tbuckley/cabot-search huggingface dataset:
Nanoparticles Based on Poly (β-Amino Ester) and HPV16-Targeting CRISPR/shRNA as Potential Drugs for HPV16-Related Cervical Malignancy
Authors: Da Zhu, Hui Shen, Songwei Tan, Zheng Hu, Liming Wang, Lan Yu, Xun Tian, Wencheng Ding, Ci Ren, Chun Gao, Jing Cheng, Ming Deng, Rong Liu, Junbo Hu, Ling Xi, Peng Wu, Zhiping Zhang, Ding Ma, Hui Wang
Journal: Molecular Therapy (2018)

Persistent high-risk HPV infection is the main cause of cervical cancer. The HPV oncogene E7 plays an important role in HPV carcinogenesis. Currently, HPV vaccines do not offer an effective treatment for women who already present with cervical disease, and recommended periodical cervical screenings are difficult to perform in countries and areas lacking medical resources. Our aim was to develop nanoparticles (NPs) based on poly (β-amino ester) (PBAE) and HPV16 E7-targeting CRISPR/short hairpin RNA (shRNA) to reduce the levels of HPV16 E7 as a preliminary form of a drug to treat HPV infection and its related cervical malignancy. Our NPs showed low toxicity in cells and mouse organs. By reducing the expression of HPV16 E7, our NPs could inhibit the growth of cervical cancer cells and xenograft tumors in nude mice, and they could reverse the malignant cervical epithelium phenotype in HPV16 transgenic mice. The performance of NPs containing shRNA is better than that of NPs containing CRISPR. HPV-targeting NPs consisting of PBAE and CRISPR/shRNA could potentially be developed as drugs to treat HPV infection and HPV-related cervical malignancy. Persistent high-risk HPV infection is the main cause of cervical cancer. The HPV oncogene E7 plays an important role in HPV carcinogenesis. Currently, HPV vaccines do not offer an effective treatment for women who already present with cervical disease, and recommended periodical cervical screenings are difficult to perform in countries and areas lacking medical resources. Our aim was to develop nanoparticles (NPs) based on poly (β-amino ester) (PBAE) and HPV16 E7-targeting CRISPR/short hairpin RNA (shRNA) to reduce the levels of HPV16 E7 as a preliminary form of a drug to treat HPV infection and its related cervical malignancy. Our NPs showed low toxicity in cells and mouse organs. By reducing the expression of HPV16 E7, our NPs could inhibit the growth of cervical cancer cells and xenograft tumors in nude mice, and they could reverse the malignant cervical epithelium phenotype in HPV16 transgenic mice. The performance of NPs containing shRNA is better than that of NPs containing CRISPR. HPV-targeting NPs consisting of PBAE and CRISPR/shRNA could potentially be developed as drugs to treat HPV infection and HPV-related cervical malignancy.
Prognostic Value of Dipyridamole-Thallium Myocardial Scintigraphy in Patients With Kawasaki Disease
Authors: MasaoMiyagawa, TeruhitoMochizuki, KenyaMurase, ShujiTanada, JunpeiIkezoe, MichihitoSekiya, KenHamamoto, ShuheiMatsumoto, MasaharuNiino
Journal: Circulation (1998)

Background—Although coronary artery lesions are critical complications of Kawasaki disease, their long-term outcome is still unclear. It is sometimes difficult to monitor progressive changes from aneurysms to stenotic lesions because coronary angiography (CAG) cannot be repeated very often, especially in infants. Our prospective study was designed to evaluate the prognostic value of dipyridamole-thallium single-photon-emission CT (SPECT) in the long-term follow-up of patients with Kawasaki disease. Methods and Results—Of 459 consecutive patients with Kawasaki disease, coronary aneurysms were detected in 90 cases by echocardiography during the acute stage. After paired studies of selective CAG and SPECT were conducted, all patients were followed up and monitored for the occurrence of any cardiac events for ≥8 years. During the follow-up interval, there were 15 cardiac events (1 death, 5 infarctions, 2 coronary artery bypass graft operations, and 7 occurrences of unstable angina). Of patients who had some e...
Noncovalent inhibition of C481S Bruton tyrosine kinase by GDC-0853: a new treatment strategy for ibrutinib-resistant CLL
Authors: Sean D. Reiff, Elizabeth M. Muhowski, Daphne Guinn, Amy Lehman, Catherine A. Fabian, Carolyn Cheney, Rose Mantel, Lisa Smith, Amy J. Johnson, Wendy B. Young, Adam R. Johnson, Lichuan Liu, John C. Byrd, Jennifer A. Woyach
Journal: Blood (2018)
Abstract 20145: Anemone Toxin II Unmasks Dilated Cardiomyopathy Phenotype in Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model
Authors: Karim Sallam, Wu Haodi, Nazish Sayed, June-Wha Rhee, Jared M Churko, Ian Y Chen, Alexa Wnorowski, Vittavat Termglinchan, Joseph C Wu
Journal: Circulation (2017)

