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  • Orphan neuropeptides and receptors: Novel therapeutic targets
    Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-22
    Lloyd D. Fricker, Lakshmi A. Devi

    Neuropeptides are the largest class of intercellular signaling molecules, contributing to a wide variety of physiological processes. Neuropeptide receptors are therapeutic targets for a broad range of drugs, including medications to treat pain, addiction, sleep disorders, and nausea. In addition to > 100 peptides with known functions, many peptides have been identified in mammalian brain for which the cognate receptors have not been identified. Similarly, dozens of “orphan” G protein-coupled receptors have been identified in the mammalian genome. While it would seem straightforward to match the orphan peptides and receptors, this is not always easily accomplished. In this review we focus on peptides named PEN and big LEN, which are among the most abundant neuropeptides in mouse brain, and their recently identified receptors: GPR83 and GPR171. These receptors are co-expressed in some brain regions and are able to interact. Because PEN and big LEN are produced from the same precursor protein and co-secreted, the interaction of GPR83 and GPR171 is physiologically relevant. In addition to interactions of these two peptides/receptors, PEN and LEN are co-localized with neuropeptide Y and Agouti-related peptide in neurons that regulate feeding. In this review, using these peptide receptors as an example, we highlight the multiple modes of regulation of receptors and present the emerging view that neuropeptides function combinatorially to generate a network of signaling messages. The complexity of neuropeptides, receptors, and their signaling pathways is important to consider both in the initial deorphanization of peptides and receptors, and in the subsequent development of therapeutic applications.

    更新日期:2017-11-23
  • Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-23
    Mei-Miao Zhan, Yang Yang, Jinfeng Luo, Xing-Xing Zhang, Xuan Xiao, Shiyu Li, Kai Cheng, Zhouling Xie, Zhengchao Tu, Chenzhong Liao

    Polo-like kinase 2 (Plk2) is a potential target for the treatment of cancer, which displays an important role in tumor cell proliferation and survival. In this report, according to the analysis of critical amino acid residue differences among Plk1, Plk2 and Plk3, and structure-based drug design strategies, two novel series of selective Plk2 inhibitors based on tetrahydropteridin chemical scaffold were designed and synthesized to target two specific residues, Lys86 and Tyr161 of Plk2. All compounds were evaluated for their inhibitory activity against Plk1-Plk3 and the cellular inhibition activity on six different human cancer cell lines. All efforts led to the identification of the most potent compounds C2 (3.40 nM against Plk2) and C21 (4.88 nM against Plk2) from the first and second series of selective Plk2 inhibitors respectively. Additionally, the selectivity of C21 over Plk1/3 was significantly increased with the selectivity indexes of 12.57 and 910.06. Moreover, most of our compounds exhibited antitumor activity in the nanomolar range in the MTT assay, indicating that our compounds, especially C2 and C21 could be promising Plk2 inhibitors for further anticancer research.

    更新日期:2017-11-23
  • Substituted carbamothioic amine-1-carbothioic thioanhydrides as novel trichomonicidal fungicides: Design, synthesis, and biology ☆
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-23
    Dhanaraju Mandalapu, Bhavana Kushwaha, Sonal Gupta, Shagun Krishna, Nidhi Srivastava, Mahendra Shukla, Pratiksha Singh, Bhavana S. Chauhan, Ravi Goyani, Jagdamba P. Maikhuri, Koneni V. Sashidhara, Brijesh Kumar, Renu Tripathi, Praveen K. Shukla, Mohammad I. Siddiqi, Jawahar lal, Gopal Gupta, Vishnu L. Sharma

    Sexually transmitted diseases like trichomoniasis along with opportunistic fungal infections like candidiasis are major global health burden in female reproductive health. In this context a novel non-nitroimidazole class of substituted carbamothioic amine-1-carbothioic thioanhydride series was designed, synthesized, evaluated for trichomonacidal and fungicidal activities, and was found to be more active than the standard drug Metronidazole (MTZ). Compounds were trichomonicidal in the MIC ranges of 4.77–294.1 μM and 32.46–735.20 μM against MTZ-susceptible and -resistant strains, respectively. Further, compounds inhibited the growth of at least two out of ten fungal strains tested at MIC of 7.50–240.38 μM. The most active compound (20) of this series was 3.8 and 9.5 fold more active than the MTZ against the two Trichomonas strains tested. Compound 20 also significantly inhibited the sulfhydryl groups present over Trichomonas vaginalis and was found to be more active than the MTZ in vivo. Further, a docking analysis carried out with cysteine proteases supported their thiol inhibiting ability and preliminary pharmacokinetic study has shown good distribution and systemic clearance.

    更新日期:2017-11-23
  • Potent aromatase inhibitors and molecular mechanism of inhibitory action
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-22
    Hongjun Kang, Xingqing Xiao, Chao Huang, Yan Yuan, Dongyan Tang, Xiaochang Dai, Xianghui Zeng

    Estrogen is a significant factor in the maintenance and progression of hormone-dependent breast cancer. As well known, aromatase mediates the production of estrogen. Thus, reduction of aromatase with chemical molecules has been considered to be an effective treatment for estrogen receptor-positive (ER+) breast cancer. In this work, we designed and synthesized a series of novel non-steroidal molecules containing 2-phenylindole scaffold and moiety of either imidazole or 1,2,4-triazole to enhance their binding capacity with the aromatase. Among these molecules, a compound named as 8o was confirmed experimentally to have the highest inhibitory activity to aromatase. Further cell activity assay proved that compound 8o has low cytotoxicity and is a promising lead for developing novel aromatase inhibitors. Molecular modelling and simulation techniques were performed to identify the binding modes of letrozole and 8o with the aromatase. Analysis of energy of the two compound-aromatase complexes revealed that the 8o has a low binding energy (strong binding affinity) to the aromatase as compared to letrozole, which was in accordance with the experimental results. As concluded, a combination of experimental and computational approaches facilitates us to understand the molecular mechanism of inhibitory action and discover more potent non-steroidal AIs against aromatase, thereby opening up a novel therapeutic strategy for hormone-dependent breast cancer.

