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Fiore VF, Krajnc M, Quiroz FG, Levorse J, Pasolli HA, Shvartsman SY, Fuchs E
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Mechanics of a multilayer epithelium instruct tumour architecture and function (opens in new window)

NATURE 2020 SEP 17; 585(7825):433-439
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Mathematical and experimental approaches are used to investigate the mechanical forces that shape the tumour architecture of two different common forms of skin cancer: basal cell carcinomas and invasive squamous cell carcinomas. Loss of normal tissue architecture is a hallmark of oncogenic transformation(1). In developing organisms, tissues architectures are sculpted by mechanical forces during morphogenesis(2). However, the origins and consequences of tissue architecture during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas form 'buds', while invasive squamous cell carcinomas initiate as 'folds'. Here, using computational modelling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumour architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer, epithelia. In stratified epidermis, meanwhile, softening and enhanced remodelling of the basement membrane promote tumour budding, while stiffening of the basement membrane promotes folding. Additional key forces stem from the stratification and differentiation of progenitor cells. Tumour-specific suprabasal stiffness gradients are generated as oncogenic lesions progress towards malignancy, which we computationally predict will alter extensile tensions on the tumour basement membrane. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing the stiffness of basement membranes increases membrane tensions in silico and potentiates the progression of invasive squamous cell carcinomas in vivo. Our findings suggest that mechanical forces-exerted from above and below progenitors of multilayered epithelia-function to shape premalignant tumour architectures and influence tumour progression.
Wong JJM, Ginter PS, Tyryshkin K, Yang XJ, Nanayakkara J, Zhou ZE, Tuschl T, Chen YT, Renwick N
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Classifying Lung Neuroendocrine Neoplasms through MicroRNA Sequence Data Mining (opens in new window)

CANCERS 2020 SEP; 12(9):? Article 2653
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Simple Summary Lung neuroendocrine neoplasms (NENs) are a subset of lung cancer that is difficult to diagnose. MicroRNAs (miRNAs) are small RNA molecules that are valuable markers in many cancers. In this study, we generated miRNA profiles for 55 preserved lung NEN samples (14 typical carcinoid (TC), 15 atypical carcinoid (AC), 11 small cell lung carcinoma (SCLC), and 15 large cell neuroendocrine carcinoma (LCNEC)), and randomly assigned them to either discovery or validation sets. We used machine learning and data mining algorithms to identify important miRNA that can distinguish between the types. Using the miRNAs identified with these algorithms, we were able to distinguish between carcinoids (TC and AC) and neuroendocrine carcinomas (SCLC and LCNEC) in the discovery set with 93% accuracy; in the validation set, we were able to distinguish between these groups with 100% accuracy. Using the same machine learning and data mining techniques, we also identified miRNAs that can distinguish between TC and AC, and SCLC and LCNEC, however more samples are needed to validate these findings. Lung neuroendocrine neoplasms (NENs) can be challenging to classify due to subtle histologic differences between pathological types. MicroRNAs (miRNAs) are small RNA molecules that are valuable markers in many neoplastic diseases. To evaluate miRNAs as classificatory markers for lung NENs, we generated comprehensive miRNA expression profiles from 14 typical carcinoid (TC), 15 atypical carcinoid (AC), 11 small cell lung carcinoma (SCLC), and 15 large cell neuroendocrine carcinoma (LCNEC) samples, through barcoded small RNA sequencing. Following sequence annotation and data preprocessing, we randomly assigned these profiles to discovery and validation sets. Through high expression analyses, we found that miR-21 and -375 are abundant in all lung NENs, and that miR-21/miR-375 expression ratios are significantly lower in carcinoids (TC and AC) than in neuroendocrine carcinomas (NECs; SCLC and LCNEC). Subsequently, we ranked and selected miRNAs for use in miRNA-based classification, to discriminate carcinoids from NECs. Using miR-18a and -155 expression, our classifier discriminated these groups in discovery and validation sets, with 93% and 100% accuracy. We also identified miR-17, -103, and -127, and miR-301a, -106b, and -25, as candidate markers for discriminating TC from AC, and SCLC from LCNEC, respectively. However, these promising findings require external validation due to sample size.
Saeed M, Kapell S, Hertz NT, Wu XF, Bell K, Ashbrook AW, Mark MT, Zebroski HA, Neal ML, Flodstrom-Tullberg M, MacDonald MR, Aitchison JD, Molina H, Rice CM
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Defining the proteolytic landscape during enterovirus infection (opens in new window)

