Unraveling of the major genetic defects in prostate cancer

In developed countries, prostate cancer is the most common malignancy in men and a major cause of cancer-related death (1). In The Netherlands 93 new cases per 100,000 men were detected in 2003 (The Netherlands Cancer Registry). Prostate cancer incidence varies between different ethnic groups. African-American men have the highest incidence rates, followed by Caucasian-American men and men in Western Europe and Australia. The lowest incidence rates are observed in the Asian population. These differences may be explained by environmental and dietary factors. However, genetic factors, i.e. polymorphisms in genes that can predispose to cancer, may also play a role in prostate cancer development. A major risk factor of prostate cancer is age, since it is predominantly a disease of the senior adult (i.e. men over the age of 65 years). Below the age of 55 the incidence of prostate cancer is very low (2, 3)

Multidrug-resistant Streptococcus pneumoniae in Poland: identification of emerging clones

Penicillin resistance among Streptococcus pneumoniae isolates has rapidly emerged in Poland during the last decade and has reached prevalence levels of up to 14.4% in 1997. In order to investigate the nature of this increase, a molecular epidemiological analysis of non-penicillin-susceptible multidrug-resistant pneumococci isolated in 1995 and 1996 was conducted. Thirty-seven patients who suffered mainly from upper respiratory tract infections and pneumococcal pneumonia were enrolled in this study. The medical centers to which the patients were admitted were located in 16 Polish towns across the country. Eight distinct BOX PCR types were observed, representing 14 subtypes. Restriction fragment end labeling (RFEL) analysis divided the pneumococcal strains into 16 distinct types. By combining the BOX PCR and RFEL data, four genetically distinct clusters of strains were identified. Two clusters represented the genetic clones 23F and 9V, which have recently emerged all over the world. The two other genetic clusters, which represented serotypes 23F and 6B, clearly predominated in the analyzed collection of Polish non-penicillin-susceptible pneumococcal strains. Since the latter clusters did not match any of the 133 RFEL types of non-penicillin-susceptible pneumococci collected in 15 other countries, their Polish clonal origin is most likely

The Pneumococcal Serine-Rich Repeat Protein Is an Intra-Species Bacterial Adhesin That Promotes Bacterial Aggregation In Vivo and in Biofilms

The Pneumococcal serine-rich repeat protein (PsrP) is a pathogenicity island encoded adhesin that has been positively correlated with the ability of Streptococcus pneumoniae to cause invasive disease. Previous studies have shown that PsrP mediates bacterial attachment to Keratin 10 (K10) on the surface of lung cells through amino acids 273-341 located in the Basic Region (BR) domain. In this study we determined that the BR domain of PsrP also mediates an intra-species interaction that promotes the formation of large bacterial aggregates in the nasopharynx and lungs of infected mice as well as in continuous flow-through models of mature biofilms. Using numerous methods, including complementation of mutants with BR domain deficient constructs, fluorescent microscopy with Cy3-labeled recombinant (r) BR, Far Western blotting of bacterial lysates, co-immunoprecipitation with rBR, and growth of biofilms in the presence of antibodies and competitive peptides, we determined that the BR domain, in particular amino acids 122-166 of PsrP, promoted bacterial aggregation and that antibodies against the BR domain were neutralizing. Using similar methodologies, we also determined that SraP and GspB, the Serine-rich repeat proteins (SRRPs) of Staphylococcus aureus and Streptococcus gordonii, respectively, also promoted bacterial aggregation and that their Non-repeat domains bound to their respective SRRPs. This is the first report to show the presence of biofilm-like structures in the lungs of animals infected with S. pneumoniae and show that SRRPs have dual roles as host and bacterial adhesins. These studies suggest that recombinant Non-repeat domains of SRRPs (i.e. BR for S. pneumoniae) may be useful as vaccine antigens to protect against Gram-positive bacteria that cause infection

The StoryMapper: Piloting a Traveling Placemaking Interface for Inclusion and Emplacement

As aresponse to traditional (top‐down) urban planning processes, placemaking engages local citizens in the process of shaping the form, social activity, and meaning of places around them. However, placemaking practices similarly face political challenges regarding inclusion and emplacement. These challenges relate to who participates, facilitation through linguistic discourse, and place engagement itself. Attempting to address these challenges, this article (based on a pilot study) reports on the design and deployment of the StoryMapper, a traveling placemaking interface that uses a participant‐driven “chain of engagement” recruiting process to invite participants to create emplaced “morphings” (i.e., visually produced stories superimposed on public space) to spark dialogue on a digitally facilitated living map. This pilot study took place within a larger placemaking project that engages citizens to share their ideas regarding the reconversion of a community church. Plugging the Storymapper into this larger project, we discuss preliminary findings relating to the role of placemaking facilitators in citizen‐driven recruitment and the role of multimodality in placemaking processes. This pilot study suggests that inclusion should not only be evaluated based on who participates and who does not, but also on how the tool itself, in its capacity to engage participants to visualize complex emplaced ideas, may facilitate inclusion of different publics

ID1 and ID3 Regulate the Self-Renewal Capacity of Human Colon Cancer-Initiating Cells through p21