    更新日期:2017-11-23
  • Effect of side chain hydrophobicity and cationic charge on antimicrobial activity and cytotoxicity of helical peptoids
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-23
    Jiyoun Lee, Dahyun Kang, Jieun Choi, Wei Huang, Mayken Wadman, Annelise E. Barron, Jiwon Seo

    Peptoids are peptidomimetic polymers that are resistant to proteolysis and less prone to immune responses; thus, they can provide a practical alternative to peptides. Among the various therapeutic applications that have been explored, cationic amphipathic peptoids have demonstrated broad-spectrum antibacterial activity, including activity towards drug-resistant bacterial strains. While their potency and activity spectrum can be manipulated by sequence variations, bacterial selectivity and systemic toxicity need to be improved for further clinical development. To this aim, we incorporated various hydrophobic or cationic residues to improve the selectivity of the previously developed antibacterial peptoid 1. The analogs with hydrophobic residues demonstrated non-specific cytotoxicity, while those with an additional cationic residue showed improved selectivity and comparable antibacterial activity. Specifically, compared to 1, peptoid 7 showed much lower hemolysis and cytotoxicity, while maintaining the antibacterial activity. Therefore, we believe that peptoid 7 has the potential to serve as a promising alternative to current antimicrobial therapies.

    更新日期:2017-11-23
  • Comprehensive Pancancer Genomic Analysis Reveal (RTK)-RAS-RAF-MEK as a key Dysregulated Pathway in Cancer: its Clinical Implications
    Semin. Cancer Biol. (IF 9.141) Pub Date : 2017-11-22
    Robin Imperial, Omer M Toor, Arif Hussain, Janakiraman Subramanian, Ashiq Masood

    Recent advances in Next Generation Sequencing (NGS) have provided remarkable insights into the genomic characteristics of human cancers that have spurred a revolution in the field of oncology. The mitogen-activated protein kinase pathway (MAPK) and its activating cell receptor, the receptor tyrosine kinases (RTKs), which together encompass the (RTK)-RAS-RAF-MEK-ERK axis, are central to oncogenesis. A pan-cancer genomics analysis presented in this review is made possible by large collaborative projects, including The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and others. Landmark studies contributing to these projects have revealed alterations in cell signaling cascades that vary between cancer types and within tumors themselves. We review several of these studies in major tumor types to highlight recent advances in our understanding of the role of (RTK)-RAS-RAF alterations in cancer. Further studies are needed to increase the statistical power to detect clinically relevant low-frequency mutations, in addition to the known (RTK)-RAS-RAF pathway alterations, and to refine the resolution of the genomic landscape that defines these cancer mutations. The (RTK)-RAS-RAF-MEK-ERK mutation status, and their prognostic value, are also examined and correlated with clinical phenotypes. Treatments targeting various components of this pathway are ongoing, and are often effective initially in defined subgroups of patients. However, resistance to these agents can develop through adaptive mechanisms. With our steady increase in understanding the molecular biology of cancer, ongoing evaluation and monitoring through genomic analysis will continue to provide important information to the clinician in the context of treatment selection, response, resistance and outcomes.

    更新日期:2017-11-23
  • Efficacy of Ledipasvir and Sofosbuvir Treatment of HCV Infection in Patients Coinfected with HBV
    Gastroenterology (IF 18.392) Pub Date : 2017-11-22
    Chun-Jen Liu, Wan-Long Chuang, I-Shyan Sheen, Horng-Yuan Wang, Chi-Yi Chen, Kuo-Chih Tseng, Ting-Tsung Chang, Benedetta Massetto, Jenny C. Yang, Chohee Yun, Steven J. Knox, Anu Osinusi, Gregory Camus, Deyuan Jiang, Diana M. Brainard, John G. McHutchison, Tsung-Hui Hu, You-Chun Hsu, Gin-Ho Lo, Chi-Jen Chu, Jyh-Jou Chen, Cheng-Yuan Peng, Ron-Nan Chien, Pei-Jer Chen

    Background & Aims There have been reports of reactivation of hepatitis B virus (HBV) infection during treatment of hepatitis C virus (HCV) infection with direct-acting antiviral agents. We performed a prospective study of risks and outcomes of HCV infection treatment with ledipasvir and sofosbuvir in patients with HBV infection. Methods We performed a phase 3b, multicenter, open-label study in Taiwan of 111 patients with HCV infection (61% HCV genotype 1, 39% HCV genotype 2 infection; 62% women, 16% with compensated cirrhosis) along with HBV infection. All but 1 were positive for the hepatitis B surface antigen (HBsAg); 1 patient who was HBsAg positive at screening was found to be HBsAg negative at baseline. Overall, 33% of participants had received prior treatment for HCV and 5% had previously been treated for HBV; no patient was on HBV therapy at the start of the study. All patients received a fixed-dose combination of 90 mg of the HCV NS5A inhibitor ledipasvir with 400 mg of the NS5B nucleotide analogue inhibitor sofosbuvir, once daily for 12 weeks. The primary endpoint was sustained virologic response (SVR) 12 weeks after the end of therapy. Results All 111 patients (100%) achieved an SVR. Of the 37 patients with baseline HBV DNA below 20 IU/mL, 31 (84%) had at least 1 episode of quantifiable HBV DNA through post-treatment week 12. Of the 74 patients with baseline HBV DNA levels of 20 IU/mL or more, 39 (53%) had increases of HBV DNA greater than 1 log10 IU/mL through post-treatment week 12. Overall, 5 patients had increased levels of HBV DNA concomitant with a level of alanine aminotransferase more than 2-fold the upper limit of normal though post-treatment Week 12. Of these, 3 patients started HBV treatment. In addition, one patient with HBV reactivation since Week 8 and concomitant ALT elevation > 2 x ULN at post treatment Week 48 started treatment at post treatment Week 53. This patient had clinical signs and symptoms associated with HBV reactivation. The most common adverse events were headache, upper respiratory infection, and fatigue. Conclusions In a prospective study, the combination of ledipasvir and sofosbuvir for 12 weeks produced an SVR in 100% of patients with HCV infection who were co-infected with HBV. Most patients had an increase in level of HBV DNA not associated with signs or symptoms. ClinicalTrials.gov no: NCT02613871

    更新日期:2017-11-23
  • Self-reported adverse food reactions and anaphylaxis in the SchoolNuts study: A population-based study of adolescents
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-23
    Vicki L. McWilliam, Jennifer J. Koplin, Michael J. Field, Mari Sasaki, Shyamali C. Dharmage, Mimi L.K. Tang, Susan M. Sawyer, Rachel L. Peters, Katrina J. Allen

