tbuckley/cabot-search huggingface dataset:
Plasma pharmacokinetics, oral bioavailability, and interspecies scaling of the hypoxically activated prodrug, TH-302, in mice, rats, dogs and monkeys.
Authors: Donald Jung, Lin Lin
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

1447 

Purpose: To define the pharmacokinetics of TH-302, a nitroimidazole-linked prodrug that is activated in hypoxic regions of tumors to a brominated version of isophosphoramide mustard (Br-IPM), in mice, rats, dogs and monkeys. Materials and Methods: Pharmacokinetic studies were performed in male CD-1 (50 mg/kg i.p. or p.o.) and female nude mice (50 mg/kg i.v. or i.p.), male Sprague-Dawley rats (1, 5, 20 or 50 mg/kg i.v. and 100 mg/kg p.o.), beagle dogs (20 mg/kg i.v.) and cynomologus monkeys (20 mg/kg i.v.). Plasma TH-302 concentrations were analyzed using a LC/MS method and the pharmacokinetic parameters computed using a noncompartmental method. Interspecies scaling was performed according to standard methods. Results: In CD-1 mice, plasma TH-302 concentrations declined with terminal half-lives (t1/2) of 7.9 and 25.7 min after 50 mg/kg i.p. and p.o., respectively. In nude mice, the respective half-lives were 8.2 and 9.7 min after 50 mg/kg i.v. and p.o. The total body clearance (Cl) and apparent steady-state volume of distribution (Vss) in nude mice were 4.37 L/h/kg and 0.542 L/kg, respectively. In rats, TH-302 exhibited linear pharmacokinetics over the dose range studied. The mean terminal plasma t1/2 ranged between 1.32 - 4.37 h following the i.v. dose. Mean Cl was high (4.69 - 6.14 L/h/kg) and mean Vss was large (1.67 - 5.09 L/kg). After p.o. dosing, TH-302 was rapidly and well absorbed with mean peak plasma concentration reached at the first sampled time point of 15 minutes and an absolute oral bioavailability of 77.3%. The terminal plasma t1/2 of TH-302 was 1.59 h. After i.v. dosing in dogs, the mean Cl and Vss were 3.28 L/h/kg and 1.98 L/kg, respectively. The mean t1/2 was 49.2 min. In monkeys, TH-302 had high Cl (7.66 L/h/kg) and a large Vss (2.92 L/kg). Terminal plasma t1/2 was 24.9 min. Interspecies scaling using a complex Dedrick analysis predicts a Cl and Vss of 109 L/h and 493L for a 70-kg human. Conclusions: TH-302 exhibits linear pharmacokinetics and excellent oral bioavailability. In all species, TH-302 has a high Cl and large Vss. The high clearance observed indicates that there may be an extrahepatic clearance pathway involved.
Coronavirus Disease 2019 Case Surveillance — United States, January 22–May 30, 2020
Authors: Erin K. Stokes, Laura D. Zambrano, Kayla N. Anderson, Ellyn P. Marder, Kala M. Raz, Suad El Burai Felix, Yunfeng Tie, Kathleen E. Fullerton
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

§ CDC official counts of cases and deaths, released daily on https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html, are aggregate counts from reporting jurisdictions.Throughout the COVID-19 pandemic, CDC has been tracking both aggregate and individual (i.e., line-list) counts of cases and deaths.For aggregate counts, from January 22 to March 2, 2020, CDC provided laboratory confirmation for all U.S. confirmed cases.Starting March 3, jurisdiction partners validated aggregate counts each night for report out at 12 p.m. the following day by CDC.For individual counts, jurisdiction partners electronically submit standardized information for individual cases of COVID-19 to CDC.From April 14, aggregate and individual counts included confirmed and probable cases and deaths, according to the Council of State and Territorial Epidemiologists position statement Interim 20-ID-01 (https:// cdn.ymaws.com/www.cste.org/resource/resmgr/2020ps/interim-20-id-01_covid-19.pdf;https://wwwn.cdc.gov/nndss/conditions/coronavirus-disease-2019-covid-19/case-definition/2020/).¶ Incidence was calculated per 100,000 population using 2018 U.S. Census population estimates for U.S. states and the District of Columbia obtained from CDC WONDER (https://wonder.cdc.gov/single-
Antagomir‐155 Attenuates Acute Cardiac Rejection Using Ultrasound Targeted Microbubbles Destruction
Authors: Luyang Yi, Yihan Chen, Qiaofeng Jin, Cheng Deng, Ya Wu, Huiling Li, Tianshu Liu, Yuman Li, Yali Yang, Jing Wang, Qing Lv, Li Zhang, Mingxing Xie
Journal: Advanced Healthcare Materials (2020)