Introduction: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have been used to as a cellular model of cardiac disorders including dilated cardiomyopathy (DCM) demonstrating excelle...
The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors
Authors: Diana Spiegelberg, Anja C. Mortensen, Sara Lundsten, Christopher J. Brown, David P. Lane, Marika Nestor
Journal: Cancer Research (2018)

Radiotherapy amplifies p53 expression in cancer cells with wild-type (wt) p53. Blocking the negative regulators MDM2 and MDMX stabilizes p53 and may therefore potentiate radiotherapy outcomes. In this study, we investigate the efficacy of the novel anti-MDM2/X stapled peptide PM2 alone and in combination with external gamma radiation in vitro and in vivo PM2 therapy combined with radiotherapy elicited synergistic therapeutic effects compared with monotherapy in cells with wt p53 in both in vitro and in vivo assays, whereas these effects did not manifest in p53 -/- cells. Biodistribution and autoradiography of 125I-PM2 revealed high and retained uptake homogenously distributed throughout the tumor. In mice carrying wt p53 tumors, PM2 combined with radiotherapy significantly prolonged the median survival by 50%, whereas effects of PM2 therapy on mutant and p53 -/- tumors were negligible. PM2-dependent stabilization of p53 was confirmed with ex vivo immunohistochemistry. These data demonstrate the potential of the stapled peptide PM2 as a radiotherapy potentiator in vivo and suggest that clinical application of PM2 with radiotherapy in wt p53 cancers might improve tumor control.Significance: These findings contribute advances to cancer radiotherapy by using novel p53-reactivating stapled peptides as radiosensitizers in wild-type p53 cancers. Cancer Res; 78(17); 5084-93. ©2018 AACR.
Large-for-Gestational-Age Neonates in Type 1 Diabetes and Pregnancy: Contribution of Factors Beyond Hyperglycemia
Authors: Rachel T. McGrath, Sarah J. Glastras, Samantha L. Hocking, Gregory R. Fulcher
Journal: Diabetes Care (2018)

Despite significant reductions in serious adverse perinatal outcomes for women with type 1 diabetes in pregnancy, the opposite effect has been observed for fetal overgrowth and associated complications, such as neonatal hypoglycemia, shoulder dystocia, and admission to the neonatal intensive care unit. In addition, infants born large for gestational age (LGA) have an increased lifetime risk of obesity, diabetes, and chronic disease. Although exposure to hyperglycemia plays an important role, women who seemingly achieve adequate glycemic control in pregnancy continue to experience a greater risk of excess fetal growth, leading to LGA neonates and macrosomia. We review potential contributors to excess fetal growth in pregnancies complicated by type 1 diabetes. In addition to hyperglycemia, we explore the role of glycemic variability, prepregnancy overweight and obesity, gestational weight gain, and maternal lipid levels. Greater understanding of the stimuli that drive excess fetal growth could lead to targeted management strategies in pregnant women with type 1 diabetes, potentially reducing the incidence of LGA neonates and the inherent risk of acute and long-term complications.
Saving Thyroids — Overtreatment of Small Papillary Cancers
Authors: H. Gilbert Welch, Gerard M. Doherty
Journal: New England Journal of Medicine (2018)

