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https://www.readbyqxmd.com/read/28214087/targeting-the-pd-1-pd-l1-axis-in-non-small-cell-lung-cancer
#1
REVIEW
Rajiv Kumar, Dearbhaile Collins, Saoirse Dolly, Fiona McDonald, Mary E R O'Brien, Timothy A Yap
The last decade has witnessed rapid advances in the discovery and development of immune checkpoint inhibitors in cancer medicine, particularly drugs targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). The proven antitumor efficacy coupled with low rates of drug-related toxicities observed, albeit idiosyncratic, with these novel immunotherapeutics have led to the registration of multiple PD-1 and PD-L1 inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, in second-line advanced NSCLC, whereas durvalumab and avelumab are in late-phase clinical testing...
December 23, 2016: Current Problems in Cancer
https://www.readbyqxmd.com/read/28213817/breakthrough-cancer-pain-and-rational-drug-use
#2
Juan Manuel Núñez Olarte
Recent data indicate that there are large disparities in the use of opioid analgesics to control breakthrough cancer pain (BTcP) in Europe and worldwide. While it is clear that affordability is a key factor, it is certainly not the only one, and other factors, such as cultural differences and overall awareness, are undoubtedly responsible. More work remains to be done to overcome barriers in the use of these medications when warranted. When prescribing a medication for BTcP, it must be considered that its time profile is different from chronic persistent pain...
February 18, 2017: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
https://www.readbyqxmd.com/read/28212290/defining-clinical-response-criteria-and-early-response-criteria-for-precision-oncology-current-state-of-the-art-and-future-perspectives
#3
Vivek Subbiah, Hubert H Chuang, Dhiraj Gambhire, Kalevi Kairemo
In this era of precision oncology, there has been an exponential growth in the armamentarium of genomically targeted therapies and immunotherapies. Evaluating early responses to precision therapy is essential for "go" versus "no go" decisions for these molecularly targeted drugs and agents that arm the immune system. Many different response assessment criteria exist for use in solid tumors and lymphomas. We reviewed the literature using the Medline/PubMed database for keywords "response assessment" and various known response assessment criteria published up to 2016...
February 15, 2017: Diagnostics
https://www.readbyqxmd.com/read/28210763/artemisinin-and-its-derivatives-in-cancer-therapy-status-of-progress-mechanism-of-action-and-future-perspectives
#4
REVIEW
Archana Bhaw-Luximon, Dhanjay Jhurry
Since the late 1990s, there has been rapid multiplication of data on the anti-cancer properties of artemisinins. This article reviews the status of progress of artemisinin and its derivatives as anti-cancer agents in clinical trials, case reports, and in vitro/in vivo studies. Particular attention is laid on the combinations of artemisinins and synthetic chemodrugs to enhance the latter's efficacy. An attempt is here made to rationalize the synergistic effects of a few common anti-cancer drugs of the anthracycline, taxane, anti-metabolite, and platinum-based drug families...
February 16, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28208215/nanoparticle-delivery-systems-general-approaches-and-their-implementation-in-multiple-myeloma
#5
REVIEW
Pilar de la Puente, Abdel Kareem Azab
Multiple myeloma (MM) is a hematological malignancy that remains incurable, with relapse rates greater than 90%. The main limiting factor for the effective use of chemotherapies in MM is the serious side effects caused by these drugs. The emphasis in cancer treatment has shifted from cytotoxic, non-specific chemotherapies to molecularly targeted and rationally designed therapies showing greater efficacy and fewer side effects. Traditional chemotherapy has shown several disadvantages such as lack of targeting capabilities, systemic toxicity and side effects; low therapeutic index, as well as, most anticancer drugs have poor water solubility...
February 16, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28206763/rational-design-of-a-polymer-with-robust-efficacy-for-intracellular-protein-and-peptide-delivery
#6
Hong Chang, Jia Lv, Xin Gao, Xing Wang, Hui Wang, Hui Chen, Xu He, Lei Li, Yiyun Cheng
The efficient delivery of biopharmaceutical drugs such as proteins and peptides into the cytosol of target cells poses substantial challenges owing to their large size and susceptibility to degradation. Current protein delivery vehicles have limitations such as the need for protein modification, insufficient delivery of large-size proteins or small peptides, and loss of protein function after the delivery. Here, we adopted a rational approach to design a polymer with robust efficacy for intracellular protein and peptide delivery...
February 20, 2017: Nano Letters
https://www.readbyqxmd.com/read/28202514/mcl-1-degradation-is-required-for-targeted-therapeutics-to-eradicate-colon-cancer-cells
#7
Jingshan Tong, Peng Wang, Shuai Tan, Dongshi Chen, Zaneta Nikolovska-Coleska, Fangdong Zou, Jian Yu, Lin Zhang
The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28195463/target-elucidation-by-co-crystal-structures-of-nadh-ubiquinone-oxidoreductase-of-plasmodium-falciparum-pfndh2-with-small-molecule-to-eliminate-drug-resistant-malaria
#8
Yiqing Yang, You Yu, Xiaolu Li, Jing Li, Yue Wu, Jie Yu, Jingpeng Ge, Zhenghui Huang, Lubin Jiang, Yu Rao, Maojun Yang
Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new anti-malarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for anti-malarial drug development. However, the absence of structural information of PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH- and RYL-552 (a new inhibitor)-bound states...