    Background Adolescents are at the highest risk of death from anaphylaxis, yet few population-based studies have described the frequencies and risk factors for allergic reactions caused by accidental allergen ingestion in this group. Methods We describe the prevalence, frequency, and associated risk factors for recent adverse food reactions in 10- to 14-year-olds in Melbourne, Australia, recruited from a stratified, random, population-based sample of schools (SchoolNuts, n = 9663; 48% response rate). Self-reported food allergy and adverse reaction details, including anaphylaxis, were identified by using a student questionnaire over the past year. Results Of 547 students with possible IgE-mediated food allergy, 243 (44.4%; 95% CI, 40.3% to 48.7%) reported a reaction to a food. Fifty-three (9.7%; 95% CI, 7.2% to 12.2%) students reported 93 anaphylaxis episodes. Peanut and tree nuts were the most common food triggers. Among students with current IgE-mediated food allergy, those with resolved or current asthma (adjusted odds ratio [aOR], 1.9 [95% CI, 1.1-1.3] and 1.7 [95% CI, 1.1-2.6]) and those with more than 2 food allergies (aOR, 1.9 [95% CI, 1.1-3.1]) were at greatest risk of any adverse food reaction, and those with nut allergy were most at risk of severe reactions (aOR, 2.9 [95% CI, 1.1-4.4]). Resolved or current asthma was not associated with increased risk of severe reactions (aOR, 0.8 [95% CI, 0.3-2.2] and 1.6 [95% CI, 0.7-3.7]). Conclusions Adolescents with food allergy are frequently exposed to food allergens. Those with asthma and more than 2 food allergies were at the greatest risk for adverse food reactions. Those with nut allergies were most at risk of severe reactions.

    更新日期:2017-11-23
  • Increased surface expression of HIV-1 envelope is associated with improved antibody response in vaccinia prime/protein boost immunization
    Virology (IF 3.353) Pub Date : 2017-11-22
    Michael J. Hogan, Angela Conde-Motter, Andrea P.O. Jordan, Lifei Yang, Brad Cleveland, Wenjin Guo, Josephine Romano, Houping Ni, Norbert Pardi, Celia C. LaBranche, David C. Montefiori, Shiu-Lok Hu, James A. Hoxie, Drew Weissman

    HIV-1 envelope (Env)-based vaccines have so far largely failed to induce antibodies that prevent HIV-1 infection. One factor proposed to limit the immunogenicity of cell-associated Env is its low level of expression on the cell surface, restricting accessibility to antibodies. Using a vaccinia prime/protein boost protocol in mice, we explored the immunologic effects of mutations in the Env cytoplasmic tail (CT) that increased surface expression, including partial truncation and ablation of a tyrosine-dependent endocytosis motif. After vaccinia primes, CT-modified Envs induced up to 7-fold higher gp120-specific IgG, and after gp120 protein boosts, they elicited up to 16-fold greater Tier-1 HIV-1 neutralizing antibody titers, although results were variable between isolates. These data indicate that the immunogenicity of HIV-1 Env in a prime/boost vaccine can be enhanced in a strain-dependent manner by CT mutations that increase Env surface expression, thus highlighting the importance of the prime in this vaccine format.

    更新日期:2017-11-23
  • Modeling the pathology, immune responses, and kinetics of HSV-1 replication in the lip scarification model
    Virology (IF 3.353) Pub Date : 2017-11-22
    Kevin P. Egan, Alexander G. Allen, Brian Wigdahl, Stephen R. Jennings
    更新日期:2017-11-23
  • Establishment of robust HCV genotype 4d, 5a, and 6a replicon systems
    Virology (IF 3.353) Pub Date : 2017-11-22
    Gregory Camus, Simin Xu, Bin Han, Julia Lu, Hadas Dvory-Sobol, Mei Yu, Guofeng Cheng, Michael D. Miller, Brian P. Doehle, Hongmei Mo

    Hepatitis C Virus (HCV) is a diverse human pathogen which displays ~15% divergence at the subtype level. To facilitate development of antivirals with pan-genotype activity, we developed the first genotype 4d subgenomic replicon, as well as new replicons for genotypes 5a, and 6a. Adaptive mutations developed in these replicons differ greatly across genotypes. Their impacts on the replication capacity were tested using site-directed mutants. In the genotype 4d replicon, single mutations have moderate effect, but the double mutation NS4A-Q34R+NS5A-S232G increased the replication capacity by 161-fold. These new stable replicon cell lines were used to determine the antiviral activity of HCV inhibitors. The NS3 protease inhibitor voxilaprevir, NS5A second generation inhibitor velpatasvir, and NS5B nucleoside analog inhibitor sofosbuvir, had similar antiviral activities across the different genotypes/subtypes tested, while the NS5A first generation inhibitor, ledipasvir, had very good antiviral activity against GT1, 4, 5, and 6 in vitro.

    更新日期:2017-11-23
  • Crystal arthritis: Stepping up febuxostat to treat gout flares
    Nat. Rev. Rheumatol. (IF 12.188) Pub Date : 2017-11-23
    Joanna Collison

    Crystal arthritis: Stepping up febuxostat to treat gout flares Crystal arthritis: Stepping up febuxostat to treat gout flares, Published online: 23 November 2017; doi:10.1038/nrrheum.2017.193 Crystal arthritis: Stepping up febuxostat to treat gout flares

    更新日期:2017-11-23
  • Systemic lupus erythematosus: Effects of disease activity on pregnancy outcomes
    Nat. Rev. Rheumatol. (IF 12.188) Pub Date : 2017-11-23
    Joanna Collison

    Systemic lupus erythematosus: Effects of disease activity on pregnancy outcomes Systemic lupus erythematosus: Effects of disease activity on pregnancy outcomes, Published online: 23 November 2017; doi:10.1038/nrrheum.2017.195 Systemic lupus erythematosus: Effects of disease activity on pregnancy outcomes

    更新日期:2017-11-23
  • Osteoporosis: Teriparatide preferable for fracture prevention
    Nat. Rev. Rheumatol. (IF 12.188) Pub Date : 2017-11-23
    Joanna Collison

    Osteoporosis: Teriparatide preferable for fracture prevention Osteoporosis: Teriparatide preferable for fracture prevention, Published online: 23 November 2017; doi:10.1038/nrrheum.2017.194 Osteoporosis: Teriparatide preferable for fracture prevention

    更新日期:2017-11-23
  • Rheumatoid arthritis: Tocilizumab prevents progression of bone erosions
    Nat. Rev. Rheumatol. (IF 12.188) Pub Date : 2017-11-23
    Joanna Collison

    Rheumatoid arthritis: Tocilizumab prevents progression of bone erosions Rheumatoid arthritis: Tocilizumab prevents progression of bone erosions, Published online: 23 November 2017; doi:10.1038/nrrheum.2017.196 Rheumatoid arthritis: Tocilizumab prevents progression of bone erosions

    更新日期:2017-11-23
  • Crystal arthritis: Stepping up febuxostat to treat gout flares
    Nat. Rev. Rheumatol. (IF 12.188) Pub Date : 2017-11-23
    Joanna Collison

