614 research outputs found
Induction chemotherapy in the treatment of nasopharyngeal carcinoma: Clinical outcomes and patterns of care
Get PDFEther phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance
Get PDFView full abstracthttps://openworks.mdanderson.org/leading-edge/1062/thumbnail.jp
Bringing emotion to work: Emotional intelligence, resistance, and the reinvention of character
Get PDFThis article centrally examines the sociological significance of emotional intelligence (EI) as a nascent managerial discourse. Through developing a three-way reading of the writers Richard Sennett, Daniel Goleman, and George Ritzer, it is contended that EI can be understood to signal ânew rulesâ for work involving demands for workers to develop moral character better attuned to the dynamics of the flexible workplace - character that is more âintelligentâ, adaptive, and reflexive. Furthermore, it is argued that while EI appears in some important respects to open the scope for worker discretion, it might also signal diminished scope for worker resistance. However, ultimately, the case of EI is used to problematise recent discussions of worker resistance - to suggest the possibility of âresistantâ worker agency exercised through collusion with, as well as transgression of, corporate norms and practices
PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma
Get PDFPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.
Statement of significance
PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors
<html>Efficacy of the combination of MEK and CDK4/6 inhibitors <i>in vitro</i> and <i>in vivo</i> in KRAS mutant colorectal cancer models</html>
Get PDFThough the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers (CRC), early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity. Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation. Since ERK increases cyclin D expression and increases entry into the cell cycle, we hypothesized that the combination of MEK inhibitors and CDK4/6 inhibitors would have synergistic antitumor activity and cause tumor regression in vivo
Ether Phospholipids Are Required for Mitochondrial Reactive Oxygen Species Homeostasis
Get PDFMitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The contributions of mitochondrial metabolism to tumor growth and therapy resistance are evident, but drugs targeting mitochondrial metabolism have repeatedly failed in the clinic. Our study in pancreatic ductal adenocarcinoma (PDAC) finds that cellular and mitochondrial lipid composition influence cancer cell sensitivity to pharmacological inhibition of electron transport chain complex I. Profiling of patient-derived PDAC models revealed that monounsaturated fatty acids (MUFAs) and MUFA-linked ether phospholipids play a critical role in maintaining ROS homeostasis. We show that ether phospholipids support mitochondrial supercomplex assembly and ROS production; accordingly, blocking de novo ether phospholipid biosynthesis sensitized PDAC cells to complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. These data identify ether phospholipids as a regulator of mitochondrial redox control that contributes to the sensitivity of PDAC cells to complex I inhibition
Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma
Get PDFCancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6- unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance
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An inhibitor of oxidative phosphorylation exploits cancer vulnerability.
Get PDFMetabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors
Why do banks promise to pay par on demand?
Get PDFWe survey the theories of why banks promise to pay par on demand and examine evidence about
the conditions under which banks have promised to pay the par value of deposits and banknotes on
demand when holding only fractional reserves. The theoretical literature can be broadly divided into four
strands: liquidity provision, asymmetric information, legal restrictions, and a medium of exchange. We
assume that it is not zero cost to make a promise to redeem a liability at par value on demand. If so, then
the conditions in the theories that result in par redemption are possible explanations of why banks
promise to pay par on demand. If the explanation based on customersâ demand for liquidity is correct,
payment of deposits at par will be promised when banks hold assets that are illiquid in the short run. If
the asymmetric-information explanation based on the difficulty of valuing assets is correct, the
marketability of banksâ assets determines whether banks promise to pay par. If the legal restrictions
explanation of par redemption is correct, banks will not promise to pay par if they are not required to do
so. If the transaction explanation is correct, banks will promise to pay par value only if the deposits are
used in transactions. After the survey of the theoretical literature, we examine the history of banking in
several countries in different eras: fourth-century Athens, medieval Italy, Japan, and free banking and
money market mutual funds in the United States. We find that all of the theories can explain some of the
observed banking arrangements, and none explain all of them
Modulation of the thalamus by microburst vagus nerve stimulation: a feasibility study protocol
Get PDFVagus nerve stimulation (VNS) was the first device-based therapy for epilepsy, having launched in 1994 in Europe and 1997 in the United States. Since then, significant advances in the understanding of the mechanism of action of VNS and the central neurocircuitry that VNS modulates have impacted how the therapy is practically implemented. However, there has been little change to VNS stimulation parameters since the late 1990s. Short bursts of high frequency stimulation have been of increasing interest to other neuromodulation targets e.g., the spine, and these high frequency bursts elicit unique effects in the central nervous system, especially when applied to the vagus nerve. In the current study, we describe a protocol design that is aimed to assess the impact of high frequency bursts of stimulation, called âMicroburst VNSâ, in subjects with refractory focal and generalized epilepsies treated with this novel stimulation pattern in addition to standard anti-seizure medications. This protocol also employed an investigational, fMRI-guided titration protocol that permits personalized dosing of Microburst VNS among the treated population depending on the thalamic blood-oxygen-level-dependent signal. The study was registered on clinicaltrials.gov (NCT03446664). The first subject was enrolled in 2018 and the final results are expected in 2023
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