Niraparib Maintenance Therapy for Brain Metastasis in Ovarian Endometrioid Adenocarcinoma With Peritoneal Carcinomatosis: A Comprehensive Case Study and Literature Review.

Brain metastasis is a rare complication of ovarian cancer, always found at the advanced stage. Even though different multimodal approaches are available, including surgical intervention and radiotherapy, there are no official guidelines for handling this serious complication. Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are a group of medications initially used for maintenance therapy in platinum-sensitive recurrent ovarian cancer. Niraparib has shown some efficacy in patients with brain metastasis due to its unique properties of penetrating the blood-brain barrier. Here, we present the case of a 51-year-old patient with advanced ovarian cancer with no germline breast cancer susceptibility gene (BRCA) mutations. Despite undergoing surgery and multiple rounds of chemotherapy, the patient's condition worsened, culminating in brain metastasis. Given her neurological issues, radiotherapy was not an option, prompting the initiation of a 300 mg dose of niraparib. To date, only sporadic case reports in the literature have described patients with ovarian cancer treated with niraparib and complicated by brain metastasis. Our case is unique because it is the first case of a patient with the endometrioid type of ovarian cancer.

Partially Reversible Bilateral Papilledema in a Patient Using Anastrozole: A Case Study.

Anastrozole is an endocrine-modifying agent used in the treatment of estrogen-sensitive breast cancer in the postmenopausal breast cancer population. Anastrozole is known for its side effect profile which includes an increased risk of osteoporosis. However, emerging evidence in the literature in the form of case studies demonstrates several potential ocular side effects due to the use of the medication. In our study, a 66-year-old female using anastrozole suffered severe bilateral papilledema that resolved after cessation of the medication. There is a growing body of evidence demonstrating the use of anastrozole and its impact on ocular health leading to deleterious side effects, such as papilledema.

Infrequent facial expressions of emotion do not bias attention.

Despite the obvious importance of facial expressions of emotion, most studies have found that they do not bias attention. A critical limitation, however, is that these studies generally present face distractors on all trials of the experiment. For other kinds of emotional stimuli, such as emotional scenes, infrequently presented stimuli elicit greater attentional bias than frequently presented stimuli, perhaps due to suppression or habituation. The goal of the current study then was to test whether such modulation of attentional bias by distractor frequency generalizes to facial expressions of emotion. In Experiment 1, both angry and happy faces were unable to bias attention, despite being infrequently presented. Even when the location of these face cues were more unpredictable-presented in one of two possible locations-still no attentional bias was observed (Experiment 2). Moreover, there was no bottom-up influence for angry and happy faces shown under high or low perceptual load (Experiment 3). We conclude that task-irrelevant posed facial expressions of emotion cannot bias attention even when presented infrequently.

Entorhinal Perfusion Predicts Future Memory Decline, Neurodegeneration, and White Matter Hyperintensity Progression in Older Adults.

BACKGROUND: Altered cerebral blood flow (CBF) has been linked to increased risk for Alzheimer's disease (AD). However, whether altered CBF contributes to AD risk by accelerating cognitive decline remains unclear. It also remains unclear whether reductions in CBF accelerate neurodegeneration and development of small vessel cerebrovascular disease. OBJECTIVE: To examine associations between CBF and trajectories of memory performance, regional brain atrophy, and global white matter hyperintensity (WMH) volume. METHOD: 147 Alzheimer's Disease Neuroimaging Initiative participants free of dementia underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure CBF and serial neuropsychological and structural MRI examinations. Linear mixed effects models examined 5-year rate of change in memory and 4-year rate of change in regional brain atrophy and global WMH volumes as a function of baseline regional CBF. Entorhinal and hippocampal CBF were examined in separate models. RESULTS: Adjusting for demographic characteristics, pulse pressure, apolipoprotein E ɛ4 positivity, cerebrospinal fluid p-tau/Aß ratio, and neuronal metabolism (i.e., fluorodeoxyglucose standardized uptake value ratio), lower baseline entorhinal CBF predicted faster rates of decline in memory as well as faster entorhinal thinning and WMH progression. Hippocampal CBF did not predict cognitive or brain structure trajectories. CONCLUSION: Findings highlight the importance of early cerebrovascular dysfunction in AD risk and suggest that entorhinal CBF as measured by noninvasive ASL MRI is a useful biomarker predictive of future cognitive decline and of risk of both.