    Crystal arthritis: Stepping up febuxostat to treat gout flares Crystal arthritis: Stepping up febuxostat to treat gout flares, Published online: 23 November 2017; doi:10.1038/nrrheum.2017.193 Crystal arthritis: Stepping up febuxostat to treat gout flares

    更新日期:2017-11-23
  • Systemic lupus erythematosus: Effects of disease activity on pregnancy outcomes
    Nat. Rev. Rheumatol. (IF 12.188) Pub Date : 2017-11-23
    Joanna Collison

    Systemic lupus erythematosus: Effects of disease activity on pregnancy outcomes Systemic lupus erythematosus: Effects of disease activity on pregnancy outcomes, Published online: 23 November 2017; doi:10.1038/nrrheum.2017.195 Systemic lupus erythematosus: Effects of disease activity on pregnancy outcomes

    更新日期:2017-11-23
  • Osteoporosis: Teriparatide preferable for fracture prevention
    Nat. Rev. Rheumatol. (IF 12.188) Pub Date : 2017-11-23
    Joanna Collison

    Osteoporosis: Teriparatide preferable for fracture prevention Osteoporosis: Teriparatide preferable for fracture prevention, Published online: 23 November 2017; doi:10.1038/nrrheum.2017.194 Osteoporosis: Teriparatide preferable for fracture prevention

    更新日期:2017-11-23
  • Immunochemotherapy mediated by thermosponge nanoparticles for synergistic anti-tumor effects
    J. Control. Release (IF 7.786) Pub Date : 2017-11-22
    Yongdan Zhao, Qingle Song, Yijia Yin, Tingting Wu, Xiaomeng Hu, Xueqin Gao, Gao Li, Songwei Tan, Zhiping Zhang

    The efficacy of immunotherapy was demonstrated to be compromised by reduced immunogenicity of tumor cells and enhanced suppressive properties of the tumor microenvironment in cancer treatment. There is growing evidence that low-dose chemotherapy can modulate the immune system to improve the anti-tumor effects of immunotherapy through multiple mechanisms, including the enhancement of tumor immunogenicity and reversal of the immunosuppressive tumor microenvironment. Here, we fabricated thermosponge nanoparticles (TSNs) for the co-delivery of chemotherapeutic drug paclitaxel (PTX) and immunostimulant interleukin-2 (IL-2) to explore the synergistic anti-tumor effects of chemotherapy and immunotherapy. The distinct temperature-responsive swelling/deswelling character facilitated the effective post-entrapment of cytokine IL-2 in nanoparticles by a facile non-solvent mild incubation method with unaffected bioactivity and favorable pharmacokinetics. PTX and IL-2 co-loaded TSNs exhibited significant inhibition on tumor growth and metastasis, and prolonged overall survival for tumor-bearing mice compared with the corresponding monotherapies. The synergistic effect was evidenced from the remodeled tumor microenvironment in which low-dose chemotherapeutics disrupted the immunosuppressive tumor microenvironment and enhanced tumor immunogenicity, and immunostimulant cytokine promoted the anti-tumor immune response of immune effector cells. The immunochemotherapy mediated by this thermosponge nanoplatform may provide a promising treatment strategy against cancer.

    更新日期:2017-11-23
  • Hollow microneedle-mediated micro-injections of a liposomal HPV E743–63 synthetic long peptide vaccine for efficient induction of cytotoxic and T-helper responses
    J. Control. Release (IF 7.786) Pub Date : 2017-11-22
    Koen van der Maaden, Jeroen Heuts, Marcel Camps, Maria Pontier, Anton Terwisscha van Scheltinga, Wim Jiskoot, Ferry Ossendorp, Joke Bouwstra

    Recent studies have shown that intradermal vaccination has great potential for T cell-mediated cancer immunotherapy. However, classical intradermal immunization with a hypodermic needle and syringe has several drawbacks. Therefore, in the present study a digitally controlled hollow microneedle injection system (DC-hMN-iSystem) with an ultra-low dead volume was developed to perform micro-injections (0.25–10 μL) into skin in an automated manner. A synthetic long peptide derived from human papilloma virus formulated in cationic liposomes, which was used as a therapeutic cancer vaccine, was administered intradermally by using the DC-hMN-iSystem. Fused silica hollow microneedles with an inner diameter of 50 μm and a bevel length of 66 ± 26 μm were successfully fabricated via hydrofluoric acid etching. Upon piercing these microneedles into the skin using a protrusion length of 400 μm, microneedles were inserted at a depth of 350 ± 55 μm. Micro-injections of 1–10 μL had an accuracy between 97 and 113% with a relative standard deviation (RSD) of 9%, and lower volumes (0.25 and 0.5 μL) had an accuracy of 86–103% with a RSD of 29% in ex vivo human skin. Intradermal administration of the therapeutic cancer vaccine via micro-injections induced strong functional cytotoxic and T-helper responses in mice, while requiring much lower volumes as compared to classical intradermal immunization. In conclusion, by using the newly developed DC-hMN-iSystem, very low vaccine volumes can be precisely injected into skin in an automated manner. Thereby, this system shows potential for minimally-invasive and potentially pain-free therapeutic cancer vaccination.

    更新日期:2017-11-23
  • Rheumatoid arthritis: Tocilizumab prevents progression of bone erosions
    Nat. Rev. Rheumatol. (IF 12.188) Pub Date : 2017-11-23
    Joanna Collison

    Rheumatoid arthritis: Tocilizumab prevents progression of bone erosions Rheumatoid arthritis: Tocilizumab prevents progression of bone erosions, Published online: 23 November 2017; doi:10.1038/nrrheum.2017.196 Rheumatoid arthritis: Tocilizumab prevents progression of bone erosions

    更新日期:2017-11-23
  • Comparison of in vivo targeting ability between cRGD and collagen-targeting peptide conjugated nano-carriers for atherosclerosis
    J. Control. Release (IF 7.786) Pub Date : 2017-11-22
    Manse Kim, Abhishek Sahu, Gi Beom Kim, Gi Hoon Nam, Wooram Um, So Jin Shin, Yong Yeon Jeong, In-San Kim, Kwangmeyung Kim, Ick Chan Kwon, Giyoong Tae

