Rowebarnett7517

Maternal embryonic leucine zipper kinase (MELK) plays an important role in the regulation of tumor cell growth. It is abundant in triple-negative breast cancers (TNBC), making it a promising target for molecular imaging and therapy. Based on the structure of a potent MELK inhibitor (OTSSP167) with high affinity, we developed a novel carbon-11 radiolabeled molecular probe 11C-methoxy-OTSSP167, and evaluated its application in positron emission tomography (PET) imaging of TNBC. 11C-methoxy-OTSSP167 was successfully synthesized and was identical to its non-radiolabeled compound methoxy-OTSSP167 in high-pressure liquid chromatography (HPLC) chromatogram. The obtained tracer had 10 ± 2% radiolabeling yield with a total synthesis time of 40 min. The radiochemical purity of the tracer was more than 95%. The maximum uptake (9.97 ± 0.70%) of 11C-methoxy-OTSSP167 in MELK-overexpressing MDA-MB-231 cells was at 60 min in vitro. On PET, MDA-MB-231 tumors were clearly visible at 30, 60, and 90 min after injection of 11C-methoxy-OTSSP167, while no obvious radioactivity accumulation was found in the low-MELK MCF-7 tumors. In vivo biodistribution data were consistent with the findings of the PET images. selleck However, the radioactive tracer showed high uptake in normal organs such as liver and intestine, which may limit the application of the tracer. In addition, a markedly different MELK expression level in MDA-MBA-231 and MCF-7 tumors was verified via IHC staining. In conclusion, 11C-methoxy-OTSSP167 was successfully developed and exhibited elevated uptake in MELK overexpressed tumor, indicating its potential for noninvasively imaging of MELK overexpressed TNBC.

Targeted therapy has demonstrated high efficacy in the treatment of advanced cancer, and protein kinase inhibitors are a major focus of that therapy; therefore, our study aimed to identify a new protein kinase inhibitor that could be used in the treatment of advanced cancers.

We analyzed the expression profile of colorectal cancer (CRC), combined the driver gene and drug target databases, and identified protein kinase kalirin RhoGEF kinase (kalirin/KALRN) which is related to CRC metastasis. Based on the structure of kalirin, we screened for the small molecular compound ZINC65387069. We first compared the kinase inhibitory activities and molecular properties of ZINC65387069 and tyrosine kinase inhibitors (TKIs). We then determined the effects of ZINC65387069 on the phosphorylation of protein kinase B-Raf. Finally, we determined the effects of ZINC65387069 on migration and apoptosis of HCT116 cells as well as RKO cells. The cell cytoskeleton was also determined.

Compared with traditional TKIs, ZINC65387069 had stronger kinase inhibitory activity, a simpler structure, higher water solubility, a smaller polar surface area, and lower molecular weight and volume. In CRC cells, ZINC65387069 could significantly inhibit the phosphorylation of B-Raf as well as inhibit cell migration, destroy the cell cytoskeleton, and promote cell apoptosis.

ZINC65387069 is a newly identified protein kinase inhibitor that deserves additional research as a lead compound for drug development to help create targeted therapy against CRC.

