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https://www.readbyqxmd.com/read/28636555/overcoming-resistance-to-targeted-therapy-with-immunotherapy-and-combination-therapy-for-metastatic-melanoma
#1
REVIEW
Hilary R Keller, Xin Zhang, Li Li, Helmut Schaider, James W Wells
Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease...
June 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636311/insights-into-integrated-lead-generation-and-target-identification-in-malaria-and-tuberculosis-drug-discovery
#2
John Okombo, Kelly Chibale
New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public-private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery...
June 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28635648/deoxyelephantopin-and-isodeoxyelephantopin-as-potential-anticancer-agents-with-effects-on-multiple-signaling-pathways
#3
REVIEW
Tahir Mehmood, Amara Maryam, Hamed A Ghramh, Muhammad Khan, Tonghui Ma
Cancer is the 2nd leading cause of death worldwide. The development of drugs to target only one specific signaling pathway has limited therapeutic success. Developing chemotherapeutics to target multiple signaling pathways has emerged as a new prototype for cancer treatment. Deoxyelephantopin (DET) and isodeoxyelephantopin (IDET) are sesquiterpene lactone components of "Elephantopus scaber and Elephantopus carolinianus", traditional Chinese medicinal herbs that have long been used as folk medicines to treat liver diseases, diabetes, diuresis, bronchitis, fever, diarrhea, dysentery, cancer, and inflammation...
June 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28633756/immunotherapy-the-wave-of-the-future-in-bladder-cancer
#4
Daniel P Petrylak
Urothelial cell carcinoma (UC) is one of the most common cancers and one of the most deadly. Metastatic UC is particularly hard to treat, because it is typically diagnosed when patients are elderly and have medical comorbidities. Many patients with metastatic UC are unable to receive cisplatin-based chemotherapy, due to older age at diagnosis and comorbidities, and even when platinum chemotherapy can be administered, it has limited success in prolonging survival. Recently, improved understanding of molecular targets and immunologic characteristics of urothelial tumor cells has resulted in new therapeutic approaches that may help optimize first- and second-line therapy...
June 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28633563/mammalian-synthetic-biology-engineering-biological-systems
#5
Joshua B Black, Pablo Perez-Pinera, Charles A Gersbach
The programming of new functions into mammalian cells has tremendous application in research and medicine. Continued improvements in the capacity to sequence and synthesize DNA have rapidly increased our understanding of mechanisms of gene function and regulation on a genome-wide scale and have expanded the set of genetic components available for programming cell biology. The invention of new research tools, including targetable DNA-binding systems such as CRISPR/Cas9 and sensor-actuator devices that can recognize and respond to diverse chemical, mechanical, and optical inputs, has enabled precise control of complex cellular behaviors at unprecedented spatial and temporal resolution...
June 21, 2017: Annual Review of Biomedical Engineering
https://www.readbyqxmd.com/read/28631980/orexin-research-patent-news-from-2016
#6
Christoph Boss, Catherine Roch
The orexin (hypocretin) system consists of two G-protein-coupled receptors, orexin 1 (Ox1) and orexin 2 (Ox2) and two endogenous peptidic ligands, orexin A (OxA) and orexin B (OxB). It is evolutionarily highly conserved. In the brain, it is involved in the promotion of wakefulness under motivational circumstances as well as in anxiety and addictive disorders. In addition, its activation via the Ox1 receptor triggers apoptosis in several cancer cell lines. Dual orexin receptor antagonists (DORAs) such as suvorexant are successfully used to treat primary insomnia...
