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Journal of Clinical Investigation

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https://www.readbyqxmd.com/read/28504655/transcription-factors-sohlh1-and-sohlh2-coordinate-oocyte-differentiation-without-affecting-meiosis-i
#1
Yong-Hyun Shin, Yu Ren, Hitomi Suzuki, Kayla J Golnoski, Hyo Won Ahn, Vasil Mico, Aleksandar Rajkovic
Following migration of primordial germ cells to the genital ridge, oogonia undergo several rounds of mitotic division and enter meiosis at approximately E13.5. Most oocytes arrest in the dictyate (diplotene) stage of meiosis circa E18.5. The genes necessary to drive oocyte differentiation in parallel with meiosis are unknown. Here, we have investigated whether expression of spermatogenesis and oogenesis bHLH transcription factor 1 (Sohlh1) and Sohlh2 coordinates oocyte differentiation within the embryonic ovary...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504654/sugar-makes-neutrophils-rage-linking-diabetes-associated-hyperglycemia-to-thrombocytosis-and-platelet-reactivity
#2
Robert H Lee, Wolfgang Bergmeier
Diabetes mellitus is associated with an increased risk for cardiovascular disease, but the link between hyperglycemia and atherothrombotic disease is not completely understood. Patients with diabetes often show hyporesponsiveness to antiplatelet therapies, and it has been suggested that hyperreactive reticulated platelets underlie this altered therapeutic response. In this issue of the JCI, Kraakman et al. uncover a previously unknown link between hyperglycemia and enhanced platelet production and reactivity...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504653/metabolic-shifts-in-residual-breast-cancer-drive-tumor-recurrence
#3
Kristina M Havas, Vladislava Milchevskaya, Ksenija Radic, Ashna Alladin, Eleni Kafkia, Marta Garcia, Jens Stolte, Bernd Klaus, Nicole Rotmensz, Toby J Gibson, Barbara Burwinkel, Andreas Schneeweiss, Giancarlo Pruneri, Kiran R Patil, Rocio Sotillo, Martin Jechlinger
Tumor recurrence is the leading cause of breast cancer-related death. Recurrences are largely driven by cancer cells that survive therapeutic intervention. This poorly understood population is referred to as minimal residual disease. Here, using mouse models that faithfully recapitulate human disease together with organoid cultures, we have demonstrated that residual cells acquire a transcriptionally distinct state from normal epithelium and primary tumors. Gene expression changes and functional characterization revealed altered lipid metabolism and elevated ROS as hallmarks of the cells that survive tumor regression...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504652/a-smap-in-the-face-for-cancer
#4
Shirish Shenolikar
Observed deficits in protein phosphatase 2A (PP2A) function in a variety of human cancers have stimulated drug discovery efforts aimed at restoring PP2A function to inhibit tumor growth. Work published by Sangodkar et al. in this issue of the JCI describes the characterization of orally available small molecule activators of PP2A (SMAPs). These SMAPs attenuated mitogenic signaling and triggered apoptosis in KRAS-mutant lung cancer cells and inhibited tumor growth in murine models. Tumors with mutations in the SMAP-binding site of the PP2A A subunit displayed resistance to SMAPs...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504651/aging-and-the-immune-response-to-organ-transplantation
#5
Monica M Colvin, Candice A Smith, Stefan G Tullius, Daniel R Goldstein
An increasing number of older people receive organ transplants for various end-stage conditions. Although organ transplantation is an effective therapy for older patients (i.e., older than 65 years of age), such as in end-stage renal disease, this therapy has not been optimized for older patients because of our lack of understanding of the effect of aging and the immune response to organ transplantation. Here, we provide an overview of the impact of aging on both the allograft and the recipient and its effect on the immune response to organ transplantation...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504650/neutrophil-derived-s100-calcium-binding-proteins-a8-a9-promote-reticulated-thrombocytosis-and-atherogenesis-in-diabetes
