TCS 359

TCS 359 is a potent inhibitor against the fms-like tyrosine kinase-3 (FLT3) [1] [2] with an IC50 value of 0.042 ±0.03 µM [2].

FLT3 is a receptor tyrosine kinase. Via hematopoietic regulation, it plays its important role in the pathogenesis of acute myeloid leukemia (AML) [3].

To the proliferation of MV4-11 cell line (a human acute myeloid leukemia cell line expressing a constitutively activated mutant FLT3), the IC50 of TCS 359 was 0.34 µM [2].

TCS 359 blocked the ability of FLT3 ligand to promote the development of two-cell-embryos to the hatched blastocyst stage in mice. TCS 359 also decreased the expression of FLT3 ligand in early embryos after the four-cell stage. Without exogenous FLT3 ligand, TCS 359 did not affect embryo development [4]. Treated with another FLT3 inhibitor SU5416, 21 of 22 analyzed patients expressed FLT3 protein, 17 expressed phosphorylated FLT3 at baseline. Among these 17 patients expressed phosphorylated FLT3, inhibition of more than 50% relative to baseline was apparent in seven cases, while inhibition ranged from 20-50% relative to baseline was apparent in an additional three cases. FLT3 phosphorylation was detected in whole blood lysates in the majority of AML patients treated with SU5416. Activated FLT3 was detectable in bone marrow aspirates from approximately 50% AML patients [5].

References:
[1].  Trzci´nska-Daneluti A.M., Nguyen L., Jiang C., et al. Use of Kinase Inhibitors to Correct ΔF508-CFTR Function. Molecular & Cellular Proteomics, 2012, 11(9):745-757.
[2].  Patch R.J., Baumann C.A., Liu J., et al. Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3. Bioorganic & Medicinal Chemistry Letters, 2006, 16: 3282-3286.
[3].  Kar R.K., Suryadevara P., Roushan R., et al. Quantifying the Structural Requirements for Designing Newer FLT3 Inhibitors. Medicinal Chemistry, 2012, 8:913-927.
[4].  Nishijima C., Kawamura K., Okamoto N., et al. Regulation of Preimplantation Embryo Development in Mice by FMS-like Tyrosine Kinase 3 Ligand. Journal of Mammalian Ova Research, 2014, 31(1):45-51.
[5].  O'Farrell A.M., Yuen H.A., Smolich B., et al. Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia. Leuk. Res., 2004, 28(7):679-89.

Predictors and impact of time to clinical stability in community-acquired pneumococcal pneumonia.[Pubmed:24589380]

Respir Med. 2014 May;108(5):806-12.

BACKGROUND: A clinical stability (CS) evaluation is thought to be important in community-acquired pneumonia (CAP) treatment, but evidence concerning the time to CS (TCS) remains lacking. METHODS: Among consecutive patients hospitalized with pneumococcal pneumonia, relationships between TCS and other clinical outcomes were examined, and predictors and a predictive TCS score were derived from patient characteristics on admission. RESULTS: A total of 144 patients were enrolled, including 46% and 27% with moderate and severe pneumonia, respectively, defined by the pneumonia severity index (PSI). The median TCS was 2 days, and was significantly correlated with the length of hospital stay (r = 0.595); a longer TCS was significantly associated with the more presence of poor clinical outcomes and ICU stays (adjusted odds ratios: 1.359 and 1.366, respectively). A multivariate Cox proportional hazard model revealed an absence of bilateral pneumonia (hazard rate (HR): 2.107) or bacteremia (HR: 2.520), and mild or moderate pneumonia (HR: 2.798 and 2.515, respectively, versus severe) as predictors of CS. A predictive score had moderate discriminating power for the prolonged TCS (area under the curve: 0.76), and provided similar predictive values for poor clinical outcomes and ICU stays. A score of 3 or more points indicated the prolonged TCS, with a sensitivity and specificity of 73.3% and 70.9%, respectively. CONCLUSIONS: Because TCS has a significant relationship with other clinical outcomes of pneumococcal CAP, the prediction of TCS might lead to the prevention of complications or an earlier transition to oral therapy. Future studies are warranted to validate these results.

Skin telocytes.[Pubmed:22226149]

Ann Anat. 2012 Jul;194(4):359-67.

A distinctive stromal cell-type, the telocyte (TC), has recently been described to send specific long prolongations (telopodes) alternating thin segments (podomers) with dilations (podoms). Even though one would expect TCs to be identified in various stromal tissues, there were not yet reported evidence of skin TCs. We aimed to check for the presence of TCs in human skin dermis. Transmission electron microscopy revealed the presence in dermis of TCs projecting specific telopodes. Skin TCs were closely related to or contacting fibroblasts, mast cells, adipocytes, and connective fiber bundles (collagenous and elastic). As it appears, skin TCs exist and are related to other stromal cells. The structural association of TCs to elastic fibers deserves further investigation.

Salmonella transfer potential onto tomatoes during laboratory-simulated in-field debris removal.[Pubmed:24988010]

J Food Prot. 2014 Jul;77(7):1062-8.

