Prostate-Specific Membrane Antigen-Based Therapeutics

Prostate cancer (PC) is the most common noncutaneous malignancy affecting men in the US, leading to significant morbidity and mortality. While significant therapeutic advances have been made, available systemic therapeutic options are lacking. Prostate-specific membrane antigen (PSMA) is a highly-restricted prostate cell-surface antigen that may be targeted. While initial anti-PSMA monoclonal antibodies were suboptimal, the development of monoclonal antibodies such as J591 which are highly specific for the external domain of PSMA has allowed targeting of viable, intact prostate cancer cells. Radiolabeled J591 has demonstrated accurate and selective tumor targeting, safety, and efficacy. Ongoing studies using anti-PSMA radioimmunotherapy with 177Lu-J591 seek to improve the therapeutic profile, select optimal candidates with biomarkers, combine with chemotherapy, and prevent or delay the onset of metastatic disease for men with biochemical relapse. Anti-PSMA monoclonal antibody-drug conjugates have also been developed with completed and ongoing early-phase clinical trials. As PSMA is a selective antigen that is highly overexpressed in prostate cancer, anti-PSMA-based immunotherapy has also been studied and utilized in clinical trials

Post-harvest handling practices and associated food losses and limitations in the sweetpotato value chain of southern Ethiopia

Household food insecurity is a chronic problem in Ethiopia; the situation is being exacerbated by high population growth rates and recurring droughts in the country. The interest to address post-harvest value chain (VC) constraints leading to food losses has increased significantly to provide adequate nutrition to the growing population. In this study, mapping of sweetpotato VC not only quantifies the degree of losses but establish links between distinct VC constraints and respective food losses and limitations. Harvest and handling at farm level and shelf life issues at distribution were identified as vulnerable hot-spots of the sweetpotato food losses. Apart from physical and biological factors, demand and supply mismatch during the main harvest season at the wet markets leads to food (up to 25%) and economic losses (33–75%) followed by deficiencies in the lean season. A multi-stakeholder cooperation is required to mitigate food losses, which can have a high impact on the nutritional and financial status of the producers, market operators, and the consumers

Physiotherapists and Osteopaths’ Attitudes: Training in Management of Temporomandibular Disorders

Temporomandibular disorders (TMDs) are a condition which has multifactorial etiology. The most acknowledged method to classify TMDs is the diagnostic criteria (DC) introduced firstly by Dworkin. This protocol considers different aspects that are not only biological, but even psychosocial. Diagnosis is often based on anamnesis, physical examination and instrumental diagnosis. TMDs are classified as intra-articular and/or extra-articular disorders. Common signs and symptoms include jaw pain and dysfunction, earache, headache, facial pain, limitation to opening the mouth, ear pain and temporomandibular joint (TMJ) noises. This study regards two kind of clinicians that started in the last years to be more involved in the treatment of TMDs: osteopaths (OOs) and physiotherapists (PTs). The purpose is to analyze their attitude and clinical approach on patients affected by TMDs. Four hundred therapists answered an anonymous questionnaire regarding TMJ and TMDs. OOs showed greater knowledges on TMDs and TMJ and, the therapists with both qualifications seemed to be most confident in treating patients with TMDs. In conclusion this study highlights OOs and all the clinicians with this qualification, have a higher confidence in treating patients with TMD than the others. Dentists and orthodontists, according to this study, should co-work with OOs and PTs, because they are the specialists more requested by them than other kinds of specialists

Japanese haemodialysis anaemia management practices and outcomes (1999–2006): results from the DOPPS

Background. Japanese haemodialysis (HD) patients not only have a very low mortality and hospitalization risk but also low haemoglobin (Hb) levels. Internationally, anaemia is associated with mortality, hospitalization and health-related quality of life (QoL) measures of HD patients

GEOSPATIAL MULTI-CRITERIA DECISION BASED SITE SUITABILITY ANALYSIS FOR SOLID WASTE DISPOSAL USING TOPSIS ALGORITHM

The problem of Urban Municipal solid waste disposal is a challenging task faced by civic bodies and planning authorities in almost all the cities of rapidly developing countries like India. A similar situation is being faced by Dehradun, the capital, and the fastest growing city of Uttarakhand, India. In the current study, an attempt has been made to find out the suitable sites for waste disposal in the area around Dehradun city using Geospatial Multi-criteria Decision Analysis (MCDA) techniques from remote sensing data. Two different decision rules of MCDA are used, namely, Analytical Hierarchical Process based Weighted Linear Combination (AHP – WLC) and Technique for Order Preference by Similarity to the Ideal Solution (TOPSIS). WLC has been used previously for similar studies for its ease and simplicity to apply in raster format but TOPSIS has an advantage over WLC, it orders a set of alternatives on the basis of their separation from the ideal point. It defines the best alternative as the one that is simultaneously closest to the ideal alternative and farthest from the negative ideal point. Raster-based suitability analysis has been done and the results obtained by the two methods are compared. Identical results with minor differences identifying best suitable sites outside the eastern boundary of the city where the existing dumping site is located are obtained. Also, new potential sites are identified in the western part of the city which faces the problem of waste disposal more acutely because of expansion of the city in that direction