#6
Michael J Kraakman, Man K S Lee, Annas Al-Sharea, Dragana Dragoljevic, Tessa J Barrett, Emilie Montenont, Debapriya Basu, Sarah Heywood, Helene L Kammoun, Michelle Flynn, Alexandra Whillas, Nordin M J Hanssen, Mark A Febbraio, Erik Westein, Edward A Fisher, Jaye Chin-Dusting, Mark E Cooper, Jeffrey S Berger, Ira J Goldberg, Prabhakara R Nagareddy, Andrew J Murphy
Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504649/activation-of-tumor-suppressor-protein-pp2a-inhibits-kras-driven-tumor-growth
#7
Jaya Sangodkar, Abbey Perl, Rita Tohme, Janna Kiselar, David B Kastrinsky, Nilesh Zaware, Sudeh Izadmehr, Sahar Mazhar, Danica D Wiredja, Caitlin M O'Connor, Divya Hoon, Neil S Dhawan, Daniela Schlatzer, Shen Yao, Daniel Leonard, Alain C Borczuk, Giridharan Gokulrangan, Lifu Wang, Elena Svenson, Caroline C Farrington, Eric Yuan, Rita A Avelar, Agnes Stachnik, Blake Smith, Vickram Gidwani, Heather M Giannini, Daniel McQuaid, Kimberly McClinch, Zhizhi Wang, Alice C Levine, Rosalie C Sears, Edward Y Chen, Qiaonan Duan, Manish Datt, Shozeb Haider, Avi Ma'ayan, Analisa DiFeo, Neelesh Sharma, Matthew D Galsky, David L Brautigan, Yiannis A Ioannou, Wenqing Xu, Mark R Chance, Michael Ohlmeyer, Goutham Narla
Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504648/the-so-h-l-h-o-drivers-of-oocyte-growth-and-survival-but-not-meiosis-i
#8
T Rajendra Kumar
The spermatogenesis/oogenesis helix-loop-helix (SOHLH) proteins SOHLH1 and SOHLH2 play important roles in male and female reproduction. Although previous studies indicate that these transcriptional regulators are expressed in and have in vivo roles in postnatal ovaries, their expression and function in the embryonic ovary remain largely unknown. Because oocyte differentiation is tightly coupled with the onset of meiosis, it is of significant interest to determine how early oocyte transcription factors regulate these two processes...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504647/identification-of-a-nucleoside-analog-active-against-adenosine-kinase-expressing-plasma-cell-malignancies
#9
Utthara Nayar, Jouliana Sadek, Jonathan Reichel, Denise Hernandez-Hopkins, Gunkut Akar, Peter J Barelli, Michelle A Sahai, Hufeng Zhou, Jennifer Totonchy, David Jayabalan, Ruben Niesvizky, Ilaria Guasparri, Duane Hassane, Yifang Liu, Shizuko Sei, Robert H Shoemaker, J David Warren, Olivier Elemento, Kenneth M Kaye, Ethel Cesarman
Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504646/the-rna-binding-protein-tristetraprolin-schedules-apoptosis-of-pathogen-engaged-neutrophils-during-bacterial-infection
#10
Florian Ebner, Vitaly Sedlyarov, Saren Tasciyan, Masa Ivin, Franz Kratochvill, Nina Gratz, Lukas Kenner, Andreas Villunger, Michael Sixt, Pavel Kovarik
Protective responses against pathogens require a rapid mobilization of resting neutrophils and the timely removal of activated ones. Neutrophils are exceptionally short-lived leukocytes, yet it remains unclear whether the lifespan of pathogen-engaged neutrophils is regulated differently from that in the circulating steady-state pool. Here, we have found that under homeostatic conditions, the mRNA-destabilizing protein tristetraprolin (TTP) regulates apoptosis and the numbers of activated infiltrating murine neutrophils but not neutrophil cellularity...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504645/molecular-isoforms-of-high-mobility-group-box-1-are-mechanistic-biomarkers-for-epilepsy
#11
Lauren Elizabeth Walker, Federica Frigerio, Teresa Ravizza, Emanuele Ricci, Karen Tse, Rosalind E Jenkins, Graeme John Sills, Andrea Jorgensen, Luca Porcu, Thimmasettappa Thippeswamy, Tiina Alapirtti, Jukka Peltola, Martin J Brodie, Brian Kevin Park, Anthony Guy Marson, Daniel James Antoine, Annamaria Vezzani, Munir Pirmohamed
Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28481227/long-lived-keratin-15-esophageal-progenitor-cells-contribute-to-homeostasis-and-regeneration
#12
