Anticancer Gene Transfer for Cancer Gene Therapy

Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by non-specific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field

Apoptosis-Like Death in Bacteria Induced by HAMLET, a Human Milk Lipid-Protein Complex

Background: Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. Methodology/Principal Findings: We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity) to execute cell death. Conclusions/Significance: Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells

Identification and Characterization of Inhibitors of Human Apurinic/apyrimidinic Endonuclease APE1

APE1 is the major nuclease for excising abasic (AP) sites and particular 3′-obstructive termini from DNA, and is an integral participant in the base excision repair (BER) pathway. BER capacity plays a prominent role in dictating responsiveness to agents that generate oxidative or alkylation DNA damage, as well as certain chain-terminating nucleoside analogs and 5-fluorouracil. We describe within the development of a robust, 1536-well automated screening assay that employs a deoxyoligonucleotide substrate operating in the red-shifted fluorescence spectral region to identify APE1 endonuclease inhibitors. This AP site incision assay was used in a titration-based high-throughput screen of the Library of Pharmacologically Active Compounds (LOPAC1280), a collection of well-characterized, drug-like molecules representing all major target classes. Prioritized hits were authenticated and characterized via two high-throughput screening assays – a Thiazole Orange fluorophore-DNA displacement test and an E. coli endonuclease IV counterscreen – and a conventional, gel-based radiotracer incision assay. The top, validated compounds, i.e. 6-hydroxy-DL-DOPA, Reactive Blue 2 and myricetin, were shown to inhibit AP site cleavage activity of whole cell protein extracts from HEK 293T and HeLa cell lines, and to enhance the cytotoxic and genotoxic potency of the alkylating agent methylmethane sulfonate. The studies herein report on the identification of novel, small molecule APE1-targeted bioactive inhibitor probes, which represent initial chemotypes towards the development of potential pharmaceuticals

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Search for transient optical counterparts to high-energy IceCube neutrinos with Pan-STARRS1

In order to identify the sources of the observed diffuse high-energy neutrino flux, it is crucial to discover their electromagnetic counterparts. To increase the sensitivity of detecting counterparts of transient or variable sources by telescopes with a limited field of view, IceCube began releasing alerts for single high-energy (E-v > 60 TeV) neutrino detections with sky localisation regions of order 1 degrees radius in 2016. We used Pan-STARRS1 to follow-up five of these alerts during 2016-2017 to search for any optical transients that may be related to the neutrinos. Typically 10-20 faint m(ip1) less than or similar to 22.5 mag) extragalactic transients are found within the Pan-STARRS1 footprints and are generally consistent with being unrelated field supernovae (SNe) and AGN. We looked for unusual properties of the detected transients, such as temporal coincidence of explosion epoch with the IceCube timestamp, or other peculiar light curve and physical properties. We found only one transient that had properties worthy of a specific follow-up. In the Pan-STARRS1 imaging for IceCube-160427A (probability to be of astrophysical origin of similar to 50%), we found a SN PS16cgx, located at 10.0' from the nominal IceCube direction. Spectroscopic observations of PS16cgx showed that it was an H-poor SN at redshift z = 0.2895 +/- 0.0001. The spectra and light curve resemble some high-energy Type Ic SNe, raising the possibility of a jet driven SN with an explosion epoch temporally coincident with the neutrino detection. However, distinguishing Type Ia and Type Ic SNe at this redshift is notoriously difficult. Based on all available data we conclude that the transient is more likely to be a Type Ia with relatively weak Sin absorption and a fairly normal rest-frame r-band light curve. If, as predicted, there is no high-energy neutrino emission from Type Ia SNe, then PS16cgx must be a random coincidence, and unrelated to the IceCube-160427A. We find no other plausible optical transient for any of the five IceCube events observed down to a 5 sigma limiting magnitude of mip1 approximate to 22 mag, between 1 day and 25 days after detection

The contribution of formal schooling to the increase in intellectual capital

Substantial IQ gains from one generation to the next have been recorded for men in many industrial societies since the 1950s. Some authors have attempted to argue away these results by claiming that intelligence tests do not measure general IQ but rather something with a weak causal link to IQ. Others have taken the evidence emerging from, for example, The Netherlands as showing that the massive increase in the nation's intellectual capital is accounted for by environmental factors, not the least of which is formal schooling. By using the Linear Structural Relations (LISREL) method and longitudinal data collected in Sweden for a male cohort, the influences of home background and formal schooling on adult IQ test scores are estimated. This study shows the importance of formal schooling in enhancing the intellectual capital of a nation. The implications for educational policy and practice are discussed