A Novel Role of Kruppel-like Factor 8 in DNA Repair in Breast Cancer Cells

Kruppel-like factor 8 (KLF8) regulates critical gene transcription and cellular events associated with cancer. However, the role of KLF8 in cancer remains largely unknown. Here, we report a surprisingly novel role for KLF8 inDNArepair in breast cancer cells. Comet, clonogenic, and WST-1 assays showed that KLF8 expression is required for protecting human breast cancer cells from doxorubicin-induced DNA damage and cell death. Western blotting indicated that overexpression of ectopic KLF8 attenuated the levels of the DNA damage marker gamma H2A.X in doxorubicin-treated PARP-1(+/+) but not PARP-1(-/-) mouse embryonic fibroblasts, whereas the PARP-1-binding-defective KLF8 mutant failed to do so. Interestingly, in response to the DNA damage, KLF8 was phosphorylated by the DNA-dependent protein kinase catalytic subunit and, subsequently, SUMOylated by SUMO E3 ligases protein inhibitors of activated STAT (PIASs), which depends upon the interaction of KLF8 with DNA-dependent protein kinase catalytic subunit, PIASs, and PARP-1 as well as their enzymatic activities. Lastly, we show evidence that KLF8 was recruited to the DNA damage site. These results suggest a novel role and mechanism for KLF8 in the regulation of DNA repair and therapeutic resistance in breast cancer cells

Power spectrum of the maxBCG sample: detection of acoustic oscillations using galaxy clusters

We use the direct Fourier method to calculate the redshift-space power spectrum of the maxBCG cluster catalog -- currently by far the largest existing galaxy cluster sample. The total number of clusters used in our analysis is 12,616. After accounting for the radial smearing effect caused by photometric redshift errors and also introducing a simple treatment for the nonlinear effects, we show that currently favored low matter density "concordance" LCDM cosmology provides a very good fit to the estimated power. Thanks to the large volume (~0.4 h^{-3}Gpc^{3}), high clustering amplitude (linear effective bias parameter b_{eff} ~3x(0.85/sigma_8)), and sufficiently high sampling density (~3x10^{-5} h^{3}Mpc^{-3}) the recovered power spectrum has high enough signal to noise to allow us to find evidence (~2 sigma CL) for the baryonic acoustic oscillations (BAO). In case the clusters are additionally weighted by their richness the resulting power spectrum has slightly higher large-scale amplitude and smaller damping on small scales. As a result the confidence level for the BAO detection is somewhat increased: ~2.5 sigma. The ability to detect BAO with relatively small number of clusters is encouraging in the light of several proposed large cluster surveys.Comment: MNRAS accepted, extended analysis of arXiv:0705.1843, 15 page

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

Post-transcriptional regulation of ATG1 is a critical node that modulates autophagy during distinct nutrient stresses

Macroautophagy/autophagy is a highly conserved nutrient-recycling pathway that eukaryotes utilize to combat diverse stresses including nutrient depletion. Dysregulation of autophagy disrupts cellular homeostasis leading to starvation susceptibility in yeast and disease development in humans. In yeast, the robust autophagy response to starvation is controlled by the upregulation of ATG genes, via regulatory processes involving multiple levels of gene expression. Despite the identification of several regulators through genetic studies, the predominant mechanism of regulation modulating the autophagy response to subtle differences in nutrient status remains undefined. Here, we report the unexpected finding that subtle changes in nutrient availability can cause large differences in autophagy flux, governed by hitherto unknown post-transcriptional regulatory mechanisms affecting the expression of the key autophagyinducing kinase Atg1 (ULK1/ULK2 in mammals). We have identified two novel post-transcriptional regulators of ATG1 expression, the kinase Rad53 and the RNA-binding protein Ded1 (DDX3 in mammals). Furthermore, we show that DDX3 regulates ULK1 expression post-transcriptionally, establishing mechanistic conservation and highlighting the power of yeast biology in uncovering regulatory mechanisms that can inform therapeutic approaches

Increased Secreted Amyloid Precursor Protein-α (sAPPα) in Severe Autism: Proposal of a Specific, Anabolic Pathway and Putative Biomarker

