Synthesis and Characterization of Comb‐Like Copolymers Based on Poly(ε‐caprolactone) and Poly(α‐olefin)

Comb‐like copolymers based on a polyolefin backbone of poly(10‐undecene‐1‐ol) (PUol) with poly(ε‐caprolactone) (PCL) side chains are synthesized in two steps. After synthesis of PUol by metallocene‐catalyzed polymerization, the side‐chain hydroxyl functionalities of this polar polyolefin are used as an initiator for the ring‐opening polymerization (ROP) of ε‐caprolactone (CL). In this context, copolymers with different lengths of PCL grafts are prepared. The chemical structure and the composition of the synthesized copolymers are characterized by ¹H and ¹³C NMR spectroscopy. It is shown that the hydroxyl end groups of PUol act effectively as initiating sites for the CL ROP. Size‐exclusion chromatography (SEC) measurements confirm the absence of non‐attached PCL and the expected increase in molar mass after grafting. The thermal and decomposition behaviors are investigated by DSC and thermogravimetric analysis (TGA). The effect of the length of the PCL grafts on the crystallization behavior of the comb‐like copolymers is investigated by DSC and wide‐angle X‐ray scattering (WAXS).

     

Distribution of exogenous [125I]-3-iodothyronamine in mouse in vivo: relationship with trace amine-associated receptors

3-Iodothyronamine (T1AM) is a novel chemical messenger, structurally related to thyroid hormone, able to interact with G protein-coupled receptors known as trace amine-associated receptors (TAARs). Little is known about the physiological role of T1AM. In this prospective, we synthesized [125I]-T1AM and explored its distribution in mouse after injecting in the tail vein at a physiological concentration (0.3?nM). The expression of the nine TAAR subtypes was evaluated by quantitative real-time PCR. [125I]-T1AM was taken up by each organ. A significant increase in tissue vs blood concentration occurred in gallbladder, stomach, intestine, liver, and kidney. Tissue radioactivity decreased exponentially over time, consistent with biliary and urinary excretion, and after 24?h, 75% of the residual radioactivity was detected in liver, muscle, and adipose tissue. TAARs were expressed only at trace amounts in most of the tissues, the exceptions being TAAR1 in stomach and testis and TAAR8 in intestine, spleen, and testis. Thus, while T1AM has a systemic distribution, TAARs are only expressed in certain tissues suggesting that other high-affinity molecular targets besides TAARs exist.     

Red cell distribution width and mortality in newly hospitalized patients

ObjectivePrevious studies suggest that red cell distribution width, a measure of erythrocyte size variability, may predict long-term mortality, particularly in cardiovascular disease. Less research has focused on the prognostic utility of red cell distribution width in an acutely hospitalized population.MethodsWe performed a secondary analysis of prospectively collected data on 74,784 consecutive hospitalized adults with red cell distribution width measured on admission. The primary outcome of interest was in-hospital mortality; a secondary outcome was unplanned transfer to the intensive care unit. We calculated multivariable logistic models adjusted for age, gender, race, and comorbid conditions.ResultsThe overall in-hospital mortality rate was 1.3% (95% confidence interval [CI], 1.2-1.4). As red cell distribution width increased, so did mortality, from 0.2% (lowest red cell distribution width decile) to 4.4% (highest red cell distribution width decile). Unadjusted red cell distribution width significantly discriminated between hospital survivors and nonsurvivors (area under the curve 0.74). In multivariate analyses, for every 1% increment in red cell distribution width at the time of admission, the odds for in-hospital mortality increased by 24% (odds ratio 1.24; 95% CI, 1.20-1.27); findings were robust across comorbidity subgroups. The rate of unplanned intensive care unit transfer was 7.0% (95% CI, 6.8-7.2) and in unadjusted analyses increased more than 2-fold from 4.5% in the lowest to 11.6% in the highest red cell distribution width decile. This relationship was significantly confounded but remained significant in multivariate analysis (odds ratio 1.04 per 1% red cell distribution width increment; 95% CI, 1.03-1.06).ConclusionRed cell distribution width strongly and independently predicted in-hospital mortality in this large cohort of hospitalized patients. It also was associated with acute decompensation among patients on the general ward, but to a lesser degree. The mechanisms underlying these findings are unknown.     