Véronique Giroux, Ashley A Lento, Mirazul Islam, Jason R Pitarresi, Akriti Kharbanda, Kathryn E Hamilton, Kelly A Whelan, Apple Long, Ben Rhoades, Qiaosi Tang, Hiroshi Nakagawa, Christopher J Lengner, Adam J Bass, E Paul Wileyto, Andres J Klein-Szanto, Timothy C Wang, Anil K Rustgi
The esophageal lumen is lined by a stratified squamous epithelium comprised of proliferative basal cells that differentiate while migrating toward the luminal surface and eventually desquamate. Rapid epithelial renewal occurs, but the specific cell of origin that supports this high proliferative demand remains unknown. Herein, we have described a long-lived progenitor cell population in the mouse esophageal epithelium that is characterized by expression of keratin 15 (Krt15). Genetic in vivo lineage tracing revealed that the Krt15 promoter marks a long-lived basal cell population able to self-renew, proliferate, and generate differentiated cells, consistent with a progenitor/stem cell population...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28481226/neonatal-expression-of-rna-binding-protein-igf2bp3-regulates-the-human-fetal-adult-megakaryocyte-transition
#13
Kamaleldin E Elagib, Chih-Huan Lu, Goar Mosoyan, Shadi Khalil, Ewelina Zasadzińska, Daniel R Foltz, Peter Balogh, Alejandro A Gru, Deborah A Fuchs, Lisa M Rimsza, Els Verhoeyen, Miriam Sansó, Robert P Fisher, Camelia Iancu-Rubin, Adam N Goldfarb
Hematopoietic transitions that accompany fetal development, such as erythroid globin chain switching, play important roles in normal physiology and disease development. In the megakaryocyte lineage, human fetal progenitors do not execute the adult morphogenesis program of enlargement, polyploidization, and proplatelet formation. Although these defects decline with gestational stage, they remain sufficiently severe at birth to predispose newborns to thrombocytopenia. These defects may also contribute to inferior platelet recovery after cord blood stem cell transplantation and may underlie inefficient platelet production by megakaryocytes derived from pluripotent stem cells...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28481225/impact-of-environmental-factors-on-alloimmunity-and-transplant-fate
#14
Leonardo V Riella, Jessamyn Bagley, John Iacomini, Maria-Luisa Alegre
Although gene-environment interactions have been investigated for many years to understand people's susceptibility to autoimmune diseases or cancer, a role for environmental factors in modulating alloimmune responses and transplant outcomes is only now beginning to emerge. New data suggest that diet, hyperlipidemia, pollutants, commensal microbes, and pathogenic infections can all affect T cell activation, differentiation, and the kinetics of graft rejection. These observations reveal opportunities for novel therapeutic interventions to improve graft outcomes as well as for noninvasive biomarker discovery to predict or diagnose graft deterioration before it becomes irreversible...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28481224/intermittent-glucocorticoid-steroid-dosing-enhances-muscle-repair-without-eliciting-muscle-atrophy
#15
Mattia Quattrocelli, David Y Barefield, James L Warner, Andy H Vo, Michele Hadhazy, Judy U Earley, Alexis R Demonbreun, Elizabeth M McNally
Glucocorticoid steroids such as prednisone are prescribed for chronic muscle conditions such as Duchenne muscular dystrophy, where their use is associated with prolonged ambulation. The positive effects of chronic steroid treatment in muscular dystrophy are paradoxical because these steroids are also known to trigger muscle atrophy. Chronic steroid use usually involves once-daily dosing, although weekly dosing in children has been suggested for its reduced side effects on behavior. In this work, we tested steroid dosing in mice and found that a single pulse of glucocorticoid steroids improved sarcolemmal repair through increased expression of annexins A1 and A6, which mediate myofiber repair...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28481223/ca2-channel-clustering-with-insulin-containing-granules-is-disturbed-in-type-2-diabetes
