3-D Printed Guns: A Developing Technology with Dangerous Potential

As an up-and-coming technology, the full potential of 3-D printing has yet to be realized, and its movement toward at-home consumers may cause problems that still remain undiscovered. Paired with the inconsistencies between various state and federal laws, the continued development of 3-D printed weapons could pose a major threat to our nation’s security. Left untouched, current trends could allow for the issue of untraceable weapons to spiral out of control and beyond repair. 3-D printing is undoubtedly one of the world’s most revolutionary technologies, but it could become one of the world’s most dangerous if left without limits.

Glutamatergic-dopaminergic balance in the brain. Its importance in motor disorders and schizophrenia

Dopamine appears to be of less importance in the regulation of psychomotor functions than was previously thought. A central dopaminergic-glutamatergic balance may be important for both akinetic motor disorders and psychosis. In Parkinson's disease glutamate antagonists may counteract central glutamatergic hyperactivity and may be of value as anti-parkinsonian drugs. An increase of dopaminergic activity and/or a reduction of glutamatergic activity may contribute to the development of paranoid hallucinatory psychosis in schizophrenic patients and of pharmacotoxic psychosis in Parkinson's disease. Because of possibly severe side-effects of glutamatergic antagonists and agonists in the treatment of akinesia and psychosis, the development of partial glutamate agonists/antagonists could be an alternative strategy capable of producing antipsychotic or anti-kinetic effects with only mild adverse reaction

Meeting the Coast Guard's Needs for Radiation Protection While Conducting Inspections of Freight Containers Containing Radioactive Materials Through Survey Instrumentation and Safe Work Practices

United States Coast Guard (USCG) personnel may be exposed to ionizing radiation during inspections of radioactive material (RAM) shipments. This study assesses the potential exposures to USCG inspectors and reviews the requirements for survey instrumentation through a survey of regulatory requirements. It also examines isotopes shipped, quantities shipped, ports involved with RAM, and current work practices. While the frequency of RAM inspections is low — approximately 150 reported RAM movements in 20 United States ports from 1988-90 — the dose rates encountered, up to 200 mrem/hour, are not. This high dose rate situation is further complicated by USCG offices not having standardized portable survey meters, adequate training on RAM, or consistent safe work practices for conducting RAM inspections. In order to fill the requirements for instrumentation needs, seven portable survey meters were tested using American National Standards Institute (ANSI) procedures. These instruments were tested for System Accuracy, Spectral Dependence, Exposure Rate Limitations, Angular Dependence/Geotropism, Reproducibility, Response/Decay Time, Coefficient of Variance, Temperature Influences/Shock, Battery Lifetime in accordance with ANSI N13.4-1971: American National Standard for the Specification of Portable X- or Gamma Radiation Survey Instruments; N42.17A-1989: American National Standard Performance Specification for Health Physics Instrumentation - Portable Instrumentation for Use in Normal Environmental Conditions; N42.3-1969: American National Standard and IEEE Standard Test Procedure for Geiger-MuUer Counters; and N323-1978: American National Standard Radiation Protection Instrumentation Test and Calibration. All survey instruments were exposed to sources of Cesium 137 with an effective energy of 662 KeV, Americium 241 with an effective energy of 60 KeV, and Radium 226 with an effective energy of 830 KeV. Based on overall instrument response and cost, recommendations for standardized survey instruments for RAM shipment inspections and general contamination monitors were provided. Also recommended were training topics, use of check sources, calibration frequency, and safe work practices.Master of Science in Public Healt

Glyco-Engineered Anti-Human Programmed Death-Ligand 1 Antibody Mediates Stronger CD8 T Cell Activation Than Its Normal Glycosylated and Non-Glycosylated Counterparts

