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https://www.readbyqxmd.com/read/29052609/neuro-ophthalmic-side-effects-of-molecularly-targeted-cancer-drugs
#1
REVIEW
M T Bhatti, A K S Salama
The past two decades has been an amazing time in the advancement of cancer treatment. Molecularly targeted therapy is a concept in which specific cellular molecules (overexpressed, mutationally activated, or selectively expressed proteins) are manipulated in an advantageous manner to decrease the transformation, proliferation, and/or survival of cancer cells. In addition, increased knowledge of the role of the immune system in carcinogenesis has led to the development of immune checkpoint inhibitors to restore and enhance cellular-mediated antitumor immunity...
October 20, 2017: Eye
https://www.readbyqxmd.com/read/29052093/emerging-small-molecule-approaches-to-enhance-the-antimyeloma-benefit-of-proteasome-inhibitors
#2
James J Driscoll, Magen Brailey
Multiple myeloma (MM) is a clonal plasma cell malignancy which, despite recent treatment advances, remains incurable in the vast majority of the over 118,000 patients in the USA afflicted with this disease. Treatment of MM has dramatically improved in the past decade with the introduction of new drugs into therapeutic strategies in both the frontline and relapse settings that has led to a significant improvement in the median overall survival (OS). These drugs have been incorporated into clinical guidelines and transformed the treatment approach to MM...
October 19, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29051279/expansion-of-epor-negative-macrophages-besides-erythroblasts-by-elevated-epor-signaling-in-erythrocytosis-mouse-models
#3
Jieyu Wang, Yoshihiro Hayashi, Asumi Yokota, Zefeng Xu, Yue Zhang, Rui Huang, Xiaomei Yan, Hongyun Liu, Liping Ma, Mohammad Azam, James P Bridges, Jose A Cancelas, Theodosia A Kalfa, Xiuli An, Zhijian Xiao, Gang Huang
Activated EPO receptor (EPOR) signaling causes erythrocytosis. The important role of macrophages for the erythroid expansion and differentiation process has been reported, both in baseline and stress erythropoiesis. However, the significance of EPOR signaling for regulation of macrophages contributing to erythropoiesis has not been fully understood. Here we show that EPOR signaling activation quickly expands both erythrocytes and macrophages in vivo in mouse models of primary and secondary erythrocytosis. To mimic the chimeric condition and expansion of the disease clone in the polycythemia vera patients, we combined Cre-inducible Jak2V617F/+ allele with LysM-Cre allele which expresses in mature myeloid cells and some of the HSC/Ps (LysM-Cre;Jak2V617F/+ mice)...
October 19, 2017: Haematologica
https://www.readbyqxmd.com/read/29051147/organic-anion-transporting-polypeptides-oatps-mediated-drug-drug-interaction-study-between-rosuvastatin-and-cyclosporine-a-in-chimeric-mice-with-humanized-liver
#4
Masashi Uchida, Yoriko Tajima, Masakazu Kakuni, Yutaka Kageyama, Taro Okada, Eri Sakudara, Chise Tateno, Ryoji Hayashi
The influence of transporters on the pharmacokinetics of drugs is being increasingly recognized, and DDIs via transporters may be a risk factor for adverse events. Cyclosporine A, a strong OATP-inhibitor, has been reported to increase the systemic exposure of rosuvastatin, an OATP-substrate, by 7.1-fold in clinical studies. PXB-mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes, and have been widely used for drug discovery in DMPK studies. In the present study, we examined in vivo and in vitro DDIs between rosuvastatin and cyclosporine A in PXB-mice and fresh human hepatocytes (PXB-cells) obtained from PXB-mice...