PLOS PATHOGENS 2020 SEP; 16(9):? Article e1008927
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Viruses cleave cellular proteins to remodel the host proteome. The study of these cleavages has revealed mechanisms of immune evasion, resource exploitation, and pathogenesis. However, the full extent of virus-induced proteolysis in infected cells is unknown, mainly because until recently the technology for a global view of proteolysis within cells was lacking. Here, we report the first comprehensive catalog of proteins cleaved upon enterovirus infection and identify the sites within proteins where the cleavages occur. We employed multiple strategies to confirm protein cleavages and assigned them to one of the two enteroviral proteases. Detailed characterization of one substrate, LSM14A, a p body protein with a role in antiviral immunity, showed that cleavage of this protein disrupts its antiviral function. This study yields a new depth of information about the host interface with a group of viruses that are both important biological tools and significant agents of disease. Author summary Enteroviruses are associated with a variety of human diseases, including gastroenteritis, the common cold, hand-foot-and-mouth disease, acute hemorrhagic conjunctivitis, and skin rash. In some cases, the infection can lead to myocarditis, encephalitis, progressive muscle weakness, and paralysis. Exactly how enteroviruses invade human tissues, defeat the host immune system, and alter normal cell biology is unknown. Understanding these cellular and molecular mechanisms will blaze the trail for the development of novel vaccine and therapeutic strategies. Here, we have applied a global N-terminomics approach to investigate how various enteroviruses recruit their proteases to remodel an infected cell, disarm host immunity, and create a favorable environment for their replication. This effort identified several new protease substrates, which we then confirmed by other experimental approaches. To our knowledge, this is the first systematic analysis of host proteins targeted for cleavage during enterovirus infection. The data generated in this study will serve as a valuable resource for the research community in the quest to uncover the molecular details of enterovirus cell biology and disease pathogenesis.
Yu ZL, Yu YD, Wang F, Myasnikov AG, Coffino P, Cheng YF
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Allosteric coupling between alpha-rings of the 20S proteasome (opens in new window)

NATURE COMMUNICATIONS 2020 SEP 11; 11(1):? Article 4580
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Proteasomal machinery performs essential regulated protein degradation in eukaryotes. Classic proteasomes are symmetric, with a regulatory ATPase docked at each end of the cylindrical 20S. Asymmetric complexes are also present in cells, either with a single ATPase or with an ATPase and non-ATPase at two opposite ends. The mechanism that populates these different proteasomal complexes is unknown. Using archaea homologs, we construct asymmetric forms of proteasomes. We demonstrate that the gate conformation of the two opposite ends of 20S are coupled: binding one ATPase opens a gate locally, and also opens the opposite gate allosterically. Such allosteric coupling leads to cooperative binding of proteasomal ATPases to 20S and promotes formation of proteasomes symmetrically configured with two identical ATPases. It may also promote formation of asymmetric complexes with an ATPase and a non-ATPase at opposite ends. We propose that in eukaryotes a similar mechanism regulates the composition of the proteasomal population.
Marrocco J
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Bruce S. McEwen: the evolution of stress (opens in new window)

STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS 2020 SEP 2; 23(5):497-498
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Kereiakes DJ, Henry TD, DeMaria AN, Bentur O, Carlson M, Yue CS, Martin LH, Midkiff J, Mueller M, Meek T, Garza D, Gibson CM, Coller BS
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First Human Use of RUC-4: A Nonactivating Second-Generation Small-Molecule Platelet Glycoprotein IIb/IIIa (Integrin alpha IIb beta 3) Inhibitor Designed for Subcutaneous Point-of-Care Treatment of ST-Segment-Elevation Myocardial Infarction (opens in new window)