In addition to reducing overdiagnosis of thyroid cancer, we need to reduce overtreatment. As compared with total thyroidectomy, thyroid lobectomy carries fewer risks and preserves thyroid tissue, often obviating the need for permanent thyroid hormone–replacement therapy.
Digital Media and Symptoms of Attention-Deficit/Hyperactivity Disorder in Adolescents
Authors: Jenny Radesky
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Intravitreal Sirolimus for the Treatment of Noninfectious Uveitis
Authors: Quan Dong Nguyen, Pauline T. Merrill, Yasir J. Sepah, Mohamed A. Ibrahim, Alay Banker, Andrea Leonardi, Michelle Chernock, Sri Mudumba, Diana V. Do
Journal: Ophthalmology (2018)

In recent decades, the treatment paradigm for noninfectious intermediate uveitis, posterior uveitis, and panuveitis, a group of intraocular inflammatory diseases, has included systemic and local (periocular or intraocular) corticosteroids, biologics, and other steroid-sparing immunomodulatory therapy agents. Recently, an intravitreal formulation of sirolimus, an immunosuppressant that inhibits the mammalian target of rapamycin, a key regulator of cell growth in the immune system, was developed. On the basis of this mechanism and the local method of delivery, it was hypothesized that intravitreal sirolimus can improve ocular inflammation in patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis, with minimal systemic exposure and systemic adverse events (AEs). This review summarizes the pharmacokinetics, efficacy, and safety results of intravitreal sirolimus from 3 preclinical studies and 4 phase 1-3 clinical studies. Preclinical studies in rabbits showed that 22 to 220 μg intravitreal sirolimus results in sustained release of sirolimus in the vitreous for 2 months or more, with systemic concentrations below the threshold for systemic immunosuppression (approximately 8 ng/ml). Subsequently, 2 phase 1 studies (n = 50 and n = 30) established that intravitreal sirolimus improves ocular inflammation in humans. Further investigation in phase 2 and 3 studies (n = 24 and n = 347, respectively) suggested that 440 μg has the best benefit-to-risk profile. In the phase 3 study, the proportion of patients who showed complete resolution of ocular inflammation at month 5 was significantly higher in the 440-μg group than in the 44-μg group (22.8% vs. 10.3%; P = 0.025, Fisher exact test). In addition, 47 of 69 patients (68.1%) who were treated with systemic corticosteroids at baseline discontinued corticosteroid use at month 5. No sirolimus-related systemic AEs were reported in phase 1-3 studies. Collectively, these preclinical and clinical study data of intravitreal sirolimus support the therapeutic rationale of treating noninfectious uveitis with a local mammalian target of rapamycin inhibitor and suggest that 440 μg intravitreal sirolimus has the potential to be an effective and well-tolerated anti-inflammatory and corticosteroid-sparing treatment for noninfectious intermediate uveitis, posterior uveitis, and panuveitis.
Halogenated Aza‐BODIPY for Imaging‐Guided Synergistic Photodynamic and Photothermal Tumor Therapy
Authors: Menglong Zhao, Yunjian Xu, Mingjuan Xie, Liang Zou, Zhaoli Wang, Shujuan Liu, Qiang Zhao
Journal: Advanced Healthcare Materials (2018)

Abstract It is always a huge challenge to develop novel near‐infrared (NIR) phototherapeutic agents suitable for imaging‐guided cancer therapy. In order to clarify the positive heavy atom effects on the photodynamic and photothermal efficiencies of phototherapeutic agents, a series of chlorine‐, bromide‐, or iodine‐substituted aza‐BODIPYs (B2, B3, and B4, respectively) are designed and synthesized. Among them, B4 exhibits both excellent photodynamic and photothermal effects (singlet oxygen yield of B4 is 1.57 times more than that of B3) and excellent photothermal effects (1.3 °C higher than that of B3). Then, nanoparticles of B4 (IABNs) with excellent biocompatibility are prepared by coating hydrophobic B4 with hydrophilic polymer DSPE‐mPEG 5000 . IABN exhibits high photostability, excellent biocompatibility, and low dark toxicity both in vivo and in vitro. Furthermore, IABN shows the enhanced photodynamic effect and high photothermal conversion efficiency (34.8%). In addition, the strong fluorescence emission of IABN makes it suitable for fluorescence imaging‐guided tumor therapy in vivo. Finally, IABN has successfully healed the Hela tumor‐bearing mice under NIR fluorescence imaging‐ and photothermal imaging‐guided synergistic photothermal and photodynamic therapy with low side effects, demonstrating that it is promising for future clinical applications.
Low incidence of JAK2 and FLT3 mutations in patients with chronic myelomonocytic leukemia (CMML)
Authors: Eric V. Sechman, Jan Cerny, Murtaza Mehdi, Mohammad Mumtaz, Jessica Maguire, Peter Westervelt, Naomi Galili, Azra Raza
Journal: Cancer Research (2006)

