Authors: Martin D, Degese MS, Vitale-Cross L, Iglesias-Bartolome R, Valera JLC, Wang Z, Feng X, Yeerna H, Vadmal V, Moroishi T, Thorne RF, Zaida M, Siegele B, Cheong SC, Molinolo AA, Samuels Y, Tamayo P, Guan KL, Lippman SM, Lyons JG, Gutkind JS
Journal: Nat Commun. 2018 Jul 9;9(1):2372. doi: 10.1038/s41467-018-04590-1.
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.
Authors: Loftfield E, Cornelis MC, Caporaso N, Yu K, Sinha R, Freedman N
Journal: JAMA Intern Med. 2018 Jul 2. doi: 10.1001/jamainternmed.2018.2425. [Epub ahead of print]
IMPORTANCE: Prospective cohorts in North America, Europe, and Asia show consistent inverse associations between coffee drinking and mortality, including deaths from cardiovascular disease and some cancers. However, concerns about coffee, particularly among people with common genetic polymorphisms affecting caffeine metabolism and among those drinking more than 5 cups per day, remain.
OBJECTIVE: To evaluate associations of coffee drinking with mortality by genetic caffeine metabolism score.
DESIGN, SETTING, AND PARTICIPANTS: The UK Biobank is a population-based study that invited approximately 9.2 million individuals from across the United Kingdom to participate. We used baseline demographic, lifestyle, and genetic data form the UK Biobank cohort, with follow-up beginning in 2006 and ending in 2016, to estimate hazard ratios (HRs) for coffee intake and mortality, using multivariable-adjusted Cox proportional hazards models. We investigated potential effect modification by caffeine metabolism, defined by a genetic score of previously identified polymorphisms in AHR, CYP1A2, CYP2A6, and POR that have an effect on caffeine metabolism. Of the 502 641 participants who consented with baseline data, we included those who were not pregnant and had complete data on coffee intake and smoking status (n = 498 134).
EXPOSURES: Total, ground, instant, and decaffeinated coffee intake.
MAIN OUTCOMES AND MEASURES: All-cause and cause-specific mortality.
RESULTS: The mean age of the participants was 57 years (range, 38-73 years); 271 019 (54%) were female, and 387 494 (78%) were coffee drinkers. Over 10 years of follow-up, 14 225 deaths occurred. Coffee drinking was inversely associated with all-cause mortality. Using non-coffee drinkers as the reference group, HRs for drinking less than 1, 1, 2 to 3, 4 to 5, 6 to 7, and 8 or more cups per day were 0.94 (95% CI, 0.88-1.01), 0.92 (95% CI, 0.87-0.97), 0.88 (95% CI, 0.84-0.93), 0.88 (95% CI, 0.83-0.93), 0.84 (95% CI, 0.77-0.92), and 0.86 (95% CI, 0.77-0.95), respectively. Similar associations were observed for instant, ground, and decaffeinated coffee, across common causes of death, and regardless of genetic caffeine metabolism score. For example, the HRs for 6 or more cups per day ranged from 0.70 (95% CI, 0.53-0.94) to 0.92 (95% CI, 0.78-1.10), with no evidence of effect modification across strata of caffeine metabolism score (P = .17 for heterogeneity).
CONCLUSIONS AND RELEVANCE: Coffee drinking was inversely associated with mortality, including among those drinking 8 or more cups per day and those with genetic polymorphisms indicating slower or faster caffeine metabolism. These findings suggest the importance of noncaffeine constituents in the coffee-mortality association and provide further reassurance that coffee drinking can be a part of a healthy diet.
Authors: Banerjee A, Kikuchi Y, Mishkin M, Rauschecker JP, Horwitz B
Journal: eNeuro. 2018 Jul 3;5(3). pii: ENEURO.0420-17.2018. doi: 10.1523/ENEURO.0420-17.2018. eCollection 2018 May-Jun.
Animals and humans rapidly detect specific features of sounds, but the time courses of the underlying neural response for different stimulus categories is largely unknown. Furthermore, the intricate functional organization of auditory information processing pathways is poorly understood. Here, we computed neuronal response latencies from simultaneously recorded spike trains and local field potentials (LFPs) along the first two stages of cortical sound processing, primary auditory cortex (A1) and lateral belt (LB), of awake, behaving macaques. Two types of response latencies were measured for spike trains as well as LFPs: (1) onset latency, time-locked to onset of external auditory stimuli; and (2) selection latency, time taken from stimulus onset to a selective response to a specific stimulus category. Trial-by-trial LFP onset latencies predominantly reflecting synaptic input arrival typically preceded spike onset latencies, assumed to be representative of neuronal output indicating that both areas may receive input environmental signals and relay the information to the next stage. In A1, simple sounds, such as pure tones (PTs), yielded shorter spike onset latencies compared to complex sounds, such as monkey vocalizations ("Coos"). This trend was reversed in LB, indicating a hierarchical functional organization of auditory cortex in the macaque. LFP selection latencies in A1 were always shorter than those in LB for both PT and Coo reflecting the serial arrival of stimulus-specific information in these areas. Thus, chronometry on spike-LFP signals revealed some of the effective neural circuitry underlying complex sound discrimination.