JOURNAL OF THE AMERICAN HEART ASSOCIATION 2020 SEP 1; 9(17):? Article e016552
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Background: Despite reductions in door-to-balloon times for primary coronary intervention, mortality from ST-segment-elevation myocardial infarction has plateaued. Early pre-primary coronary intervention treatment of ST-segment-elevation myocardial infarction with glycoprotein IIb/IIIa inhibitors improves pre-primary coronary intervention coronary flow, limits infarct size, and improves survival. We report the first human use of a novel glycoprotein IIb/IIIa inhibitor designed for subcutaneous first point-of-care ST-segment-elevation myocardial infarction treatment. Methods and Results: Healthy volunteers and patients with stable coronary artery disease receiving aspirin received escalating doses of RUC-4 or placebo in a sentinel-dose, randomized, blinded fashion. Inhibition of platelet aggregation (IPA) to ADP (20 mu mol/L), RUC-4 blood levels, laboratory evaluations, and clinical assessments were made through 24 hours and at 7 days. Doses were increased until reaching the biologically effective dose (the dose producing >= 80% IPA within 15 minutes, with return toward baseline within 4 hours). In healthy volunteers, 15 minutes after subcutaneous injection, mean +/- SD IPA was 6.9%+7.1% after placebo and 71.8%+/- 15.0% at 0.05 mg/kg (n=6) and 84.7%+/- 16.7% at 0.075 mg/kg (n=6) after RUC-4. IPA diminished over 90 to 120 minutes. In patients with coronary artery disease, 15 minutes after subcutaneous injection of placebo or 0.04 mg/kg (n=2), 0.05 mg/kg (n=6), and 0.075 mg/kg (n=18) of RUC-4, IPA was 14.6%+/- 11.7%, 53.6%+/- 17.0%, 76.9%+/- 10.6%, and 88.9%+/- 12.7%, respectively. RUC-4 blood levels correlated with IPA. Aspirin did not affect IPA or RUC-4 blood levels. Platelet counts were stable and no serious adverse events, bleeding, or injection site reactions were observed. Conclusions: RUC-4 provides rapid, high-grade, limited-duration platelet inhibition following subcutaneous administration that appears to be safe and well tolerated. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NTC03844191.
Hoshino A, Kim HS, Bojmar L, Gyan KE, Cioffi M, Hernandez J, Zambirinis CP, Rodrigues G, Molina H, Heissel S, Mark MT, Steiner L, Benito-Martin A, Lucotti S, Di Giannatale A, Offer K, Nakajima M, Williams C, Nogues L, Vatter FAP, Hashimoto A, Davies AE, Freitas D, Kenific CM, Ararso Y, Buehring W, Lauritzen P, Ogitani Y, Sugiura K, Takahashi N, Aleckovic M, Bailey KA, Jolissant JS, Wang HJ, Harris A, Schaeffer LM, Garcia-Santos G, Posner Z, Balachandran VP, Khakoo Y, Raju GP, Scherz A, Sagi I, Scherz-Shouval R, Yarden Y, Oren M, Malladi M, Petriccione M, De Braganca KC, Donzelli M, Fischer C, Vitolano S, Wright GP, Ganshaw L, Marrano M, Ahmed A, DeStefano J, Danzer E, Roehrl MHA, Lacayo NJ, Vincent TC, Weiser MR, Brady MS, Meyers PA, Wexler LH, Ambati SR, Chou AJ, Slotkin EK, Modak S, Roberts SS, Basu EM, Diolaiti D, Krantz BA, Cardoso F, Simpson AL, Berger M, Rudin CM, Simeone DM, Jain M, Ghajar CM, Batra SK, Stanger B, Bui J, Brown KA, Rajasekhar VK, Healey JH, de Sousa M, Kramer K, Sheth S, Baisch J, Pascual V, Heaton TE, La Quaglia MP, Pisapia DJ, Schwartz R, Zhang HY, Liu Y, Shukla A, Blavier L, DeClerck YA, LaBarge M, Bissell MJ, Caffrey TC, Grandgenett PM, Hollingsworth MA, Bromberg J, Costa-Silva B, Peinado H, Kang YB, Garcia BA, O'Reilly EM, Kelsen D, Trippett TM, Jones DR, Matei IR, Jarnagin WR, Lyden D
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Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers (opens in new window)