Antagomir-155 is an artificial inhibitor of miRNA-155, which is expected to be a promising therapeutic target to attenuate acute cardiac rejection (ACR). However, its vulnerability of being degraded by endogenous nuclease and potential off-target effect make the authors seek for a more suitable way to delivery it. In attribution of efficiency and safety, ultrasound targeted microbubbles destruction (UTMD) turns out to be an appropriate method to deliver gene to target tissues. Here, cationic microbubbles to deliver antagomir-155 downregulating miRNA-155 in murine allograft hearts triggered by UTMD are synthesized. The viability of this therapy is verified by fluorescent microscopy. The biodistribution of antagomir-155 is analyzed by optical imaging system. The results show antagomir-155 delivered by UTMD which significantly decreases the levels of miR-155. Also, this therapy downregulates the expression of cytokines and inflammation infiltration. And allograft survival time is significantly prolonged. Therefore, antagomir-loaded microbubbles trigged by UTMD may provide a novel platform for ACR target treatment.
Benralizumab rapidly improves asthma control in Austrian real‐life severe eosinophilic asthmatics
Authors: Andreas Renner, Katharina Marth, Karin Patocka, Marco Idzko, Wolfgang Pohl
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
AB0861 СURRENT PHARMACOTHERAPY FOR KNEE OSTEOARTHRITIS: SPECIFIC FEATURES OF SYMPTOMATIC AND DISEASE MODIFYING EFFECTS
Authors: L. Denisov, E. Tsvetkova, N. Ionichenok, A. Lila
Journal: Annals of the Rheumatic Diseases (2020)

Objectives: to study the specific features of the symptomatic effect and tolerability of paracetamol (P), glucosamine sulfate (GS), chondroitin sulfate (CS), and meloxicam (M) in patients with knee osteoarthritis (OA). Methods: An 18-month open-label randomized prospective parallel-group trial enrolled 80 patients with knee OA who fulfilled the American College of Rheumatology criteria and signed the informed consent. They had Kellgren and Lawrence grades I-III OA with visual analogue scale pain intensity of &gt; 40mm in the target knee, a body mass index of &lt; 35 rg/m 2 , and no clinical dysfunctions of vital organs and systems. The patients were randomized into 4 groups: 1) P 2g daily; 2) a standard GS regimen; 3) a standard CS regimen; 4) M 15mg daily. The patients were followed up for 18 months, The effectiveness was evaluated by the WOMAC questionnaire, Lequesne index, and OMERACT-OARSI (D scenario) during 8 visits. Laboratory and clinical examination as well as electrocardiography were performed. Adverse events were recorded during each visit. Results: After 4 weeks of treatment, symptomatic improvement was noted in all groups; however, the best effect was achieved by the use of M and continued to the end of the study. The percentage of patients reacting to the therapy by the OMERACT-OARSI criteria was highest in M group (100%), reached 90% in GS, 85% in CS groups and 75% in P group. In the groups of P, GS and CS failed to respond to treatment 25, 10, and 15% correspondingly. However, medium narrowing of articular space (NAS) was measured at the end of the study and was significantly lower in GS group (-0.07; p=0,0002), CS (-0.1; p=0.004) and M (-0.06; p=0.006). Besides, the quota of patients without heavy NAS (&gt; 0.5 mm in medial KJ) was the lowest in GS group as compared with three other groups. Conclusion: The results of this trial suggest that it is expedient to use GS, CS and M long, support the recent guidelines of the European Society for Clinical and Economic aspects of Osteoporosis and OA (ESCEO), and can give proofs of the efficiency and safety of GS, CS, and M used in the treatment of knee OA. Disclosure of Interests: None declared
A Land of Controversy: Fibroblast Growth Factor-23 and Uremic Cardiac Hypertrophy
Authors: Jing-Fu Bao, Pan-Pan Hu, Qin-Ying She, Aiqing Li
Journal: Journal of the American Society of Nephrology (2020)

