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https://www.readbyqxmd.com/read/29691279/assessment-of-the-molecular-mechanisms-of-action-of-novel-4-phenylpyridine-2-one-and-6-phenylpyrimidin-4-one-allosteric-modulators-at-the-m1-muscarinic-acetylcholine-receptors
#1
Emma T van der Westhuizen, Arthur Spathis, Elham Khajehali, Maneula Jorg, Shailesh N Mistry, Ben Capuano, Andrew B Tobin, Patrick M Sexton, Peter J Scammells, Celine Valant, Arthur Christopoulos
Positive allosteric modulators (PAMs) that target the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) are potential treatments for cognitive deficits in conditions such as Alzheimer's disease and schizophrenia. We recently reported novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one M1 mAChR PAMs with the potential to display different modes of positive allosteric modulation and/or agonism (Mistry et al., 2016), but their molecular mechanisms of action remain undetermined. The current study compared the pharmacology of three such novel PAMs with the prototypical first-generation PAM, BQCA, in a recombinant Chinese hamster ovary (CHO) cell line stably expressing the human M1 mAChR...
April 24, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29691127/digenic-heterozigosity-in-scn5a-and-cacna1c-explains-the-variable-expressivity-of-the-long-qt-phenotype-in-a-spanish-family
#2
Paloma Nieto-Marín, Juan Jiménez-Jáimez, David Tinaquero, Silvia Alfayate, Raquel G Utrilla, María Del Mar Rodríguez Vázquez Del Rey, Francesca Perin, Geòrgia Sarquella-Brugada, Lorenzo Monserrat, Josep Brugada, Luis Tercedor, Juan Tamargo, Eva Delpón, Ricardo Caballero
INTRODUCTION AND OBJECTIVES: A known long QT syndrome-related mutation in Nav1.5 cardiac channels (p.R1644H) was found in 4 members of a Spanish family but only 1 of them showed prolongation of the QT interval. In the other 3 relatives, a novel missense mutation in Cav1.2 cardiac channels was found (p.S1961N). Here, we functionally analyzed p.S1961N Cav1.2 channels to elucidate whether this mutation regulates the expressivity of the long QT syndrome phenotype in this family. METHODS: L-type calcium current (ICaL ) recordings were performed by using the whole-cell patch-clamp technique in Chinese hamster ovary cells transiently transfected with native and/or p...
April 21, 2018: Revista Española de Cardiología
https://www.readbyqxmd.com/read/29688494/discordance-between-serum-anti-m%C3%A3-llerian-hormone-concentrations-and-antral-follicle-counts-not-only-technical-issues
#3
M Š Alebic, N Stojanovic, D Dewailly
STUDY QUESTION: Do patient-specific features contribute to the differences between measured serum anti-Müllerian hormone (AMH) concentrations and AMH values expected from the corresponding antral follicle count (AFC)? SUMMARY ANSWER: Patient-specific features contribute to the differences between measured AMH values and AMH values expected from the corresponding AFC (AMHp), potentially through their effect on follicular AMH production. WHAT IS KNOWN ALREADY: Both patient counselling and patient management could be hampered by finding of disagreement between AFC and AMH if both are used for the prediction of ovarian response...
April 24, 2018: Human Reproduction
https://www.readbyqxmd.com/read/29688269/polycystic-ovary-syndrome-possible-involvement-of-androgen-induced-chemerin-mediated-ovarian-recruitment-of-monocytes-macrophages
#4
Patricia D A Lima, Anne-Laure Nivet, Qi Wang, Yi-An Chen, Arthur Leader, Annie Cheung, Chii-Ruey Tzeng, Benjamin K Tsang
Polycystic ovary syndrome (PCOS) is a continuum of endocrine and reproductive disorders characterized by hyperandrogenism, antral follicle growth arrest and chronic inflammation. Macrophages play key role in inflammation and the balance between M1 (inflammatory) and M2 (anti-inflammatory) macrophages determines physiological/pathological outcomes. Here, we investigated if hyperandrogenism increases ovarian chemerin altering the balance of M1 and M2 macrophages and the granulosa cell death. Ovarian chemerin was up-regulated by 5α-dihydrotestosterone (DHT) in lean and overweight rats; while increased serum chemerin levels were only evident in overweight rats, suggesting that the serum chemerin may be reflective of a systemic response and associated with obesity, whereas increased ovarian chemerin expression is a localized response independent of the metabolic status...
