tbuckley/cabot-search huggingface dataset:
Limited effectiveness of four oral antifungal drugs (fluconazole, griseofulvin, itraconazole and terbinafine) in the current epidemic of altered dermatophytosis in India: results of a randomized pragmatic trial*
Authors: S. Singh, U. Chandra, V.N. Anchan, P. Verma, R. Tilak
Journal: British Journal of Dermatology (2020)

Dermatophytic infections have undergone unprecedented changes in India in the recent past. Clinical trials to find out the effectiveness of the four main oral antifungal drugs are lacking.We tested the effectiveness of oral fluconazole, griseofulvin, itraconazole and terbinafine in chronic and chronic relapsing tinea corporis, tinea cruris and tinea faciei in an investigator-initiated, randomized, pragmatic trial.Two hundred patients with microscopy-confirmed tinea were allocated to four groups (50 patients in each group): fluconazole 5 mg kg-1 per day, griseofulvin 10 mg kg-1 per day, itraconazole 5 mg kg-1 per day and terbinafine 7·5 mg kg-1 per day. Allocation was performed by concealed block randomization and the patients were treated for 8 weeks or until cure. Effectiveness was calculated based on intention-to-treat analysis. The trial was registered with the Clinical Trials Registry India (CTRI/2017/04/008281).At 4 weeks, all drugs were similarly ineffective, with cure rates being 8% or less (P = 0·42). At 8 weeks, the numbers of patients cured were as follows: fluconazole 21 (42%), griseofulvin seven (14%), itraconazole 33 (66%) and terbinafine 14 (28%) (P < 0·001). Itraconazole was superior to fluconazole, griseofulvin and terbinafine (adjusted P ≤ 0·048). Relapse rates after 4 and 8 weeks of cure with the four treatments were not different (P ≥ 0·42). Numbers needed to treat (vs. griseofulvin), calculated on the basis of cure rates at 8 weeks, were as follows: fluconazole 4, itraconazole 2 and terbinafine 8.The results show limited effectiveness of all four antifungal drugs. In view of cure rates and the number needed to treat, itraconazole is the most effective drug, followed by fluconazole (daily), terbinafine and then griseofulvin, in chronic and chronic relapsing dermatophytosis in India. What is already known about this topic? Oral antifungal drugs are considered to have a high cure rate in tinea corporis, tinea cruris and tinea faciei. Unprecedented changes have been noticed in the last few years in India in the morphology, course and treatment responsiveness of tinea; however, data about the effectiveness of oral antifungals are lacking. What does this study add? Our results show limited effectiveness of four oral antifungal drugs (fluconazole, griseofulvin, itraconazole and terbinafine) in the current epidemic of altered dermatophytosis in India. Among the four drugs tested, oral itraconazole is the most effective. Linked Comment: Elewski. Br J Dermatol 2020; 183:798-799.
BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment
Authors: Branko Cirovic, L. Charlotte J. de Bree, Laszlo Groh, Bas A. Blok, Joyce Chan, Walter J.F.M. van der Velden, M.E.J. Bremmers, Reinout van Crevel, Kristian Händler, Simone Picelli, Jonas Schulte-Schrepping, Kathrin Klee, Marije Oosting, Valerie A.C.M. Koeken, Jakko van Ingen, Yang Li, Christine S. Benn, Joachim L. Schultze, Leo A.B. Joosten, Nigel Curtis, Mihai G. Netea, Andreas Schlitzer
Journal: Cell Host & Microbe (2020)
AB1069 CONSIDERATION OF YAO SYNDROME AS A DIFFERENTIAL DIAGNOSIS FOR HEREDITARY PERIODIC FEVER SYNDROMES
Authors: Q. Yao
Journal: Annals of the Rheumatic Diseases (2020)