June 20, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28631844/sonic-hedgehog-wnt-and-brain-derived-neurotrophic-factor-cell-signaling-pathway-crosstalk-potential-therapy-for-depression
#7
REVIEW
Mohd Tayyab, Mehdi H Shahi, Shirin Farheen, Mubeena P M Mariyath, Nabeela Khanam, Javier S Castresana, M Mobarak Hossain
There are various theories to explain the pathophysiology of depression and support its diagnosis and treatment. The roles of monoamines, brain-derived neurotrophic factor (BDNF), and Wnt signaling are well researched, but sonic hedgehog (Shh) signaling and its downstream transcription factor Gli1 are not well studied in depression. Shh signaling plays a fundamental role in embryonic development and adult hippocampal neurogenesis and also involved in the growth of cancer. In this article, we summarize the evidence for the Shh signaling pathway in depression and the potential crosstalk of Shh with Wnt and BDNF...
June 20, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28630454/treatment-with-a-non-toxic-self-replicating-anti-prion-delays-or-prevents-prion-disease-in-vivo
#8
R Diaz-Espinoza, R Morales, L Concha-Marambio, I Moreno-Gonzalez, F Moda, C Soto
Transmissible spongiform encephalopathies (TSEs) are fatal neurological disorders caused by prions, which are composed of a misfolded protein (PrP(Sc)) that self-propagates in the brain of infected individuals by converting the normal prion protein (PrP(C)) into the pathological isoform. Here, we report a novel experimental strategy for preventing prion disease based on producing a self-replicating, but innocuous PrP(Sc)-like form, termed anti-prion, which can compete with the replication of pathogenic prions...
June 20, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28630190/%C3%AE-lactam-antibiotics-with-a-high-affinity-for-pbp2-act-synergistically-with-the-ftsz-targeting-agent-txa707-against-methicillin-resistant-staphylococcus-aureus
#9
Edgar Ferrer-González, Malvika Kaul, Ajit K Parhi, Edmond J LaVoie, Daniel S Pilch
Methicillin-resistant Staphylococcus aureus (MRSA) is a multi-drug resistant pathogen that poses a significant risk to global health today. We have developed a promising new FtsZ-targeting agent (TXA707) with potent activity against MRSA isolates resistant to current standard-of-care antibiotics. Here we present results that demonstrate differing extents of synergy between TXA707 and a broad range of β-lactam antibiotics (including six cephalosporins, two penicillins, and two carbapenems) against MRSA. To explore whether there is a correlation between the extent of synergy and the preferential antibacterial target of each β-lactam, we determined the binding affinities of the β-lactam antibiotics for each of the four native penicillin binding proteins (PBPs) of S...
June 19, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28629760/cardiac-overexpression-of-epac1-in-transgenic-mice-rescues-lipopolysaccharide-induced-cardiac-dysfunction-and-inhibits-jak-stat-pathway
#10
Huiling Jin, Takayuki Fujita, Meihua Jin, Reiko Kurotani, Iyuki Namekata, Shogo Hamaguchi, Yuko Hidaka, Wenqian Cai, Kenji Suita, Yoshiki Ohnuki, Yasumasa Mototani, Kouichi Shiozawa, Rajesh Prajapati, Chen Liang, Masanari Umemura, Utako Yokoyama, Motohiko Sato, Hikaru Tanaka, Satoshi Okumura, Yoshihiro Ishikawa
Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic stimulation leads to coupling of the β-adrenergic receptor/Gs/adenylyl cyclase, a membrane-bound enzyme that catalyzes the conversion of ATP to cAMP, thereby stimulating protein kinase A (PKA) and ultimately compensating for cardiac dysfunction. The mechanism of such compensation by catecholamine has been traditionally understood as PKA-mediated enforcement of cardiac contractility...
June 16, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28629006/a-colon-targeted-drug-delivery-system-based-on-alginate-modificated-graphene-oxide-for-colorectal-liver-metastasis
#11
Bin Zhang, Yayuan Yan, Qiujuan Shen, Dong Ma, Langhuan Huang, Xiang Cai, Shaozao Tan
A major problem associated with colon cancer is liver metastasis. A colon-targeted drug delivery system is one way to address this problem after the resection of colorectal cancer. However, traditional drug delivery systems face many challenges, such as an inability to control the release rate, inaccurate targeting, susceptibility to the microenvironment and poor stability. Here, we report the development of a graphene oxide (GO)-based, sodium alginate (ALG) functionalized colon-targeting drug delivery system, that is loaded with 5-fluorouracil (5-FU) as the anti-cancer drug (denoted as GO-ALG/5-FU)...