    Atherosclerosis plaque is a major cause of cardiovascular diseases across the globe and a silent killer. There are no physical symptoms of the disease in its early stage and current diagnostic techniques cannot detect the small plaques effectively or safely. Plaques formed in blood vessels can cause serious clinical problems such as impaired blood flow or sudden death, regardless of their size. Thus, detecting early stage of plaques is especially more important to effectively reduce the risk of atherosclerosis. Nanoparticle based delivery systems are recognized as a promising option to fight against this disease, and various targeting ligands are typically used to improve their efficiency. So, the choice of appropriate targeting ligand is a crucial factor for optimal targeting efficiency. cRGD peptide and collagen IV targeting peptide, which binds with the αvβ3 integrin overexpressed in the neovasculature of the plaque and collagen type IV present in the plaque, respectively, are frequently used for the targeting of nanoparticles. However, at present no study has directly compared these two peptides. Therefore, in this study, we have prepared cRGD or collagen IV targeting (Col IV-tg-) peptide conjugated and iron oxide nanoparticle (IONP) loaded Pluronic based nano-carriers for systemic comparison of their targeting ability towards in vivo atherosclerotic plaque in Apolipoprotein E deficient (Apo E−/−) mouse model. Nano-carriers with similar size, surface charge, and IONP loading content but with different targeting ligands were analyzed through in vitro and in vivo experiments. Near infrared fluorescence imaging and magnetic resonance imaging techniques as well as Prussian blue staining were used to compare the accumulation of different ligand conjugated nano-caariers in the aorta of atherosclerotic mice. Our results indicate that cRGD based targeting is more efficient than Col IV-tg-peptide in the early stage of atherosclerosis.

    更新日期:2017-11-23
  • Prevention: Saving lives: the importance of having Resolve
    Nat. Rev. Cardiol. (IF 14.299) Pub Date : 2017-11-23
    Rajesh Vedanthan, Valentin Fuster

    Prevention: Saving lives: the importance of having Resolve Prevention: Saving lives: the importance of having Resolve, Published online: 23 November 2017; doi:10.1038/nrcardio.2017.187 Cardiovascular disease is the world's leading cause of death, with a disproportionate burden in low-income and middle-income countries. The Resolve initiative — eliminating artificial trans fats, reducing dietary sodium, and improving treatment of elevated blood pressure — is a substantial step in the right direction, but more combined efforts will be required.

    更新日期:2017-11-23
  • Prevention: Saving lives: the importance of having Resolve
    Nat. Rev. Cardiol. (IF 14.299) Pub Date : 2017-11-23
    Rajesh Vedanthan, Valentin Fuster

    Prevention: Saving lives: the importance of having Resolve Prevention: Saving lives: the importance of having Resolve, Published online: 23 November 2017; doi:10.1038/nrcardio.2017.187 Cardiovascular disease is the world's leading cause of death, with a disproportionate burden in low-income and middle-income countries. The Resolve initiative — eliminating artificial trans fats, reducing dietary sodium, and improving treatment of elevated blood pressure — is a substantial step in the right direction, but more combined efforts will be required.

    更新日期:2017-11-23
  • Mechanism informed repurposing of minocycline overcomes resistance to topoisomerase inhibition for peritoneal carcinomatosis
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Huang-Chiao Huang, Joyce Liu, Yan Baglo, Imran Rizvi, Sriram Anbil, Michael Pigula, Tayyaba Hasan

    Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and a rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL-8 respectively, thereby reinforcing the benefits of each modality. These mechanistic interactions result in synergistic enhancement of irinotecan-induced platinum-resistant epithelial ovarian cancer cell death, reduced micrometastases in the omenta and mesentery by >75%, and an extended overall survival by 50% in a late-stage peritoneal carcinomatosis mouse model. Economic incentives and easy translatability make the repurposing of minocycline as a reinforcer of the topoisomerase class of chemotherapeutics extremely valuable and merits further investigations.

    更新日期:2017-11-23
  • Wnt/{beta}-catenin pathway activation mediates adaptive resistance to BRAF inhibition in colorectal cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Guangming Chen, Chenxi Gao, Xuan Gao, Dennis Han Zhang, Shih-Fan Kuan, Timothy F. Burns, Jing Hu

    One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC). While many studies on BRAF inhibitor resistance in CRC have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on CRC resistance to BRAF inhibition. We found that treatment with BRAF inhibitors (both current and next generation BRAF inhibitors) upregulated the Wnt/β-catenin pathway in BRAFV600E-mutant CRC cell lines through activating the cytoplasmic tyrosine kinase FAK (focal adhesion kinase). The results showed that FAK activation upon BRAF inhibitor treatment did not require EGFR (Epidermal Growth Factor Receptor) or ERK1/2 (extracellular-signal-regulated kinases1/2) activation, implying that BRAF inhibitor treatment-induced hyperactivation of Wnt signaling is "pathway reactivation"-independent. BRAF inhibition-induced Wnt pathway activation was further validated in preclinical models of BRAFV600E-mutant CRC including cell line xenograft model and a PDX (patient-derived xenograft) model. Combined inhibition of BRAF/Wnt pathways or BRAF/FAK pathways exerted strong synergistic antitumor effects in cell culture model and mouse xenograft model. Overall, the current study has identified activation of the Wnt/β-catenin pathway as a novel fundamental cause of colon cancer resistance to BRAF inhibition. Our results suggest that while complete vertical pathway blockade is pivotal for effective and durable control of BRAF-mutant CRC, co-targeting parallel adaptive signaling-the Wnt/β-catenin pathway-is also essential.

    更新日期:2017-11-23
  • A Novel YAP1 Inhibitor targets CSCs-enriched Radiation Resistant Cells and Exerts Strong Antitumor Activity in Esophageal Adenocarcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Shumei Song, Min Xie, Ailing W Scott, Jiankang Jin, Lang Ma, Xiaochuan Dong, Heath D. Skinner, Randy L. Johnson, Sheng Ding, Jaffer A. Ajani

    Mounting evidence suggests that the Hippo co-activator Yes-associated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma (EAC). However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on EAC cell growth especially on YAP1 high expressing EAC cells both in vitro and in vivo. Remarkably, radiation resistant cells acquire strong CSC properties and aggressive phenotype, while CA3 can effectively suppresses these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Further, CA3 combined with 5-FU, synergistically inhibits EAC cell growth especially in YAP1 high EAC cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy resistant EC cells endowed with CSCs properties.

