission as a practice of what Simone Browne calls dark sousveillance.
Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or ...inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.
Colorectal cancer remains a deadly cancer due to metastatic disease. To understand the molecular mechanisms of metastasis in colon cancer, we investigated whether the copper chaperone antioxidant-1 ...(Atox1) protein plays a role in this process. Recent findings indicate that Atox1 protein has transcription factor activities and plays a vital role in cell proliferation in cancer cells. However, the role of Atox1 in metastasis has not been examined.
Atox1 expression was determined by immunofluorescence in a tissue microarray generated from a spectrum of CRC patients. Subcellular fractionation of colon cancer cell lines SW480 and SW620 cells was used to examine the cellular location of Atox1 in the face of activin A, a cytokine that stimulates colon cancer metastasis. Atox1 expression was genetically manipulated and cellular migration measured through trans-well assay and proliferation measured by colony formation assays.
Here we demonstrate that in patients with metastatic colon cancer, there is a significant increase in the expression of nuclear Atox1. Interestingly, the metastatic CRC cell line SW620 has increased nuclear localization of Atox1 compared to its related non-metastatic cell line SW480. Further, inhibition of endogenous Atox1 by siRNA in SW620 decreased colony formation and reactive oxygen species generation via decreased expression of Atox1 targets cyclin D1 and NADPH oxidase subunit p47 phox, respectively. Additionally, overexpression of nuclear-targeted but not copper binding domain-mutated Atox1 in SW480 cells increased colony formation and cell migration that was further augmented by activin A stimulation, a known enhancer of colon cancer metastasis.
Our findings suggest that nuclear Atox1 might be a new therapeutic target as well as a new biomarker for metastatic colorectal cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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