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101.
    
Focal adhesion kinase (FAK) is an attractive drug target due to its overexpression in cancer. FAK functions as a non-receptor tyrosine kinase and scaffolding protein, coordinating several downstream signaling effectors and cellular processes. While drug discovery efforts have largely focused on targeting FAK kinase activity, FAK inhibitors have failed to show efficacy as single agents in clinical trials. Here, using structure-guided design, we report the development of a selective FAK inhibitor (BSJ-04-175) and degrader (BSJ-04-146) to evaluate the consequences and advantages of abolishing all FAK activity in cancer models. BSJ-04-146 achieves rapid and potent FAK degradation with high proteome-wide specificity in cancer cells and induces durable degradation in mice. Compared to kinase inhibition, targeted degradation of FAK exhibits pronounced improved activity on downstream signaling and cancer cell viability and migration. Together, BSJ-04-175 and BSJ-04-146 are valuable chemical tools to dissect the specific consequences of targeting FAK through small-molecule inhibition or degradation.  相似文献   
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Shiga-like toxin (SLT) and endotoxin may participate in the pathogenesis of enterohemorrhagic Escherichia coli (EHEC) infection. Levels of release of SLT and endotoxin from EHEC treated in vitro with antibiotics were estimated. There were differential levels of release of SLT and endotoxin from EHEC treated with different antibiotics. Treatment of EHEC strains, namely, E. coli O157, O111, and O26, with imipenem induced much lower levels of release of SLT and endotoxin than treatment with ceftazidime.  相似文献   
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Fullerene functionalization with heterocycles is reviewed, focusing attention on cycloaddition methodology and oxidative heterocyclization.1  相似文献   
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Lipoarabinomannan (LAM) is a major surface lipoglycan of Mycobacterium tuberculosis. In the present study, we demonstrated that arabinofuranosyl-terminated LAM (AraLAM) derived from a rapidly growing Mycobacterium sp., but not extensively mannosylated LAM derived from the Erdman strain, is capable of inducing interleukin-12 (IL-12) expression in murine macrophages. Since IL-12 is known to drive the differentiation of naive T cells toward T-helper type 1 (Th1) cell development, AraLAM may be an effective adjuvant in vaccines and immunotherapies that need Th1 responses.  相似文献   
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To develop an improved method for diagnosing restenosis using treadmill exercise electrocardiography (ECG) following percutaneous transluminal coronary angioplasty (PTCA), we prospectively evaluated 46 patients who underwent PTCA for the treatment of single-vessel coronary artery disease and who did not have a history of myocardial infarction. Treadmill exercise ECG and coronary angiography were performed 3 months after PTCA to determine their accuracy in diagnosing restenosis based on standard ST-segment depression criteria, the difference between the maximum ST-segment depression before and 3 months after PTCA (< or =0.5 mm: positive; >0.5 mm: negative), and the difference between sigmaST-segment depression before PTCA and 3 months after PTCA (< or = 1.5 mm: positive; > 1.5 mm: negative). The sensitivity, specificity, and diagnostic accuracy of standard ST-segment depression criteria were 65%, 66%, and 65%, respectively. The sensitivity, specificity, and accuracy for the difference in maximum ST-segment depression were 77%, 76%, and 76%, respectively, whereas the values for the difference in sigmaST-segment depression were 77%, 83%, and 80%, respectively. Based on these results, we conclude that using the difference between ST-segment depression before and after PTCA improves the accuracy of treadmill exercise ECG for diagnosing restenosis.  相似文献   
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OBJECTIVES: We sought to determine whether the ameliorative effects of microtubule depolymerization on cellular contractile dysfunction in pressure overload cardiac hypertrophy apply at the tissue level. BACKGROUND: A selective and persistent increase in microtubule density causes decreased contractile function of cardiocytes from cats with hypertrophy produced by chronic right ventricular (RV) pressure overloading. Microtubule depolymerization by colchicine normalizes contractility in these isolated cardiocytes. However, whether these changes in cellular function might contribute to changes in function at the more highly integrated and complex cardiac tissue level was unknown. METHODS: Accordingly, RV papillary muscles were isolated from 25 cats with RV pressure overload hypertrophy induced by pulmonary artery banding (PAB) for 4 weeks and 25 control cats. Contractile state was measured using physiologically sequenced contractions before and 90 min after treatment with 10(-5) mol/liter colchicine. RESULTS: The PAB significantly increased RV systolic pressure and the RV weight/body weight ratio in PAB; it significantly decreased developed tension from 59+/-3 mN/mm2 in control to 25+/-4 mN/mm2 in PAB, shortening extent from 0.21+/-0.01 muscle lengths (ML) in control to 0.12+/-0.01 ML in PAB, and shortening rate from 1.12+/-0.07 ML/s in control to 0.55+/-0.03 ML/s in PAB. Indirect immunofluorescence confocal microscopy showed that PAB muscles had a selective increase in microtubule density and that colchicine caused complete microtubule depolymerization in both control and PAB papillary muscles. Microtubule depolymerization normalized myocardial contractility in papillary muscles of PAB cats but did not alter contractility in control muscles. CONCLUSIONS: Excess microtubule density, therefore, is equally important to both cellular and to myocardial contractile dysfunction caused by chronic, severe pressure-overload cardiac hypertrophy.  相似文献   
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