April 24, 2018: Biology of Reproduction
https://www.readbyqxmd.com/read/29681721/progesterone-hypersensitivity-a-challenge-for-luteal-support
#5
Astha Gupta, Deepak Goenka, Mohan L Goenka
Progesterone hypersensitivity is a rare phenomenon which can occur after both endogenous and exogenous exposures. We present a case of hypersensitivity to various forms and routes of exogenous progesterone. A 27-year-old female presented with primary infertility. Investigations revealed Grade 1 endometriosis and polycystic ovary syndrome. Three cycles of intrauterine insemination were attempted which were unsuccessful and in vitro fertilization was proceeded. Six blastocysts of Grade A were formed and cryopreserved...
January 2018: Journal of Human Reproductive Sciences
https://www.readbyqxmd.com/read/29681714/tamoxifen-is-better-than-low-dose-clomiphene-or-gonadotropins-in-women-with-thin-endometrium-7-mm-after-clomiphene-in-intrauterine-insemination-cycles-a-prospective-study
#6
Sunita Sharma, Geetha Rani, Gunja Bose, Indranil Saha, Sikha Bathwal, B N Chakravarty
Aim: Gonadotropin stimulation is used as the second line of treatment in patients with thin endometrium following clomiphene citrate (CC) administration, which is associated with higher cost, multiple births, and ovarian hyperstimulation syndrome. Tamoxifen (TMX), a selective estrogen receptor modulator, acts as an agonist on the endometrium. The objective of the present study was to compare the efficacy of low-dose CC, TMX, and gonadotropins in women with thin endometrium (<7 mm) following Clomiphene in intrauterine insemination (IUI) cycles...
January 2018: Journal of Human Reproductive Sciences
https://www.readbyqxmd.com/read/29680975/increased-fibulin-1-plasma-levels-in-polycystic-ovary-syndrome-pcos-patients-possible-contribution-to-the-link-between-pcos-and-cardiovascular-risk
#7
E Scarinci, A Tropea, G Russo, G Notaristefano, C Messana, O Alesiani, S M Fabozzi, A Lanzone, R Apa
PURPOSE: To investigate a possible relation between fibulin-1 plasma levels and PCOS. DESIGN: ELISA quantitative determination of human fibulin-1. METHODS: 50 women with PCOS and 40 control patients who attended the Unit of Human Reproductive Pathophysiology, Università Cattolica del Sacro Cuore, Rome, were enrolled. Ultrasonographic pelvic examinations, hormonal profile assays, oral tolerance test OGTT, lipid profile and ELISA quantitative determination of human fibulin-1 were performed...