SummaryThere is increasing evidence that some cancers are hierarchically organized, sustained by a relatively rare population of cancer-initiating cells (C-ICs). Although the capacity to initiate tumors upon serial transplantation is a hallmark of all C-ICs, little is known about the genes that control this process. Here, we establish that ID1 and ID3 function together to govern colon cancer-initiating cell (CC-IC) self-renewal through cell-cycle restriction driven by the cell-cycle inhibitor p21. Regulation of p21 by ID1 and ID3 is a central mechanism preventing the accumulation of excess DNA damage and subsequent functional exhaustion of CC-ICs. Additionally, silencing of ID1 and ID3 increases sensitivity of CC-ICs to the chemotherapeutic agent oxaliplatin, linking tumor initiation function with chemotherapy resistance

The putative proteinase maturation protein A of Streptococcus pneumoniae is a conserved surface protein with potential to elicit protective immune responses

Surface-exposed proteins often play an important role in the interaction between pathogenic bacteria and their host. We isolated a pool of hydrophobic, surface-associated proteins of Streptococcus pneumoniae. The opsonophagocytic activity of hyperimmune serum raised against this protein fraction was high and species specific. Moreover, the opsonophagocytic activity was independent of the capsular type and chromosomal genotype of the pneumococcus. Since the opsonophagocytic activity is presumed to correlate with in vivo protection, these data indicate that the protein fraction has the potential to elicit species-specific immune protection with cross-protection against various pneumococcal strains. Individual proteins in the extract were purified by two-dimensional gel electrophoresis. Antibodies raised against three distinct proteins contributed to the opsonophagocytic activity of the serum. The proteins were identified by mass spectrometry and N-terminal amino acid sequencing. Two proteins were the previously characterized pneumococcal surface protein A and oligopeptide-binding lipoprotein AmiA. The third protein was the recently identified putative proteinase maturation protein A (PpmA), which showed homology to members of the family of peptidyl-prolyl cis/trans isomerases. Immunoelectron microscopy demonstrated that PpmA was associated with the pneumococcal surface. In addition, PpmA was shown to elicit species-specific opsonophagocytic antibodies that were cross-reactive with various pneumococcal strains. This antibody cross-reactivity was in line with the limited sequence variation of ppmA. The importance of PpmA in pneumococcal pathogenesis was demonstrated in a mouse pneumonia model. Pneumococcal ppmA-deficient mutants showed reduced virulence. The properties of PpmA reported here indicate its potential for inclusion in multicomponent protein vaccines

Clinical pharmacokinetics of antipsychotics in pediatric populations:a scoping review focusing on dosing regimen

Introduction:Achieving optimal clinical responses and minimizing side effects through precision dosing of antipsychotics in children and adolescents with psychiatric disorders remains a challenge. Identifying patient characteristics (covariates) that affect pharmacokinetics can inform more effective dosing strategies and ultimately improve patient outcomes. This review aims to provide greater insight into the impact of covariates on the clinical pharmacokinetics of antipsychotics in pediatric populations. Areas covered: A comprehensive literature search was conducted, and the main findings regarding the effects of the covariates on the pharmacokinetics of antipsychotics in children and adolescents are presented. Expert opinion: Our study highlights significant covariates, including age, sex, weight, CYP2D6 phenotype, co-medication, and smoking habits, which affect the pharmacokinetics of antipsychotics. However, the findings were generally limited by the small sample sizes of naturalistic, open-label, observational studies, and the homogeneous subgroups. Dosing based on weight and preemptive genotyping could prove beneficial for optimizing the dosing regimen in pediatric populations. Future research is needed to refine dosing recommendations and establish therapeutic reference ranges critical for precision dosing and Therapeutic Drug Monitoring (TDM). The integration of individual patient characteristics with TDM can further optimize the efficacy and safety of antipsychotics for each patient.</p

Advancing measurements and representations of subsurface heterogeneity and dynamic processes: towards 4D hydrogeology

Essentially all hydrogeological processes are strongly influenced by the subsurface spatial heterogeneity and the temporal variation of environmental conditions, hydraulic properties, and solute concentrations. This spatial and temporal variability generally leads to effective behaviors and emerging phenomena that cannot be predicted from conventional approaches based on homogeneous assumptions and models. However, it is not always clear when, why, how, and at what scale the 4D (3D + time) nature of the subsurface needs to be considered in hydrogeological monitoring, modeling, and applications. In this paper, we discuss the interest and potential for the monitoring and characterization of spatial and temporal variability, including 4D imaging, in a series of hydrogeological processes: (1) groundwater fluxes, (2) solute transport and reaction, (3) vadose zone dynamics, and (4) surface–subsurface water interactions. We first identify the main challenges related to the coupling of spatial and temporal fluctuations for these processes. We then highlight recent innovations that have led to significant breakthroughs in high-resolution space–time imaging and modeling the characterization, monitoring, and modeling of these spatial and temporal fluctuations. We finally propose a classification of processes and applications at different scales according to their need and potential for high-resolution space–time imaging. We thus advocate a more systematic characterization of the dynamic and 3D nature of the subsurface for a series of critical processes and emerging applications. This calls for the validation of 4D imaging techniques at highly instrumented observatories and the harmonization of open databases to share hydrogeological data sets in their 4D components