Autism is a neurodevelopmental disorder characterized by deficits in verbal communication, social interactions, and the presence of repetitive, stereotyped and compulsive behaviors. Excessive early brain growth is found commonly in some patients and may contribute to disease phenotype. Reports of increased levels of brain-derived neurotrophic factor (BDNF) and other neurotrophic-like factors in autistic neonates suggest that enhanced anabolic activity in CNS mediates this overgrowth effect. We have shown previously that in a subset of patients with severe autism and aggression, plasma levels of the secreted amyloid-β (Aβ) precursor protein-alpha form (sAPPα) were significantly elevated relative to controls and patients with mild-to-moderate autism. Here we further tested the hypothesis that levels of sAPPα and sAPPβ (proteolytic cleavage products of APP by α- and β-secretase, respectively) are deranged in autism and may contribute to an anabolic environment leading to brain overgrowth. We measured plasma levels of sAPPα, sAPPβ, Aβ peptides and BDNF by corresponding ELISA in a well characterized set of subjects. We included for analysis 18 control, 6 mild-to-moderate, and 15 severely autistic patient plasma samples. We have observed that sAPPα levels are increased and BDNF levels decreased in the plasma of patients with severe autism as compared to controls. Further, we show that Aβ1-40, Aβ1-42, and sAPPβ levels are significantly decreased in the plasma of patients with severe autism. These findings do not extend to patients with mild-to-moderate autism, providing a biochemical correlate of phenotypic severity. Taken together, this study provides evidence that sAPPα levels are generally elevated in severe autism and suggests that these patients may have aberrant non-amyloidogenic processing of APP

Charge Transport in Polycrystalline Graphene: Challenges and Opportunities

Graphene has attracted significant interest both for exploring fundamental science and for a wide range of technological applications. Chemical vapor deposition (CVD) is currently the only working approach to grow graphene at wafer scale, which is required for industrial applications. Unfortunately, CVD graphene is intrinsically polycrystalline, with pristine graphene grains stitched together by disordered grain boundaries, which can be either a blessing or a curse. On the one hand, grain boundaries are expected to degrade the electrical and mechanical properties of polycrystalline graphene, rendering the material undesirable for many applications. On the other hand, they exhibit an increased chemical reactivity, suggesting their potential application to sensing or as templates for synthesis of one-dimensional materials. Therefore, it is important to gain a deeper understanding of the structure and properties of graphene grain boundaries. Here, we review experimental progress on identification and electrical and chemical characterization of graphene grain boundaries. We use numerical simulations and transport measurements to demonstrate that electrical properties and chemical modification of graphene grain boundaries are strongly correlated. This not only provides guidelines for the improvement of graphene devices, but also opens a new research area of engineering graphene grain boundaries for highly sensitive electrobiochemical devices

Drug Development for Alzheimer's Disease: Recent Progress

Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development

Expression of DDX3 Is Directly Modulated by Hypoxia Inducible Factor-1 Alpha in Breast Epithelial Cells

DEAD box protein, DDX3, is aberrantly expressed in breast cancer cells ranging from weakly invasive to aggressive phenotypes and functions as an important regulator of cancer cell growth and survival. Here, we demonstrate that hypoxia inducible factor-1α is a transcriptional activator of DDX3 in breast cancer cells. Within the promoter region of the human DDX3 gene, we identified three putative hypoxia inducible factor-1 responsive elements. By luciferase reporter assays in combination with mutated hypoxia inducible factor-1 responsive elements, we determined that the hypoxia inducible factor-1 responsive element at position -153 relative to the translation start site is essential for transcriptional activation of DDX3 under hypoxic conditions. We also demonstrated that hypoxia inducible factor-1 binds to the DDX3 promoter and that the binding is specific, as revealed by siRNA against hypoxia inducible factor-1 and chromatin immunoprecipitation assays. Thus, the activation of DDX3 expression during hypoxia is due to the direct binding of hypoxia inducible factor-1 to hypoxia responsive elements in the DDX3 promoter. In addition, we observed a significant overlap in the protein expression pattern of hypoxia inducible factor-1α and DDX3 in MDA-MB-231 xenograft tumors. Taken together, our results demonstrate, for the first time, the role of DDX3 as a hypoxia-inducible gene that exhibits enhanced expression through the interaction of hypoxia inducible factor-1 with hypoxia inducible factor-1 responsive elements in its promoter region

Application of infrared thermography in computer aided diagnosis

The invention of thermography, in the 1950s, posed a formidable problem to the research community: What is the relationship between disease and heat radiation captured with Infrared (IR) cameras? The research community responded with a continuous effort to find this crucial relationship. This effort was aided by advances in processing techniques, improved sensitivity and spatial resolution of thermal sensors. However, despite this progress fundamental issues with this imaging modality still remain. The main problem is that the link between disease and heat radiation is complex and in many cases even non-linear. Furthermore, the change in heat radiation as well as the change in radiation pattern, which indicate disease, is minute. On a technical level, this poses high requirements on image capturing and processing. On a more abstract level, these problems lead to inter-observer variability and on an even more abstract level they lead to a lack of trust in this imaging modality. In this review, we adopt the position that these problems can only be solved through a strict application of scientific principles and objective performance assessment. Computing machinery is inherently objective; this helps us to apply scientific principles in a transparent way and to assess the performance results. As a consequence, we aim to promote thermography based Computer-Aided Diagnosis (CAD) systems. Another benefit of CAD systems comes from the fact that the diagnostic accuracy is linked to the capability of the computing machinery and, in general, computers become ever more potent. We predict that a pervasive application of computers and networking technology in medicine will help us to overcome the shortcomings of any single imaging modality and this will pave the way for integrated health care systems which maximize the quality of patient care