    更新日期:2017-11-23
  • Inhibition of O-GlcNAcase sensitizes apoptosis and reverses bortezomib resistance in mantle cell lymphoma through modification of truncated Bid
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Sudjit Luanpitpong, Nawin Chanthra, Montira Janan, Jirarat Poohadsuan, Parinya Samart, Yaowalak U-Pratya, Yon Rojanasakul, Surapol Issaragrisil

    Aberrant energy metabolism represents a hallmark of cancer and contributes to numerous aggressive behaviors of cancer cells, including cell death and survival. Despite the poor prognosis of mantle cell lymphoma (MCL), due to the inevitable development of drug resistance, metabolic reprograming of MCL cells remains an unexplored area. Post-translational modification of proteins via O-GlcNAcylation is an ideal sensor for nutritional changes mediated by O-GlcNAc transferase (OGT) and is removed by O-GlcNAcase (OGA). Using various small molecule inhibitors of OGT and OGA, we found for the first time that O-GlcNAcylation potentiates MCL response to bortezomib (BTZ). CRISPR interference of MGEA5 (encoding OGA) validated the apoptosis sensitization by O-GlcNAcylation and OGA inhibition. To identify the potential clinical candidates, we tested MCL response to drug-like OGA inhibitor, ketoconazole (KCZ), and verified that it exerts similar sensitizing effect on BTZ-induced apoptosis. Investigations into the underlying molecular mechanisms reveal that BTZ and KCZ act in concert to cause the accumulation of truncated Bid (tBid). Not only does KCZ potentiate tBid induction, but also increases tBid stability through O-GlcNAcylation that interferes with tBid ubiquitination and proteasomal degradation. Remarkably, KCZ strongly enhances BTZ-induced apoptosis in de novo BTZ-resistant MCL cells and in patient-derived primary cells with minimal cytotoxic effect on normal peripheral blood mononuclear cells and hepatocytes, suggesting its potential utility as a safe and effective adjuvant for MCL. Together, our findings provide novel evidence that combination of BTZ and KCZ or other OGA inhibitors may present a promising strategy for the treatment of drug-resistant MCL.

    更新日期:2017-11-23
  • Integrated genomic and interfacility patient-transfer data reveal the transmission pathways of multidrug-resistant Klebsiella pneumoniae in a regional outbreak
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Evan S. Snitkin, Sarah Won, Ali Pirani, Zena Lapp, Robert A. Weinstein, Karen Lolans, Mary K. Hayden

    Development of effective strategies to limit the proliferation of multidrug-resistant organisms requires a thorough understanding of how such organisms spread among health care facilities. We sought to uncover the chains of transmission underlying a 2008 U.S. regional outbreak of carbapenem-resistantKlebsiella pneumoniaeby performing an integrated analysis of genomic and interfacility patient-transfer data. Genomic analysis yielded a high-resolution transmission network that assigned directionality to regional transmission events and discriminated between intra- and interfacility transmission when epidemiologic data were ambiguous or misleading. Examining the genomic transmission network in the context of interfacility patient transfers (patient-sharing networks) supported the role of patient transfers in driving the outbreak, with genomic analysis revealing that a small subset of patient-transfer events was sufficient to explain regional spread. Further integration of the genomic and patient-sharing networks identified one nursing home as an important bridge facility early in the outbreak—a role that was not apparent from analysis of genomic or patient-transfer data alone. Last, we found that when simulating a real-time regional outbreak, our methodology was able to accurately infer the facility at which patients acquired their infections. This approach has the potential to identify facilities with high rates of intra- or interfacility transmission, data that will be useful for triggering targeted interventions to prevent further spread of multidrug-resistant organisms.

    更新日期:2017-11-23
  • TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Yinmeng Yang, M. Eric Kohler, Christopher D. Chien, Christopher T. Sauter, Elad Jacoby, Chunhua Yan, Ying Hu, Kelsey Wanhainen, Haiying Qin, Terry J. Fry

    Chimeric antigen receptor (CAR)–expressing T cells induce durable remissions in patients with relapsed/refractory B cell malignancies. CARs are synthetic constructs that, when introduced into mature T cells, confer a second, non–major histocompatibility complex–restricted specificity in addition to the endogenous T cell receptor (TCR). The implications of TCR activation on CAR T cell efficacy has not been well defined. Using an immunocompetent, syngeneic murine model of CD19-targeted CAR T cell therapy for pre–B cell acute lymphoblastic leukemia in which the CAR is introduced into T cells with known TCR specificity, we demonstrate loss of CD8 CAR T cell efficacy associated with T cell exhaustion and apoptosis when TCR antigen is present. CD4 CAR T cells demonstrate equivalent cytotoxicity to CD8 CAR T cells and, in contrast, retain in vivo efficacy despite TCR stimulation. Gene expression profiles confirm increased exhaustion and apoptosis of CD8 CAR T cells upon dual receptor stimulation compared to CD4 CAR T cells and indicate inherent differences between CD4 and CD8 CAR T cells in the use of T cell–associated signaling pathways. These results provide insights into important aspects of CAR T cell immune biology and indicate opportunities to rationally design CAR constructs to optimize clinical efficacy.

    更新日期:2017-11-23
  • New skin in the game
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Leah C. Byrne

    Transplantation of autologous transgenic stem cells resulted in near complete skin regeneration in a 7-year-old patient with severe junctional epidermolysis bullosa.

    更新日期:2017-11-23
  • It’s what’s inside that counts for nanoparticle vaccines
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Miles A. Miller

    Plasma membranes of tumor cells induce antitumor immunity when wrapped around a nanoformulated CpG adjuvant.

    更新日期:2017-11-23
  • Apoptotic debris goes in the Bim
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Jonathan Miner

    Lack of Bim expression in myeloid cells induces lupus nephritis in mice

    更新日期:2017-11-23
  • The vicious epigenetic cycle of neuronal activation
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Gaia Novarino

    Seizure-induced increase in ΔFosB expression reduces calbindin-28k and might explain cognitive impairments in seizure disorders.

    更新日期:2017-11-23
  • What evidence do we need for biomarker qualification?
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Chris Leptak, Joseph P. Menetski, John A. Wagner, Jiri Aubrecht, Linda Brady, Martha Brumfield, William W. Chin, Steve Hoffmann, Gary Kelloff, Gabriela Lavezzari, Rajesh Ranganathan, John-Michael Sauer, Frank D. Sistare, Tanja Zabka, David Wholley

    Biomarkers can facilitate all aspects of the drug development process. However, biomarker qualification—the use of a biomarker that is accepted by the U.S. Food and Drug Administration—needs a clear, predictable process. We describe a multistakeholder effort including government, industry, and academia that proposes a framework for defining the amount of evidence needed for biomarker qualification. This framework is intended for broad applications across multiple biomarker categories and uses.

