Ecological comparison of the risks of mother-to-child transmission and clinical manifestations of congenital toxoplasmosis according to prenatal treatment protocol

We compared the relative risks of mother-to-child transmission of Toxoplasma gondii and clinical manifestations due to congenital toxoplasmosis associated with intensive prenatal treatment in Lyon and Austria, short term treatment in 51% of Dutch women, and no treatment in Danish women. For each cohort, relative risks were standardized for gestation at seroconversion. In total, 856 mother–child pairs were studied: 549 in Lyon, 133 in Austria, 123 in Denmark and 51 in The Netherlands. The relative risk for mother-to-child transmission compared to Lyon was 1·24 (95% CI: 0·88, 1·59) in Austria; 0·59 (0·41, 0·81) in Denmark; and 0·65 (0·37, 1·01) in The Netherlands. Relative risks for clinical manifestations compared with Lyon (adjusted for follow-up to age 3 years) were: Austria 0·19 (0·04, 0·51); Denmark 0·60 (0·13, 1·08); and The Netherlands 1·46 (0·51, 2·72). There was no clear evidence that the risk of transmission or of clinical manifestations was lowest in centres with the most intensive prenatal treatment

GILZ-mimics as novel therapeutic agents for progressive multiple sclerosis

poster abstractMultiple sclerosis (MS), a leading cause of neurological disability is an inflammatory demyelinating disease of the central nervous system (CNS). The clinical course of MS is highly variable ranging from isolated neurologic episodes to frequently relapsing or progressive disease. Currently there are no effective treatments for progressive MS. The long-term goal of this project is to evaluate a novel therapeutic strategy for progressive MS. Under physiological conditions signaling via the transcription factor, nuclear factor-kappa B (NF-κB) and glucocorticoid (GC) stimulation pathways regulate the immuno-inflammatory responses of the CNS resident glial cells. While NF-κB induces transcriptional activation, signaling via GC receptor functions to suppress immune responses. Persistent activation of NF-κB in the glial cells precipitates neuronal degeneration and axonal loss characteristic of progressive MS. Interactome analysis between the GC and NF-κB pathways suggested a novel strategy to inhibit NF-κB. Glucocorticoid-induced leucine zipper (GILZ) is a GC inducible protein that binds p65, the functionally critical subunit of NF-κB, and prevent transactivation of pathological mediators. The sites of interaction are localized to the proline rich region of the GILZ protein and the p65 transactivation domain. A 23 residue GILZ peptide prevented nuclear translocation of p65 and suppressed disease in an animal model of MS. Structurally GILZ peptide adopted polyproline type II (PPII) helical conformation, a favorable feature for drug development. The objective of this study is to optimize the lead peptide and develop drug like analogs. Specific features of the GILZ-p65 interactions were adapted in the design of over 25 GILZ analogs such that each exhibit optimum PPII helix, bind p65 transactivation domain and potentially accommodate modified residues that enhance the binding specificity with the p65. The analogs were ranked after passing through the Lipinski filter to determine the drug like properties. The top ranked analogs will be evaluated for functional efficacy

A general electro-synthesis approach to amaryllidaceae alkaloids

Amaryllidaceae alkaloids appeal to organic chemists with their attractive structures and their impressive antitumor and acetylcholinesterase inhibitory properties. We demonstrate a highly versatile access to this family of natural products. A general protocol with high yields in a sustainable electro-organic key transformation on a metal-free anode to spirodienones facilitates functionalization to the alkaloids. The biomimetic syntheses start with the readily available, inexpensive biogenic starting materials methyl gallate, O-methyl tyramine, and vanillin derivatives. Through known dynamic resolutions, this technology provides access to both enantiomeric series of (epi-)martidine, (epi-)crinine, siculine, and galantamine, clinically prescribed for the treatment of Alzheimer's disease

The Signature Center Initiative for the Cure of Glioblastoma

poster abstractGlioblastoma multiforme (GBM, World Health Organization/WHO grade IV) is the most common form of brain cancer in the central nervous system. Although conventional treatment-surgery, radiation, and temozolomide-is somewhat effective in adults, overall survival is still < 15 months. In pediatric patients, morbidity due to GBM is the highest among all pediatric cancers. In the context of brain cancers, new and existing therapeutics typically fail due to heterogeneity of genetic mutations within tumors, and because biologically effective doses of drug cannot be delivered to the primary site and invasive perimeter of the tumor due to the blood brain barrier. The Signature Center Initiative to Cure GBM is a funding mechanism that supports a research portal to foster investigations of the Brain Tumor Working Group for development of effective treatments for the eradication of GBM. The overall mission of the Signature Center Initiative is to: 1. Interrogate the molecular mechanisms of GBM biology and develop interventions that result in improved duration and quality of life for our patients. 2. Stimulate consistent and productive exchange of ideas between clinicians and basic scientists while employing bench-to-bedside and bedside-to-bench strategies to generate and prioritize scientific questions. 3. Provide infrastructure and mentorship needed to successfully compete for external funding. 4. Engage the community through patient advocacy to positively impact brain cancer patient outcomes and enhance philanthropic initiatives. The Brain Tumor Working Group brings together scientists committed to engaging in a team-based approach to study GBM biology. Infrastructure required to advance in vivo humanized intracranial tumor models, drug delivery, target validation, and development of new therapeutic strategies are in place. Additionally a patient sample pipeline to obtain, analyze, and distribute primary patient GBM specimens from the operating room to the research laboratory has been established. In year one of funding, over $70,000 in pilot project funding derived from the Signature Center Initiative and private donations has been distributed to the membership. The Brain Tumor Working Group meets in both small and large group formats to strategize experimental design and grant submissions. A network of basic scientists and clinicians has been developed that provides an effective forum for addressing clinically relevant questions related to GBM. A team-based approach, scientific expertise, and continued development of infrastructure provide our membership with a critical foundation to obtain new knowledge related to understanding how GBM cells evade therapy. In the future, this information can be applied to development of effective treatments that will cure GBM