Cardiac hypertrophy is a common feature in patients with CKD. Recent studies revealed that two phosphate regulators, fibroblast growth factor-23 and α -Klotho, are highly involved in the pathophysiologic process of CKD-induced cardiac hypertrophy. With decreasing renal function, elevated fibroblast growth factor-23 and decreased α -Klotho may contribute to cardiac hypertrophy by targeting the heart directly or by inducing systemic changes, such as vascular injury, hemodynamic disorders, and inflammation. However, several studies have demonstrated that disturbances in the fibroblast growth factor-23/ α -Klotho axis do not lead to cardiac hypertrophy. In this review, we describe the cardiac effects of the fibroblast growth factor-23/ α -Klotho axis and summarize recent progress in this field. In addition, we present not only the main controversies in this field but also provide possible directions to resolve these disputes.
Heparin-bound folate acid-paclitaxel, a novel promising nanodrug, inhibited human prostate cancer growth and bone metastasis in mice
Authors: Chunmeng Shi, Kim Gloria, Ying Zhu, Shuming Nie, Haiyen Zhau, Yongping Su, Tianmin Cheng, Jonathan Simons, Leland W.K. Chung
Journal: Cancer Research (2007)

2270  Nanoparticle-based drug design created a new class of highly effective cancer therapeutics with lower toxicity. Abraxane, an albumin- paclitaxel nanodrug, was approved by Food and Drug Administration for the treatment of human breast cancer. However, Abraxane relies on passive targeting, which could lead to harmful side effects on normal tissues. The objective of this study is to test a novel nanodrug, covalently conjugated heparin-bound folate acid-paclitaxel (HFT), in human prostate cancer xenografts grown in mouse subcutaneous and skeletal sites for the cancer active targeting and therapy. Paclitaxel and folate were first covalently conjugated to heparin and characterized by High Performance Liquid Chromatography (HPLC), NMR, dynamic light scattering (DLS) and Transmission Electron Microscope (TEM). The 100 nm HFT nanoparticles contained 20% paclitaxel by weight. In vitro assay showed that HFT effectively induced apotosis in a host of human prostate cancer cell lines (such as LNCaP, C4-2, ARCaPE and ARCaPM). Among these cell lines, ARCaPM (C2) expressed the highest level of folate acid receptor which were evaluated by western blot and flow cytometry. In ARCaPM (C2) cells, HFT exposure for 48 hrs induced significantly apoptosis by activating caspases 3, 8, 9 and the cleavage of PARP which were documented by western blots. Effects of HFT (with equivalent paclitaxel dose of 40 mg/kg injected by tail vein weekly for 5 weeks) on previously established and highly invasive ARCaPM (C2) tumors in mouse were further evaluated. The results showed that HFT was superior to free paclitaxel in inhibiting ARCaPM (C2) tumor growth and regressing pre-established tumors at both subcutaneous and intratibial sites. Further, mice treated with HFT gained body weight like control tumor-free mice during the course of this study with no obvious systemic toxicity. In summary, HFT is a promising nanodrug which can specifically kill prostate cancer cells by undergoing receptor-mediated endocytosis and subsequently promoting apoptosis through activation of caspases. Normal tissues are virtually unaffected by this novel nano-agent. HFT is the first designed nano-agent and holds great promise for the targeted therapy of both localized and disseminated human prostate cancer.
Utilising sigmoid models to predict the spread of antimicrobial resistance at the country level
Authors: Noga Fallach, Yaakov Dickstein, Erez Silberschein, John Turnidge, Elizabeth Temkin, Jonatan Almagor, Yehuda Carmeli
Journal: Eurosurveillance (2020)