February 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28193899/structure-of-a-lipid-a-phosphoethanolamine-transferase-suggests-how-conformational-changes-govern-substrate-binding
#9
Anandhi Anandan, Genevieve L Evans, Karmen Condic-Jurkic, Megan L O'Mara, Constance M John, Nancy J Phillips, Gary A Jarvis, Siobhan S Wills, Keith A Stubbs, Isabel Moraes, Charlene M Kahler, Alice Vrielink
Multidrug-resistant (MDR) gram-negative bacteria have increased the prevalence of fatal sepsis in modern times. Colistin is a cationic antimicrobial peptide (CAMP) antibiotic that permeabilizes the bacterial outer membrane (OM) and has been used to treat these infections. The OM outer leaflet is comprised of endotoxin containing lipid A, which can be modified to increase resistance to CAMPs and prevent clearance by the innate immune response. One type of lipid A modification involves the addition of phosphoethanolamine to the 1 and 4' headgroup positions by phosphoethanolamine transferases...
February 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28193552/rational-design-and-synthesis-of-some-ppar-%C3%AE-agonists-substituted-benzylideneamino-benzylidene-thiazolidine-2-4-diones
#10
Santosh S Chhajed, Shital Chaskar, Sanjay K Kshirsagar, G M Animeshchandra Haldar, Debarshi Kar Mahapatra
The peroxisome proliferator activator receptor-γ (PPAR-γ) remained the most successful target for management of diabetes mellitus. The present work endeavors rational designing of some novel PPAR-γ agonists bearing benzylideneamino-benzylidene-thiazolidine-2,4-dione scaffold. The research involved virtual screening of 37 different molecules by molecular docking studies performed by Molecular Design Suite (MDS) into the ligand binding domain of PPAR-γ receptor to explore the binding affinity and conformations of the molecules...
February 7, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28192196/quantification-of-various-app-mrna-isoforms-and-epistasis-in-lesch-nyhan-disease
#11
Khue Vu Nguyen, William L Nyhan
The present work is the development of a simple and specific kinetic method based on RT-PCR technique coupled with direct sequencing for quantification of various amyloid precursor protein-mRNA isoforms (APP-mRNA isoforms) in biological samples, especially for identifying the most abundant one that may decisive for the normal status or disease risk. Application of this kinetic method to the Lesch-Nyhan disease (LND) was performed and results indicated an epistasis between mutated hypoxanthine phosphoribosyltransferase1 (HPRT1) and APP genes...
February 10, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28188066/synthesis-and-in-vitro-evaluation-of-sg3227-a-pyrrolobenzodiazepine-dimer-antibody-drug-conjugate-payload-based-on-sibiromycin
#12
Gary C Kemp, Arnaud C Tiberghien, Neki V Patel, Francois D'Hooge, Sanjay M Nilapwar, Lauren R Adams, Simon Corbett, David G Williams, John A Hartley, Philip W Howard
A novel pyrrolobenzodiazepine dimer payload, SG3227, was rationally designed based on the naturally occurring antitumour compound sibiromycin. SG3227 was synthesized from a dimeric core in an efficient fashion. An unexpected room temperature Diels-Alder reaction occurred during the final step of the synthesis and was circumvented by use of an iodoacetamide conjugation moiety in place of a maleimide. The payload was successfully conjugated to trastuzumab and the resulting ADC exhibited potent activity against a HER2-expressing human cancer cell line in vitro...
January 30, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28186671/modeling-neurodevelopmental-and-psychiatric-diseases-with-human-ipscs
#13
REVIEW
Zhexing Wen
Neurodevelopmental and psychiatric disorders, including autism spectrum disorder and schizophrenia, are complex and heterogeneous disorders that affect a large portion of the world's population. While the causes are still poorly understood, currently available treatments are limited; the development of rational therapeutics based on an understanding of the etiology and pathogenesis of the disease is imperative. The breakthrough technology of deriving induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of healthy subjects or patients, offers an unprecedented opportunity to recapitulate both normal and pathological development of human tissue, thereby opening up a new avenue for disease modeling and drug development in a more genetically tractable and disease-relevant system...
February 10, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28176631/grid-based-continual-analysis-of-molecular-interior-for-drug-discovery-qsar-and-qspr
#14
A V Potemkin, M A Grishina, V A Potemkin
BACKGROUND: In 1979, R.D.Cramer and M.Milne made a first realization of the above mentioned principles attempting to compare molecules by aligning them in space and by mapping their molecular fields to a 3D grid. Further, this approach was developed as the DYLOMMS (DYnamic Lattice-Oriented Molecular Modelling System) approach. In 1984, H.Wold and S.Wold proposed the use of partial least squares (PLS) analysis, instead of principal component analysis, to correlate the field values with biological activities...