April 21, 2018: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/29679326/synthetic-peg-hydrogel-for-engineering-the-environment-of-ovarian-follicles
#8
Uziel Mendez, Hong Zhou, Ariella Shikanov
The functional unit within the ovary is the ovarian follicle, which is also a morphological unit composed of three basic cell types: the oocyte, granulosa, and theca cells. Similar to human ovarian follicles, mouse follicles can be isolated from their ovarian environment and cultured in vitro to study folliculogenesis, or follicle development for days or weeks. Over the course of the last decade, follicle culture in a three-dimensional (3D) environment exponentially improved the outcomes of in vitro folliculogenesis...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29678671/the-development-of-oocytes-in-the-ovary-of-a-parthenogenetic-tick-haemaphysalis-longicornis
#9
Ryo Mihara, Rika Umemiya-Shirafuji, Yasuyuki Abe, Tomohide Matsuo, Noriyuki Horiuchi, Suguru Kawano, Kozo Fujisaki, Hiroshi Suzuki
Haemaphysalis longicornis is an important vector of various pathogens in domestic animals and humans. The tick is a unique species with bisexual and parthenogenetic races. Although mating induces oocyte development, it is possible in the parthenogenetic race to complete oogenesis without copulation. Here we examined the developmental process of oocytes from unfed to the oviposition period in parthenogenetic H. longicornis. We classified the developmental stages of oocytes into five stages: stage I, germinal vesicle occupies more than half of the cytoplasm; stage II, germinal vesicle occupies less than half of the cytoplasm; stage III, germinal vesicle migrates from the center in the oocyte to the vicinity of the pedicel cells; stage IV, the cytoplasm is filled with yolk granules of various sizes; stage V, the cytoplasm is occupied by large yolk granules...
April 17, 2018: Parasitology International
https://www.readbyqxmd.com/read/29678103/ouantitative-proteomic-analysis-of-cellular-responses-to-a-designed-amino-acid-feed-in-a-monoclonal-antibody-producing-chinese-hamster-ovary-cell-line
#10
Fatemeh Torkashvand, Fereidoun Mahboudi, Manouchehr Vossoughi, Elnaz Fatemi, Seyed Masoud Moosavi Basri, Amir Heydari, Behrouz Vaziri
Background: Chinese hamster ovary (CHO) cell line is considered as the most common cell line in the biopharmaceutical industry because of its capability in performing efficient post-translational modifications and producing the recombinant proteins, which are similar to natural human proteins. The optimization of the upstream process via different feed strategies has a great impact on the target molecule expression and yield. Methods: To determine and understand the molecular events beneath the feed effects on the CHO cell, a label-free quantitative proteomic analysis was applied...
April 21, 2018: Iranian Biomedical Journal
https://www.readbyqxmd.com/read/29675930/relationship-between-ultrasonographic-and-biochemical-markers-of-tubal-ectopic-pregnancy-and-success-of-subsequent-management
#11
Batool Nadim, Chuan Lu, Fernando Infante, Shannon Reid, George Condous
OBJECTIVES: To determine whether there is an association between morphologic types of tubal ectopic pregnancy (EP), 0-hour human chorionic gonadotropin (hCG) levels, and subsequent management success. METHODS: We conducted a prospective study (November 2006-December 2015). Women had a diagnosis of EP by transvaginal ultrasonography if they had an inhomogeneous mass adjacent to the ovary and moving separately from it ("blob" sign), a mass with a hyperechoic ring around the gestational sac ("bagel" sign), or a gestational sac with an embryonic pole with or without a yolk sac with or without cardiac activity...
April 20, 2018: Journal of Ultrasound in Medicine: Official Journal of the American Institute of Ultrasound in Medicine
https://www.readbyqxmd.com/read/29675469/noninvasive-ovarian-cancer-biomarker-detection-via-an-optical-nanosensor-implant
#12
Ryan M Williams, Christopher Lee, Thomas V Galassi, Jackson D Harvey, Rachel Leicher, Maria Sirenko, Madeline A Dorso, Janki Shah, Narciso Olvera, Fanny Dao, Douglas A Levine, Daniel A Heller
Patients with high-grade serous ovarian carcinoma (HGSC) exhibit poor 5-year survival rates, which may be significantly improved by early-stage detection. The U.S. Food and Drug Administration-approved biomarkers for HGSC-CA-125 (cancer antigen 125) and HE4 (human epididymis protein 4)-do not generally appear at detectable levels in the serum until advanced stages of the disease. An implantable device placed proximal to disease sites, such as in or near the fallopian tube, ovary, uterine cavity, or peritoneal cavity, may constitute a feasible strategy to improve detection of HGSC...
