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https://www.readbyqxmd.com/read/29151105/eryptosis-the-neglected-cause-of-anemia-in-end-stage-renal-disease
#1
Florian Lang, Rosi Bissinger, Majed Abed, Ferruh Artunc
End stage renal disease (ESRD) invariably leads to anemia which has been mainly attributed to compromised release of erythropoietin from the defective kidneys with subsequent impairment of erythropoiesis. However, erythropoietin replacement only partially reverses anemia pointing to the involvement of additional mechanisms. As shown more recently, anemia of ESRD is indeed in large part a result of accelerated erythrocyte loss due to suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the cell surface...
October 23, 2017: Kidney & Blood Pressure Research
https://www.readbyqxmd.com/read/29151104/clinical-efficacy-and-safety-of-first-line-dasatinib-therapy-and-the-relevance-of-velocity-of-bcr-abl1-transcript-decline-for-achievement-of-molecular-responses-in-newly-diagnosed-chronic-phase-chronic-myeloid-leukemia-report-from-the-juntendo-yamanashi-cooperative
#2
Tomoiku Takaku, Noriyoshi Iriyama, Toru Mitsumori, Eriko Sato, Akihiko Gotoh, Keita Kirito, Masaaki Noguchi, Michiaki Koike, Junichi Sakamoto, Koji Oba, Norio Komatsu
OBJECTIVE: The use of tyrosine kinase inhibitors led to an improvement in the prognoses of patients with chronic myeloid leukemia (CML). The aims of this study were to investigate the efficacy and safety of dasatinib in Japanese patients and to explore the factors that affect the achievement of molecular responses. METHODS: The primary endpoint was a major molecular response (MMR) by 12 months. The halving time for BCR-ABL1 transcripts was calculated using transcript levels...
November 18, 2017: Oncology
https://www.readbyqxmd.com/read/29151079/mechanisms-of-vasorelaxation-induced-by-total-flavonoids-of-euphorbia-humifusa-in-rat-aorta
#3
T T Wang, Z Q Zhou, S Wang, X W Ji, B Wu, L Y Sun, J F Wen, D G Kang, H S Lee, K W Cho, S N Jin
Euphorbia humifusa Willd. (EH), rich in flavonoids, has long been used for the treatment of bacillary dysentery and enteritis in China, and is known to have antioxidant, hypotensive and hypolipidemic properties. However, the vasorelaxant effect of total flavonoids of EH (TFEH) and action mechanisms are not clearly defined yet. The aim of the present study was to investigate the effects of TFEH on the vascular tension and its underlying mechanisms. Experiments were performed in rat thoracic aorta using the organ bath system...
August 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/29150975/downregulation-of-dusp4-enhances-cell-proliferation-and-invasiveness-in-colorectal-carcinomas
#4
Michihiro Ichimanda, Naoki Hijiya, Yoshiyuki Tsukamoto, Tomohisa Uchida, Chisato Nakada, Tomonori Akagi, Tsuyoshi Etoh, Hidekatsu Iha, Masafumi Inomata, Mutsuhiro Takekawa, Masatsugu Moriyama
It is widely accepted that aberrant activation of the Wnt signaling pathway is responsible for the development of precursor lesions of colorectal cancer (CRC). However, the molecular mechanisms involved in the process of progression from these precursor lesions to invasive lesions of CRC are not fully understood. Recently, we reported that constitutive activation of MAPK accompanied by downregulation of dual-specificity phosphatase 4 (DUSP4), a MAPK phosphatase, contributes to the progression of precursor lesions in the pancreas...
November 18, 2017: Cancer Science
https://www.readbyqxmd.com/read/29150880/a-slowly-developed-severe-cutaneous-adverse-reaction-to-idelalisib
#5
L Huilaja, O Lindgren, M Soronen, T Siitonen, K Tasanen
Intracellular signal mediator phosphatidylinositol-3-kinase (PIK3K) -δ, an isoform of PIK3K, is expressed in hematopoietic cells especially in lymphoid lineage 1. Idelalisib is a novel PIK3K-δ targeted kinase inhibitor which is approved for relapsed follicular B-cell non-Hodgkin lymphoma as a monotherapy and in combination with rituximab, an anti-CD20 antibody, for relapsed chronic lymphocytic leukemia (CLL) 2. Only one case describing the clinical features of severe cutaneous adverse reaction (SCAR) of idelalisib in detail has been previously published 3...