    更新日期:2017-11-23
  • Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Christina D. Orrú, Jue Yuan, Brian S. Appleby, Baiya Li, Yu Li, Dane Winner, Zerui Wang, Yi-An Zhan, Mark Rodgers, Jason Rarick, Robert E. Wyza, Tripti Joshi, Gong-Xian Wang, Mark L. Cohen, Shulin Zhang, Bradley R. Groveman, Robert B. Petersen, James W. Ironside, Miguel E. Quiñones-Mateu, Jiri G. Safar, Qingzhong Kong, Byron Caughey, Wen-Quan Zou

    Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible through iatrogenic routes due to abundant infectious prions [misfolded forms of the prion protein (PrPSc)] in the central nervous system (CNS). Some epidemiological studies have associated sCJD risk with non-CNS surgeries. We explored the potential prion seeding activity and infectivity of skin from sCJD patients. Autopsy or biopsy skin samples from 38 patients [21 sCJD, 2 variant CJD (vCJD), and 15 non-CJD] were analyzed by Western blotting and real-time quaking-induced conversion (RT-QuIC) for PrPSc. Skin samples from two patients were further examined for prion infectivity by bioassay using two lines of humanized transgenic mice. Western blotting revealed dermal PrPScin one of five deceased sCJD patients and one of two vCJD patients. However, the more sensitive RT-QuIC assay detected prion seeding activity in skin from all 23 CJD decedents but not in skin from any non-CJD control individuals (with other neurological conditions or other diseases) during blinded testing. Although sCJD patient skin contained ~103- to 105-fold lower prion seeding activity than did sCJD patient brain tissue, all 12 mice from two transgenic mouse lines inoculated with sCJD skin homogenates from two sCJD patients succumbed to prion disease within 564 days after inoculation. Our study demonstrates that the skin of sCJD patients contains both prion seeding activity and infectivity, which raises concerns about the potential for iatrogenic sCJD transmission via skin.

    更新日期:2017-11-23
  • Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Chatmanee Lertudomphonwanit, Reena Mourya, Lin Fei, Yue Zhang, Sridevi Gutta, Li Yang, Kevin E. Bove, Pranavkumar Shivakumar, Jorge A. Bezerra

    Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time-consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic syndromes (serving as disease controls) to identify biomarkers of disease. In a discovery cohort of 70 subjects, the lead biomarker was matrix metalloproteinase-7 (MMP-7), which retained high distinguishing features for biliary atresia in two validation cohorts. Notably, the diagnostic performance reached 95% when MMP-7 was combined with γ-glutamyltranspeptidase (GGT), a marker of cholestasis. Using human tissue and an experimental model of biliary atresia, we found that MMP-7 is primarily expressed by cholangiocytes, released upon epithelial injury, and promotes the experimental disease phenotype. Thus, we propose that serum MMP-7 (alone or in combination with GGT) is a diagnostic biomarker for biliary atresia and may serve as a therapeutic target.

    更新日期:2017-11-23
  • Targeting STUB1–tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-22
    Moshe Shashar, Mostafa E. Belghasem, Shinobu Matsuura, Joshua Walker, Sean Richards, Faisal Alousi, Keshab Rijal, Vijaya B. Kolachalama, Mercedes Balcells, Minami Odagi, Kazuo Nagasawa, Joel M. Henderson, Amitabh Gautam, Richard Rushmore, Jean Francis, Daniel Kirchhofer, Kumaran Kolandaivelu, David H. Sherr, Elazer R. Edelman, Katya Ravid, Vipul C. Chitalia

    Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute–specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box–containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute–AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.

    更新日期:2017-11-23
  • Extracellular matrix in uterine leiomyoma pathogenesis: a potential target for future therapeutics
    Hum. Reprod. Update (IF 11.748) Pub Date : 2017-11-23
    Md Soriful Islam, Andrea Ciavattini, Felice Petraglia, Mario Castellucci, Pasquapina Ciarmela

    Uterine leiomyoma (also known as fibroid or myoma) is the most common benign tumor of the uterus found in women of reproductive age. It is not usually fatal but can produce serious clinical symptoms, including excessive uterine bleeding, pelvic pain or pressure, infertility and pregnancy complications. Due to lack of effective medical treatments surgery has been a definitive choice for the management of this tumor.

    更新日期:2017-11-23
  • Prevalence and clinical association of gene mutations through Multiplex Mutation Testing in patients with NSCLC: Results from the ETOP Lungscape Project
    Ann. Oncol. (IF 11.855) Pub Date : 2017-11-23
    K M Kerr, U Dafni, K Schulze, E Thunnissen, L Bubendorf, H Hager, S Finn, W Biernat, L Vliegen, J H Losa, A Marchetti, R Cheney, A Warth, E-J Speel, F Blackhall, K Monkhorst, E Jantus Lewintre, V Tischler, C Clark, J Bertran-Alamillo, P Meldgaard, K Gately, A Wrona, P Vandenberghe, E Felip, G De Luca, S Savic, T Muley, E F Smit, A-M C Dingemans, L Priest, P Baas, C Camps, W Weder, V Polydoropoulou, T R Geiger, R Kammler, T Sumiyoshi, M A Molina, D S Shames, R A Stahel, S Peters

    Reported prevalence of driver gene mutations in non-small cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the ETOP Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathological features and patient outcome (relapse-free survival, time-to-relapse, overall survival).

    更新日期:2017-11-23
  • OV21/PETROC: A randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer
    Ann. Oncol. (IF 11.855) Pub Date : 2017-11-23
    DM Provencher, CJ Gallagher, WR Parulekar, JA Ledermann, DK Armstrong, M Brundage, C Gourley, I Romero, A Gonzalez-Martin, M Feeney, P Bessette, M Hall, JI Weberpals, G Hall, SK Lau, P Gauthier, M Fung-Kee-Fung, EA Eisenhauer, C Winch, D Tu, HJ MacKay

    The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (IP) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC).

    更新日期:2017-11-23
  • ‘Keep an eye’ on the heart: retinal microcirculation disarray in congestive heart failure
    Eur. Heart J. (IF 19.651) Pub Date : 2017-11-23
    Guido Grassi, Giuseppe Mancia

    This editorial refers to ‘Retinal microvascular dysfunction in heart failure’, by M.P. Nagele et al., doi:10.1093/eurheartj/ehx565.

    更新日期:2017-11-23
  • Cholera in Yemen — An Old Foe Rearing Its Ugly Head
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-01
    Firdausi Qadri, Taufiqul Islam, John D. Clemens
    更新日期:2017-11-23
  • Optimizing GME by Measuring Its Outcomes
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-10-04
    Debra F. Weinstein

    Assessment of the impact of individual residency graduates, the performance of graduate medical education programs, and the collective contribution of our GME “system” would help inform policy decisions and facilitate efforts to cultivate evidence-based GME.