April 2018: Science Advances
https://www.readbyqxmd.com/read/29670172/acetylcholine-and-necroptosis-are-players-in-follicular-development-in-primates
#13
Yongrui Du, Konstantin Bagnjuk, Maralee S Lawson, Jing Xu, Artur Mayerhofer
Acetylcholine (ACh) in the ovary and its actions were linked to survival of human granulosa cells in vitro and improved fertility of rats in vivo. These effects were observed upon experimental blockage of the ACh-degrading enzyme (ACH esterase; ACHE), by Huperzine A. We now studied actions of Huperzine A in a three-dimensional culture of macaque follicles. Because a form of programmed necrotic cell death, necroptosis, was previously identified in human granulosa cells in vitro, we also studied actions of necrostatin-1 (necroptosis inhibitor)...
April 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29665393/comparative-experimental-theoretical-studies-on-the-egfr-dimerization-under-the-effect-of-egf-egf-analogues-binding-highlighting-the-importance-of-egf-egfr-interactions-at-site-iii-interface
#14
Masomeh Mehrabi, Hamid Mahdiuni, Hassan Rasouli, Kamran Mansouri, Mohsen Shahlaie, Reza Khodarahmi
Epidermal growth factor receptors (EGFRs) and their cytoplasmic tyrosine kinases play significant roles in cell proliferation and signaling. All the members of the EGFR/ErbB family are primary goals for cancer therapy, particularly for tumors of breast, cervix, ovaries, kidney, esophagus, prostate and non-small-cell lung carcinoma and head and neck tumors. However, the therapeutic ability of accessible anti-ErbB agents is limited. Therefore, recognizing EGF analogues or small organic molecules with high affinity for the extracellular domain of the EGFR is a critical target on cancer research...
April 14, 2018: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29665328/effects-of-exposure-to-acetaminophen-and-ibuprofen-on-fetal-germ-cell-development-in-both-sexes-in-rodent-and-human-using-multiple-experimental-systems
#15
Pablo Hurtado-Gonzalez, Richard A Anderson, Joni Macdonald, Sander van den Driesche, Karen Kilcoyne, Anne Jørgensen, Chris McKinnell, Sheila Macpherson, Richard M Sharpe, Rod T Mitchell
BACKGROUND: Analgesic exposure during pregnancy may affect aspects of fetal gonadal development that are targeted by endocrine disruptors. OBJECTIVES: We investigated whether therapeutically relevant doses of acetaminophen and ibuprofen affect germ cell (GC) development in human fetal testes/ovaries using in vitro and xenograft approaches. METHODS: Gonocyte (TFAP2C+ ) number was reduced relative to controls in first-trimester human fetal testes exposed in vitro to acetaminophen (-28%) or ibuprofen (-22%) and also in ovaries exposed to acetaminophen (-43%) or ibuprofen (-49%)...
April 16, 2018: Environmental Health Perspectives
https://www.readbyqxmd.com/read/29665036/stable-mirna-overexpression-in-human-cap-cells-engineering-alternative-production-systems-for-advanced-manufacturing-of-biologics-using-mir-136-and-mir-3074
#16
Benjamin L Weis, Nadine Guth, Simon Fischer, Silke Wissing, Simon Fradin, Karl-Heinz Holzmann, René Handrick, Kerstin Otte
Chinese hamster ovary (CHO) cells still represent the major production host for therapeutic proteins. However, multiple limitations have been acknowledged leading to the search for alternative expression systems. CEVEC's amniocyte production (CAP) cells are human production cells demonstrated to enable efficient overexpression of recombinant proteins with human glycosylation pattern. However, CAP cells have not yet undergone any engineering approaches to optimize process parameters for a cheaper and more sustainable production of biopharmaceuticals...
