Epigenetics Underpinning the Regulation of the CXC (ELR+) Chemokines in Non-Small Cell Lung Cancer

Background: Angiogenesis may play a role in the pathogenesis of Non-Small Cell Lung cancer (NSCLC). The CXC (ELR+) chemokine family are powerful promoters of the angiogenic response. Methods: The expression of the CXC (ELR+) family members (CXCL1-3/GROα-γ, CXCL8/IL-8, CXCR1/2) was examined in a series of resected fresh frozen NSCLC tumours. Additionally, the expression and epigenetic regulation of these chemokines was examined in normal bronchial epithelial and NSCLC cell lines. Results: Overall, expression of the chemokine ligands (CXCL1, 2, 8) and their receptors (CXCR1/2) were down regulated in tumour samples compared with normal, with the exception of CXCL3. CXCL8 and CXCR1/2 were found to be epigenetically regulated by histone post-translational modifications. Recombinant CXCL8 did not stimulate cell growth in either a normal bronchial epithelial or a squamous carcinoma cell line (SKMES-1). However, an increase was observed at 72 hours post treatment in an adenocarcinoma cell line. Conclusions: CXC (ELR+) chemokines are dysregulated in NSCLC. The balance of these chemokines may be critical in the tumour microenvironment and requires further elucidation. It remains to be seen if epigenetic targeting of these pathways is a viable therapeutic option in lung cancer treatment. © 2011 Baird et al

Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production

Aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that result in reduced AGA activity. Human variants that contain either Ser or Thr in position 149 have been described, but it is unknown if this affects AGA processing or activity. Here, we have directly compared the Ser149/Thr149 variants of AGA and show that they do not differ in terms of relative specific activity or processing. Therefore, Thr149 AGA, which is the rare variant, can be considered as a neutral or benign variant. Furthermore, we have here produced codon-optimized versions of these two variants and show that they are expressed at significantly higher levels than AGA with the natural codon-usage. Since optimal AGA expression is of vital importance for both gene therapy and enzyme replacement, our data suggest that use of codon-optimized AGA may be beneficial for these therapy options

Manganese Oxide Thin Films Prepared by Nonaqueous Sol-Gel Processing: Preferential Formation of Birnessite

High quality manganese oxide thin films with smooth surfaces and even thicknesses have been prepared with a nonaqueous sol–gel process involving reduction of tetraethylammonium permanganate in methanol. Spin-coated films have been cast onto soft glass, quartz, and Ni foil substrates, with two coats being applied for optimum crystallization. The addition of alkali metal cations as dopants results in exclusive formation of the layered birnessite phase. By contrast, analogous reactions in bulk sol–gel reactions yield birnessite, tunneled, and spinel phases depending on the dopant cation. XRD patterns confirm the formation of well-crystallized birnessite. SEM images of Li-, Na-, and K–birnessite reveal extremely smooth films having uniform thickness of less than 0.5 μm. Thin films of Rb– and Cs–birnessite have more fractured and uneven surfaces as a result of some precipitation during the sol–gel transformation. All films consist of densely packed particles of about 0.1 μm. When tetrabutylammonium permanganate is used instead of tetraethylammonium permanganate, the sol–gel reaction yields amorphous manganese oxide as the result of diluted Mn sites in the xerogel film. Bilayer films have been prepared by casting an overcoat of K–birnessite onto an Na–birnessite film. However, Auger depth profiling indicates considerable mixing between the adjacent layers

Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin. We show that T122K mutated AGA is expressed in normal amounts and localized in lysosomes, but exhibits low AGA activity due to impaired processing of the precursor molecule into subunits. Coexpression of T122K with wildtype AGA results in processing of the precursor into subunits, implicating that the mutation causes a local misfolding that prevents the precursor from becoming processed. Similar data were obtained for the AGU-Fin mutant polypeptide. We have here also identified small chemical compounds that function as chemical or pharmacological chaperones for the mutant AGA. Treatment of patient fibroblasts with these compounds results in increased AGA activity and processing, implicating that these substances may be suitable for chaperone mediated therapy for AGU

Synthesis and Purification of Cyclic Peptide Autophagy Inhibitor 4B1W and Its Target LC3a

https://openworks.mdanderson.org/sumexp21/1167/thumbnail.jp

Toward tactilely transparent gloves: Collocated slip sensing and vibrotactile actuation

Tactile information plays a critical role in the human ability to manipulate objects with one\u27s hands. Many environments require the use of protective gloves that diminish essential tactile feedback. Under these circumstances, seemingly simple tasks such as picking up an object can become very difficult. This paper introduces the SlipGlove, a novel device that uses an advanced sensing and actuation system to return this vital tactile information to the user. Our SlipGlove prototypes focus on providing tactile cues associated with slip between the glove and a contact surface. Relative motion is sensed using optical mouse sensors embedded in the glove\u27s surface. This information is conveyed to the wearer via miniature vibration motors placed inside the glove against the wearer\u27s skin. The collocation of slip sensing and tactile feedback creates a system that is natural and intuitive to use. We report results from a human subject study demonstrating that the SlipGlove allows the wearer to approach the capabilities of bare skin in detecting and reacting to fingertip slip. Users of the SlipGlove also had significantly faster and more consistent reaction to fingertip slip when compared to a traditional glove design. The SlipGlove technology allows us to enhance human perception when interacting with real environments and move toward the goal of a tactilely transparent glove

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease

Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood

The Lick-Carnegie Survey: A New Two-Planet System Around the Star HD 207832

Keck/HIRES precision radial velocities of HD 207832 indicate the presence of two Jovian-type planetary companions in Keplerian orbits around this G star. The planets have minimum masses of 0.56 and 0.73 Jupiter-masses with orbital periods of ~162 and ~1156 days, and eccentricities of 0.13 and 0.27, respectively. Stromgren b and y photometry reveals a clear stellar rotation signature of the host star with a period of 17.8 days, well separated from the period of the radial velocity variations, reinforcing their Keplerian origin. The values of the semimajor axes of the planets suggest that these objects have migrated from the region of giant planet formation to closer orbits. In order to examine the possibility of the existence of additional (small) planets in the system, we studied the orbital stability of hypothetical terrestrial-sized objects in the region between the two planets and interior to the orbit of the inner body. Results indicated that stable orbits exist only in a small region interior to planet b. However, the current observational data offer no evidence for the existence of additional objects in this system.Comment: 23 pages, 4 figures, 5 tables, accepted for publication in Ap

A case of recurrent giant cell tumor of bone with malignant transformation and benign pulmonary metastases

Giant cell tumor (GCT) of bone is a locally destructive tumor that occurs predominantly in long bones of post-pubertal adolescents and young adults, where it occurs in the epiphysis. The majority are treated by aggressive curettage or resection. Vascular invasion outside the boundary of the tumor can be seen. Metastasis, with identical morphology to the primary tumor, occurs in a few percent of cases, usually to the lung. On occasion GCTs of bone undergo frank malignant transformation to undifferentiated sarcomas. Here we report a case of GCT of bone that at the time of recurrence was found to have undergone malignant transformation. Concurrent metastases were found in the lung, but these were non-transformed GCT