    更新日期:2017-11-23
  • The Promise, Growth, and Reality of Mobile Health — Another Data-free Zone
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-08
    Amira Roess

    Mobile health (mHealth) tools and apps are proliferating and are increasingly being used by patients and clinicians, many of them in low- and middle-income countries. But the evidence supporting most mHealth interventions is still limited.

    更新日期:2017-11-23
  • Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-03
    Jennifer L. Taylor-Cousar, Anne Munck, Edward F. McKone, Cornelis K. van der Ent, Alexander Moeller, Christopher Simard, Linda T. Wang, Edward P. Ingenito, Charlotte McKee, Yimeng Lu, Julie Lekstrom-Himes, J. Stuart Elborn
    更新日期:2017-11-23
  • Tezacaftor–Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-03
    Steven M. Rowe, Cori Daines, Felix C. Ringshausen, Eitan Kerem, John Wilson, Elizabeth Tullis, Nitin Nair, Christopher Simard, Linda Han, Edward P. Ingenito, Charlotte McKee, Julie Lekstrom-Himes, Jane C. Davies
    更新日期:2017-11-23
  • Shiga Toxin–Producing E. coli Infections Associated with Flour
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-22
    Samuel J. Crowe, Lyndsay Bottichio, Lauren N. Shade, Brooke M. Whitney, Nereida Corral, Beth Melius, Katherine D. Arends, Danielle Donovan, Jolianne Stone, Krisandra Allen, Jessica Rosner, Jennifer Beal, Laura Whitlock, Anna Blackstock, June Wetherington, Lisa A. Newberry, Morgan N. Schroeder, Darlene Wagner, Eija Trees, Stelios Viazis, Matthew E. Wise, Karen P. Neil
    更新日期:2017-11-23
  • A Test-and-Not-Treat Strategy for Onchocerciasis in Loa loa–Endemic Areas
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-08
    Joseph Kamgno, Sébastien D. Pion, Cédric B. Chesnais, Matthew H. Bakalar, Michael V. D’Ambrosio, Charles D. Mackenzie, Hugues C. Nana-Djeunga, Raceline Gounoue-Kamkumo, Guy-Roger Njitchouang, Philippe Nwane, Jules B. Tchatchueng-Mbouga, Samuel Wanji, Wilma A. Stolk, Daniel A. Fletcher, Amy D. Klion, Thomas B. Nutman, Michel Boussinesq
    更新日期:2017-11-23
  • Management of Acute Hip Fracture
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-22
    Caren G. Solomon
    更新日期:2017-11-23
  • Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-22
    Dan L. Longo

    Nonalcoholic steatohepatitis is a major cause of cirrhosis and liver cancer. It is associated with visceral adiposity and the metabolic syndrome and is nearly as common as type 2 diabetes. Metabolic stress, inflammation, and fibrosis are the primary pathogenic mechanisms.

    更新日期:2017-11-23
  • Strawberry Gingivitis in Granulomatosis with Polyangiitis
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-22
    Maryam Ghiasi
    更新日期:2017-11-23
  • Molluscum Contagiosum in a Patient with Atopic Dermatitis
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-22
    Katerina Damevska, Arben Emurlai
    更新日期:2017-11-23
  • Case 36-2017 — A 30-Year-Old Man with Fatigue, Rash, Anemia, and Thrombocytopenia
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-22
    Richard C. Cabot, Eric S. Rosenberg, Virginia M. Pierce, David M. Dudzinski, Meridale V. Baggett, Dennis C. Sgroi, Jo-Anne O. Shepard, Allison R. Bond, Emily K. McDonald, Sally H. Ebeling

    A 30-year-old man presented with fatigue, rash, anemia, and thrombocytopenia. Three years earlier, after an automobile accident, abdominal-wall hematomas, anemia, thrombocytopenia, and hematuria had developed but spontaneously resolved. A diagnostic test was performed.

    更新日期:2017-11-23
  • CFTR Modulator Therapy for Cystic Fibrosis
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-03
    Hartmut Grasemann
    更新日期:2017-11-23
  • Mass Administration of Ivermectin in Areas Where Loa loa Is Endemic
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-08
    Frank O. Jr. Richards

    The 2015 Nobel Prize in Medicine was shared in part by the discoverers of ivermectin.1 Donated tablets of ivermectin have been distributed in Africa since 1988 through mass drug administration programs for onchocerciasis, or river blindness (caused by Onchocerca volvulus),2 and since 2000 for lymphatic filariasis (caused by Wuchereria bancrofti).3 These vectorborne filarial parasites cause disabling and stigmatizing diseases, especially in impoverished populations. The complex lifecycles of these parasites include male and female adult worm stages, in which fertilized females in humans release microfilariae that can be ingested by simulium black flies from the skin, in the case of onchocerciasis, . . .

    更新日期:2017-11-23
  • Firearm-Related Injury and Death — A U.S. Health Care Crisis in Need of Health Care Professionals
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-10-09
    Darren B. Taichman, Howard Bauchner, Jeffrey M. Drazen, Christine Laine, Larry Peiperl

    What would happen if on one day more than 50 people died and over 10 times that many were harmed by an infectious disease in the United States? Likely, our nation’s esteemed and highly capable public health infrastructure would gear up to care for those harmed and study the problem. There would be a rush to identify the cause, develop interventions, and refine them continually until the threat is eliminated or at least contained. In light of the risks to public health (after all, over 500 people have been harmed already!), health care professionals would sound the alarm. We would . . .

    更新日期:2017-11-23
  • A Slick and Stretchable Surgical Adhesive
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-22
    Elizabeth G. Phimister
    更新日期:2017-11-23
  • Reduction of Loa loa Microfilaremia with Imatinib — A Case Report
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-22
    Elise M. O’Connell, Thomas B. Nutman
    更新日期:2017-11-23
  • Intensive Blood-Pressure Treatment and Patient-Reported Outcomes
    N. Engl. J. Med. (IF 72.406) Pub Date : 2017-11-22

    To the Editor: Berlowitz et al. (Aug. 24 issue)1 reported scores on the Patient Health Questionnaire 9-item depression scale (PHQ-9) and the Veterans RAND 12-Item Health Survey (VR-12) that were similar between patients who received standard blood-pressure treatment and those who received intensive blood-pressure treatment, although they found significant differences in clinical outcomes.2 These findings could be due to poor sensitivity of the patient-reported outcome instruments used. In their trial, summary scoring was used in a population with a considerable ceiling effect for satisfaction with blood-pressure care, satisfaction with medication, and PHQ-9 and VR-12 scores at baseline.1 The ceiling effect . . .

    更新日期:2017-11-23
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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