April 17, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29660689/quinonoid-compounds-via-reactions-of-lawsone-and-2-aminonaphthoquinone-with-%C3%AE-bromonitroalkenes-and-nitroallylic-acetates-structural-diversity-by-c-ring-modification-and-cytotoxic-evaluation-against-cancer-cells
#17
Thekke V Baiju, Renata G Almeida, Sudheesh T Sivanandan, Carlos A de Simone, Lucas M Brito, Bruno C Cavalcanti, Claudia Pessoa, Irishi N N Namboothiri, Eufrânio N da Silva Júnior
Morita-Baylis-Hillman acetates and α-bromonitroalkenes have been employed in cascade reactions with lawsone and 2-aminonaphthoquinone for the one-pot synthesis of heterocycle fused quinonoid compounds. The reactions reported here utilized the 1,3-binucleophilic potential of hydroxy- and aminonaphthoquinones and the 1,2/1,3-bielectrophilic potential of bromonitroalkenes and Morita-Baylis-Hillman acetates for the synthesis of pyrrole and furan fused naphthoquinones. The synthesized compounds were evaluated against HCT-116 (human colon carcinoma cells), PC3 (human prostate cancer cells), HL-60 (human promyelocytic leukemia cells), SF295 (human glioblastoma cells) and NCI-H460 (human lung cancer cells) and exhibited antitumor activity with IC50 values as low as < 2 μM...
April 5, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29659191/optimised-arid1a-immunohistochemistry-is-an-accurate-predictor-of-arid1a-mutational-status-in-gynaecological-cancers
#18
Saira Khalique, Kalnisha Naidoo, Ayoma D Attygalle, Divya Kriplani, Frances Daley, Anne Lowe, James Campbell, Thomas Jones, Michael Hubank, Kerry Fenwick, Nicholas Matthews, Alistair G Rust, Christopher J Lord, Susana Banerjee, Rachael Natrajan
ARID1A is a tumour suppressor gene that is frequently mutated in clear cell and endometrioid carcinomas of the ovary and endometrium and is an important clinical biomarker for novel treatment approaches for patients with ARID1A defects. However, the accuracy of ARID1A immunohistochemistry (IHC) as a surrogate for mutation status has not fully been established for patient stratification in clinical trials. Here we tested whether ARID1A immunohistochemistry could reliably predict ARID1A mutations identified by next-generation sequencing...
April 16, 2018: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/29658283/-oligo-and-polysacharides-proteoglycans
#19
Lajos Jakab
After clearing up the confusion in the previously used nomenclature, the paper discusses the family of small-leucin-rich glycoproteins. After mentioning the family and its role in the organisation of the ground substance and in the regulation of inflammation, one unique molecule of proteoglycans is presented. This molecule is the inter-α-trypsin inhibitor. It has turned out that this peculiar molecule originally contains glycosaminoglycan beside the neutral carbohydrates. After summarizing the numerous connections of the proteoglycan molecule, the "self-sacrificing" nature of the molecule is presented...
April 2018: Orvosi Hetilap
https://www.readbyqxmd.com/read/29655788/antibody-engineering-to-improve-manufacturability
#20
Sujeewa D Wijesuriya, Elizabeth Pongo, Milan Tomic, Fangjiu Zhang, Consuelo Garcia-Rodriquez, Fraser Conrad, Shauna Farr-Jones, James D Marks, Arnold H Horwitz
Expression variation among antibodies produced by stably transfected Chinese Hamster Ovary (CHO) cells is well established. While developing CHO-K1 cell lines, we encountered a human monoclonal antibody, mAb B-c, with severe manufacturability issues, including very poor expression and high levels of heavy chain (HC) dimer and high molecular weight aggregates. Using transient expression in CHO-K1 cells, we identified light chain (LC) as the source of the manufacturability issues for this antibody. While other antibodies achieved optimal expression at 1:1 or 2:1 LC to HC ratios, mAb B-c required up to a 6:1 LC:HC for maximal expression, which was still significantly lower than that for other tested antibodies...
April 12, 2018: Protein Expression and Purification
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