November 17, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29150630/inhibition-of-myeloid-differentiation-primary-response-protein-88-provides-neuroprotection-in-early-brain-injury-following-experimental-subarachnoid-hemorrhage
#6
Huiying Yan, Dingding Zhang, Yongxiang Wei, Hongbin Ni, Weibang Liang, Huasheng Zhang, Shuangying Hao, Wei Jin, Kuanyu Li, Chun-Hua Hang
Accumulating of evidence suggests that activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking pro-inflammatory and pro-apoptotic signaling. Myeloid differentiation primary response protein 88 (MyD88) is an endogenous adaptor protein in the toll-like receptors (TLRs) and interleukin (IL) -1β family signaling pathways and acts as a bottle neck in the NF-κB and MAPK pathways. Here, we used ST2825, a selective inhibitor of MyD88, to clarify whether inhibiting MyD88 could provide neuroprotection in EBI following SAH...
November 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29150397/fragment-based-design-synthesis-biological-evaluation-and-sar-of-1h-benzo-d-imidazol-2-yl-1h-indazol-derivatives-as-potent-pdk1-inhibitors
#7
Ting Chen, Venkataswamy Sorna, Susie Choi, Lee Call, Jared Bearss, Kent Carpenter, Steven L Warner, Sunil Sharma, David J Bearss, Hariprasad Vankayalapati
In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively...
October 28, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29150396/identification-of-pyruvate-dehydrogenase-kinase-1-inhibitors-with-anti-osteosarcoma-activity
#8
Aiping Fang, Huiqiang Luo, Liping Liu, Haibo Fan, Yaying Zhou, Yuqin Yao, Yue Zhang
Overexpression of pyruvate dehydrogenase kinases (PDKs), especially PDK1 has been observed in a variety of cancers. Thus, targeting PDK1 offers an attractive opportunity for the development of cancer therapies. In this letter, we reported the identification of two novel PDK1 inhibitors as anti-osteosarcoma agents. We found that TM-1 and TM-2 inhibited PDK1 with the IC50 values of 2.97 and 3.41 μM, respectively. Furthermore, TM-1 and TM-2 dose-dependently reduced phosphorylation of pyruvate dehydrogenase complex in MG-63 osteosarcoma cells...
October 31, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29150291/ruxolitinib-conjugated-gold-nanoparticles-for-topical-administration-an-alternative-for-treating-alopecia
#9
Sanda Boca, Cristian Berce, Ancuta Jurj, Bobe Petrushev, Laura Pop, Grigore-Aristide Gafencu, Sonia Selicean, Vlad Moisoiu, Daiana Temian, Wilhelm-Thomas Micu, Simion Astilean, Cornelia Braicu, Ciprian Tomuleasa, Ioana Berindan-Neagoe
Alopecia is a dermatological condition for which Janus kinase (JAK) inhibitors have recently emerged as potential therapy options, but with limited practical use because of the systemic side effects. The topical use of Ruxolitinib in alopecia universalis has been demonstrated, but little is known about the pharmacodynamics and pharmacokinetics of this way of administration. Nanomedicine provides improved therapeutics. In the current paper we present preliminary data regarding the potential use of Ruxolitinib-conjugated gold nanoparticles (GNPs) in dermatological conditions, as GNPs have been proven to have a reduced absorption rate into the systemic blood flow for cutaneous administration...
November 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/29150274/neuroprotective-potential-of-high-dose-biotin
#10
Mark F McCarty, James J DiNicolantonio
A recent controlled trial has established that high-dose biotin supplementation - 100 mg, three times daily - has a stabilizing effect on progression of multiple sclerosis (MS). Although this effect has been attributed to an optimization of biotin's essential cofactor role in the brain, a case can be made that direct stimulation of soluble guanylate cyclase (sGC) by pharmacological concentrations of biotin plays a key role in this regard. The utility of high-dose biotin in MS might reflect an anti-inflammatory effect of cGMP on the cerebral microvasculature, as well on oligodendrocyte differentiation and on Schwann cell production of neurotrophic factors thought to have potential for managing MS...