Authors: Wlaschin JJ, Gluski JM, Nguyen E, Silberberg H, Thompson JH, Chesler AT, Le Pichon CE
Journal: eLife. 2018;7:e33910. doi: 10.7554/eLife.33910.
Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify the neuronal stress sensor dual leucine zipper kinase (DLK; Map3k12) as a key molecule controlling the maladaptive pathways that lead to pain following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in a mouse model of neuropathic pain. Furthermore, DLK inhibition also prevents the spinal cord microgliosis that results from nerve injury and arises distant from the injury site. These striking phenotypes result from the control by DLK of a transcriptional program in somatosensory neurons regulating the expression of numerous genes implicated in pain pathogenesis, including the immune gene Csf1. Thus, activation of DLK is an early event, or even the master regulator, controlling a wide variety of pathways downstream of nerve injury that ultimately lead to chronic pain.
Authors: Kim J, Williams FJ, Dreger DL, Plassais J, Davis BW, Parker HG, Ostrander EA
Journal: Proc Natl Acad Sci USA. 2018 Jul 3. pii: 201800455. doi: 10.1073/pnas.1800455115. [Epub ahead of print]
Modern dogs are distinguished among domesticated species by the vast breadth of phenotypic variation produced by strong and consistent human-driven selective pressure. The resulting breeds reflect the development of closed populations with well-defined physical and behavioral attributes. The sport-hunting dog group has long been employed in assistance to hunters, reflecting strong behavioral pressures to locate and pursue quarry over great distances and variable terrain. Comparison of whole-genome sequence data between sport-hunting and terrier breeds, groups at the ends of a continuum in both form and function, reveals that genes underlying cardiovascular, muscular, and neuronal functions are under strong selection in sport-hunting breeds, including ADRB1, TRPM3, RYR3, UTRN, ASIC3, and ROBO1. We also identified an allele of TRPM3 that was significantly associated with increased racing speed in Whippets, accounting for 11.6% of the total variance in racing performance. Finally, we observed a significant association of ROBO1 with breed-specific accomplishments in competitive obstacle course events. These results provide strong evidence that sport-hunting breeds have been adapted to their occupations by improved endurance, cardiac function, blood flow, and cognitive performance, demonstrating how strong behavioral selection alters physiology to create breeds with distinct capabilities.
Authors: Yohe ME, Gryder BE, Shern JF, Song YK, Chou HC, Sindiri S, Mendoza A, Patidar R, Zhang X, Guha R, Butcher D, Isanogle KA, Robinson CM, Luo X, Chen JQ, Walton A, Awasthi P, Edmondson EF, Difilippantonio S, Wei JS, Zhao K, Ferrer M, Thomas CJ, Khan J
Journal: Sci Transl Med. 2018 Jul 4;10(448). pii: eaan4470. doi: 10.1126/scitranslmed.aan4470.
The RAS isoforms are frequently mutated in many types of human cancers, including PAX3/PAX7 fusion-negative rhabdomyosarcoma. Pediatric RMS arises from skeletal muscle progenitor cells that have failed to differentiate normally. The role of mutant RAS in this differentiation blockade is incompletely understood. We demonstrate that oncogenic RAS, acting through the RAF-MEK [mitogen-activated protein kinase (MAPK) kinase]-ERK (extracellular signal-regulated kinase) MAPK effector pathway, inhibits myogenic differentiation in rhabdomyosarcoma by repressing the expression of the prodifferentiation myogenic transcription factor, MYOG. This repression is mediated by ERK2-dependent promoter-proximal stalling of RNA polymerase II at the MYOG locus. Small-molecule screening with a library of mechanistically defined inhibitors showed that RAS-driven RMS is vulnerable to MEK inhibition. MEK inhibition with trametinib leads to the loss of ERK2 at the MYOG promoter and releases the transcriptional stalling of MYOG expression. MYOG subsequently opens chromatin and establishes super-enhancers at genes required for late myogenic differentiation. Furthermore, trametinib, in combination with an inhibitor of IGF1R, potently decreases rhabdomyosarcoma cell viability and slows tumor growth in xenograft models. Therefore, this combination represents a potential therapeutic for RAS-mutated rhabdomyosarcoma.
Authors: Liu X, Shu S, Korn ED
Journal: Proc Natl Acad Sci U S A. 2018 Jul 11. pii: 201808800. doi: 10.1073/pnas.1808800115. [Epub ahead of print]
The three mammalian nonmuscle myosin 2 (NM2) monomers, like all class 2 myosin monomers, are hexamers of two identical heavy (long) chains and two pairs of light (short) chains bound to the heavy chains. The heavy chains have an N-terminal globular motor domain (head) with actin-activated ATPase activity, a lever arm (neck) to which the two light chains bind, and a coiled-coil helical tail. Monomers polymerize into bipolar filaments, with globular heads at each end separated by a bare zone, by antiparallel association of their coiled-coil tails. NM2 filaments are highly dynamic in situ, frequently disassembling and reassembling at different locations within the cell where they are essential for multiple biological functions. Therefore, it is important to understand the mechanisms of filament polymerization and depolymerization. Monomers can exist in two states: folded and unfolded. It has been thought that unfolded monomers form antiparallel dimers that assemble into bipolar filaments. We now show that polymerization in vitro proceeds from folded monomers to folded antiparallel dimers to folded antiparallel tetramers that unfold forming antiparallel bipolar tetramers. Folded dimers and tetramers then associate with the unfolded tetramer and unfold, forming a mature bipolar filament consisting of multiple unfolded tetramers with an entwined bare zone. We also demonstrate that depolymerization is essentially the reverse of the polymerization process. These results will advance our understanding of NM2 filament dynamics in situ.