Background The spread of antimicrobial resistance (AMR) is of worldwide concern. Public health policymakers and pharmaceutical companies pursuing antibiotic development require accurate predictions about the future spread of AMR. Aim We aimed to identify and model temporal and geographical patterns of AMR spread and to predict future trends based on a slow, intermediate or rapid rise in resistance. Methods We obtained data from five antibiotic resistance surveillance projects spanning the years 1997 to 2015. We aggregated the isolate-level or country-level data by country and year to produce country–bacterium–antibiotic class triads. We fitted both linear and sigmoid models to these triads and chose the one with the better fit. For triads that conformed to a sigmoid model, we classified AMR progression into one of three characterising paces: slow, intermediate or fast, based on the sigmoid slope. Within each pace category, average sigmoid models were calculated and validated. Results We constructed a database with 51,670 country–year–bacterium–antibiotic observations, grouped into 7,440 country–bacterium–antibiotic triads. A total of 1,037 triads (14%) met the inclusion criteria. Of these, 326 (31.4%) followed a sigmoid (logistic) pattern over time. Among 107 triads for which both sigmoid and linear models could be fit, the sigmoid model was a better fit in 84%. The sigmoid model deviated from observed data by a median of 6.5%; the degree of deviation was related to the pace of spread. Conclusion We present a novel method of describing and predicting the spread of antibiotic-resistant organisms.
Patient preference for cellulitis treatment: At-home care is preferred to hospital-based treatment
Authors: Colleen Gabel, Lauren N Ko, Allison S Dobry, Anna Cristina Garza-Mayers, Leslie W Milne, Emily Nguyen, Blair Alden Parry, Adam Raff, Radhika Shah, Jessica St John, Lauren Strazzula, Priyanka Vedak, Daniela Kroshinsky
Journal: Journal of the American Academy of Dermatology (2020)
Smart battles: immunosuppression versus immunomodulation in the inflammatory RMDs
Authors: John D Isaacs, Gerd R Burmester
Journal: Annals of the Rheumatic Diseases (2020)

The past two decades have witnessed the revolution of targeted therapies for immune-mediated inflammatory diseases, largely pioneered for rheumatological indications. These include tumour necrosis factor (TNF) blockade, interleukin (IL)-6 receptor blockade, IL-1 blockade, IL-17 blockade, IL-12/23 blockade, B-cell depletion and costimulation blockade. Other targets, such as type I interferons and granulocyte macrophage-colony stimulating factor (GM-CSF) remain under investigation.1 Most recently, janus kinase (JAK) inhibition has provided a small molecule route to targeted interventions. These therapies have been revolutionary, largely because they have provided previously unprecedented efficacy with relative safety. Thus, the risk of a serious infection with a TNF inhibitor is slightly higher than with a conventional synthetic disease-modifying drug such as methotrexate but significantly less than with higher doses of glucocorticoids for example.2 3 Similarly, multiple studies have failed to demonstrate an enhanced risk of solid cancers or lymphomas with biological and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs).4 Notably, also treatment with methotrexate which is still the cornerstone of treatment in rheumatoid arthritis (RA), does not have profound immunosuppressive effects, since in the Cardiovascular Inflammation Reduction Trial (CIRT) with non-RA patients the hazard rate for infections was low (1.15 (CI: 1.01 to 1.30)) despite significant comorbidities in the population studied.5 6 These data sit in contrast to immunosuppressive drugs used for indications such as transplantation—which were also revolutionary in their time. Renal allografts have a 1-year survival of >90%, using drugs such as tacrolimus, mycophenolate and sometimes glucocorticoids.7 However, this success comes at the cost of a significantly heightened risk of serious infections and cancer.8 9 Rheumatologists are cognisant of similar risks when we use glucocorticoids, cyclophosphamide, azathioprine and mycophenolate, particularly in combination.

