Targeting the MDM2-p53 Pathway in Dedifferentiated Liposarcoma

Dedifferentiated liposarcoma (DDLPS) is an aggressive adipogenic cancer with poor prognosis. DDLPS tumors are only modestly sensitive to chemotherapy and radiation, and there is a need for more effective therapies. Genetically, DDLPS is characterized by a low tumor mutational burden and frequent chromosomal structural abnormalities including amplification of the 12q13-15 chromosomal region and the MDM2 gene, which are defining features of DDLPS. The MDM2 protein is an E3 ubiquitin ligase that targets the tumor suppressor, p53, for proteasomal degradation. MDM2 amplification or overexpression in human malignancies is associated with cell-cycle progression and worse prognosis. The MDM2-p53 interaction has thus garnered interest as a therapeutic target for DDLPS and other malignancies. MDM2 binds p53 via a hydrophobic protein interaction that is easily accessible with synthetic analogues. Multiple agents have been developed, including Nutlins such as RG7112 and small molecular inhibitors including SAR405838 and HDM201. Preclinical in vitro and animal models have shown promising results with MDM2 inhibition, resulting in robust p53 reactivation and cancer cell death. However, multiple early-phase clinical trials have failed to show a benefit with MDM2 pathway inhibition for DDLPS. Mechanisms of resistance are being elucidated, and novel inhibitors and combination therapies are currently under investigation. This review provides an overview of these strategies for targeting MDM2 in DDLPS

Targeting the Molecular and Immunologic Features of Leiomyosarcoma

Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies

Criminal Law: Customer’s Permanent Exclusion From Retail Store Due to Prior Shoplifting Arrests Held Enforceable Under Criminal Trespass Statute

In interpretive research, trustworthiness has developed to become an important alternative for measuring the value of research and its effects, as well as leading the way of providing for rigour in the research process. The article develops the argument that trustworthiness plays an important role in not only effecting change in a research project’s original setting, but also that trustworthy research contributes toward building a body of knowledge that can play an important role in societal change. An essential aspect in the development of this trustworthiness is its relationship to context. To deal with the multiplicity of meanings of context, we distinguish between contexts at different levels of the research project: the domains of the researcher, the collective, and the individual participant. Furthermore, we argue that depending on the primary purpose associated with the collective learning potential, critical potential, or performative potential of phenomenographic research, developing trustworthiness may take different forms and is related to aspects of pedagogical legitimacy, social legitimacy, and epistemological legitimacy. Trustworthiness in phenomenographic research is further analysed by distinguishing between the internal horizon – the constitution of trustworthiness as it takes place within the research project – and the external horizon, which points to the impact of the phenomenographic project in the world mediated by trustworthiness

The Grizzly, September 24, 2015

CIE Professors Lend a Hand at Columbia U. • As Rush Week Ends, Greek Numbers Defy Expectations • Getting Back on Track • Healthy Addition: HEP Welcomes Rugby Coach to Faculty Lineup • Improving the Higher Education Experience • UC Student Trains Service Dog on Campus • Students Work with College Communications Office • Main Street Life: Upperclassmen Debate Housing\u27s Pros and Cons • Opinions: The Visit Rates 5 / 10; Extra-curricular Options for Students • Going Pro : Symposium on Sports Business and the Entrepreneurial Mindset Comes to Ursinus • Looking to Three-peathttps://digitalcommons.ursinus.edu/grizzlynews/1671/thumbnail.jp

The Immune Landscape of Undifferentiated Pleomorphic Sarcoma

INTRODUCTION: Undifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes. MATERIAL AND METHODS: Surgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters. RESULTS: Samples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p\u3c0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p\u3c0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p\u3c0.0001) and DFS (p\u3c0.001). CONCLUSION: We identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers\u27 tissue of origin

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

Competition effects in visual cortex between emotional distractors and a primary task in remitted depression.

BACKGROUND: Attentional biases, particularly difficulty inhibiting attention to negative stimuli, are implicated in risk for major depressive disorder (MDD). The current study examined a neural measure of attentional bias using a continuous index of visuocortical engagement (steady-state visual evoked potentials) before and after a negative mood induction in a population at high risk for MDD recurrence because of a recently remitted MDD (rMDD) episode. Additionally, we examined working-memory (WM) capacity as a potential moderator of the link between rMDD and visuocortical responses. METHODS: Our sample consisted of 27 women with rMDD and 28 never-depressed women. To assess attentional inhibition to emotional stimuli, we measured frequency-tagged steady-state visual evoked potentials created from spatially superimposed task-relevant stimuli and emotional distractors (facial displays of emotion) oscillating at distinct frequencies. WM capacity was assessed during a visuospatial memory task. RESULTS: Women with rMDD, relative to never-depressed women, displayed difficulty inhibiting attention to all emotional distractors before a negative mood induction, with the strongest effect for negative distractors (sad faces). Following the mood induction, rMDD women’s attention to emotional distractors remained largely unchanged. Among women with rMDD, lower WM capacity predicted greater difficulty inhibiting attention to negative and neutral distractors. CONCLUSIONS: By exploiting the phenomenon of oscillatory resonance in the visual cortex, we tracked competition in neural responses for spatially superimposed stimuli differing in valence. Results demonstrated that women with rMDD display impaired attentional inhibition of emotional distractors independent of state mood and that this bias is strongest among those with lower WM capacity