Background: Yao syndrome (YAOS, OMIM 617321), formerly termed nucleotide-binding oligomerization domain 2( NOD2 )-associated autoinflammatory disease, is characterized by periodic fever, dermatitis, arthritis, and swelling of the distal extremities, as well as gastrointestinal and sicca-like symptoms. This disorder shares similar clinical phenotypes with hereditary periodic fever syndromes (HPFS) and thus can mimic one another. Objectives: This study aimed to exemplify by a comparison of YAOS vs familial Mediterranean fever (FMF). Methods: In this retrospective study, electronic medical records of a series of patients with YAOS were analyzed. All patients underwent genetic testing for periodic fever syndrome 6-gene panel (MEFV, TNFRSF1A, NLRP3, MVK, NLRP12 and NOD2). Results: All patients were Caucasian and had recurrent fever, patchy erythema, arthralgia, and gastrointestinal symptoms (Table 1). With negative DNA sequencing for MEFV, these patients were treated with colchicine for presumed FMF, with a good response in patient 2 and minimal or transient response in other two patients. Further genetic testing identified the NOD2 variants. Unlike HPFS, YAOS is generally sporadic and is mostly reported in adults; spongiotic dermatitis is common; YAOS is associated with the NOD2 variants, IVS8 + 158 in nearly all patients, IVS8 + 158/R702W in up to 30%, and IVS8 + 158/1007fs, G908R or other rarer NOD2 variants in some patients. Conclusion: YAOS can masquerade HPFS like FMF. Molecular analysis should cover NOD2 whole gene sequencing to help distinguish these diseases. References: [1]Yao Q, et al. Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations. J Am Acad Dermatol. 2013;68(4):624-31. Trueb B, et al. Coincidence of NOD2-Associated Autoinflammatory Disease (Yao Syndrome) and HCV Infection With Fatal Consequences: Interaction Between Genes and Environment. J Clin Rheumatol. 2018 Dec 28. doi: 10.1097/RHU.0000000000000963. [Epub ahead of print]. China [2]Yao Q. Research letter: Effectiveness of canakinumab for the treatment of Yao syndrome patients. J Am Acad Dermatol. 2019. [3]Yao Q, Shen M, McDonald C, Lacbawan F, Moran R, Shen B. NOD2-associated autoinflammatory disease: a large cohort study. Rheumatology (Oxford). 2015;54(10):1904-12. [4]Yao Q, Shen B. A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease. Am J Med. 2017;130(3):365 e13- e18. [5]McDonald C, et al. Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome. Autoimmunity. 2018;51(2):53-61. Acknowledgments: The author is thankful to the statistician, Ms. Erin Taub for her help with making the table. Disclosure of Interests: None declared
All‐Aqueous‐Processed Injectable In Situ Forming Macroporous Silk Gel Scaffolds for Minimally Invasive Intracranial and Osteological Therapies
Authors: Keyin Liu, Zhen Fan, Tianji Wang, Zhiheng Gao, Junjie Zhong, Geng Xiang, Wei Lei, Zhifeng Shi, Yafei Feng, Ying Mao, Tiger H. Tao
Journal: Advanced Healthcare Materials (2020)

Abstract Hydrogels are widely utilized in regenerative medicine for drug delivery and tissue repair due to their superior biocompatibility and high similarity to the extracellular matrix. For minimally invasive therapies, in situ forming gel scaffolds are desirable, but technical challenges remain to be overcome to achieve the balance between tissue‐like strength and cell‐sized porosity, especially for intracranial and osteological therapies. Here, a new method—inspired by the liquid crystalline spinning process in natural silk fibers—is reported for preparing injectable silk gel scaffolds with favorable preclinical efficacy and unique characteristics including 1) in situ gelling for minimally invasive surgeries, 2) controllable porosity for efficient cellular infiltration and desirable degradation, 3) resilient and tunable mechanical properties that are compatible with the modulus regime of native soft tissues, and 4) all‐aqueous processing that avoids toxic solvents and enables facile loading of bioactive agents. Moreover, hierarchically structured heterogeneous silk gel scaffolds with variable porosity and bioactive agent gradients within 3D matrices can be achieved for sustained drug release and guided tissue regeneration. Preclinical efficacy studies in rodent models show efficient bacterium and glioma inhibition and positive effects on bone regeneration and vascularization.
Removal of H2Aub1 by ubiquitin-specific proteases 12 and 13 is required for stable Polycomb-mediated gene repression in Arabidopsis
Authors: Lejon E. M. Kralemann, Shujing Liu, Minerva S. Trejo-Arellano, Rafael Muñoz-Viana, Claudia Köhler, Lars Hennig
Journal: Genome biology (2020)