October 1, 2017: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/28626498/tubulin-beta-3-chain-as-a-new-candidate-protein-biomarker-of-human-skin-aging-a-preliminary-study
#12
Sylvia G Lehmann, Sandrine Bourgoin-Voillard, Michel Seve, Walid Rachidi
Skin aging is a complex process, and a lot of efforts have been made to identify new and specific targets that could help to diagnose, prevent, and treat skin aging. Several studies concerning skin aging have analyzed the changes in gene expression, and very few investigations have been performed at the protein level. Moreover, none of these proteomic studies has used a global quantitative labeled proteomic offgel approach that allows a more accurate description of aging phenotype. We applied such an approach on human primary keratinocytes obtained from sun-nonexposed skin biopsies of young and elderly women...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28625312/traitement-des-rechutes-tardives-du-cancer-de-l%C3%A2-ovaire
#13
Anne Floquet, Dominique Berton-Rigaud, Gwenael Ferron, Gilles Freyer, Anne Claire Hardy-Bessard, Benoit You
Despite large improvements in treatment efficacy, the cure rate of ovarian cancer has not radically changed. Relapses both remain frequent and are still synonymous with chronic disease. Most of them are platinum-sensitive, and can be successfully treated with successive lines of chemotherapy. Surgery may have a role to play but its real impact, population selection criteria, and adequate timing still have to be established. Regarding medical treatments, the availability of new targeted therapeutics, such as bevacizumab and olaparib, complicates decision making...
May 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28624504/proinsulin-protects-against-age-related-cognitive-loss-through-anti-inflammatory-convergent-pathways
#14
Rubén Corpas, Alberto M Hernández-Pinto, David Porquet, Catalina Hernández-Sánchez, Fatima Bosch, Arantxa Ortega-Aznar, Francesc Comellas, Enrique J de la Rosa, Coral Sanfeliu
Brain inflammaging is increasingly considered as contributing to age-related cognitive loss and neurodegeneration. Despite intensive research in multiple models, no clinically effective pharmacological treatment has been found yet. Here, in the mouse model of brain senescence SAMP8, we tested the effects of proinsulin, a promising neuroprotective agent that was previously proven to be effective in mouse models of retinal neurodegeneration. Proinsulin is the precursor of the hormone insulin but also upholds developmental physiological effects, particularly as a survival factor for neural cells...
June 14, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28624398/prognostic-significance-of-remote-myocardium-alterations-assessed-by-quantitative-noncontrast-t1-mapping-in-st-segment-elevation-myocardial-infarction
#15
Sebastian J Reinstadler, Thomas Stiermaier, Johanna Liebetrau, Georg Fuernau, Charlotte Eitel, Suzanne de Waha, Steffen Desch, Jan-Christian Reil, Janine Pöss, Bernhard Metzler, Christian Lücke, Matthias Gutberlet, Gerhard Schuler, Holger Thiele, Ingo Eitel
OBJECTIVES: This study assessed the prognostic significance of remote zone native T1 alterations for the prediction of clinical events in a population with ST-segment elevation myocardial infarction (STEMI) who were treated by primary percutaneous coronary intervention (PPCI) and compared it with conventional markers of infarct severity. BACKGROUND: The exact role and incremental prognostic relevance of remote myocardium native T1 mapping alterations assessed by cardiac magnetic resonance (CMR) after STEMI remains unclear...