February 7, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28174251/a-process-engineering-approach-to-increase-organoid-yield
#15
Natasha Arora, Jasmin Imran Alsous, Jacob W Guggenheim, Michael Mak, Jorge Munera, James M Wells, Roger D Kamm, H Harry Asada, Stanislav Y Shvartsman, Linda G Griffith
Temporal manipulation of the in vitro environment and growth factors can direct differentiation of human pluripotent stem cells into organoids, aggregates with multiple tissue-specific cell types and three-dimensional structure mimicking native organs. A mechanistic understanding of early organoid formation is essential for improving the robustness of these methods, which is necessary prior to use in drug development and regenerative medicine. We investigated intestinal organoid emergence, focusing on measurable parameters of hindgut spheroids, the intermediate step between definitive endoderm and mature organoids...
February 7, 2017: Development
https://www.readbyqxmd.com/read/28169516/preparation-of-porous-polysaccharides-templated-by-coordination-polymer-with-three-dimensional-nanochannels
#16
Yuichiro Kobayashi, Kayako Honjo, Susumu Kitagawa, Takashi Uemura
Polymerization of monosaccharide monomers usually suffers from the production of polysaccharides with ill-defined structures because of the uncontrolled random reactions among many reactive hydroxyl groups on saccharide monomers. In particular, rational synthesis of polysaccharides with porosity approximating molecular dimensions is still in its infancy, despite their use-fulness as drug carriers. Here, we disclose an efficient synthetic methodology for the preparation of polysaccharides with con-trollable mesoporosity in the structure, utilizing porous coordination polymers (PCPs) as templates...
February 7, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28169164/structure-based-design-and-sar-development-of-5-6-dihydroimidazolo-1-5-f-pteridine-derivatives-as-novel-polo-like-kinase-1-inhibitors
#17
Andre Kiryanov, Srinivasa Natala, Benjamin Jones, Christopher McBride, Victoria Feher, Betty Lam, Yan Liu, Kouhei Honda, Noriko Uchiyama, Tomohiro Kawamoto, Yuichi Hikichi, Lilly Zhang, David Hosfield, Robert Skene, Hua Zou, Jeffrey Stafford, Xiaodong Cao, Takashi Ichikawa
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.
October 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28169041/treatment-of-postmenopausal-osteoporosis-a-literature-based-algorithm-for-use-in-the-public-health-care-system
#18
Ellen Luz Pereira Caires, Mailze Campos Bezerra, Ana Flávia Torquato de Araújo Junqueira, Sheila Márcia de Araújo Fontenele, Silvana Cristina de Albuquerque Andrade, Catarina Brasil d'Alva
Bisphosphonates are considered first-line agents in the treatment of postmenopausal osteoporosis based on extensive experience of use, safety, and proven efficacy in reducing vertebral, non-vertebral and femur fractures. However, post-marketing reports based on the treatment of millions of patients/year over lengthy periods of time have revealed the occurrence of initially unexpected adverse effects, such as osteonecrosis of the jaw and atypical femoral fracture, leading to the restriction of treatment duration with bisphosphonates by global regulatory agencies...
December 27, 2016: Revista Brasileira de Reumatologia
https://www.readbyqxmd.com/read/28167250/purification-and-characterization-of-human-dehydrodolychil-diphosphate-synthase-dhdds-overexpressed-in-e-%C3%A2-coli
#19
Moshe Giladi, Ilan Edri, Michal Goldenberg, Hadas Newman, Roi Strulovich, Daniel Khananshvili, Yoni Haitin, Anat Loewenstein
Protein asparagine (N)-linked glycosylation is a post-translational modification that occurs in the endoplasmic reticulum; it plays an important role in protein folding, oligomerization, quality control, sorting, and transport. Accordingly, disorders of glycosylation may affect practically every organ system. Dehydrodolichyl diphosphate synthase (DHDDS) is an eukaryotic cis prenyltransferase (cis-PT) that catalyzes chain elongation of farnesyl diphosphate via multiple condensations with isopentenyl diphosphate to form dehydrodolichyl diphosphate, a precursor for the glycosyl carrier dolichylpyrophophate involved in N-linked glycosylation...
February 3, 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28166428/design-of-experiments-doe-in-pharmaceutical-development
#20
Stavros N Politis, Paolo Colombo, Gaia Colombo, Dimitrios M Rekkas
At the beginning of the 20(th) century, Sir Ronald Fisher introduced the concept of applying statistical analysis during the planning stages of research rather than at the end of experimentation. When statistical thinking is applied from the design phase, it enables to build quality into the product, by adopting Deming's profound knowledge approach, comprising system thinking, variation understanding, theory of knowledge and psychology. The pharmaceutical industry was late in adopting these paradigms, compared to other sectors...
February 6, 2017: Drug Development and Industrial Pharmacy
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