October 19, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29050700/the-what-when-and-how-of-car-t-cell-therapy-for-all
#5
REVIEW
Noelle Frey
Chimeric Antigen Receptor (CAR) T cells that have been engineered to target CD19 have shown great promise in patients with relapsed and refractory B cell acute lymphocytic leukemia with remission rates of 70-90%. Some remissions have successfully bridged patients to a curable allogeneic stem cell transplant, some responses have been durable without further treatment, and some patients have achieved durable remissions for relapsed ALL after allogeneic stem cell transplant. Cytokine release syndrome, correlating with the in vivo activation and expansion of T cells, and neurologic toxicity are the most significant side effects and approaches to better understand and manage these events are the subject of ongoing clinical trials...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050699/how-should-we-treat-a-patient-with-relapsed-ph-negative-b-all-and-what-novel-approaches-are-being-investigated
#6
REVIEW
Nicola Gökbuget
Despite significant improvements in outcome of newly diagnosed B-precursor ALL, the results in relapsed or refractory adult ALL are overall poor. Large retrospective studies revealed significant differences in terms of outcome, with particularly poor response rates in early or refractory relapses, whereas late relapses usually respond very well to repeated standard induction. Particularly new immunotherapy compounds like the CD19 bispecific antibody Blinatumomab and the conjugated CD22 antibody Inotuzumab yielded promising response rates compared to standard therapies in randomised trials...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050075/-specific-cytotoxicity-of-a-novel-her2-based-chimeric-antigen-receptor-modified-t-lymphocytes-against-her2-positive-tumor-cells
#7
H J Tang, Y Q Liu, X C Bian, H L Feng, B Gu, H Sun, C X Zuo, F Y Zhou, J Liu
Objective: To construct the third generation chimeric antigen receptor based on a novel humanized anti-HER2 H1-2 scFv, and to investigate the specific cytotoxicity of H1-2 CAR modified T lymphocytes(CAR-T) against HER2(+) tumor cells. Method: The expression cassette of the third generation CAR gene and anti-HER2 H1-2 scFv were constructed and cloned into lentivirus transfer plasmid, and then the third generation H1-2 CAR was transduced into human T lymphocytes using lentivirus.Enzyme linked immunosorbent assay was used to detect the expression of cytokines IL2, and LDH release assay was used to detect the cytotoxic effect of the H1-2 CAR-T...
October 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/29049732/iron-chelating-drugs-enhance-cone-photoreceptor-survival-in-a-mouse-model-of-retinitis-pigmentosa
#8
Ke Wang, Bo Peng, Jia Xiao, Orly Weinreb, Moussa B H Youdim, Bin Lin
Purpose: Retinitis pigmentosa (RP) is a group of hereditary retinal degeneration in which mutations commonly result in the initial phase of rod cell death followed by gradual cone cell death. The mechanisms by which the mutations lead to photoreceptor cell death in RP have not been clearly elucidated. There is currently no effective treatment for RP. The purpose of this work was to explore iron chelation therapy for improving cone survival and function in the rd10 mouse model of RP. Methods: Two iron-chelating drugs, 5-(4-(2-hydroxyethyl) piperazin-1-yl (methyl)-8-hydroxyquinoline (VK28) and its chimeric derivative 5-(N-methyl-N-propargyaminomethyl)-quinoline-8-oldihydrochloride (VAR10303), were injected intraperitoneally to rd10 mice every other day starting from postnatal day 14...
October 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29049716/bone-marrow-derived-cell-recruitment-to-the-neurosensory-retina-and-retinal-pigment-epithelial-cell-layer-following-subthreshold-retinal-phototherapy
#9
Sergio Caballero, David L Kent, Nilanjana Sengupta, Sergio Li Calzi, Lynn Shaw, Eleni Beli, Leni Moldovan, James M Dominguez, Ramana S Moorthy, Maria B Grant
Purpose: We investigated whether subthreshold retinal phototherapy (SRPT) was associated with recruitment of bone marrow (BM)-derived cells to the neurosensory retina (NSR) and RPE layer. Methods: GFP chimeric mice and wild-type (WT) mice were subjected to SRPT using a slit-lamp infrared laser. Duty cycles of 5%, 10%, 15%, and 20% (0.1 seconds, 250 mW, spot size 50 μm) with 30 applications were placed 50 to 100 μm from the optic disc. In adoptive transfer studies, GFP+ cells were given intravenously immediately after WT mice received SRPT...
October 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29048935/chimeric-antigen-receptor-t-cell-therapy-for-solid-tumors-require-new-clinical-regimens
#10
Jinjing Xu, Kang Tian, Haixu Zhang, Liantao Li, Hongyan Liu, Jingjie Liu, Qing Zhang, Junnian Zheng
Chimeric antigen receptor modified T cell (CAR-T) therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. Nevertheless, this success has not yet been extrapolated to solid tumors. This review focuses on new clinical regimens that could improve the therapeutic efficacy of CAR-T in solid tumors. Areas covered: Herein, the authors reviewed recent clinical trials using CAR-T therapies for the treatment of solid tumors. Specifically, this review covered the following areas: (1) the current status of CAR-T cells in the treatment of solid tumors; (2) the major factors constraining the efficacy of CAR-T cells in solid tumors; and (3) opinions regarding the future of CAR-T as a treatment for solid tumors...