ZINC65387069 is a newly identified protein kinase inhibitor that deserves additional research as a lead compound for drug development to help create targeted therapy against CRC.Cancer has become an important public problem in worldwide since cancer incidence and mortality are growing rapidly. In this study, water soluble and non-aggregated silicon (IV) phthalocyanines and naphthalocyanines containing (3,5-bis3-[3-(diethylamino)phenoxy]propoxyphenyl)methoxy groups have been synthesized and characterized to investigate their anticancer potential. Their DNA binding/nuclease, topoisomerases inhibition were investigated using UV-Vis absorption, thermal denaturation and agarose gel electrophoresis. The in vitro cytotoxic properties of the compounds on human lung (A549), breast (BT-20), liver (SNU-398), prostate (DU-145), melanoma (SK-Mel 128) carcinoma and human fibroblast (HFC) normal cell lines were evaluated by using MTT assay. In order to determine the mechanism of cancer cell growth suppression, cell cycle analysis was carried out using flow cytometer on A549 cell line. The Kb values of SiPc1a and SiNc2a were 6.85 ± (0.35) × 106 and 1.72 ± (0.16) × 104 M-1 and Tm values of ct-DNA w suggested that SiPc1a is a promising candidate as an anticancer agent.Two novel series derived from nicotinic acid were synthesized and evaluated for their inhibitory activity against cyclooxygenases COX-1 and COX-2, and their selectivity indices were determined. Celecoxib, diclofenac and indomethacin were used as reference drugs. All compounds showed highly potent COX-2 inhibitory activity and higher selectivity towards COX-2 inhibition compared to indomethacin. In addition, these compounds except 3a showed clear preferential COX-2 over COX-1 inhibition compared to diclofenac. Compounds 3b, 3e, 4c and 4f showed COX-2 inhibitory activity equipotent to celecoxib. Compounds 4c and 4f demonstrated selectivity indices 1.8-1.9 fold higher than celecoxib. These two most potent and COX-2 selective compounds were further tested in vivo for anti-inflammatory activity by means of carrageenan induced rat paw edema method. Ulcerogenic activity with histopathological studies were performed. The results showed no ulceration, which implies their safe gastric profile. Compound 4f exhibited the most potent in vivo anti-inflammatory activity comparable to all reference drugs. Further, compounds 4c and 4f were investigated for their influence on certain inflammatory cytokines TNF-α and IL-1β in addition to PEG2. The findings revealed that these candidates could be identified as promising potent anti-inflammatory agents. Molecular docking of 4c and 4f in the COX-2 active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of celecoxib, explaining their remarkable COX-2 inhibitory activity.The appearance of midazolam (M) and its metabolites into the hair root following a single administration was examined by following the time course of M and α-hydroxymidazolam (αHM) in hair roots and blood from guinea pigs. The back hair of guinea pigs was shaved before drug administration and before each sampling, and hair roots (3-5 mm) were plucked at 5, 15, and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120, 144 h, and 7, 14, 21, and 28 days. The kinetic parameters of M and αHM in guinea pig blood and hair roots were determined for three doses (5, 10, and 25 mg/kg). Comparisons of drug time course between hair roots and blood indicated an association between drug concentrations in the hair root and the blood. M and αHM entered the hair root within 5 min after a single exposure. The detection windows were also longer for the hair root than for the blood. Consequently, the hair root can be a valuable specimen in acute poisonings or drug-facilitated crime (DFC) cases, if other matrices are unavailable, or if blood and urine results are negative. Hair shafts (with hair roots) were plucked at 28 days and segmented. The concentrations of M and αHM were lower in the hair shafts than in the hair roots. The concentrations of the metabolite αHM in hair shafts were barely detectable. The concentrations of M and αHM in the hair root showed a moderate correlation with dose. Comparison of drug levels in hair roots between the washed group and the unwashed group indicated a generally stable percentage between the washed and unwashed groups of 40-60 % during the entire time course. This indicates that drugs are likely to be immobilized in the hair root at the beginning of the incorporation process.

Automatic postural responses are critical to prevent falls after a loss of balance. Although responses have been shown to be delayed in people with multiple sclerosis (PwMS), the degree to which other aspects of these movements are impacted by MS remains unknown.

Do responses to in-place support-surface perturbations differ in PwMS compared to neurotypical adults? Are these responses related to a functional measure of postural response performance- center of mass (COM) displacement?.

52 PwMS and 20 neurotypical, age-matched adults (NA) experienced backward support surface perturbations resulting in forward loss of balance and requiring an in-place response. Center of pressure (COP) and torque were calculated from force plates while center of mass (COM) approximations were collected via motion capture. Primary outcomes were maximal torque production at the foot and its timing, rate, and onset.

PwMS and NA demonstrated no differences in maximal torque production (p = 0.79), timing of maximal torque (p =rate of development and maximal torque were however correlated to functional postural response outcomes. These findings suggest that while not worse in PwMS during in-place perturbations, force-responses seem to be important predictors of the effectiveness of reactive postural control responses.

Impaired movement stability is a common symptom of Parkinson's disease (PD) that leads to falls and mishandled objects. Decline in synergistic stabilization of movement in PD patients has been observed in manual and postural tasks. However, locomotor synergies have not been quantified in PD patients.

The purpose of this work was to quantify the strength of the synergy stabilizing the step length while crossing an obstacle in PD patients. We hypothesized that (1) the distances of the front and rear feet relative to the obstacle would display compensatory across-trial co-variance that stabilizes step length in PD patients and age-matched controls, and (2) the step-length stabilization would be weaker in PD patients.

Thirteen PD patients and eleven healthy age-matched controls walked up to and stepped over a 15 cm high obstacle fifteen times.We measured the distances of the rear and front foot toes from the obstacle during the crossing step. We used the uncontrolled manifold method to parse the across-triang adaptive locomotor tasks as a biomarker for early detection of locomotor impairments in PD patients.Triple negative breast cancer (TNBC) represents a small subtype of breast cancer yet it has the worst outcome. Immunotherapy using immune checkpoint inhibitors combined with chemotherapy was recently approved by the FDA raising the hope for an improved outcome. The approval was based on demonstration of a positive PD-L1 expression using the SP142 CDx assay 1. We aimed to study a cohort of TNBC patients in terms of prevalence of the PD-L1 expression using the approved assay and to investigate its association with clinicopathological variables. This is a single center retrospective study consisting of 49 TNBC patients who had available archived paraffin-embedded tissue blocks from the primary tumors. All blocks were stained using the SP142 CDx assay as per the manufacture's instruction. Clinicopathological data were collected from medical records. Eighteen of the 49 (36.7%) patients were found to have a score of 1% or more by the immune cell-scoring algorithm. PDL-1 expression was significantly associated with the degree of tumor infiltrating lymphocytes (TILs).