Florida Tomato Good Agricultural Practices (T-GAPs) mandate the removal of dirt and debris from tomatoes during harvest but do not provide any specific regulations or guidance; thus, the current practice of using cloths needs to be evaluated. This study examined Salmonella transfer from inoculated green tomatoes to uninoculated cloths and from inoculated cloths to uninoculated tomatoes, upon single and multiple touches. Tomatoes were spot inoculated with a rifampin-resistant Salmonella cocktail (10(7) CFU per tomato) and were touched with cloth (clean, dirty-dry, dirty-wet) at 0, 1, or 24 h postinoculation. Salmonella was enumerated on tryptic soy agar, followed by enrichments when necessary. The transfer direction was then reversed by touching freshly inoculated cloths with uninoculated tomatoes. Transfer coefficients (TCs) were then calculated. Salmonella TCs from inoculated tomato and cloth were highest when the inoculum was wet (0.44 +/- 0.13 to 0.32 +/- 0.12), regardless of the condition of the cloth. Although Salmonella TCs from inoculated tomato to uninoculated cloth decreased significantly when the inoculum was dried (0.17 +/- 0.23 to 0.01 +/- 0.00), low levels of Salmonella were detected on cloth even after 24 h of drying. Inoculated dirty cloth did not transfer more Salmonella compared with inoculated clean cloth, and Salmonella survival was not higher on dirty cloth. When inoculated clean cloth (wet) was touched with 25 tomatoes, significantly higher levels of Salmonella were transferred to the first, second, and fourth tomatoes (0.03 +/- 0.10 to 0.09 +/- 0.02). However, inoculated dirty-wet (below limit of detection) and dirty-dry (0.00 to 0.04 +/- 0.01) cloths transferred similar levels of Salmonella to all 25 tomatoes. Results indicate a low risk of potential Salmonella contamination when the same cloth is used multiple times for debris removal, especially under high moisture levels. Results also show that the use of dirty cloths did not increase the risk of Salmonella cross-contamination.

Prognostic value of PD-L1 expression in tumor infiltrating immune cells in cancers: A meta-analysis.[Pubmed:28453554]

PLoS One. 2017 Apr 28;12(4):e0176822.

Programmed death-ligand 1 (PD-L1) is a promising target of cancer immune therapy. It not only expressed in tumor cells (TCs) but also up regulated in tumor infiltrating immune cells (TIICs). Although the previous meta-analysis have shown that PD-L1 expression in TCs was a valuable biomarker in predicting cancer prognosis, but few researches systematic evaluated the association between its expression in TIICs and survival of cancer patients. Thus, we performed this meta-analysis to evaluate the prognostic value of PD-L1 expression in TIICs in different types of cancers. Our results are valuable supplements when using PD-L1 expression to predict the survival of cancer patients and to select the beneficial patients from PD-L1 target therapy. PubMed, Embase, Web of Science and the Cochrane Central Search Library were used to perform our systematic literature search. Overall survival (OS) at 5th years and hazard ratios (HRs) were calculated using random effects models. Eighteen studies involving 3674 patients were included. The median positive rate of PD-L1 staining in TIICs was 36.37%. PD-L1 positive expression in TIICs related to a lower risk of death (HR = 0.784, 95%CI: 0.616-0.997, P = 0.047). Subgroup analyses found that PD-L1 positive expression in TIICs indicated a better prognosis especially in breast cancer patients (HR = 0.359, P = 0.041). When using whole tissue section slides, or using 'any expression in TIICs' as a cutoff value to assessing the results of IHC staining, PD-L1 expression in TIICs had a good prognostic value in cancer prognosis (HR = 0.587, P = 0.001 and HR = 0.549, P = 0.002). Our findings suggested that PD-L1 expression in TIICs was related to a better survival of cancer. The comprehensive evaluation of tumor cells and tumor infiltrating immune cells are required when evaluating the effect of PD-L1 expression on prognosis of cancer in future research.

Novel approach for predicting the joint effects based on the enzyme-catalyzed kinetics.[Pubmed:26826939]

J Hazard Mater. 2016 Apr 15;307:359-67.

Organisms are exposed to mixtures of multiple contaminants and it is necessary to build prediction models for the joint effects, considering the high expense and the complexity of the traditional toxicity testing and the flood occurrence of environmental chemical pollutants. In this study, a new method for predicting the joint effects was developed and corresponding prediction models were constructed based on the kinetic models of enzyme-catalyzed reactions. While, we utilized Vibrio fischeri, Escherichia coli and Bacillus subtilis as model organisms and determined the chronic toxicity of the binary mixtures of sulfonamides (SAs) and sulfonamide potentiators (SAPs) (SA+SAP), the mixtures of two kinds of sulfonamides (SA+SA) and the binary mixtures of sulfonamide potentiators (SAPs) and tetracyclines (TCs) (SAP+TC) respectively. Finally, corresponding mixture toxicity data was utilized to fit and verify the prediction models for different joint effects.

Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3.[Pubmed:16580199]

Bioorg Med Chem Lett. 2006 Jun 15;16(12):3282-6.

A series of 2-acylaminothiophene-3-carboxamides has been identified which exhibit potent inhibitory activity against the FLT3 tyrosine kinase. Compound 44 inhibits the isolated enzyme (IC50 = 0.027 microM) and blocks the proliferation of MV4-11 cells (IC50 = 0.41 microM). Structure-activity relationship studies within this series are described in the context of a proposed binding model within the ATP binding site of the enzyme.