October 19, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29048529/the-rhizome-of-lokiarchaeota-illustrates-the-mosaicity-of-archaeal-genomes
#11
Anthony Levasseur, Vicky Merhej, Emeline Baptiste, Vikas Sharma, Pierre Pontarotti, Didier Raoult
Genome remodeling and exchange of sequences are widespread in the prokaryotic world and mosaic genomes challenge the classification of prokaryotes, which cannot be properly achieved in terms of a single gene or group of genes. Here, we studied individually the gene collection of the archaic microorganism Lokiarchaeum sp., suggested as an archaeal host close to the emergence of the eukaryotes. The network or rhizome of all Lokiarchaeum sp. genes revealed that the genomic repertoire is mainly composed of genes from archaeal (∼36%) and bacterial origin (∼28%), distantly followed by components of eukaryotic origin (∼2%)...
October 1, 2017: Genome Biology and Evolution
https://www.readbyqxmd.com/read/29048102/high-interpatient-variability-of-treosulfan-exposure-is-associated-with-early-toxicity-in-paediatric-hsct-a-prospective-multicentre-study
#12
M Y Eileen C van der Stoep, Alice Bertaina, Marloes H Ten Brink, Robbert G Bredius, Frans J Smiers, Dominique C M Wanders, Dirk Jan A R Moes, Franco Locatelli, Henk-Jan Guchelaar, Juliëtte Zwaveling, Arjan C Lankester
Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m(2) , administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m(2) in children ≥1 year old (n = 65)...
October 19, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/29046964/differences-in-maxillomandibular-morphology-among-patients-with-mucopolysaccharidoses-i-ii-iii-iv-and-vi-a-retrospective-mri-study
#13
Till Koehne, Anja Köhn, Reinhard E Friedrich, Uwe Kordes, Thorsten Schinke, Nicole Muschol, Bärbel Kahl-Nieke
OBJECTIVE: The aims of this study were to analyze the maxillomandibular morphology of patients with mucopolysaccharidosis (MPS) type I, II, III, IVa and VI and to evaluate the craniofacial effect of hematopoietic stem cell transplantation (HCST) in MPS I. MATERIALS AND METHODS: One hundred head magnetic resonance images were retrospectively analyzed from 41 MPS and 27 control individuals. The width, height and length of the maxilla and mandible were plotted against age and the means of controls, MPS I, MPS II and MPS III were statistically compared...
October 18, 2017: Clinical Oral Investigations
https://www.readbyqxmd.com/read/29046826/incorporation-of-functional-elements-enhances-the-antitumor-capacity-of-car-t-cells
#14
REVIEW
Le Qin, Ruocong Zhao, Peng Li
As chimeric antigen receptor (CAR) T cells have displayed an unprecedented efficacy in the treatment of CD19-positive malignances, it is believed that this cell therapy will be a milestone in the history of mankind's conquering of cancer. However, there are some issues that restrict CAR T cells from reaching their optimal anti-tumor capacity, especially in the treatment of solid tumors. Inhibitory cytokines, immune checkpoint molecules, hypoxia and other adverse factors have been reported to be involved in this process...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/29046683/the-diversity-of-sequence-and-chromosomal-distribution-of-new-transposable-element-related-segments-in-the-rye-genome-revealed-by-fish-and-lineage-annotation
#15
Yingxin Zhang, Chengming Fan, Shuangshuang Li, Yuhong Chen, Richard R-C Wang, Xiangqi Zhang, Fangpu Han, Zanmin Hu
Transposable elements (TEs) in plant genomes exhibit a great variety of structure, sequence content and copy number, making them important drivers for species diversity and genome evolution. Even though a genome-wide statistic summary of TEs in rye has been obtained using high-throughput DNA sequencing technology, the accurate diversity of TEs in rye, as well as their chromosomal distribution and evolution, remains elusive due to the repetitive sequence assembling problems and the high dynamic and nested nature of TEs...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29046484/t-cells-expressing-chimeric-antigen-receptor-promote-immune-tolerance
#16
Antonio Pierini, Bettina P Iliopoulou, Heshan Peiris, Magdiel Pérez-Cruz, Jeanette Baker, Katie Hsu, Xueying Gu, Ping-Ping Zheng, Tom Erkers, Sai-Wen Tang, William Strober, Maite Alvarez, Aaron Ring, Andrea Velardi, Robert S Negrin, Seung K Kim, Everett H Meyer
Cellular therapies based on permanent genetic modification of conventional T cells have emerged as a promising strategy for cancer. However, it remains unknown if modification of T cell subsets, such as Tregs, could be useful in other settings, such as allograft transplantation. Here, we use a modular system based on a chimeric antigen receptor (CAR) that binds covalently modified mAbs to control Treg activation in vivo. Transient expression of this mAb-directed CAR (mAbCAR) in Tregs permitted Treg targeting to specific tissue sites and mitigated allograft responses, such as graft-versus-host disease...