Abstract Background Stable gene repression is essential for normal growth and development. Polycomb repressive complexes 1 and 2 (PRC1&amp;2) are involved in this process by establishing monoubiquitination of histone 2A (H2Aub1) and subsequent trimethylation of lysine 27 of histone 3 (H3K27me3). Previous work proposed that H2Aub1 removal by the ubiquitin-specific proteases 12 and 13 (UBP12 and UBP13) is part of the repressive PRC1&amp;2 system, but its functional role remains elusive. Results We show that UBP12 and UBP13 work together with PRC1, PRC2, and EMF1 to repress genes involved in stimulus response. We find that PRC1-mediated H2Aub1 is associated with gene responsiveness, and its repressive function requires PRC2 recruitment. We further show that the requirement of PRC1 for PRC2 recruitment depends on the initial expression status of genes. Lastly, we demonstrate that removal of H2Aub1 by UBP12/13 prevents loss of H3K27me3, consistent with our finding that the H3K27me3 demethylase REF6 is positively associated with H2Aub1. Conclusions Our data allow us to propose a model in which deposition of H2Aub1 permits genes to switch between repression and activation by H3K27me3 deposition and removal. Removal of H2Aub1 by UBP12/13 is required to achieve stable PRC2-mediated repression.
Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level
Authors: Douglas J. Kenny, Damian R. Plichta, Dmitry Shungin, Nitzan Koppel, A. Brantley Hall, Beverly Fu, Ramachandran S. Vasan, Stanley Y. Shaw, Hera Vlamakis, Emily P. Balskus, Ramnik J. Xavier
Journal: Cell Host & Microbe (2020)
Angiotensin-(1-7) reduces lung tumor incidence in a novel bitransgenic Ki-rasG12C mouse model of lung tumorigenesis through a reduction in cyclooxygenase-2
Authors: Jyotsana Menon, Mark Miller, David Soto-Pantoja, Michael Callahan, E. Ann Tallant, Patricia Gallagher
Journal: Cancer Research (2008)

4654  Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone of the renin-angiotensin system with vasodilator and anti-proliferative properties. Epidemiological studies showed that treatment of patients with angiotensin converting enzyme (ACE) inhibitors which elevate Ang-(1-7) reduced the incidence of cancer, particularly lung cancer, suggesting that the heptapeptide may prevent lung cancer. In this study, we investigated whether Ang-(1-7) reduced the formation of lung tumors using a novel tetracycline-inducible, lung-specific bitransgenic Ki-rasG12C mouse model. Bi-transgenic mice were produced by crossing mono-transgenic Ki-rasG12C mice with Clara cell secretory protein-reverse tet trans-activator (CCSP-rtTA) transgenic mice. Doxycycline (500 µg /mL) was administered to the mice in their drinking water, beginning at 2 months of age and continuing throughout the study, to induce expression of the Ki-rasG12C transgene. Induction of the mutant Ki-rasG12C transgene resulted in the formation of proliferative pulmonary lesions morphologically diagnosed as bronchoalveolar hyperplasias and adenomas. Ang-(1-7) (24 µg/kg/h) or saline (6 µL/24 h) was administered into the jugular vein by osmotic minipumps beginning at 5 months of age and animals were sacrificed 3 months later. Infusion of Ang-(1-7) increased plasma concentrations of the heptapeptide approximately 3-fold over saline-treated animals (from 59.7 ± 12 pg/mL to 168 ± 36.6 pg/mL, p
Abstract 20: Targeting difficult targets with lysine-covalent ligands: Expanding the druggable space for covalent drugs
Authors: Maurizio Pellecchia
Journal: Clinical Cancer Research (2020)

Abstract Oncology drugs osimertinib, ibrutinib, neratinib, and afatinib have all been approved in very recent years by the FDA, and all target a cysteine that is present in proximity to the binding site of their respective targets. More recently, Amgen reported on AMG 510 as a first-in-class investigational drug designed to selectively and irreversibly target the KRAS G12C protein. These drugs rely on acrylamides moieties strategically incorporated in their chemical structures to selectively and efficiently react with binding site cysteine residues. Obviously, the approach is limited to drug targets that present a cysteine residue in proximity to the binding site, which often is not the case. This druggable target space for covalent drugs is called the Cysteinome. My laboratory has been developing and applying novel strategies aimed at deriving potent, selective, cell-permeable, and efficacious covalent therapeutics by designing agents that can selectively react with lysine residues (1,2). The approach relies on introducing stable aryl-fluorosulfates or sulfonyl-fluorides in drug leads to selectively and efficiently react with lysine residues. Because lysines are more ubiquitously found within the binding pocket of the target oncogenes, the approach defines a much larger target space for covalent drugs: the Lysinome. In addition, I will demonstrate that the approach is amenable also to tackle difficult targets such as those involving protein-protein interactions (PPIs). Hence, our work widens the available target space beyond cysteine and also allows the development of novel drug candidates against PPIs, which represent an untapped large class of therapeutic targets in oncology. Examples will include potent and selective Lys-covalent agents targeting antiapoptotic proteins in the IAP and Bcl-2 families of proteins, including particularly exciting, yet to be published results. References: 1. Gambini L, Baggio C, Udompholkul P, Jossart J, Salem AF, Perry JJP, Pellecchia M. Covalent inhibitors of protein-protein interactions targeting lysine, tyrosine, or histidine residues. J Med Chem 2019;13;62(11):5616-27. 2. Baggio C, Udompholkul P, Gambini L, Salem AF, Jossart J, Perry JJP, Pellecchia M. Aryl-fluorosulfate-based lysine covalent pan-inhibitors of apoptosis protein (IAP) antagonists with cellular efficacy. J Med Chem 2019;Oct. 8. doi: 10.1021/acs.jmedchem.9b01108. Citation Format: Maurizio Pellecchia. Targeting difficult targets with lysine-covalent ligands: Expanding the druggable space for covalent drugs [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 20.
Psychiatric Disorders Are Associated with Increased Risk of Sepsis Following a Cancer Diagnosis
Authors: Qianwei Liu, Huan Song, Therese M.-L. Andersson, Patrik K.E. Magnusson, Jianwei Zhu, Karin E. Smedby, Fang Fang
Journal: Cancer Research (2020)

