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The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression ( n  = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients’ progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes. Lineage plasticity is increasingly recognized as an emergent resistance mechanism after treatment with androgen receptor signalling inhibitors. To understand determinants of resistance, the authors analyzed the transcriptomes of patient tumor biopsies before enzalutamide treatment and at progression and identified a gene expression program associated with lineage plasticity risk and poor outcomes.

Many plants accumulate large quantities of specialized metabolites in secretory glandular trichomes (SGTs), which are specialized epidermal cells. In the genus Solanum , SGTs store a diverse collection of glucose and sucrose esters. Profiling of extracts from two accessions (LA1777 and LA1392) of Solanum habrochaites using ultra-high performance liquid chromatography–mass spectrometry (UHPLC/MS) revealed wide acylsugar diversity, with up to 11 isomers annotated for each individual elemental formula. These isomers arise from differences in ester chain lengths and their positions of substitution or branching. Since fragment ion masses were not sufficient to distinguish all isomers, 24 acylsucroses were purified from S. habrochaites accessions and cultivated tomato ( Solanum lycopersicum M82) and characterized using NMR spectroscopy. Two-dimensional NMR spectra yielded assignments of positions of substitution of specific acyl groups, and locations of branching. The range of substitution was wider than reported earlier, and in contrast to previous reports, tetra- and penta-acylsucroses were substituted at position 2 with acyl groups other than acetate. Because UHPLC/MS fails to yield sufficient information about structure diversity, and quantitative NMR of acylsugar mixtures is confounded by structural redundancy, the strategic combination of NMR and UHPLC/MS provides a powerful approach for profiling a class of metabolites with great structural diversity across genotypes.

We performed a prospective trial to assess the clinical benefit of a tailored gene set built on a next-generation sequencing (NGS) platform in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Archived tumor tissue obtained from patients with recurrent or metastatic HNSCC was analyzed for variants by a tailored Comprehensive Cancer Gene set of 40 genes (CCG-40) performed on a NGS platform. These data were provided to clinicians to inform treatment decisions. The primary endpoint was clinical benefit (disease control) that resulted from selection and administration of a targeted therapy based on results of the CCG-40. Barriers to performance and implementation of the assay were recorded. Forty patients enrolled. Primary tumor sites included oropharynx (14), larynx/hypopharynx (14), oral cavity (9), and nasopharynx (3). The CCG-40 assay was performed in 23 patients (57.5%), but not in 17 patients due inadequate financial coverage (12) or insufficient tumor tissue (5). Potentially actionable tumor variants were identified in 3 patients (7.5%); all were PIK3CA variants. Due to inability to obtain access to candidate drugs (2) or rapid decline in performance status (1), none of these patients received targeted therapy informed by the CCG-40 results. The CCG-40 assay did not provide clinical benefit to the patients on this trial. Identification of limitations of the assay and barriers to the test’s performance and application may be used to optimize this strategy in future trials.

Analogous to the business model of customer satisfaction and retention, patient satisfaction could serve as an innovative, patient-centered focus for increasing retention in HIV care and adherence to HAART, and ultimately HIV suppression. To test, through structural equation modeling (SEM), a model of HIV suppression in which patient satisfaction influences HIV suppression indirectly through retention in HIV care and adherence to HAART. We conducted a cross-sectional study of adults receiving HIV care at two clinics in Texas. Patient satisfaction was based on two validated items, one adapted from the Consumer Assessment of Healthcare Providers and Systems survey (\"Would you recommend this clinic to other patients with HIV?) and one adapted from the Delighted-Terrible Scale, (\"Overall, how do you feel about the care you got at this clinic in the last 12 months?\"). A validated, single-item question measured adherence to HAART over the past 4 weeks. Retention in HIV care was based on visit constancy in the year prior to the survey. HIV suppression was defined as plasma HIV RNA <48 copies/mL at the time of the survey. We used SEM to test hypothesized relationships. The analyses included 489 patients (94% of eligible patients). The patient satisfaction score had a mean of 8.5 (median 9.2) on a 0- to 10- point scale. A total of 46% reported \"excellent\" adherence, 76% had adequate retention, and 70% had HIV suppression. In SEM analyses, patient satisfaction with care influences retention in HIV care and adherence to HAART, which in turn serve as key determinants of HIV suppression (all p<.0001). Patient satisfaction may have direct effects on retention in HIV care and adherence to HAART. Interventions to improve the care experience, without necessarily targeting objective clinical performance measures, could serve as an innovative method for optimizing HIV outcomes.

Alterations in both cell metabolism and transcriptional programs are hallmarks of cancer that sustain rapid proliferation and metastasis 1 . However, the mechanisms that control the interaction between metabolic reprogramming and transcriptional regulation remain unclear. Here we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) regulates transcriptional reprogramming by activating the oncogenic steroid receptor coactivator-3 (SRC-3). We used a kinome-wide RNA interference-based screening method to identify potential kinases that modulate the intrinsic SRC-3 transcriptional response. PFKFB4, a regulatory enzyme that synthesizes a potent stimulator of glycolysis 2 , is found to be a robust stimulator of SRC-3 that coregulates oestrogen receptor. PFKFB4 phosphorylates SRC-3 at serine 857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient Ser857Ala mutant SRC-3 abolishes the SRC-3-mediated transcriptional output. Functionally, PFKFB4-driven SRC-3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase. In addition, the two enzymes adenosine monophosphate deaminase-1 (AMPD1) and xanthine dehydrogenase (XDH), which are involved in purine metabolism, were identified as SRC-3 targets that may or may not be directly involved in purine synthesis. Mechanistically, phosphorylation of SRC-3 at Ser857 increases its interaction with the transcription factor ATF4 by stabilizing the recruitment of SRC-3 and ATF4 to target gene promoters. Ablation of SRC-3 or PFKFB4 suppresses breast tumour growth in mice and prevents metastasis to the lung from an orthotopic setting, as does Ser857Ala-mutant SRC-3. PFKFB4 and phosphorylated SRC-3 levels are increased and correlate in oestrogen receptor-positive tumours, whereas, in patients with the basal subtype, PFKFB4 and SRC-3 drive a common protein signature that correlates with the poor survival of patients with breast cancer. These findings suggest that the Warburg pathway enzyme PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC-3 to promote aggressive metastatic tumours. The glycolytic enzyme PFKFB4 directly phosphorylates and regulates binding of the coactivator SRC-3 to ATF4 and thereby increases the transcriptional activity of this complex, leading to increased expression of metabolic genes, and enhancing tumour growth and metastasis.

Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we used a genome-wide RNA interference screen to search for Myc-synthetic lethal genes and uncovered a role for the SUMO-activating enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death upon Myc hyperactivation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for growth of Myc-dependent tumors in mice, and gene expression analyses of Myc-high human breast cancers suggest that low SAE1 and SAE2 abundance in the tumors correlates with longer metastasis-free survival of the patients. Thus, inhibition of SUMOylation may merit investigation as a possible therapy for Myc-driven human cancers.

Brazilian free-tailed bats (Tadarida brasiliensis) form enormous summer breeding colonies, mostly in caves and under bridges, in south-central Texas and northern Mexico. Their prey includes several species of adult insects whose larvae are known to be important agricultural pests, including the corn earworm or cotton bollworm (Helicoverpa zea). We estimate the bats' value as pest control for cotton production in an eight-county region in south-central Texas. Our calculations show an annual value of $741 000 per year, with a range of $121000-$1 725 000, compared to a $4.6-$6.4 million per year annual cotton harvest.

Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that α-Syn and tau overlap pathologically. The connections between α-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of α-Syn and tau. We found that TRIM28 regulates α-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and α-Syn-mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points. Behind many neurodegenerative diseases are specific proteins that abnormally accumulate inside neurons and damage the cells. In Parkinson’s disease, the protein alpha-synuclein accumulates; in Alzheimer’s disease, the protein tau is one of the toxic culprits; and in other neurodegenerative diseases, alpha-synuclein and tau both accumulate. Genetic studies suggest that accumulation of the two proteins may be linked, but little is known about the factors that regulate the levels of these proteins inside neurons. Rousseaux et al. set out to identify how these proteins are regulated in the hope of finding new ways of targeting them and reducing their toxicity. Screening a subset of human genes led to one that encodes a protein called TRIM28, which regulates the levels of both alpha-synuclein and tau. When the TRIM28 protein was depleted in human and mouse cells, the levels of alpha-synuclein and tau also went down. This effect was specific because the levels of other proteins with the potential to cause neurodegeneration remained unaffected. Models of neurodegenerative disease in fruit flies and mice were then used to explore how TRIM28 affects the levels of tau and alpha-synuclein in animals. In each case, the proteins’ levels dropped when TRIM28 was suppressed and this in turn protected the neurons from damage. Rousseaux et al. went on to show that TRIM28 affected how alpha-synuclein and tau were cleared in cells. Overexpressing TRIM28 revealed that it could encourage both alpha-synuclein and tau to accumulate in the nucleus of cells over time. Finally, Rousseaux et al. compared post-mortem brain tissue from people who had neurodegenerative conditions that are driven by or associated with tau and alpha-synuclein with tissue from those who did not. The cell nuclei in the diseased tissue had much more TRIM28 associated with alpha-synuclein and tau than those in the healthy tissues. Overall, the findings show that TRIM28 promotes the accumulation and damaging effects of both alpha-synuclein and tau. The next steps will be to understand how TRIM28 does this. It will also be important to determine if this effect can be targeted, whilst leaving others roles of TRIM28 intact, in order to explore it as a potential target to treat or prevent neurodegenerative diseases.

The propensity of cancer cells to transition between epithelial and mesenchymal phenotypic states via the epithelial–mesenchymal transition (EMT) program can regulate metastatic processes, cancer progression, and treatment resistance. Transcriptional investigations using reversible models of EMT, revealed the mesenchymal-to-epithelial reverting transition (MErT) to be enriched in clinical samples of metastatic castrate resistant prostate cancer (mCRPC). From this enrichment, a metastasis-derived gene signature was identified that predicted more rapid cancer relapse and reduced survival across multiple human carcinoma types. Additionally, the transcriptional profile of MErT is not a simple mirror image of EMT as tumour cells retain a transcriptional “memory” following a reversible EMT. This memory was also enriched in mCRPC samples. Cumulatively, our studies reveal the transcriptional profile of epithelial–mesenchymal plasticity and highlight the unique transcriptional properties of MErT. Furthermore, our findings provide evidence to support the association of epithelial plasticity with poor clinical outcomes in multiple human carcinoma types.

Many neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein’s resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS–MAPK–MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases. Cross-species genetic screens reveal that decreased mitogen-activated protein kinase signalling reduces polyglutamine-expanded ataxin 1 levels and toxicity in models of spinocerebellar ataxia type 1. Targeting neurodegenerative diseases The toxic accumulation of mutant — or sometimes wild-type — protein in the brain is a common cause of pathology in inherited neurodegenerative diseases. Decreasing this accumulation can reverse disease phenotype. Huda Zoghbi and colleagues have developed a cross-species genetic-screening strategy for the identification of druggable targets that could decrease the levels of ataxin 1, the disease-causing protein of spinocerebellar ataxia type 1. This strategy uncovered multiple therapeutic targets (RAS–MAPK–MSK1) that, when inhibited, decrease ataxin 1 levels and suppress its toxicity in human, mouse and Drosophila systems.