Authors: Zhu S, Hu Z, Tian R, Yung BC, Yang Q, Zhao S, Kiesewetter DO, Niu G, Sun H, Antaris AL, Chen X
Journal: Adv Mater. 2018 Jul 9:e1802546. doi: 10.1002/adma.201802546. [Epub ahead of print]
The significantly reduced tissue autofluorescence and scattering in the NIR-II region (1000-1700 nm) opens many exciting avenues for detailed investigation of biological processes in vivo. However, the existing NIR-II fluorescent agents, including many molecular dyes and inorganic nanomaterials, are primarily focused on complicated synthesis routes and unknown immunogenic responses with limited potential for clinical translation. Herein, the >1000 nm tail emission of conventional biocompatible NIR cyanine dyes with emission peaks at 700-900 nm is systematically investigated, and a type of bright dye for NIR-II imaging with high potential for accelerating clinical translation is identified. The asymmetry of the π domain in the S1 state of NIR cyanine dyes is proven to result in a twisted intramolecular charge-transfer process and NIR-II emission, establishing a general rule to guide future NIR-I/II fluorophore synthesis. The screened NIR dyes are identified to possess a bright emission tail in the NIR-II region along with high quantum yield, high molar-extinction coefficient, rapid fecal excretion, and functional groups amenable for bioconjugation. As a result, NIR cyanine dyes can be used for NIR-II imaging to afford superior contrast and real-time imaging of several biological models, facilitating the translation of NIR-II bioimaging to clinical theranostic applications.
Authors: Akkaya M, Traba J, Roesler AS, Miozzo P, Akkaya B, Theall BP, Sohn H, Pena M, Smelkinson M, Kabat J, Dahlstrom E, Dorward DW, Skinner J, Sack MN, Pierce SK
Journal: Nat Immunol. 2018 Jul 9. doi: 10.1038/s41590-018-0156-5. [Epub ahead of print]
B cells are activated by two temporally distinct signals, the first provided by the binding of antigen to the B cell antigen receptor (BCR), and the second provided by helper T cells. Here we found that B cells responded to antigen by rapidly increasing their metabolic activity, including both oxidative phosphorylation and glycolysis. In the absence of a second signal, B cells progressively lost mitochondrial function and glycolytic capacity, which led to apoptosis. Mitochondrial dysfunction was a result of the gradual accumulation of intracellular calcium through calcium response-activated calcium channels that, for approximately 9 h after the binding of B cell antigens, was preventable by either helper T cells or signaling via the receptor TLR9. Thus, BCR signaling seems to activate a metabolic program that imposes a limited time frame during which B cells either receive a second signal and survive or are eliminated.
Authors: Sima N, Sun W, Gorshkov K, Shen M, Huang W, Zhu W, Xie X, Zheng W, Cheng X
Journal: Transl Oncol. 2018 Jul 4;11(4):1053-1064. doi: 10.1016/j.tranon.2018.06.002. [Epub ahead of print]
Drug resistance to chemotherapy occurs in many ovarian cancer patients resulting in failure of treatment. Exploration of drug resistance mechanisms and identification of new therapeutics that overcome the drug resistance can improve patient prognosis. Following a quantitative combination screen of 6060 approved drugs and bioactive compounds in a cisplatin-resistant A2780-cis ovarian cancer cell line, 38 active compounds with IC50s under 1 μM suppressed the growth of cisplatin-resistant ovarian cancer cells. Among these confirmed compounds, CUDC-101, OSU-03012, oligomycin A, VE-821, or Torin2 in a combination with cisplatin restored cisplatin's apoptotic response in the A2780-cis cells, while SR-3306, GSK-923295, SNX-5422, AT-13387, and PF-05212384 directly suppressed the growth of A2780-cis cells. One of the mechanisms for overcoming cisplatin resistance in these cells is mediated by the inhibition of epidermal growth factor receptor (EGFR), though not all the EGFR inhibitors are equally active. The increased levels of total EGFR and phosphorylated-EGFR (p-EGFR) in the A2780-cis cells were reduced after the combined treatment of cisplatin with EGFR inhibitors. In addition, a knockdown of EGFR mRNA reduced cisplatin resistance in the A2780-cis cells. Therefore, the top active compounds identified in this work can be studied further as potential treatments for cisplatin-resistant ovarian cancer. The quantitative combinational screening approach is a useful method for identifying effective compounds and drug combinations against drug-resistant cancer cells.