Cell-Intrinsic Tumorigenic Functions of PPARγ in Bladder Urothelial Carcinoma.

The role of PPAR gamma (PPARγ) has been well characterized in the developmental process of adipogenesis, yet its aberrant expression patterns and functions in cancer subtypes are less understood. Although PPARγ has been recently demonstrated to play non-cell-autonomous roles in promoting bladder urothelial carcinoma (UC) progression, underlying mechanisms of the cell-intrinsic oncogenic activity remain unknown. Here, we report robust expression and nuclear accumulation of PPARγ in 47% of samples of patients with UC, exceeding mRNA expression patterns published by The Cancer Genome Atlas. In vitro assays revealed for the first time that treatment of UC cells with PPARγ inverse agonist or PPARG knockout by CRISPR-Cas9 reduces proliferation, migration, and invasion of multiple established UC cell lines, most strongly in those characterized by PPARG genomic amplification or activating mutations of RXRA, the obligate heterodimer of PPARγ. Through genome-wide approaches including chromatin immunoprecipitation sequencing and RNA sequencing, we define a novel set of PPARγ-regulated genes in UC, including Sonic Hedgehog (SHH). Similar to PPARγ, genetic inhibition of SHH reduces proliferation and motility. Finally, we demonstrate the PPARγ dependency of UC tumors in vivo by genetic and pharmacologic PPARγ inhibition in subcutaneous xenografts. Collectively, our data indicate that PPARγ promotes UC progression in a subset of patients, at least in part, through cell-autonomous mechanisms linked to SHH signaling. IMPLICATIONS: Genome-wide analysis of DNA-binding sites for oncogenic factor PPARγ revealed SHH as a novel downstream target involved in UC progression, providing important insight into the tumorigenic nature and molecular mechanism of PPARγ signaling in UC.

Regional Hypoperfusion Predicts Decline in Everyday Functioning at Three-Year Follow-Up in Older Adults without Dementia.

BACKGROUND: Increasing evidence indicates that cerebrovascular dysfunction may precede cognitive decline in aging and Alzheimer's disease (AD). Reduced cerebral blood flow (CBF) is associated with cognitive impairment in older adults. However, less is known regarding the association between CBF and functional decline, and whether CBF predicts functional decline beyond cerebrovascular and metabolic risk factors. OBJECTIVE: To examine the association between regional CBF and functional decline in nondemented older adults. METHOD: One hundred sixty-six (N = 166) participants without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent neuropsychological testing and neuroimaging. Pulsed arterial spin labeling magnetic resonance imaging was acquired to quantify resting CBF. Everyday functioning was measured using the Functional Assessment Questionnaire at baseline and annual follow-up visit across three years. RESULTS: Adjusting for age, education, sex, cognitive status, depression, white matter hyperintensity volume, cerebral metabolism, and reference (precentral) CBF, linear mixed effects models showed that lower resting CBF at baseline in the medial temporal, inferior temporal, and inferior parietal lobe was significantly associated with accelerated decline in everyday functioning. Results were similar after adjusting for conventional AD biomarkers, including cerebrospinal fluid (CSF) amyloid-ß (Aß) and hyperphosphorylated tau (p-tau) and apolipoprotein E (APOE) ɛ4 positivity. Individuals who later converted to dementia had lower resting CBF in the inferior temporal and parietal regions compared to those who did not. CONCLUSION: Lower resting CBF in AD vulnerable regions including medial temporal, inferior temporal, and inferior parietal lobes predicted faster rates of decline in everyday functioning. CBF has utility as a biomarker in predicting functional declines in everyday life and conversion to dementia.

Use of a controlled experiment and computational models to measure the impact of sequential peer exposures on decision making.

It is widely believed that one's peers influence product adoption behaviors. This relationship has been linked to the number of signals a decision-maker receives in a social network. But it is unclear if these same principles hold when the "pattern" by which it receives these signals vary and when peer influence is directed towards choices which are not optimal. To investigate that, we manipulate social signal exposure in an online controlled experiment using a game with human participants. Each participant in the game decides among choices with differing utilities. We observe the following: (1) even in the presence of monetary risks and previously acquired knowledge of the choices, decision-makers tend to deviate from the obvious optimal decision when their peers make a similar decision which we call the influence decision, (2) when the quantity of social signals vary over time, the forwarding probability of the influence decision and therefore being responsive to social influence does not necessarily correlate proportionally to the absolute quantity of signals. To better understand how these rules of peer influence could be used in modeling applications of real world diffusion and in networked environments, we use our behavioral findings to simulate spreading dynamics in real world case studies. We specifically try to see how cumulative influence plays out in the presence of user uncertainty and measure its outcome on rumor diffusion, which we model as an example of sub-optimal choice diffusion. Together, our simulation results indicate that sequential peer effects from the influence decision overcomes individual uncertainty to guide faster rumor diffusion over time. However, when the rate of diffusion is slow in the beginning, user uncertainty can have a substantial role compared to peer influence in deciding the adoption trajectory of a piece of questionable information.

