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Target to treat

Lukas Tomas, Andreas Edsfeldt, Inês G Mollet, Ljubica Perisic Matic, Cornelia Prehn, Jerzy Adamski, Gabrielle Paulsson-Berne, Ulf Hedin, Jan Nilsson, Eva Bengtsson, Isabel Gonçalves, Harry Björkbacka
Aims: Identification and treatment of the rupture prone atherosclerotic plaque remains a challenge for reducing the burden of cardiovascular disease. The interconnection of metabolic and inflammatory processes in rupture prone plaques is poorly understood. Herein, we investigate associations between metabolite profiles, inflammatory mediators and vulnerability in carotid atherosclerotic plaques. Methods and results: We collected 159 carotid plaques from patients undergoing endarterectomy and measured 165 different metabolites in a targeted metabolomics approach...
March 19, 2018: European Heart Journal
Shivaji Thadke, J Dinithi R Perera, V M Hridya, Kirti Bhatt, Ashif Yasin Shaikh, Wei-Che Hsieh, Mengshen David Chen, Chakicherla Gayathri, Roberto R Gil, Gordon S Rule, Arnab Mukherjee, Charles A Thornton, Danith H Ly
We report the development of a new class of nucleic acid ligands that is comprised of Janus bases and MPPNA backbone and is capable of binding rCAG-repeats in a sequence-specific and selective manner via, inference, bivalent H-bonding interactions. Individually, the interactions between ligands and RNA are weak and transient. However, upon the installation of C-terminal thioester and N-terminal cystine and the reduction of disulfide bond, they undergo template-directed native chemical ligation to form concatenated oligomeric products that bind tightly to the RNA template...
March 21, 2018: Biochemistry
S Rusta-Sallehy, M Gooderham, K Papp
Interleukin (IL)-17 is important in the pathophysiology of psoriasis and has proven to be an effective therapeutic target. Brodalumab, the third commercially available IL-17 antagonist, was approved by the US FDA in February 2017 for the treatment of moderate-tosevere plaque psoriasis. As brodalumab enters the marketplace, it is imperative to investigate its safety profile. We conducted a safety assessment of brodalumab using publically available adverse event data from phase II and III clinical trials. The most common adverse events were nasopharyngitis, upper respiratory tract infection, and candidiasis...
March 2018: Skin Therapy Letter
Chrysovalantis Voutouri, Triantafyllos Stylianopoulos
Hyaluronan is abundant in the extracellular matrix of many desmoplastic tumors and determines in large part the tumor biochemical and mechanical microenvironment. Additionally, it has been identified as one of the major physiological barriers to the effective delivery of drugs to solid tumors and its targeting with the use of pharmaceutical agents has shown to decompress tumor blood vessels, and thus improve tumor perfusion and efficacy of cytotoxic drugs. In this study, we investigated the contribution of hyaluronan to the accumulation of mechanical forces in tumors...
2018: PloS One
Riccardo Moia, Fary Diop, Chiara Favini, Ahad Ahmed Kodipad, Gianluca Gaidano
Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease. Deregulation of apoptosis is a major pathogenetic feature, and represents a therapeutic target. TP53 disrupted patients are categorized as high risk patients and are treated with novel target therapies. Among these new drugs, venetoclax, an orally bioavailable BCL2 inhibitor, has shown high efficacy also in relapsed/refractory CLL with TP53 disruption. Venetoclax has also been tested in combination with other drugs without compromising venetoclax dose and with a good safety profile...
March 21, 2018: Expert Review of Hematology
Jian Wang, Yuxin Wen, Guanggui Ding, Peikun Ding, Lu Zhang, Jing Liu, Tengfei Zhang, Lin Yang
Afatinib exhibits therapeutic efficacy for lung adenocarcinoma patients harboring HER2 exon 20 insertions. HER2 S310Y single site substitution was discovered in recent years and afatinib efficacy for adenocarcinoma patients harboring S310Y mutation has not been reported. We presented a case of a 41-year-old male patient with lung adenocarcinoma harboring the HER2 S310Y mutation obtained clinical response to the treatment of afatinib, an oral HER family blocker. After the treatment of afatinib, the patient achieved partial response (PR) in chest lesions and almost complete response (CR) in intracranial lesions...