November 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/29150249/accuracy-of-the-cobas-egfr-mutation-assay-in-non-small-cell-lung-cancer-compared-with-three-laboratory-developed-tests
#11
Haruhiko Nakamura, Hirotaka Koizumi, Hiroki Sakai, Hiroyuki Kimura, Tomoyuki Miyazawa, Hideki Marushima, Hisashi Saji, Masayuki Takagi
BACKGROUND: The reliability of the cobas EGFR assay to detect epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) as an in vitro diagnostic test was compared with 3 laboratory-developed tests (LDTs). MATERIALS AND METHODS: After screening for EGFR mutations using formalin-fixed-paraffin-embedded NSCLC tissue sections using the cobas EGFR assay, 151 samples were further tested with 3 LDTs; the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PCR) clamp, PCR invader, and Cycleave assays...
October 28, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/29149649/chk1-inhibitors-overcome-imatinib-resistance-in-chronic-myeloid-leukemia-cells
#12
Hu Lei, Jin Jin, Meng Liu, Xiangyun Li, Hao Luo, Li Yang, Hanzhang Xu, Yingli Wu
Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem of chronic myelogenous leukemia (CML). Bcr-Abl protein depletion is considered as a way to overcome drug resistance to TKIs. In our study, Chk1 inhibitors, AZD7762 and MK-8776, had strong antitumor effects on CML cell line KBM5 and imatinib-resistant form KBM5(T315I). Moreover, Chk1 inhibitors showed a strong cytotoxic effect on leukemia cells from primary CML and imatinib-resistance CML patients, but low cytotoxic effect on normal human mononuclear cells...
November 11, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29149643/the-role-of-the-p38-activated-protein-kinase-signaling-pathway-mediated-autophagy-in-cadmium-exposed-monogonont-rotifer-brachious-koreanus
#13
Hye-Min Kang, Chang-Bum Jeong, Min-Sub Kim, Jin-Sol Lee, Jiaying Zhou, Young Hwan Lee, Duck-Hyun Kim, Eunyoung Moon, Hee-Seok Kweon, Su-Jae Lee, Jae-Seong Lee
Autophagy is a 'self-eating' system that regulates the degradation of cellular components and is involved in various biological processes including survival and development. However, despite its crucial role in organisms, the regulatory mechanism of autophagy remains largely unclear, particularly in invertebrates. In this study, conserved autophagy in the rotifer Brachionus koreanus in response to cadmium (Cd) exposure was verified by measuring acidic vesicle organelles using acridine orange (AO) and neutral red (NR) staining, and by detecting LC3 I/II on Western blot and immunofluorescence...
November 10, 2017: Aquatic Toxicology
https://www.readbyqxmd.com/read/29149610/first-approved-kinase-inhibitor-for-aml
#14
John E J Rasko, Timothy P Hughes
Activating mutations of FLT3 occur in about 30% of acute myeloid leukemia (AML) cases and are associated with relapse and poor prognosis. Midostaurin is the first drug approved for AML since 2000, and the first multi-kinase inhibitor approved for the FLT3-mutant subtype. To view this Bench to Bedside, open or download the PDF.
November 16, 2017: Cell
https://www.readbyqxmd.com/read/29149186/cell-cycle-time-series-gene-expression-data-encoded-as-cyclic-attractors-in-hopfield-systems
#15
Anthony Szedlak, Spencer Sims, Nicholas Smith, Giovanni Paternostro, Carlo Piermarocchi
Modern time series gene expression and other omics data sets have enabled unprecedented resolution of the dynamics of cellular processes such as cell cycle and response to pharmaceutical compounds. In anticipation of the proliferation of time series data sets in the near future, we use the Hopfield model, a recurrent neural network based on spin glasses, to model the dynamics of cell cycle in HeLa (human cervical cancer) and S. cerevisiae cells. We study some of the rich dynamical properties of these cyclic Hopfield systems, including the ability of populations of simulated cells to recreate experimental expression data and the effects of noise on the dynamics...