Use of Precision Medicine Molecular Profiling of Baseline Tumor Specimen May Not Benefit Outcomes in Children With Relapsed or Refractory Pediatric Sarcomas

Given the poor prognosis of pediatric patients with relapsed or refractory sarcomas, discovery and implementation of innovative approaches and tools to guide therapy are urgent needs. This retrospective pilot study evaluated the impact of relapse and refractory therapies aligned with molecular characterization of biopsies collected at the time of primary diagnosis

Defective antigen presentation by monocytes in ESRD patients not responding to hepatitis B vaccination: impaired HBsAg internalization and expression of ICAM-1 and HLA-DR/Ia molecules

This study was undertaken to evaluate the monocyte function of uraemic non-responders to hepatitis B vaccination. Therefore, some parameters concerning antigen processing by monocytes (Mo) as antigen presenting cells (APC) were analysed. It was found that in uraemic non-responders, (1) the internalization of HBsAg by monocytes was significantly decreasjed—HBsAg complexed with specific IgG or as immune complex isolated from patients is better internalized compared with free HBsAg; (2) during antigen presentation the expression of adhesion (ICAM-1) and accessory (HLA-DR/Ia) molecules was significantly decreased in uraemic patients, especially in non-responders; and (3) impaired internalization of HBsAg as well as a decrease in ICAM-1 and HLA-DR/Ia expression, correlated well with the blunted proliferation of CD4+ T cells stimulated by autologous monocytes induced by HBsAg

Impact of gender identity in the inflammatory bowel disease population: an evidence review and practical steps for gastroenterologists

There has been greater societal awareness of differences in gender identity and sexual orientation in recent years. The rates of identifying as transgender or gender non-conforming (TGNC) are increasing and are known to be higher in the younger population and will therefore be over-represented in the inflammatory bowel disease (IBD) subpopulation. However, despite this there is very little in the literature with regards to those who identify as TGNC and are diagnosed with IBD (TGNC-IBD). Many TGNC individuals have poor experiences when seeking healthcare and many physicians find it a challenging and daunting clinical situation to be faced with. We reviewed the available literature with regards to TGNC-IBD population demographics, physical, mental and sexual health considerations, medication interactions and implications for surgery in this heterogenous group. We have identified areas that need further research and suggested simple and practical steps that can be adopted in order to help healthcare providers improve the experience for TGNC individuals diagnosed with IBD and the quality of care they provide

Whole Slide Image Analysis Quantification using Aperio Digital Imaging in a Mouse Lung Metastasis Model

poster abstractDigital whole slide imaging is the technique of digitizing a microscope slide at the highest resolution to produce a “digital virtual microscope slide”. This digital image can be viewed in three or four fields, from low to high power, which can be commonly used to evaluate the tissue. Many of these systems have whole slide software image analysis capability. The goal of this study was to determine if the Aperio positive pixel algorithm (image analysis) could effectively quantitate metastatic mouse lung tumors in a lung section using a H&E stain. Lung sections from a mouse lung metastasis model of 8 mice per group were evaluated: control, 50mg/kg, and 75mg/kg carboplatin. H&E and Ki67 immunostain slides were scanned using the Aperio whole slide scanning system (Scanscope CS). A single field of view from each slide representing a whole lung lobe with multiple lung metastases was selected for image analysis. The standard positive pixel algorithm was altered to read the H&E slides. Various histology slides were used to validate the altered algorithm. The immunostain (Ki67) was generated using the standard positive pixel algorithm analysis. The Aperio automated positive pixel count for a Ki67 immunostain was consistent with the H&E image analysis. The values decreased with a dose dependent treatment (control vs. 50mg/kg and 75mg/kg carboplatin) and were (H&E) 37%, 28%, and 22%, and (Ki67) 9%, 5%, and 3%. The analysis had decreasing values for both the H&E and Ki67 analysis on a dose dependent drug treatment. The metastases decreased in both treatment groups compared to controls with both the H&E and Ki67 analyses. The Aperio Image Analysis positive pixel algorithm allows large areas of the lung tissue section to be examined and not just a single 25x or 40x field like many common image analyses systems

Using clinical cases to guide healthcare.

Evidence-based practice (EBP) has been the gold standard in healthcare for nearly three centuries and aims to assist physicians in providing the safest and most effective healthcare for their patients. The well-established hierarchy of evidence lists systematic reviews and meta-analyses at the top however these methodologies are not always appropriate or possible and in these instances case-control studies, case series and case reports are utilised to support EBP. Case-control studies allow simultaneous study of multiple risk factors and can be performed rapidly and relatively cheaply. A recent example was during the Coronavirus pandemic where case-control studies were used to assess the efficacy of personal protective equipment for healthcare workers. Case series and case reports also play a role in EBP and are particularly useful to study rare diseases such as inflammatory bowel disease in transgender and gender non-conforming individuals. They are also vital in generating and disseminating early signals and encouraging further research. Whilst these methodologies have weaknesses, particularly with regards to bias and loss of patient confidentiality for rare pathologies, they have an important part to play in EBP and when appropriately utilised can significantly impact upon clinical practice