March 21, 2018: Cancer Biology & Therapy
Liang Ouyang, Lan Zhang, Shouyue Zhang, Dahong Yao, Yuqian Zhao, Guan Wang, Leilei Fu, Peng Lei, Bo Liu
UNC-51-like kinase 1 (ULK1), the yeast Atg1 ortholog, is the sole serine-threonine kinase and initiating enzyme in autophagy, which may be regarded as a target in Parkinson's disease (PD). Herein, we discovered a small molecule 33i (BL-918) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg18, Lys50, Asn86 and Tyr89) were found to be crucial to the binding pocket between ULK1 and 33i by site-directed mutagenesis. Moreover, we found that 33i induced autophagy via the ULK complex in SH-SY5Y cells...
March 21, 2018: Journal of Medicinal Chemistry
Adel Schwertani, Hong Y Choi, Jacques Genest
PURPOSE OF REVIEW: Plasma levels of HDL cholesterol are a biomarker of cardiovascular health but not a therapeutic target, as demonstrated by the failure of pharmacological modulation of HDL cholesterol to prevent or treat atherosclerotic cardiovascular disease. In health, HDL particles exert pleiotropic effects against atherosclerosis, including cholesterol removal from foam cells, vasodilatory effects through vascular endothelial cell nitric oxide production, decreased vascular inflammation and oxidative damage, endothelial cell proliferation and antiapoptotic effects...
March 19, 2018: Current Opinion in Cardiology
Nicolette Kapp, Xiao X Stander, Barend A Stander
This project investigated the in-vitro effects of a glycolytic inhibitor, 3-bromopyruvate (3-BrP), in combination with and a new in silico-designed inhibitor of the bromodomain-4 (BRD-4) protein, ITH-47, on the U937 acute myeloid leukemia cell line. 3-BrP is an agent that targets the altered metabolism of cancer cells by interfering with glucose metabolism in the glycolytic pathway. ITH-47 is an acetyl-lysine inhibitor that displaces bromdomain 4 proteins from chromatin by competitively binding to the acetyl-lysine recognition pocket of this bromodomain and extraterminal (BET) BRD protein, thereby preventing transcription of cancer-associated genes and further cell growth...
March 20, 2018: Anti-cancer Drugs
Xuechuan Gao, Ruixue Cui, Guanfeng Ji, Zhiliang Liu
Benefiting from their porous structures, metal-organic frameworks (MOFs) have attracted intensive attention for use in drug release. However, the controllable synthesis of MOFs with proper particle sizes is still very challenging, which largely limits its applications. Here, UIO-66-NH2 with controlled particle sizes in the range of 20-200 nm has been achieved successfully. The amine on UIO-66-NH2 is demonstrated for the feasible post-modifying of UIO-66-NH2 to obtain multifunctional MOFs, overcoming the limitations of functional simplicity and broadening the range of applications...
March 21, 2018: Nanoscale
Heather M O'Leary, Walter E Kaufmann, Katherine V Barnes, Kshitiz Rakesh, Kush Kapur, Daniel C Tarquinio, Nicole G Cantwell, Katherine J Roche, Suzanne A Rose, Alexandra C Walco, Natalie M Bruck, Grace A Bazin, Ingrid A Holm, Mark E Alexander, Lindsay C Swanson, Lauren M Baczewski, Juan M Mayor Torres, Charles A Nelson, Mustafa Sahin
Objective: To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design. Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week washout period...
March 2018: Annals of Clinical and Translational Neurology
David D Bushart, Ravi Chopra, Vikrant Singh, Geoffrey G Murphy, Heike Wulff, Vikram G Shakkottai
Objective: Purkinje neuron dysfunction is associated with cerebellar ataxia. In a mouse model of spinocerebellar ataxia type 1 (SCA1), reduced potassium channel function contributes to altered membrane excitability resulting in impaired Purkinje neuron spiking. We sought to determine the relationship between altered membrane excitability and motor dysfunction in SCA1 mice. Methods: Patch-clamp recordings in acute cerebellar slices and motor phenotype testing were used to identify pharmacologic agents which improve Purkinje neuron physiology and motor performance in SCA1 mice...
March 2018: Annals of Clinical and Translational Neurology
Brian B Silver, Celeste M Nelson
Cancer is a complex, heterogeneous group of diseases that can develop through many routes. Broad treatments such as chemotherapy destroy healthy cells in addition to cancerous ones, but more refined strategies that target specific pathways are usually only effective for a limited number of cancer types. This is largely due to the multitude of physiological variables that differ between cells and their surroundings. It is therefore important to understand how nature coordinates these variables into concerted regulation of growth at the tissue scale...