The way we describe our tools and our actions has a profound effect on the understanding of our patients and …
FRI0374 PLASMA LEVELS OF 14-3-3 PROTEIN, S100A8/S100A9-PROTEIN, INTERLEUKIN-6, INTERLEUKIN-18, INTERLEUKIN-4, INTERLEUKIN-17, INTERLEUKIN-1Β AND TUMOR NECROSIS FACTOR-Α IN CHRONIC NON-BACTERIAL OSTEOMYEILITIS AND NON-SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS
Authors: M. Kostik, M. Makhova, D. Kozlova, D. Vasilyev, L. Sorokina, E. Isupova, A. Maletin, A. Mushkin
Journal: Annals of the Rheumatic Diseases (2020)

Background: Chronic non-bacterial osteomyelitis (CNO) is an immune-mediated disease associated with cytokine dysbalance. Objectives: The aim of our study was to evaluate the cytokines levels in CNO and compare to juvenile idiopathic arthritis (JIA) – disease with immune-mediated mechanism. Methods: The diagnosis of CNO made with criteria, proposed by Jansson (2007, 2009), after the exclusion of other causes of bone disease [1]. We included 42 patients with NBO, 28 patients with non-systemic juvenile idiopathic arthritis (JIA). We evaluated plasma levels of 14-3-3 protein, S100A8/S100A9-protein, interleukine-6 (IL-6), interleukine-18 (IL-18), interleukine-4 (IL-4), interleukine-17 (IL-17), interleukine-1β (IL-1 β) and tumor necrosis factor-α (TNFα) in 2 groups by the ELISA. Statistical analysis was carried out with Statistica 10.0 software. We utilized descriptive statistics (Me; IQR), Mann-Whitney tests. Results: We have found differences in the proinflammatory biomarkers between CNO, JIA. Patients with NBO had lower levels of studied cytokines, exclude14-3-3-protein, S100A8/S100A9 and interleukin-6 compare to JIA patients (table 1). Table 1. Comparison the cytokine levels between CNO, JIA N Parameter NBO (n=42) JIA (n=28) p Hemoglobin, g/l 112 (104; 124) 120 (114.5; 126.0) 0.02 WBC x 10 9 /l 7.9 (7.0; 10.5) 8.0 (6.7; 10.0) 0.86 PLT x 10 9 /l 347 (259; 408) 336.5 (274.0; 390.5) 0.98 ESR. mm/h 25.0 (9.0; 46.0) 8.5 (2.5; 13.0) 0.013 CRP, mg/l 6.1 (0.6; 2.4) 1.8 (0.4; 11.9) 0.027 14-3-3, ng/ml 21.4 (18.5; 27.1) 19.9 (18.0; 27.8) 0.77 S100A8/S100A9, ng/ml 5.9 (5.2; 6.5) 5.9 (5.0; 6.2) 0.76 IL-6, ng/ml 126,2 (112.8; 137.5) 132.4 (117.4; 142.9) 0.16 IL-18, ng/ml 270.1 (200.1; 316.1) 388.3 (373.9; 405.1) 0.0000001 IL-4, ng/ml 15.3 (11.5; 18.2) 18.7 (16.2; 20.2) 0.003 IL-17, ng/ml 83.1 (71.1; 97.3) 99.2 (87.3; 115.8) 0.003 IL-1b, ng/ml 47.4 (42.0; 51.3) 70.8 (65.3; 73.6) 0.0000001 TNFa, ng/ml 19.4 (17.8; 21.3) 23.1 (20.2; 25.9) 0.0006 Conclusion: Patients with CNO had less proinflammatory activity then JIA patients, besides IL-6 and S100A8/S100A9. Further investigations required for finding new more precise biomarkers and finding possible molecular targets for treatment. This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001) References: [1]Jansson AF, et al. Clinical score for nonbacterial osteitis in children and adults. Arthritis Rheum. 2009;60(4):1152-9. Disclosure of Interests: None declared
Racism: the other pandemic
Authors: Fiona Godlee
Journal: BMJ (2020)