Psychiatric disorders and infections are both common comorbidities among patients with cancer. However, little is known about the role of precancer psychiatric disorders on the subsequent risk of sepsis as a complication of infections among patients with cancer. We conducted a cohort study of 362,500 patients with newly diagnosed cancer during 2006-2014 in Sweden. We used flexible parametric models to calculate the HRs of sepsis after cancer diagnosis in relation to precancer psychiatric disorders and the analyses were performed in two models. In model 1, analyses were adjusted for sex, age at cancer diagnosis, calendar period, region of residence, and type of cancer. In model 2, further adjustments were made for marital status, educational level, cancer stage, infection history, and Charlson Comorbidity Index score. During a median follow-up of 2.6 years, we identified 872 cases of sepsis among patients with cancer with precancer psychiatric disorders (incidence rate, IR, 14.8 per 1,000 person-years) and 12,133 cases among patients with cancer without such disorders (IR, 11.6 per 1000 person-years), leading to a statistically significant association between precancer psychiatric disorders and sepsis in both the simplified (HR, 1.31; 95% CI, 1.22-1.40) and full (HR, 1.26; 95% CI, 1.18-1.35) models. The positive association was consistently noted among patients with different demographic factors or cancer characteristics, for most cancer types, and during the entire follow-up after cancer diagnosis. Collectively, preexisting psychiatric disorders were associated with an increased risk of sepsis after cancer diagnosis, suggesting a need of heightened clinical awareness in this patient group. SIGNIFICANCE: These results call for extended prevention and surveillance of sepsis among patients with cancer with psychiatric comorbidities.
Abstract 15512: Protective Effects of Flavonoids on Atherosclerosis Depend on Dietary Fiber and Gut Microbial Colonization
Authors: Kazuyuki Kasahara, Tzu-Wen L Cross, Eugenio I Vivas, Federico E Rey
Journal: Circulation (2019)

Epidemiologic studies have shown that there is evidence for the prevention of cardiovascular diseases associated with the intake of flavonoids which are polyphenolic compounds that occur ubiquitous...
Retzius-sparing Robot-assisted Radical Prostatectomy Leads to Durable Improvement in Urinary Function and Quality of Life Versus Standard Robot-assisted Radical Prostatectomy Without Compromise on Oncologic Efficacy: Single-surgeon Series and Step-by-step Guide
Authors: Jillian Egan, Shawn Marhamati, Filipe L.F. Carvalho, Meghan Davis, John O’Neill, Harry Lee, John H. Lynch, Ryan A. Hankins, Jim C. Hu, Keith J. Kowalczyk
Journal: European Urology (2020)
Imatinib restores normal maturation and trafficking of KIT juxtamembrane domain mutants
Authors: Severine Tabone-Eglinger, Frederic Subra, Jean-Francois Emile, Jean-Yves Blay
Journal: Cancer Research (2007)