CELL 2020 AUG 20; 182(4):1044-1061.e18
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There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n =151) and plasma-derived (n =120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
Randesi M, Rotrosen J, Nunes EV, Lee JD, Novo P, Levran O, Ott J, Pavlicova M, Scodes J, Kreek MJ
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Variants of opioid genes and response to treatment of opioid use disorder with buprenorphine-naloxone versus extended-release naltrexone in Caucasians (opens in new window)

AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2020 AUG 27; ?(?):1-8
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Background Sublingual buprenorphine-naloxone (BUP-NX), an FDA-approved treatment for opioid use disorder (OUD), combines buprenorphine (a partial mu/kappa agonist) with naloxone (a mu/ kappa antagonist). Extended-release injection naltrexone (XR-NTX; a mu receptor antagonist and kappa receptor partial agonist) is also an FDA-approved treatment for OUD. However, while some patients respond well to these medications, many others leave treatment and relapse. Objectives Determine whether gene variants in the opioid gene system are associated with better or worse treatment response. Methods In a 24-week, multisite, randomized, comparative effectiveness trial of daily, sublingual self-administration of BUP-NX versus monthly injection of XR-NTX conducted in the National Drug Abuse Clinical Trials Network, DNA was collected and four opioid gene variants were evaluated: (1) mu opioid receptor 118A>G; (2) 68-bp repeat in prodynorphin; (3) prodynorphin SNP rs910080; and (4) kappa opioid receptor SNP rs6473797. In non-Hispanic Caucasians (N= 334), two outcomes measures were assessed: received first dose (yes/no) and received last dose (yes/no). Separate logistic regressions were used to each model outcome measure as a function of treatment (XR-NTX vs BUP-NX), each gene variant, and their interaction. Results There were no significant main effects of gene variant on receiving first dose or last dose. There were also no significant gene variant by treatment interactions. Conclusions The outcome of treatment of OUD with medications is likely a complex function of multiple factors, including environmental, psychosocial, and possibly genetic, such that major effects of genetic variants may be unlikely.
Liu XS, Zhao XL, Wang Y, Hong JB, Shi M, Pfaff D, Guo LX, Tang HW
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Triphenyl phosphate permeates the blood brain barrier and induces neurotoxicity in mouse brain (opens in new window)

CHEMOSPHERE 2020 AUG; 252(?):? Article 126470
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Concerns have been raised over the neurotoxicity of triphenyl phosphate (TPP), but there have been few studies of the neurotoxic effects of TPP on mammals and the underlying mechanisms. In this study, weaned male mice (C57/BL6) were used and exposed to 0, 50, or 150 mg/kg TPP daily by oral gavage for 30 days. The blood brain barrier (BBB) permeability of TPP and its metabolite diphenyl phosphate (DPP) in the brain, and TPP induced metabolomic and transcriptomic changes of the brain were investigated. The results showed that TPP and DPP can cross the BBB of mice. Histopathological examination of the brain revealed abnormalities in the hippocampus, cortex and thalamus, and mice treated with high doses showed a potential inflammation in the thalamus and hippocampus. Untargeted metabolomic results revealed that the changed level of glutamic acid, N-acetyl CoA metabolites, and organic acid in the brain of treated mice, suggest that amino acid and lipid metabolism was interfered. RNA-seq data indicated that neuronal transcription processes and cell apoptosis pathway (forkhead box (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways) were significantly affected by TPP exposure. RT-PCR showed proinflammation cytokine tumor necrosis factor alpha (TNIF-alpha) and interleukin-6 (IL-6)) levels were increased, while antioxidant genes including nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase1 (HO-1) and superoxide dismutase (SOD1) decreased. These results suggest that TPP could cause a degree of neurotoxicity by inducing neuroinflammation and neuronal apoptosis, which are related to oxidative stress. The potential implications for neurophysiology and behavioral regulation cannot be ignored. (C) 2020 Elsevier Ltd. All rights reserved.
Page KM, Suarez-Farinas M, Suprun M, Zhang WD, Garcet S, Fuentes-Duculan J, Li X, Scaramozza M, Kieras E, Banfield C, Clark JD, Fensome A, Krueger JG, Peeva E
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Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor PF-06700841 Reveal Reduction of Skin Inflammation in Plaque Psoriasis (opens in new window)

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2020 AUG; 140(8):1546-1555.e4
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The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus kinase 1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3(+)/CD8(+) (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus kinase 1 for signal transduction.