Pattern of regional white matter hyperintensity volume in mild cognitive impairment subtypes and associations with decline in daily functioning.

White matter hyperintensities (WMHs), a marker of small-vessel cerebrovascular disease, increase risk for mild cognitive impairment (MCI). Less is known about whether regional WMHs distinguish MCI subtypes and predict decline in everyday functioning. About 618 Alzheimer's Disease Neuroimaging Initiative participants (301 cognitively normal [CN]; 232 amnestic MCI [aMCI]; 85 nonamnestic MCI [naMCI]) underwent neuropsychological testing, MRI, and assessment of everyday functioning. aMCI participants showed greater temporal (p = 0.002) and occipital WMHs (p = 0.030) relative to CN whereas naMCI participants had greater frontal (p = 0.045), temporal (p = 0.003), parietal (p = 0.018), and occipital (p < 0.001) WMH compared with CN. Relative to those with aMCI, individuals with naMCI showed greater occipital WMH (p = 0.013). Greater WMH in temporal (p = 0.001) and occipital regions (p = 0.006) was associated with faster decline in everyday functioning across the sample. Temporal lobe WMHs were disproportionately associated with accelerated functional decline among naMCI (p = 0.045). Regional WMH volumes vary across cognitive groups and predict functional decline. Cerebrovascular markers may help identify individuals at risk for decline and distinguish subtypes of cognitive impairment.

Gamma-Glutamyltransferase 1 Promotes Clear Cell Renal Cell Carcinoma Initiation and Progression.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. While the localized form of this disease can be treated surgically, advanced and metastatic stages are resistant to chemotherapies. Although more innovative treatments, such as targeted or immune-based therapies, exist, the need for new therapeutic options remains. ccRCC presents unique metabolic signatures and multiple studies have reported a significant increase in levels of reduced glutathione (GSH) and its precursors in ccRCC tumor samples compared with normal kidney tissues. These observations led us to investigate the effects of blocking the GSH pathway, particularly the gamma-glutamyltransferase 1 (GGT1) enzyme, in multiple ccRCC cell lines. In this study, we provide in vitro and in vivo evidence that GGT1/GSH pathway inhibition impacts ccRCC cell growth, through increased cell-cycle arrest. Of note, GGT1 inhibition also impairs ccRCC cell migration. Finally, pharmacologic GSH pathway inhibition decreases ccRCC cell proliferation and increases sensitivity to standard chemotherapy. Our results suggest that GGT1/GSH pathway inhibition represents a new strategy to overcome ccRCC chemoresistance. IMPLICATIONS: GGT1/GSH pathway inhibition represents a promising therapeutic strategy to overcome chemoresistance and inhibit progression of ccRCC tumors.

Genetic and metabolic hallmarks of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by deregulated hypoxia-inducible factor signaling, mutation of several key chromatin modifying enzymes, and numerous alterations in cellular metabolism. Pre-clinical studies have historically been limited to cell culture models, however, the identification of critical tumor suppressors and oncogenes from large-scale patient sequencing data has led to several new genetically engineered mouse models with phenotypes reminiscent of ccRCC. In this review, we summarize recent literature on these topics and discuss how they inform targeted therapeutic approaches for the treatment of ccRCC.

PPARγ is dispensable for clear cell renal cell carcinoma progression.

OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is a subtype of kidney cancer defined by robust lipid accumulation, which prior studies have indicated plays an important role in tumor progression. We hypothesized that the peroxisome proliferator-activated receptor gamma (PPARγ), detected in both ccRCC tumors and cell lines, promotes lipid storage in ccRCC and contributes to tumorigenesis in this setting. PPARγ transcriptionally regulates a number of genes involved in lipid and glucose metabolism in adipocytes, yet its role in ccRCC has not been described. The objective of this study was to elucidate endogenous PPARγ function in ccRCC cells. METHODS AND RESULTS: Using chromatin immunoprecipitation followed by deep sequencing (ChIP-seq), we found that PPARγ and its heterodimer RXR occupy the canonical DR1 PPAR binding motif at approximately 1000 locations throughout the genome that can be subdivided into adipose-shared and ccRCC-specific sites. CRISPR-Cas9 mediated, loss-of-function studies determined that PPARγ is dispensable for viability, proliferation, and migration of ccRCC cells in vitro and in vivo. Also, surprisingly, PPARγ deletion had little effect on the robust lipid accumulation that typifies the "clear cell" phenotype of kidney cancer. CONCLUSION: Our results suggest that PPARγ plays neither a tumor suppressive nor oncogenic role in advanced ccRCC, and thus single-agent therapeutics targeting PPARγ are unlikely to be effective for the treatment of this disease. The unique cistrome of PPARγ in ccRCC cells demonstrates the importance of cell type in determining the functions of PPARγ.

IRE1α RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers.

Myc activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting that Myc-dependent downstream effectors may be more tractable therapeutic targets. Here, we show that Myc overexpression induces endoplasmic reticulum (ER) stress and engages the inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) pathway through multiple molecular mechanisms in a variety of c-Myc- and N-Myc-dependent cancers. In particular, Myc-overexpressing cells require IRE1α/XBP1 signaling for sustained growth and survival in vitro and in vivo, dependent on elevated stearoyl-CoA-desaturase 1 (SCD1) activity. Pharmacological and genetic XBP1 inhibition induces Myc-dependent apoptosis, which is alleviated by exogenous unsaturated fatty acids. Of note, SCD1 inhibition phenocopies IRE1α RNase activity suppression in vivo. Furthermore, IRE1α inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc-overexpressing Burkitt's lymphoma, suggesting that inhibiting the IRE1α/XBP1 pathway is a useful general strategy for treatment of Myc-driven cancers.

HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma.

UNLABELLED: Two hallmarks of clear-cell renal cell carcinoma (ccRCC) are constitutive hypoxia-inducible factor (HIF) signaling and abundant intracellular lipid droplets (LD). However, regulation of lipid storage and its role in ccRCC are incompletely understood. Transcriptional profiling of primary ccRCC samples revealed that expression of the LD coat protein gene PLIN2 was elevated in tumors and correlated with HIF2α, but not HIF1α, activation. HIF2α-dependent PLIN2 expression promoted lipid storage, proliferation, and viability in xenograft tumors. Mechanistically, lipid storage maintained integrity of the endoplasmic reticulum (ER), which is functionally and physically associated with LDs. Specifically, PLIN2-dependent lipid storage suppressed cytotoxic ER stress responses that otherwise result from elevated protein synthetic activity characteristic of ccRCC cells. Thus, in addition to promoting ccRCC proliferation and anabolic metabolism, HIF2α modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival. SIGNIFICANCE: We demonstrate that HIF2α promotes lipid storage, ER homeostasis, and cell viability in ccRCC via upregulation of the LD coat protein PLIN2, revealing a novel function for the well-documented "clear-cell" phenotype and identifying ER stress as a targetable vulnerability created by HIF2α/PLIN2 suppression in this common renal malignancy.

Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells.

Trisomy 21 is associated with hematopoietic abnormalities in the fetal liver, a preleukemic condition termed transient myeloproliferative disorder, and increased incidence of acute megakaryoblastic leukemia. Human trisomy 21 pluripotent cells of various origins, human embryonic stem (hES), and induced pluripotent stem (iPS) cells, were differentiated in vitro as a model to recapitulate the effects of trisomy on hematopoiesis. To mitigate clonal variation, we isolated disomic and trisomic subclones from the same parental iPS line, thereby generating subclones isogenic except for chromosome 21. Under differentiation conditions favoring development of fetal liver-like, γ-globin expressing, definitive hematopoiesis, we found that trisomic cells of hES, iPS, or isogenic origins exhibited a two- to fivefold increase in a population of CD43(+)(Leukosialin)/CD235(+)(Glycophorin A) hematopoietic cells, accompanied by increased multilineage colony-forming potential in colony-forming assays. These findings establish an intrinsic disturbance of multilineage myeloid hematopoiesis in trisomy 21 at the fetal liver stage.