The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis plays a central role in suppression of anti-tumor immunity. Blocking the axis by targeting PD-L1 with monoclonal antibodies is an effective and already clinically approved approach to treat cancer patients. Glyco-engineering technology can be used to optimize different properties of monoclonal antibodies, for example, binding to FcγRs. We generated two glycosylation variants of the same anti-PD-L1 antibody: one bearing core fucosylated N-glycans in its Fc part (92%) and its de-fucosylated counterpart (4%). The two glycosylation variants were compared to a non-glycosylated commercially available anti-PD-L1 antibody in various assays. No differences were observed regarding binding to PD-L1 and blocking of this interaction with its counter receptors PD-1 or CD80. The de-fucosylated anti-PD-L1 antibody showed increased FcγRIIIa binding resulting in enhanced antibody dependent cellular cytotoxicity (ADCC) activity against PD-L1+ cancer cells compared to the “normal”-glycosylated variant. Both glycosylation variants showed no antibody-mediated lysis of B cells and monocytes. The non-glycosylated reference antibody showed no FcγRIIIa engagement and no ADCC activity. Using mixed leukocyte reaction it was observed that the de-fucosylated anti-PD-L1 antibody induced the strongest CD8 T cell activation determined by expression of activation markers, proliferation, and cytotoxicity against cancer cells. The systematic comparison of anti-PD-L1 antibody glycosylation variants with different Fc-mediated potencies demonstrates that our glyco-optimization approach has the potential to enhance CD8 T cell-mediated anti-tumor activity which may improve the therapeutic benefit of anti-PD-L1 antibodies

Targeting a cancer-specific LYPD3 glycoform for tumor therapy

Introduction: One of the most drastic changes in cancer is the altered glycosylation of proteins and lipids, giving rise to truncated O-glycans like the Thomsen Friedenreich (TF) or Thomsen nouvelle (Tn) antigen, which are almost absent on normal cells. Combined protein-carbohydrate epitopes comprising these specific glycans are ideal candidates for potent targeted therapies given their excellent tumor specificity and broad cancer expression.Methods and results: We have generated GT-002, a monoclonal antibody specifically targeting the epithelial glycoprotein LYPD3 only in the presence of a TF glycosylation. It does not cross-react with non-glycosylated LYPD3 or TF on other glycoproteins in ELISA and flow cytometry. GT-002 binds to various tumor cell lines and stains tumor tissues of different cancer indications including squamous cell carcinoma of the head and neck. The remarkable tumor specificity was confirmed in an immunohistochemistry study on a normal human tissue panel including several LYPD3-positive organs, where GT-002 elicited almost completely abolished normal tissue binding. Consequently, we observed markedly reduced binding of GT-002 to normal human tissues compared to Lupartumab, a conventional anti-LYPD3 antibody previously in clinical development as antibody-drug conjugate (BAY1129980). Neuraminidase treatment of healthy tissues, resulting in cleavage of sialic acid residues, re-established binding of GT-002 comparable to Lupartumab, showing that the GT-002 epitope is masked by sialic acid in normal cells.Discussion: We believe that GT-002 is a promising candidate for development of antibody-drug- and radio-conjugates as well as bispecific molecules and chimeric antigen receptor therapeutics and highlights the powerful potential of antibodies against combined protein-carbohydrate epitopes to reduce on-target/off-tumor cytotoxicity

Rise and Fall of an Anti-MUC1 Specific Antibody

So far, human antibodies with good affinity and specificity for MUC1, a transmembrane protein overexpressed on breast cancers and ovarian carcinomas, and thus a promising target for therapy, were very difficult to generate.A human scFv antibody was isolated from an immune library derived from breast cancer patients immunised with MUC1. The anti-MUC1 scFv reacted with tumour cells in more than 80% of 228 tissue sections of mamma carcinoma samples, while showing very low reactivity with a large panel of non-tumour tissues. By mutagenesis and phage display, affinity of scFvs was increased up to 500fold to 5,7×10(-10) M. Half-life in serum was improved from below 1 day to more than 4 weeks and was correlated with the dimerisation tendency of the individual scFvs. The scFv bound to T47D and MCF-7 mammalian cancer cell lines were recloned into the scFv-Fc and IgG format resulting in decrease of affinity of one binder. The IgG variants with the highest affinity were tested in mouse xenograft models using MCF-7 and OVCAR tumour cells. However, the experiments showed no significant decrease in tumour growth or increase in the survival rates. To study the reasons for the failure of the xenograft experiments, ADCC was analysed in vitro using MCF-7 and OVCAR3 target cells, revealing a low ADCC, possibly due to internalisation, as detected for MCF-7 cells.Antibody phage display starting with immune libraries and followed by affinity maturation is a powerful strategy to generate high affinity human antibodies to difficult targets, in this case shown by the creation of a highly specific antibody with subnanomolar affinity to a very small epitope consisting of four amino acids. Despite these "best in class" binding parameters, the therapeutic success of this antibody was prevented by the target biology