Independent inheritance of genes regulating two subpopulations of mouse clonogenic keratinocyte stem cells

Mouse keratinocyte stem cells originate from the bulge of hair follicle, and, according to definition, possess a clonogenic activity in vitro. We have investigated seven inbred (C57BL/6, C3H, DBA/2, BALB/c, FVB) and outbred (SENCAR, CD-1) mouse strains and found that three genetically distinct subsets of mouse strains differ significantly in the frequency of clonogenic activity in vitro. The analysis of keratinocyte colonies in two reciprocal backcross [C57BL/6 x (BALB/c x C57BL/6); BALB/c x (BALB/c x C57BL/6)] and intercross [(BALB/c x C57BL/ 6)F2] of BALB/c and C57BL/6 mice allowed us to identify two subpopulations of clonogenic keratinocytes able to produce small (less than 2 mm2) and large (more than 2 mm2) colonies. We conducted linkage analysis and found that small colonies associated with mouse chromosomes 1, 6, 7, 8, and 9; but large colonies--with the chromosome 4. We defined locus on the chromosome 9 that associated with small colonies as keratinocyte stem cell locus 1 (Ksc1), and locus on the mouse chromosome 4 associated with large colonies-keratinocyte stem cell locus 2 (Ksc2). Ksc1 and loci on chromosomes 6 and 7 are close if not equal to loci associated with sensitivity to skin carcinogenesis. We conclude that two subpopulations of stem cells able to produce small and large colonies regulated by different genes and genes regulating small colonies might be responsible for sensitivity to skin carcinogenesis.     

Surface modification of tricalcium phosphate for improvement of the interfacial compatibility with biodegradable polymers

The surface of tricalcium phosphate (TCP) filler particles was activated by treatment with dilute aqueous phosphoric acid. ATR-IR spectra indicated the formation of calcium hydrogen phosphate dihydrate at the surface. Oligo(lactone)s were formed by the subsequent reaction of the activated TCP with L-lactide and epsilon -caprolactone, respectively, at 150 degrees C without any additional catalysts. After extraction of the oligo(lactide), the residue of modified TCP-included calcium lactate whereas the water of crystallization of the dihydrate disappeared as shown by ATR-IR spectroscopy.Owing to the insolubility of TCP in common solvents, the analogous reaction between water-soluble disodium hydrogen phosphate dihydrate and L-lactide was used to study the kind of chemical bonds by high-resolution NMR spectroscopy. The 1H and 13C NMR spectra of the reaction product also pointed out the presence of calcium lactate. Additionally, signals were found indicating a covalent attachment of lactic acid units onto the phosphorus.For the preparation of composites, poly(L,DL-lactide) was mixed with TCP and modified TCP, respectively, in a ratio of 75/25 (w/w) and directly injection moulded into tensile test specimens at a barrel temperature of 180 degrees C. Although mechanical properties were not improved, scanning electron microscopy (SEM) indicated a better interfacial phase interaction in the composite with the modified TCP. Chemical bonds between filler and polymer matrix are assumed to be formed by transesterification reactions.     

Insulin-like growth factor-I enhances lymphoid and myeloid reconstitution after allogeneic bone marrow transplantation

BACKGROUND: Prolonged immunodeficiency after allogeneic bone marrow transplantation (allo BMT) results in significant morbidity and mortality from infection. Previous studies in murine syngeneic BMT models have demonstrated that posttransplantation insulin-like growth factor (IGF)-I administration could enhance immune reconstitution. METHODS: To analyze the effects of IGF-I on immune reconstitution and graft-versus-host disease (GVHD) after allo BMT, we used murine models for MHC-matched and -mismatched allo BMT. Young (3-month-old) recipient mice received 4 mg/kg per day of human IGF-I from days 14 to 28 by continuous subcutaneous administration. RESULTS: IGF-I administration resulted in increased thymic precursor populations (triple negative-2 and triple negative-3) as determined on day 28 but had no effect on overall thymic cellularity. In the periphery, the numbers of donor-derived splenic CD3+ T cells were increased and these cells had an improved proliferative response to mitogen stimulation. IGF-I treatment also significantly increased the numbers of pro-, pre-, and mature B cells and myeloid cell populations in the spleens of allo BMT recipients on day 28. The administration of IGF-I in combination with interleukin 7 had a remarkable additive effect on B-cell, but not on T-cell, lymphopoiesis. Finally, we tested the effects of IGF-I administration on the development of GVHD in three different MHC-matched and -mismatched models and found no changes in GVHD morbidity and mortality. CONCLUSION: IGF-I administration can enhance lymphoid and myeloid reconstitution after allo BMT without aggravating GVHD.     

Positron emission tomography agent 2-deoxy-2-[<Superscript>18</Superscript>F]fluoro-D-glucose has a therapeutic potential in breast cancer

Background  

Novel approaches are needed for breast cancer patients in whom standard therapy is not effective. 2-Deoxy-2-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) was evaluated as a potential radiomolecular therapy agent in breast cancer animal models and, retrospectively, in patients with metastatic breast cancer.     