October 19, 2017: JCI Insight
https://www.readbyqxmd.com/read/29046433/a-multimechanistic-antibody-targeting-the-receptor-binding-site-potently-cross-protects-against-influenza-b-viruses
#17
Chenguang Shen, Junyu Chen, Rui Li, Mengya Zhang, Guosong Wang, Svetlana Stegalkina, Limin Zhang, Jing Chen, Jianli Cao, Xingjian Bi, Stephen F Anderson, Timothy Alefantis, Minwei Zhang, Xiaoyang Cai, Kunyu Yang, Qingbing Zheng, Mujing Fang, Hai Yu, Wenxin Luo, Zizheng Zheng, Quan Yuan, Jun Zhang, James Wai-Kuo Shih, Harry Kleanthous, Honglin Chen, Yixin Chen, Ningshao Xia
Influenza B virus causes considerable disease burden worldwide annually, highlighting the limitations of current influenza vaccines and antiviral drugs. In recent years, broadly neutralizing antibodies (bnAbs) against hemagglutinin (HA) have emerged as a new approach for combating influenza. We describe the generation and characterization of a chimeric monoclonal antibody, C12G6, that cross-neutralizes representative viruses spanning the 76 years of influenza B antigenic evolution since 1940, including viruses belonging to the Yamagata, Victoria, and earlier lineages...
October 18, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29046274/genetic-depletion-or-hyperresponsiveness-of-natural-killer-cells-do-not-affect-atherosclerosis-development
#18
Wared Nour Eldine, Jeremie Joffre, Kazem Zibara, Andreas Giraud, Bruno Esposito, Lynda Zeboudj, José Vilar, Megumi Terada, Patrick Bruneval, Eric Vivier, Hafid Ait-Oufella, Ziad Mallat, Sophie Ugolini, Alain Tedgui
Rationale: Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunity are involved. Although several studies have evaluated the functions of NK cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or pro-atherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss- or gain-of-function of NK cells. Objective: We used two selective genetic approaches to investigate the role of NK cells in atherosclerosis: 1) Ncr1i(Cre/+)R26(lsl-DTA/+) mice in which NK cells were depleted, 2) Noé mice in which NK cells are hyperresponsive...
October 18, 2017: Circulation Research
https://www.readbyqxmd.com/read/29046143/influence-of-length-and-amino-acid-composition-on-dimer-formation-of-immunoglobulin-based-chimera
#19
Patidar Manoj, Yadav Naveen, Sarat Kumar Dalai
BACKGROUND: The dimeric immunoglobulin (Ig) chimeras used for drug targeting and delivery are preferred biologics over their monomeric forms. Designing these Ig chimeras involves critical selection of a suitable Ig base that ensures dimer formation. In the present study, we systematically analyzed several factors that influence the formation of dimeric chimera. We designed and predicted 608 cytokine-Ig chimeras where we tested the contributions of (1) different domains of Ig constant heavy chain, (2) length of partner proteins, (3) amino acid (AA) composition and (4) position of cysteine in the formation of homodimer...
October 18, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29045863/high-pressure-driven-reversible-dissociation-of-%C3%AE-synuclein-fibrils-reveals-structural-hierarchy
#20
Federica Piccirilli, Nicoletta Plotegher, Maria Grazia Ortore, Isabella Tessari, Marco Brucale, Francesco Spinozzi, Mariano Beltramini, Paolo Mariani, Valeria Militello, Stefano Lupi, Andrea Perucchi, Luigi Bubacco
The analysis of the α-synuclein (aS) aggregation process, which is involved in Parkinson's disease etiopathogenesis, and of the structural feature of the resulting amyloid fibrils may shed light on the relationship between the structure of aS aggregates and their toxicity. This may be considered a paradigm of the ground work needed to tackle the molecular basis of all the protein-aggregation-related diseases. With this aim, we used chemical and physical dissociation methods to explore the structural organization of wild-type aS fibrils...
October 17, 2017: Biophysical Journal
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