Clinical correlations of miR-21 expression in colorectal cancer patients and effects of its inhibition on DLD1 colon cancer cells

Purpose

MicroRNA-21 (miR-21) is one of the miRNAs that are frequently and highly overexpressed in tumor tissue of colorectal cancer (CRC) patients; however, only a little is known about its functional role in CRC.

Methods

We examined the expression level of miR-21 in 44 paired samples of tumoral and non-tumoral colon tissues diagnosed for CRC using TaqMan real-time PCR method. Furthermore, we used miR-21 inhibitor (anti-miR-21) to transient knockdown of miR-21 in DLD-1 colon cancer cells and examined the effects of miR-21 silencing on viability, apoptosis, chemosensitivity, cell cycle, and migration of DLD1 cells.

Results

The expression levels of miR-21 were significantly increased in CRC tumor tissue (P?<?0.0001). Significant differences in miR-21 levels were observed also between CRC tissues of patients with CRC in different clinical stages: I vs. II (P?=?0.033) and I vs. IV (P?=?0.021). Kaplan–Meier analysis proved that the miR-21 expression levels are correlated to shorter overall survival of CRC patients (P?=?0.0341). MiR-21 silencing in DLD1 cell line had no effect on the cell viability; however, when combined with chemotherapeutics (5-FU, L-OHP, and SN38), it contributed to the decrease of cell viability. Suppression of miR-21 decreased cell migration ability of DLD-1 cells by nearly 30?% (P?=?0.016).

Conclusion

We have confirmed the overexpression of miR-21 in CRC samples and its correlation with advanced disease and shorter overall survival. These findings could be described in part by the fact that CRC cells with increased expression of miR-21 have higher migration ability.     

Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3

Whole exome sequencing in two-generational kindred from Bangladesh with early onset spasticity, mild intellectual disability, distal amyotrophy, and cerebellar atrophy transmitted as an autosomal recessive trait identified the following two missense mutations in the EXOSC3 gene: a novel p.V80F mutation and a known p.D132A change previously associated with mild variants of pontocerebellar hypoplasia type 1. This study confirms the involvement of RNA processing proteins in disorders with motor neuron and cerebellar degeneration overlapping with spinocerebellar ataxia 36 and rare forms of hereditary spastic paraplegia with cerebellar features.     

Diagnostic evaluation of the MRP-8/14 for the emergency assessment of chest pain

Elevated levels of myeloid-related protein (MRP)-8/14 (S100A8/A9) are associated with first cardiovascular events in healthy individuals and worse prognosis in patients with acute coronary syndrome (ACS). The diagnostic utility of MRP-8/14 in patients presenting to the emergency room with symptoms concerning for ACS is uncertain. MRP-8/14 was measured in serial serum and plasma samples in a single center prospective cohort-study of patients presenting to the emergency room with non-traumatic chest pain concerning for ACS. Final diagnosis was adjudicated by an endpoint committee. Of patients with baseline MRP-8/14 results (n = 411), the median concentration in serum was 1.57 μg/ml (25th, 75th: 0.87, 2.68) and in plasma was 0.41 μg/ml (<0.4, 1.15) with only moderate correlation between serum and plasma (ρ = 0.40). A final diagnosis of MI was made in 106 (26%). Peak serum MRP-8/14 was higher in patients presenting with MI (p < 0.001). However, the overall diagnostic performance of MRP-8/14 was poor: sensitivity 28% (95% CI 20-38), specificity 82% (78-86), positive predictive value 36% (26-47), and negative predictive value 77% (72-81). The area under the ROC curve for diagnosis of MI with MRP-8/14 was 0.55 (95% CI 0.51-0.60) compared with 0.95 for cTnI. The diagnostic performance was not improved in early-presenters, patients with negative initial cTnI, or using later MRP-8/14 samples. Patients presenting with MI had elevated levels of serum MRP-8/14 compared to patients with non-cardiac chest pain. However, overall diagnostic performance of MRP-8/14 was poor and neither plasma nor serum MRP-8/14 offered diagnostic utility comparable to cardiac troponin.