2018: Frontiers in Cell and Developmental Biology
Faisal Akhtar, Sabah Rehman
Congenital syphilis is one of the preventable diseases caused by the gram-negative bacteria Treponema pallidum; yet, it imposes a serious global health and economic burden, with more than half of the cases resulting in serious adverse outcomes, including infant mortality. Mother-to-child transmission (MTCT) of syphilis is estimated at 3.6 million adjusted life years (DALYs) and around $309 million in medical costs. In 2006, an estimated 9.7 million children of age less than five years died in developing countries; almost four million were neonatal deaths...
January 16, 2018: Curēus
Youhei Okada, Ting Wang, Kazuhiro Kasai, Kazuyuki Suzuki, Yasuhiro Takikawa
Transforming growth factor-beta (TGF-β) is critical in cancer cell invasion and metastasis. The effects of a treatment that targets TGF-β using the combination of interferon alpha (IFNα)-2b and 5-fluorouracil (5-FU) are unknown. Here, we show that the serum levels of TGF-β1 prior to the therapy correlate with increased maximum tumor diameter, which is significantly ( p  < 0.01) decreased after the combination therapy. 5-FU increased both the expression and secretion levels of TGF-β1 in hepatoma cells, but not in normal hepatocytes...
2018: Cell Death Discovery
Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine, Michal Brylinski
Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning...
2018: NPJ Systems Biology and Applications
Pengming Sun, Lifang Xue, Yiyi Song, Xiaodan Mao, Lili Chen, Binhua Dong, Elena Loana Braicu, Jalid Sehouli
The effects of specific and non-specific regulation of matriptase on endometrial cancer cells in vitro were investigated. Messenger ribonucleic acid (mRNA) and protein expression of matriptase and hepatocyte growth factor activator inhibitor-1 (HAI-1) in RL-952, HEC-1A, and HEC-1B endometrial cancer cells were detected by real-time quantitative PCR (RT-qPCR) and western blot. The cells were infected with lentivirus-mediated small-interfering RNA (siRNA) targeted on matriptase (MA-siRNA) or treated with different cisplatin (DDP) concentrations...
February 27, 2018: Oncotarget
Jean-David Fumet, Aurélie Bertaut, Leila Bengrine, Patricia Lapierre, Julie Vincent, François Ghiringhelli, Nicolas Falvo
Background: Bevacizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody targeting VEGF-A. It is currently used with chemotherapy as the first- or second-line therapy in metastatic colorectal cancer. Previous studies have showed that anti-angiogenic agents decrease capillary density. We evaluated the link between decreased capillary density and the response to bevacizumab-based chemotherapy. Results: Overall, 43 patients with metastatic colorectal cancer treated with first-line bevacizumab-based chemotherapy were enrolled...
February 27, 2018: Oncotarget
Khaled Elmasry, Riyaz Mohamed, Isha Sharma, Nehal M Elsherbiny, Yutao Liu, Mohamed Al-Shabrawey, Amany Tawfik
To study Hyperhomocysteinemia (HHcy)-induced epigenetic modifications as potential mechanisms of blood retinal barrier (BRB) dysfunction, retinas isolated from three- week-old mice with elevated level of Homocysteine (Hcy) due to lack of the enzyme cystathionine β-synthase ( cbs-/- , cbs+/- and cbs+/+ ), human retinal endothelial cells (HRECs), and human retinal pigmented epithelial cells (ARPE-19) treated with or without Hcy were evaluated for (1) histone deacetylases (HDAC), (2) DNA methylation (DNMT), and (3) miRNA analysis...
February 27, 2018: Oncotarget
Nannan Pan, Yongxin Yang, Xin Du, Xin Qi, Guijin Du, Yang Zhang, Xiaodong Li, Quan Zhang
With the development of the Internet, an increasing number of adolescents play online game excessively, which leads to adverse effects on individuals and society. Previous studies have demonstrated altered gray-matter volume (GMV) in individuals with Internet gaming disorder (IGD), but the relationship between the tendency to IGD and the GMV across whole brain is still unclear in adolescents. In the present study, anatomical imaging with high resolution was performed on 67 male adolescents who played online game; and Young's Internet addiction test (IAT) was conducted to test the tendency to IGD...
2018: Frontiers in Psychiatry
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