3265  Mutations of the KIT tyrosine kinase receptor are critical event in gastrointestinal stromal tumors (GISTs) oncogenesis. The most frequent KIT mutations in GISTs are reported in the juxtamembrane domain coded by the exon 11, but the prognosis and the response to imatinib therapy are uncertain. KIT deletions of codons 562-579 have been reported to be more strongly associated with metastases than deletions of codons 550-561 and deletions in the distal part of exon 11 (565-579) translates to the worse response to imatinib therapy.  To gain more understanding about these differential biological effects of KIT exon 11 deletions, NIH3T3 cells were stably transfected with the human wild type KIT gene or two mutated KIT (KITdel557-558 or KITdel564-581). The differential effects of the mutation type, on KIT expression, activation and response to imatinib were analyzed.  Transfected cell lines expressed a functional KIT, and mutants are constitutively activated and have transforming activity. Wild type KIT was mainly present at the plasma membrane, in a mature unphosphorylated form, and its activation by SCF, induced phosphorylation and raft-dependent internalization. By constrast, cells transfected with mutant had a weak expression at the cell surface of the KIT mature form but expressed mainly the intracellular immature form, which was constitutively phosphorylated. Constitutive activation of mutants did not lead to higher internalization. Moreover, immunocytochemistry analysis revealed that, mutant KIT was mainly localized in perinuclear areas, in transfected cells and in GISTs patients with homozygous deletions, while it was cytoplasmic in KIT WT. Interestingly imatinib not only dramatically decreased KIT tyrosine kinase activity but also enhanced KIT maturation and expression at cell surface.  In conclusion, we showed, in NIH3T3 cells transfected with the most frequent of KIT human mutations reported in GISTs, that constitutively activated mutants bypassed the normal post-translational maturation and trafficking. Activation of the immature intracellular form of KIT may be a general mechanism of gain-of-function mutations of TKR in tumors. Moreover we highlighted a new mechanism of imatinib action where the blockade of the immature form of KIT resulting in the restoration of a normal KIT trafficking. These results suggest that both normal and bypass pathways should be targeted and might change common use of tyrosine kinase receptor inhibitors in next years.
AB0611 STRAIN ANALYSIS OF THE RIGHT VENTRICLE USING 2D-SPECKLE TRACKING ECHOCARDIOGRAPHY IN A COHORT OF PATIENTS WITH SYSTEMIC SCLEROSIS
Authors: A. Spinella, P. Macripo’, E. Cocchiara, E. Galli, F. Lumetti, L. Magnani, F. Coppi, A. V. Mattioli, R. Rossi, G. Boriani, C. Salvarani, D. Giuggioli
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic Sclerosis (SSc) is a rare and life-threatening connective tissue disease with multiple organ impairment. Cardio-pulmonary involvement is common: pulmonary fibrosis, pulmonary hypertension (PH), and electrical disorders are the most serious complications and causes of increased mortality. Objectives: We evaluated features related with the onset and development of PH in a cohort of SSc patients. We further studied ecocardiographic abnormalities, by means of 2D-speckle tracking echocardiography (STE) with specific reference to the right ventricular strain measure (RV-strain). Methods: We analyzed data from 50 SSc patients (pts) referred to our University-based Rheumatology Centre and SSc Unit from January 2007 to June 2019 (F/M 45/5; lc/dcSSc 45/5; mean age 59.20±14.357 years; mean disease duration 12.08±8.75 years). All pts underwent general and cardio-pulmonary assessment in our Cardio-Rheumatology Clinic. The following parameters were considered: blood exams, in particular inflammation indexes, uric acid test and serum autoantibodies; pulmonary function tests; high resolution scan of the lungs (HRCT); standard electrocardiogram (ECG) and RV-strain measured by 2D-STE. These examinations were performed according to clinical picture and current methodologies. We compared SSc subjects with (10/50) and without (40/50) PH diagnosis during follow-up regardless of treatments. Results: SSc pts with PH didn’t show significant alterations concerning RV-strain if compared with pts without PH (p=0.707). Nevertheless, RV-strain value was modified in relation to TAPSE alterations in all pts but this data correlated with right ventricular dilatation only in PH subjects. Furthermore, interesting significant values about dilatation of right and left atria (p=0.007, p=0.048), dilatation of inferior vena cava (p=0.037) and right ventricle (p=0.023) were observed. Left ventricular hypertrophy (p=0.012) as well as valvular insufficiencies (mitral and aortic) were more frequent in PH group too (p=0.016). These pts showed higher incidence of skin ulcers (p=0.0001), higher values of blood pressure (p=0.004), elevated uric acid levels (p=0,027) and anti-centromere antibodies positivity (p=0.0001). Conclusion: Our research provides further evidence of the prognostic value of echocardiographic findings in SSc subjects, with focus on PH. Population enlargement is ongoing in order to identify more accurate results about RV-strain, considering the efficacy of PH treatments on cardiac contractility. Speckle tracking echocardiography proves to be a sensitive, low-cost, non-invasive and reliable tool to detect early cardiac impairment in Ssc, full of potential future prospects. Disclosure of Interests: None declared