June 9, 2017: JACC. Cardiovascular Imaging
https://www.readbyqxmd.com/read/28624262/dibenzazepine-loaded-nanoparticles-induce-local-browning-of-white-adipose-tissue-to-counteract-obesity
#16
Chunhui Jiang, Mario Alberto Cano-Vega, Feng Yue, Liangju Kuang, Naagarajan Narayanan, Gozde Uzunalli, Madeline P Merkel, Shihuan Kuang, Meng Deng
Inhibition of Notch signaling via systemic drug administration triggers conversion of white adipocytes into beige adipocytes (browning) and reduces adiposity. However, translation of this discovery into clinical practice is challenged by potential off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Here, we demonstrate an alternative approach to stimulate browning using nanoparticles (NPs) composed of FDA-approved poly(lactide-co-glycolide) that enable sustained local release of a Notch inhibitor (dibenzazepine, DBZ)...
June 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28623668/impact-of-pci-appropriateness-in-the-long-term-outcomes-of-consecutive-patients-treated-with-second-generation-drug-eluting-stents
#17
Ana Cristina Seixas, Amanda Sousa, Jose de Ribamar Costa, Adriana Costa Moreira, Ricardo Costa, Lucas Damiani, Cantídio Campos Neto, Galo Maldonado, Manuel Cano, J Eduardo Sousa
BACKGROUND: Appropriate use criteria (AUC) for coronary revascularization were developed to deliver high-quality care; however, the prognostic impact of these criteria remains unclear. We sought to assess the outcomes of patients treated with second-generation drug-eluting stent (DES) classified according to the updated American College of Cardiology Foundation/American Heart Association/Society for Cardiac Angiography and Intervention AUC for percutaneous coronary intervention (PCI)...
June 15, 2017: Journal of Invasive Cardiology
https://www.readbyqxmd.com/read/28623462/in-silico-investigations-of-chemical-constituents-of-clerodendrum-colebrookianum-in-the-anti-hypertensive-drug-targets-rock-ace-and-pde5
#18
Hemant Arya, Safiulla Basha Syed, Sorokhaibam Sureshkumar Singh, Dinakar R Ampasala, Mohane Selvaraj Coumar
Understanding the molecular mode of action of natural product is a key step for developing drugs from them. In this regard, this study is aimed to understand the molecular-level interactions of chemical constituents of Clerodendrum colebrookianum Walp., with anti-hypertensive drug targets using computational approaches. The plant has ethno-medicinal importance for the treatment of hypertension and reported to show activity against anti-hypertensive drug targets-Rho-associated coiled-coil protein kinase (ROCK), angiotensin-converting enzyme, and phosphodiesterase 5 (PDE5)...
June 16, 2017: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/28623367/bovine-antibodies-targeting-primary-and-recurrent-clostridium-difficile-disease-are-a-potent-antibiotic-alternative
#19
Melanie L Hutton, Bliss A Cunningham, Kate E Mackin, Shelley A Lyon, Meagan L James, Julian I Rood, Dena Lyras
The increased incidence of antibiotic resistant 'superbugs' has amplified the use of broad spectrum antibiotics worldwide. An unintended consequence of antimicrobial treatment is disruption of the gastrointestinal microbiota, resulting in susceptibility to opportunistic pathogens, such as Clostridium difficile. Paradoxically, treatment of C. difficile infections (CDI) also involves antibiotic use, leaving patients susceptible to re-infection. This serious health threat has led to an urgent call for the development of new therapeutics to reduce or replace the use of antibiotics to treat bacterial infections...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28623298/constraint-based-modeling-identifies-new-putative-targets-to-fight-colistin-resistant-a-baumannii-infections
#20
Luana Presta, Emanuele Bosi, Leila Mansouri, Lenie Dijkshoorn, Renato Fani, Marco Fondi
Acinetobacter baumannii is a clinical threat to human health, causing major infection outbreaks worldwide. As new drugs against Gram-negative bacteria do not seem to be forthcoming, and due to the microbial capability of acquiring multi-resistance, there is an urgent need for novel therapeutic targets. Here we have derived a list of new potential targets by means of metabolic reconstruction and modelling of A. baumannii ATCC 19606. By integrating constraint-based modelling with gene expression data, we simulated microbial growth in normal and stressful conditions (i...
June 16, 2017: Scientific Reports
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