1293  The recent finding of a somatic point mutation in the JAK2 tyrosine kinase (V617F) pseudokinase domain of the majority of patients with myloproliferative disorders has greatly increased the understanding of the molecular pathways deregulated in these diseases and has provided a potential therapeutic target. FLT3, a receptor tyrosine kinase, has been shown to contain internal duplications in 25 - 30% of patients with acute myeloid leukemia and is correlated with poor prognosis. The association of these mutations with abnormal proliferation of myeloid cells prompted us to study patients with CMML, a myelodysplastic disorder that can also present with myeloproliferative characteristics of leukocytosis and splenomegaly. Mutations of JAK2 or FLT3 would provide both a biologic insight and treatment strategies for this subgroup of CMML which until now has been identified by WBC counts greater that 13,000/uL. We isolated DNA from bone marrow mononuclear cells of 67 patients with CMML, 28 with WBCs greater than 13,000/uL, and 39 with lower WBCs. Using PCR followed by sequencing, only one patient was found to have a JAK2 mutation. Similarly only one patient was found to be carrying a FLT3 internal duplication. Both of these patients however, had proliferative clinical features. These data confirm the previous low incidence of JAK2 mutations in 3/119 patients with CMML1. Thus, it appears that mutations in the JAK2 and FLT3 tyrosine kinase genes are only infrequently involved in the pathobiology of CMML. It remains possible that other genes in these two pathways are deregulated in CMML, or that other tyrosine kinase genes are mutated leading to similar clinical features. 1. Steensma DP, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes. Blood 106;4:1207-1209, 2005.
Mechanisms of acute adductor longus injuries in male football players: a systematic visual video analysis
Authors: Andreas Serner, Andrea Britt Mosler, Johannes L Tol, Roald Bahr, Adam Weir
Journal: British Journal of Sports Medicine (2018)

Change of direction and kicking have been described as the main actions resulting in adductor longus injury. Video descriptions of inciting events are lacking.Perform a standardised visual video analysis of a series of acute adductor longus injuries in football.Cross-sectional.Video footage was reviewed by players, and assessed independently by five sports medicine professionals. Inciting events were described and categorised using standardised scoring, including playing situation, player/opponent behaviour, movement and body positions.Videos of acute adductor longus injuries in 17 professional male football players were analysed. Most injuries occurred in non-contact situations (71%), following a quick reaction to a change in play (53%). Injury actions were: change of direction (35%), kicking (29%), reaching (24%) and jumping (12%). Change of direction and reaching injuries were categorised as closed chain movements (59%), characterised by hip extension and abduction with external rotation. Kicking and jumping injuries were categorised as open chain (41%), characterised by a change from hip extension to hip flexion, and hip abduction to adduction, with external rotation.Acute adductor longus injuries in football occur in a variety of situations. Player actions can be categorised into closed (change of direction and reaching) and open (kicking and jumping) chain movements involving triplanar hip motion. A rapid muscle activation during a rapid muscle lengthening appears to be the fundamental injury mechanism for acute adductor longus injuries.
An Adventure in Open Payments
Authors: Michael Ribadeneyra
Journal: Annals of Internal Medicine (2018)