Patient radiation dose and fluoroscopy time during ERCP: a single-center,retrospective study of influencing factors

Objectives: Recently, both the number and the complexity with associated increased technical difficulty of therapeutic ERCP procedures have significantly increased resulting in longer procedural and fluoroscopy times. During ERCP, the patient is exposed to ionizing radiation and the consequent radiation dose depends on multiple factors. The aim of this study was to identify factors affecting fluoroscopy time and radiation dose in patients undergoing ERCP.

Materials and methods: Data related to patient demographics, procedural characteristics and radiation exposure in ERCP procedures (n?=?638) performed between August 2013 and August 2015 was retrospectively reviewed and analyzed. Statistically significant factors identified by univariate analyses were included in multivariate analysis with fluoroscopy time (FT) and dose area product (DAP) as dependent variables. Effective dose (ED) was estimated from DAP measurements using conversion coefficient.

Results: The factors independently associated with increased DAP during ERCP were age, gender, radiographer, complexity level of ERCP, cannulation difficulty grade, bile duct injury and biliary stent placement. In multivariate analysis the endoscopist, the complexity level of ERCP, cannulation difficulty grade, pancreatic duct leakage, bile duct dilatation and brushing were identified as predictors for a longer FT. The mean DAP, FT, number of acquired images and ED for all ERCP procedures were 2.33 Gy·cm², 1.84?min, 3 and 0.61 mSv, respectively.

Conclusions: Multiple factors had an effect on DAP and FT in ERCP. The awareness of these factors may help to predict possible prolonged procedures causing a higher radiation dose to the patient and thus facilitate the use of appropriate precautions.     

Information processing bottlenecks in macaque posterior parietal cortex: an attentional blink?

When two brief stimuli are presented in rapid succession, our ability to attend and recognize the second stimulus is impaired if our attentional resources are devoted to processing the first. Such inability (termed the “attentional blink” in human studies) arises around 200–500 ms following the onset of the first stimulus. We trained two monkeys on a delayed-match-to-sample task where both the location and orientation of two successively presented grating patches had to be matched. When the delay between the two gratings was varied, monkey’s behavioral performance (d′) was affected in a way that was analogous to the attentional blink in humans. Furthermore, a subset of neurons in the monkey’s lateral intraparietal area, known to be crucial in the control of attention, closely followed the variation in d′, even on occasions when d′ followed an atypical pattern. Our results provide the first behavioral demonstration of an attentional bottleneck in the macaque of a type similar to the human attentional blink as well as a possible single-neuron correlate of the phenomenon.     

Synthesis and biological evaluation of 2‐acylbenzofuranes as novel α‐glucosidase inhibitors with hypoglycemic activity

A series of benzofuran derivatives was synthesized as analogues of known natural α‐glucosidase inhibitors. Their activity was evaluated in enzymatic assay and in rat model of diabetes mellitus. Newly identified inhibitors demonstrate significant potency with IC₅₀ values ranging from 6.50 to 722.2 μm , as well as hypoglycemic activity exceeding the reference drug acarbose. Docking simulations provided insight into structure‐activity relationships to direct further development of these novel hypoglycemic agents.     

Review of lisdexamfetamine dimesylate in children and adolescents with attention deficit/hyperactivity disorder

Abstract

Objective

Lisdexamfetamine dimesylate is a stimulant prodrug with low abuse and diversion potential that is used in treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults. This current literature review article aims to examine safety and efficacy of LDX in children and adolescents for the treatment of ADHD based on currently available data.     

High‐throughput Screening for Identification of Inhibitors of EpCAM‐Dependent Growth of Hepatocellular Carcinoma Cells

The cancer stem cell marker, EpCAM, is an important indicator of Wnt/β‐catenin signaling activation and a functional component of hepatocellular tumor‐initiating cells. A high‐throughput screening assay was developed to identify inhibitors of EpCAM‐dependent growth of hepatocellular carcinoma (HCC) cells. EpCAM(+) and EpCAM(?) HCC cell lines were assessed for differential sensitivity to a Wnt/β‐catenin pathway inhibitor. Libraries comprising 22 668 pure compounds and 107 741 crude or partially purified natural product extracts were tested, and 12 pure compounds and 67 natural product extracts were identified for further study. Three active compounds and the positive control were further characterized in terms of effects on EpCAM expression. Treatment of EpCAM(+) Hep3B cells resulted in loss of EpCAM expression as assessed by flow cytometry. This reduction was incomplete (most cells continued to express EpCAM), but resulted in generation of cell populations expressing lower levels of EpCAM. Sublethal concentrations (~IC₅₀) reduced median EpCAM expression to 28% of control after 1 day and 19% of control after 2 days. Reduction in EpCAM expression preceded growth inhibition suggesting that a threshold of EpCAM expression may be required for growth of EpCAM‐dependent cells. The identification of compounds with a variety of possible molecular targets suggests a likelihood of multiple mechanisms for modulation of EpCAM‐dependent cell growth.