#16
Nikhil R Gandasi, Peng Yin, Michela Riz, Margarita V Chibalina, Giuliana Cortese, Per-Eric Lund, Victor Matveev, Patrik Rorsman, Arthur Sherman, Morten G Pedersen, Sebastian Barg
Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic β cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human β cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high probability and minimal latency...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28481222/hepatic-metal-ion-transporter-zip8-regulates-manganese-homeostasis-and-manganese-dependent-enzyme-activity
#17
Wen Lin, David R Vann, Paschalis-Thomas Doulias, Tao Wang, Gavin Landesberg, Xueli Li, Emanuela Ricciotti, Rosario Scalia, Miao He, Nicholas J Hand, Daniel J Rader
Genetic variants at the solute carrier family 39 member 8 (SLC39A8) gene locus are associated with the regulation of whole-blood manganese (Mn) and multiple physiological traits. SLC39A8 encodes ZIP8, a divalent metal ion transporter best known for zinc transport. Here, we hypothesized that ZIP8 regulates Mn homeostasis and Mn-dependent enzymes to influence metabolism. We generated Slc39a8-inducible global-knockout (ZIP8-iKO) and liver-specific-knockout (ZIP8-LSKO) mice and observed markedly decreased Mn levels in multiple organs and whole blood of both mouse models...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28481221/gene-expression-and-mutation-guided-synthetic-lethality-eradicates-proliferating-and-quiescent-leukemia-cells
#18
Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Grazyna Hoser, Silvia Maifrede, Esteban Martinez, Daniela Di Marcantonio, Elisabeth Bolton-Gillespie, Kimberly Cramer-Morales, Jaewong Lee, Min Li, Artur Slupianek, Daniel Gritsyuk, Sabine Cerny-Reiterer, Ilona Seferynska, Tomasz Stoklosa, Lars Bullinger, Huaqing Zhao, Vera Gorbunova, Katarzyna Piwocka, Peter Valent, Curt I Civin, Markus Muschen, John E Dick, Jean C Y Wang, Smita Bhatia, Ravi Bhatia, Kolia Eppert, Mark D Minden, Stephen M Sykes, Tomasz Skorski
Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase-mediated (DNA-PK-mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK-deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28481220/mrna-mediated-glycoengineering-ameliorates-deficient-homing-of-human-stem-cell-derived-hematopoietic-progenitors
#19
Jungmin Lee, Brad Dykstra, Joel A Spencer, Laurie L Kenney, Dale L Greiner, Leonard D Shultz, Michael A Brehm, Charles P Lin, Robert Sackstein, Derrick J Rossi
Generation of functional hematopoietic stem and progenitor cells (HSPCs) from human pluripotent stem cells (PSCs) has been a long-sought-after goal for use in hematopoietic cell production, disease modeling, and eventually transplantation medicine. Homing of HSPCs from bloodstream to bone marrow (BM) is an important aspect of HSPC biology that has remained unaddressed in efforts to derive functional HSPCs from human PSCs. We have therefore examined the BM homing properties of human induced pluripotent stem cell-derived HSPCs (hiPS-HSPCs)...
May 8, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28463232/bispecific-antibody-targets-multiple-pseudomonas-aeruginosa-evasion-mechanisms-in-the-lung-vasculature
#20
Ajitha Thanabalasuriar, Bas G J Surewaard, Michelle E Willson, Arpan S Neupane, Charles K Stover, Paul Warrener, George Wilson, Ashley E Keller, Bret R Sellman, Antonio DiGiandomenico, Paul Kubes
Pseudomonas aeruginosa is a major cause of severe infections that lead to bacteremia and high patient mortality. P. aeruginosa has evolved numerous evasion and subversion mechanisms that work in concert to overcome immune recognition and effector functions in hospitalized and immunosuppressed individuals. Here, we have used multilaser spinning-disk intravital microscopy to monitor the blood-borne stage in a murine bacteremic model of P. aeruginosa infection. P. aeruginosa adhered avidly to lung vasculature, where patrolling neutrophils and other immune cells were virtually blind to the pathogen's presence...
May 2, 2017: Journal of Clinical Investigation
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