Letters17 July 2018An Adventure in Open PaymentsMichael Ribadeneyra, MDMichael Ribadeneyra, MDShelby Medical Associates, Shelby, North Carolina (M.R.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0203 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I read Barry's essay (1) with interest. That every payment for every lunch is recorded and reported is absurd. What a waste of time and resources. What other industry does this? Yes, we are professionals held to a higher standard, but do we ask our attorneys, accountants, and pastors to report such data? Of course not.Reference1. Barry MJ. Let the sun shine in! An adventure in open payments. Ann Intern Med. 2018;168:151-2. [PMID: 29335735]. doi:10.7326/M17-1911 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Shelby Medical Associates, Shelby, North Carolina (M.R.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0203. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoLet the Sun Shine In! An Adventure in Open Payments Michael J. Barry An Adventure in Open Payments Helen Chen An Adventure in Open Payments Michael J. Barry Metrics 17 July 2018Volume 169, Issue 2Page: 135KeywordsDisclosureResearch design ePublished: 17 July 2018 Issue Published: 17 July 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Heterogeneity assessment of two PD-L1 clones: 22C3 and SP142 in patients with non-small cell lung cancer (NSCLC).
Authors: Haipeng Xu, Chao Li, Lin Gen, Rong Xi Fang, Dong xian Lin, Yunjian Huang, Wu Zhuang, Qian Miao, Kan Jiang, Cheng Huang
Journal: Journal of Clinical Oncology (2017)

e14515 Background: Pembrolizumab proves to be effective for clinical treatment of non-small cell lung cancer (NSCLC). The clinical application of pembrolizumab should be hinged on the magnitude of PDL1 expression justified by 22C3 assay on Dako platform. However, whether another diagnostic assay, SP142, can replace 22C3 in pembrolizumab-based immunotherapy thus far remains largely unknown. Methods: Forty-nine cases were randomly collected from 207 NSCLC patients with known PD-L1 expression detected by 22C3. Each case was stained with SP142 on ventana platform. The scores obtained with SP142 were compared with 22C3 , according to the interpretation of 22C3 standard. The concordance of PD-L1 expression between 22C3 and SP142 were assessed by weighted Kappa Coefficient and McNemar-Bowker test, respectively. Results: Based on Dako 22C3-IHC platform, 5 (10.2%), 9 (18.4%) and 35 (71.4%) of 49 cases were classified into groups of strongly positive, weakly positive, and negative for PD-L1, respectively. Yet, 37 (75.5%) of 49 cases had the same results with SP142 protocol (Kappa value: 0.472, p &lt; 0.001). Six cases with weakly positive PD-L1, 3 cases with strongly positive PD-L1 and 1 case with negative PD-L1 according to the 22C3 were misdiagnosed as negative, weak positive and weak positive PD-L1 by SP142, respectively (McNemar-Bowker analysis: p = 0.037). When using the 50% tumor cell PD-L1 expression as the cut-off point, overall sensitivity and specificity of SP142 were 40% (95% [CI], 5.3%-85.3%) and 100% (95% CI, 87.1%-100%), respectively (Kappa value: 0.545, p = 0.009; McNemar-Bowker analysis: p = 0.125). When using the 1% tumor cell PD-L1 expression as the cut-off point, adoption of SP142 yielded the sensitivity of 57.1% (95% CI, 28.9%-82.3%) and the specificity of 97.1% (95% CI, 83.3%-99.9%), respectively (Kappa value: 0.608, p &lt; 0.001; McNemar-Bowker analysis: p = 0.063). Conclusions: Compared with 22C3 assay, PD-L1 expression scores were usually underestimated by the SP142, and it has a higher specificity but lower sensitivity. Our findings collectively suggest that it is not applicable to adopt the SP142-PD-L1 IHC Ventana platform to stratify NSCLC patients for pembrolizumab-based immunotherapy.
Visual Experience-Dependent Expression of Fn14 Is Required for Retinogeniculate Refinement
Authors: Lucas Cheadle, Christopher P. Tzeng, Brian T. Kalish, David A. Harmin, Samuel Rivera, Emi Ling, M. Aurel Nagy, Sinisa Hrvatin, Linda Hu, Hume Stroud, Linda C. Burkly, Chinfei Chen, Michael E. Greenberg
Journal: Neuron (2018)