Large scale analytic calculations in quantum field theories

We present a survey on the mathematical structure of zero- and single scale quantities and the associated calculation methods and function spaces in higher order perturbative calculations in relativistic renormalizable quantum field theories.Comment: 25 pages Latex, 1 style fil

Extra-Thymic Physiological T Lineage Progenitor Activity Is Exclusively Confined to Cells Expressing either CD127, CD90, or High Levels of CD117

T cell development depends on continuous recruitment of progenitors from bone marrow (BM) to the thymus via peripheral blood. However, both phenotype and functional characteristics of physiological T cell precursors remain ill-defined. Here, we characterized a putative CD135+CD27+ T cell progenitor population, which lacked expression of CD127, CD90, and high levels of CD117 and was therefore termed triple negative precursor (TNP). TNPs were present in both BM and blood and displayed robust T lineage potential, but virtually no myeloid or B lineage potential, in vitro. However, TNPs did not efficiently generate T lineage progeny after intravenous or intrathymic transfer, suggesting that a physiological thymic microenvironment does not optimally support T cell differentiation from TNPs. Thus, we propose that physiological T cell precursors are confined to populations expressing either CD127, CD90, or high levels of CD117 in addition to CD135 and CD27 and that TNPs may have other physiological functions

Apoptosis screening of human chromosome 21 proteins reveals novel cell death regulators

The functional analysis of chromosome 21 (Chr21) proteins is of great medical relevance. This refers, in particular, to the trisomy of human Chr21, which results in Down’s syndrome, a complex developmental and neurodegenerative disease. In a previous study we analyzed 89 human Chr21 genes for the subcellular localization of their encoded proteins using a transfected-cell array technique. In the present study, the results of the follow-up investigation are presented in which 52 human Chr21 genes were over-expressed in HEK cells using the transfected-cell array platform, and the effect of this protein over-expression on the induction of apoptosis has been analyzed. We found that the over-expression of two Chr21 proteins (claudin-14 and -8) induced cell death independent of the classic caspase-mediated apoptosis. Our results strongly suggest the functional involvement of claudins in the control of the cell cycle and regulation of the cell death induction mechanism

Expression of miRNAs miR-133b and miR-206 in the Il17a/f Locus Is Co-Regulated with IL-17 Production in alpha beta and gamma delta T Cells

Differentiation of T helper 17 cells (Th17) is a multistep process that involves the cytokines IL-6, TGF-beta, and IL-23 as well as IL-1 beta, IL-21, and TNF-alpha. Thereby, robust induction of the capacity to produce IL-17 involves epigenetic modifications of the syntenic Il17a/f locus. Using inbred mouse strains, we identified co-regulation of gene transcription at the Il17a/f locus with the nearby microRNAs miR-133b and miR-206 that are clustered approximately 45 kb upstream of Il17a/f. Expression of these microRNAs was specific for Th17 as compared to other CD4(+) T cell subsets and this was equally valid for in vitro polarized and ex vivo derived cells. From all factors analyzed, IL-23 was the most important cytokine for the in vitro induction of miR-133b and miR-206 in naive CD4(+) T cells of wild type mice. However, analysis of IL-23R deficient mice revealed that IL-23R signaling was not essential for the induction of miR-133b and miR-206. Importantly, we found a similar co-regulation in CCR6(+) and other gamma delta T cell subsets that are predisposed to production of IL-17. Taken together, we discovered a novel feature of T cell differentiation towards an IL-17-producing phenotype that is shared between alpha beta and gamma delta T cells. Notably, the specific co-regulation of miR-133b and miR-206 with the Il17a/f locus also extended to human Th17 cells. This qualifies expression of miR-133b and miR-206 in T cells as novel biomarkers for Th17-type immune reactions

Template-Directed Ligation of Tethered Mononucleotides by T4 DNA Ligase for Kinase Ribozyme Selection

Background: In vitro selection of kinase ribozymes for small molecule metabolites, such as free nucleosides, will require partition systems that discriminate active from inactive RNA species. While nucleic acid catalysis of phosphoryl transfer is well established for phosphorylation of 59 or 29 OH of oligonucleotide substrates, phosphorylation of diffusible small molecules has not been demonstrated. Methodology/Principal Findings: This study demonstrates the ability of T4 DNA ligase to capture RNA strands in which a tethered monodeoxynucleoside has acquired a 59 phosphate. The ligation reaction therefore mimics the partition step of a selection for nucleoside kinase (deoxy)ribozymes. Ligation with tethered substrates was considerably slower than with nicked, fully duplex DNA, even though the deoxynucleotides at the ligation junction were Watson-Crick base paired in the tethered substrate. Ligation increased markedly when the bridging template strand contained unpaired spacer nucleotides across from the flexible tether, according to the trends: A2.A1.A3.A4.A0.A6.A8.A10 and T2.T3.T4.T6<T1.T8.T10. Bridging T’s generally gave higher yield of ligated product than bridging A’s. ATP concentrations above 33 mM accumulated adenylated intermediate and decreased yields of the gap-sealed product, likely due to re-adenylation of dissociated enzyme. Under optimized conditions, T4 DNA ligase efficiently (.90%) joined a correctly paired, or T:G wobble-paired, substrate on the 39 side of the ligation junction while discriminating approximately 100-fold against most mispaire