November 17, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/29149180/roles-of-vegf-flt-1-signaling-in-malignant-behaviors-of-oral-squamous-cell-carcinoma
#16
Ajiravudh Subarnbhesaj, Mutsumi Miyauchi, Chea Chanbora, Aki Mikuriya, Phuong Thao Nguyen, Hisako Furusho, Nurina Febriyanti Ayuningtyas, Minoru Fujita, Shigeaki Toratani, Masaaki Takechi, Shumpei Niida, Takashi Takata
BACKGROUND: Vascular endothelial growth factor (VEGF) is a highly specific signaling protein for vascular endothelial cells that plays a critical role in tumor growth and invasion through angiogenesis, and may contribute to cell migration and activation of pre-osteoclasts, osteoclasts and some tumor cells. OBJECTIVES: We aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells. RESULTS: Forty-two (42) of 54 cases with gingival SCC (77...
2017: PloS One
https://www.readbyqxmd.com/read/29148875/repurposing-of-kinase-inhibitors-as-broad-spectrum-antiviral-drugs
#17
Stanford Schor, Shirit Einav
The high cost of drug development and the narrow spectrum of coverage typically provided by direct-acting antivirals limit the scalability of this antiviral approach. This review summarizes progress and challenges in the repurposing of approved kinase inhibitors as host-targeted broad-spectrum antiviral therapies.
November 17, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/29148180/dna-methylation-in-the-central-and-efferent-limbs-of-the-chemo-reflex-requires-carotid-body-neural-activity
#18
Jayasri Nanduri, Ying-Jie Peng, Ning Wang, Shakil A Khan, Gregg L Semenza, Nanduri R Prabhakar
Long-term exposure to intermittent hypoxia (LT-IH; 30 days), simulating blood O2 profiles during sleep apnea, has been shown to repress anti-oxidant enzyme (AOE) gene expression by DNA methylation in the carotid body (CB) reflex pathway, resulting in persistent elevation of plasma catecholamine levels and blood pressure. The present study examined the mechanisms by which LT-IH induces DNA methylation. Adult rats exposed to LT-IH showed elevated reactive oxygen species (ROS) in the CB, nucleus tractus solitarius (nTS) and rostroventrolateral medulla (RVLM) and adrenal medulla (AM), which represent the central and efferent limbs of the CB reflex, respectively...
November 17, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29148068/gastrodin-protects-myocardial-cells-against-hypoxia-reoxygenation-injury-in-neonatal-rats-by-inhibiting-cell-autophagy-through-the-activation-of-mtor-signals-in-pi3k-akt-pathway
#19
Xiang Li, Qinhui Zhu, Yuanyuan Liu, Zhiyong Yang, Bin Li
OBJECTIVES: This study aimed to investigate the protective effect of gastrodin (GAS) on myocardial cells with hypoxia/reoxygenation (H/R) injury in neonatal rats and explore the underlying mechanism. METHODS: Myocardial cells were extracted from neonatal rats and divided into six groups: control, H/R, H/R + Low-Concentration GAS, H/R + Middle-Concentration GAS, H/R + High-Concentration GAS and H/R + High-Concentration GAS + AKT Inhibitor groups. After 48-h treatment, cell viability, autophagosome quantity and the expression levels of LC3-II, p62, Akt, pAkt, mammalian target of rapamycin (mTOR) and uncoordinated 51-like kinase 1 (ULK1) in myocardial cells were made comparisons among each group...
November 17, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/29147869/hematological-adverse-effects-in-breast-cancer-patients-treated-with-cyclin-dependent-kinase-4-and-6-inhibitors-a-systematic-review-and-meta-analysis
#20
REVIEW
Loay Kassem, Kyrillus S Shohdy, Shaimaa Lasheen, Omar Abdel-Rahman, Thomas Bachelot
BACKGROUND: The introduction of specific cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly improved progression-free survival in hormone receptor-positive metastatic breast cancer. CDK 4/6 inhibitors induce cell cycle arrest via liberating the tumor suppressor retinoblastoma protein from CDK4/6 inhibitory effect. Preliminary studies suggested an increase in the hematological toxicities which might affect the quality of life in such palliative setting. METHODS: We searched PubMed, ASCO, ESMO and San Antonio meeting databases for randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors with safety data provided on the incidence of hematological adverse effects...
November 16, 2017: Breast Cancer: the Journal of the Japanese Breast Cancer Society
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