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61.
Andrew M. Thompson Patrick D. OConnor Vanessa Yardley Louis Maes Delphine Launay Stephanie Braillard Eric Chatelain Baojie Wan Scott G. Franzblau Zhenkun Ma Christopher B. Cooper William A. Denny 《ACS medicinal chemistry letters》2021,12(2):275
Antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines were previously shown to exhibit potent antileishmanial and antitrypanosomal activities, culminating in a new clinical investigational drug for visceral leishmaniasis (DNDI-0690). To offset development risks, we continued to seek further leads with divergent candidate profiles, especially analogues possessing greater aqueous solubility. Starting from an efficacious monoaryl derivative, replacement of the side chain ether linkage by novel amine, amide, and urea functionality was first explored; the former substitution was well-tolerated in vitro and in vivo but elicited marginal alterations to solubility (except through a less stable benzylamine), whereas the latter groups resulted in significant solubility improvements (up to 53-fold) but an antileishmanial potency reduction of at least 10-fold. Ultimately, we discovered that O-carbamate 66 offered a more optimal balance of increased solubility, suitable metabolic stability, excellent oral bioavailability (100%), and strong in vivo efficacy in a visceral leishmaniasis mouse model (97% parasite load reduction at 25 mg/kg). 相似文献
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Liver transplantation has become a highly standardized, acceptable option for selected patients with end-stage liver disease and/or hepatocellular carcinoma in the setting of cirrhosis. Both conditions are associated with loss of skeletal muscle mass (sarcopenia) and physical deconditioning. Both conditions result in a dramatic decrease in the patients’ quality of life, negatively impacting on the pre- and post-transplant prognosis. In this context, awareness of the advantages of physical activity in both the pre- and post-transplant setting is key. However, the importance of regular, individualized and patient-adapted physical activity is still understudied and underestimated. This article describes a three-sided perspective on the importance of physical activity in the setting of liver transplantation, including a patient's, transplant surgeon's and hepatologist’s point of view. 相似文献
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Lyra Razanadrakoto Fran?oise Cormier Vanessa Laurienté Elisabetta Dondi Laura Gardano Shulamit Katzav Lionel Guittat Nadine Varin-Blank 《Oncotarget》2015,6(4):2524-2538
Vav family members function as remarkable scaffold proteins that exhibit both GDP/GTP exchange activity for Rho/Rac GTPases and numerous protein-protein interactions via three adaptor Src-homology domains. The exchange activity is under the unique regulation by phosphorylation of tyrosine residues hidden by intra-molecular interactions. Deletion of the autoinhibitory N-terminal region results in an oncogenic protein, onco-Vav, leading to a potent activation of Rac GTPases whereas the proto-oncogene barely leads to transformation. Substitution of conserved residues of the SH2-SH3 adaptor region in onco-Vav reverses oncogenicity. While a unique substitution D797N did not affect transformation induced by onco-Vav, we demonstrate that this single substitution leads to transformation in the Vav1 proto-oncogene highlighting the pivotal role of the adaptor region. Moreover, we identified the cell junction protein β-catenin as a new Vav1 interacting partner. We show that the oncogenicity of activated Vav1 proto-oncogene is associated with a non-degradative phosphorylation of β-catenin at residues important for its functions and its redistribution along the cell membrane in fibroblasts. In addition, a similar interaction is evidenced in epithelial lung cancer cells expressing ectopically Vav1. In these cells, Vav1 is also involved in the modulation of β-catenin phosphorylation. Altogether, our data highlight that only a single mutation in the proto-oncogene Vav1 enhances tumorigenicity. 相似文献
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Investigation of the clinical features of geographic tongue: unveiling its relationship with oral psoriasis 下载免费PDF全文
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Rosacea or photodamaged skin? Use of brimonidine gel in differentiating erythema in the two conditions 下载免费PDF全文
In this case report, we detail the response of a 37‐year‐old Caucasian man with an overlap of erythematotelangiectatic rosacea and telangiectatic photoaging to brimonidine tartrate gel. With the application of brimonidine only on half of his face, skin analysis images, clinician's and patient's assessment showed that there was significant improvement in the erythema. This case has lent insight into how brimonidine can be used to assess the extent of photoaging by eliminating the erythema of rosacea to some degree. We propose that it can be used as a non‐invasive test to differentiate between the two conditions, sparing patients from skin biopsies and molecular analysis. 相似文献
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Davide Firinu Vanessa Garcia-Larsen Paolo Emilio Manconi Stefano R. Del Giacco 《Current rheumatology reports》2016,18(6):35
SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare autoimmune disease which, due to its clinical presentation and symptoms, is often misdiagnosed and unrecognized. Its main features are prominent inflammatory cutaneous and articular manifestations. Treatments with immunosuppressive drugs have been used for the management of SAPHO with variable results. To date, the use of anti-TNF-α agents has proved to be an effective alternative to conventional treatment for unresponsive or refractory SAPHO cases. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 β, IL-6, and IL-8, involved in inflammation, acute-phase response induction, and chemotaxis. IL-1 inhibition strategies with anakinra have shown efficacy as first and second lines of treatment. In this review, we will describe the main characteristics of biological drugs currently used for SAPHO syndrome. We also describe some of the promising therapeutic effects of ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and anakinra. We discuss the use and impact of the new anti-IL-1 antagonists involved in the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases. 相似文献