Racism is suddenly and at last everyone's business, and acting against it is everyone's responsibility.More so at this time than ever, we now realise, since we cannot tackle covid-19 unless we tackle racism.This realisation may be less obvious to some, who see the global outpouring of grief and anger at the killing of George Floyd in Minneapolis as either a distraction from or in conflict with efforts to contain the virus.Commentators in The BMJ make it clear that these two things are deeply interconnected and must be dealt with together.Racism is a public health issue because it kills people (doi:10.
Intensifying Treatment in Childhood B-Lymphoblastic Leukemia with IKZF1 Deletions Negates Its Adverse Outcome: Results of Ma-Spore ALL 2003 and 2010 Studies
Authors: Yi Lu, Winnie Hui Ni Chin, Evelyn Huizi Lim, Shirley Kow Yin Kham, Ah Moy Tan, Hany Ariffin, Allen Eng Juh Yeoh
Journal: Blood (2017)
Vaping-Associated Pulmonary Injury
Authors: Randol W. Hooper, Jamie L. Garfield
Journal: Annals of Internal Medicine (2020)

Letters16 June 2020Vaping-Associated Pulmonary InjuryRandol W. Hooper II, MBBS and Jamie L. Garfield, MDRandol W. Hooper II, MBBSTemple University Hospital, Philadelphia, Pennsylvania (R.W.H., J.L.G.)Search for more papers by this author and Jamie L. Garfield, MDTemple University Hospital, Philadelphia, Pennsylvania (R.W.H., J.L.G.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-0280 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Dr. Norris' comment underscores some important considerations about the historical context of the epidemic of vaping-associated pulmonary injury. What is now termed e-cigarette, or vaping, product use–associated lung injury (EVALI) has been described in conjunction with many histopathologic findings, including lipoid pneumonia. Case reports have proposed an association between e-cigarettes and lipoid pneumonia (1). However, e-cigarettes have been sold widely in the United States for more than a decade, and there is little evidence to support a diagnosis of undetected lipoid pneumonia among the tens of millions of nicotine-based e-cigarette users.In contrast to nicotine, cannabis had been ...References1. McCauley L, Markin C, Hosmer D. An unexpected consequence of electronic cigarette use. Chest. 2012;141:1110-1113. [PMID: 22474155] doi:10.1378/chest.11-1334 CrossrefMedlineGoogle Scholar2. Vethanayagam D, Pugsley S, Dunn EJ, et al. Exogenous lipid pneumonia related to smoking weed oil following cadaveric renal transplantation. Can Respir J. 2000 Jul-Aug;7:338-342. [PMID: 10980460] CrossrefMedlineGoogle Scholar3. Ghinai I, Navon L, Gunn JKL, et al. Characteristics of persons who report using only nicotine-containing products among interviewed patients with E-cigarette, or vaping, product use-associated lung injury—Illinois, August-December 2019. MMWR Morb Mortal Wkly Rep. 2020;69:84-89. [PMID: 31971930] doi:10.15585/mmwr.mm6903e1 CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Temple University Hospital, Philadelphia, Pennsylvania (R.W.H., J.L.G.)Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-2908. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAn Emerging Crisis: Vaping-Associated Pulmonary Injury Randol W. Hooper II and Jamie L. Garfield Vaping-Associated Pulmonary Injury Matthew R. Norris Metrics 16 June 2020Volume 172, Issue 12Page: 841-842KeywordsCannabisCannabis useCase seriesConflicts of interestDisclosureLungsNicotineOilsPneumonia ePublished: 16 June 2020 Issue Published: 16 June 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: a multicentre study
Authors: M. Gao, J. Gao, L. Xie, G. Wu, W. Chen, Y. Chen, Y. Pei, G. Li, Y. Liu, W. Shu, L. Fan, Q. Wu, J. Du, X. Chen, P. Tang, Y. Xiong, M. Li, Q. Cai, L. Jin, Z. Mei, Y. Pang, L. Li
Journal: Clinical Microbiology and Infection (2020)