Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies

We would like to thank all patients whose samples were used in this study. We are also thankful to the Northern Ireland Biobank and Grampian Biorepository for providing us with tissue blocks and patient data; and Dr HG Coleman (Queen’s University Belfast) for her advice on statistical analyses. This work has been carried out with financial support from Cancer Research UK (grant: C11512/A18067), Experimental Cancer Medicine Centre Network (grant: C36697/A15590 from Cancer Research UK and the NI Health and Social Care Research and Development Division), the Sean Crummey Memorial Fund and the Tom Simms Memorial Fund. The Northern Ireland Biobank is funded by HSC Research and Development Division of the Public Health Agency in Northern Ireland and Cancer Research UK through the Belfast CRUK Centre and the Northern Ireland Experimental Cancer Medicine Centre; additional support was received from Friends of the Cancer Centre. The Northern Ireland Molecular Pathology Laboratory which is responsible for creating resources for the Northern Ireland Biobank has received funding from Cancer Research UK, Friends of the Cancer Centre and Sean Crummey Foundation.Peer reviewedPublisher PD

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered

Evaluation of an immunodot blot technique for the detection of antibodies against Taenia solium larval antigens

Immunodiagnostic tests represent an important tool for diagnosis of cysticercosis, the disease caused by cysticerci of Taenia solium. Accurate diagnosis of neurocysticercosis (NCC) requires costly neuroimaging techniques (magnetic resonance imaging and computed tomography), which are seldom affordable for people in endemic countries. Hence, new low-cost diagnostic methods offering good sensitivity and specificity are needed. Here, we studied four immunodiagnostic tests immunodot blot Tsol-p27, a commercial ELISA, and Western blot Tsol-p27/TsolHSP36, and compared them with a commercial enzyme-linked immunoelectrotransfer blot (EITB) that we regarded as the gold standard method. The analyzed serum samples were obtained from 160 patients: 94 epileptics suspected of NCC, six individuals confirmed NCC-positive, and 60 with positive (30) or negative (30) serology for Chagas diseases. Of the 100 serum samples from epileptic patients, 13 were positive and 87 negative by EITB. Compared to Western blot Tsol-p27, immunodot blot Tsol-p27 offered similar specificity (97.8% vs. 95.6%) but better sensitivity (86.7% vs. 76.4%). The ELISA was similar to the immunodot blot Tsol-p27 regarding both sensitivity and specificity. Western blot TsolHSP36 provided the lowest sensitivity (61.9%) and specificity (86.1%). None of the antibodies in the serum samples from the Chagas control groups were recognized by immunodot blot Tsol-p27. Our results indicate that the immunodot blot Tsol-p27 provides good sensitivity and specificity. Furthermore, considering the simplicity and low cost of this test, it might be preferable as a diagnostic method in poorly equipped laboratories in endemic countries

Isolation and purification of Cu-free methanobactin from Methylosinus trichosporium OB3b

<p>Abstract</p> <p>Background</p> <p>The isolation of highly pure copper-free methanobactin is a prerequisite for the investigation of the biogeochemical functions of this chalkophore molecule produced by methane oxidizing bacteria. Here, we report a purification method for methanobactin from <it>Methylosinus trichosporium </it>OB3b cultures based on reversed-phase HPLC fractionation used in combination with a previously reported resin extraction. HPLC eluent fractions of the resin extracted product were collected and characterized with UV-vis, FT-IR, and C-1s NEXAFS spectroscopy, as well as with elemental analysis and ESI-MS.</p> <p>Results</p> <p>The results showed that numerous compounds other than methanobactin were present in the isolate obtained with resin extraction. Molar C/N ratios, mass spectrometry measurements, and UV-vis spectra indicated that methanobactin was only present in one of the HPLC fractions. On a mass basis, methanobactin carbon contributed only 32% to the total organic carbon isolated with resin extraction. Our spectroscopic results implied that besides methanobactin, the organic compounds in the resin extract comprised breakdown products of methanobactin as well as polysaccharide-like substances.</p> <p>Conclusion</p> <p>Our results demonstrate that a purification step is indispensable in addition to resin extraction in order to obtain pure methanobactin. The proposed HPLC purification procedure is suitable for semi-preparative work and provides copper-free methanobactin.</p

Intracellular chloride concentration influences the GABAA receptor subunit composition

GABAA receptors (GABAARs) exist as different subtype variants showing unique functional properties and defined spatio-temporal expression pattern. The molecular mechanisms underlying the developmental expression of different GABAAR are largely unknown. The intracellular concentration of chloride ([Cl−]i), the main ion permeating through GABAARs, also undergoes considerable changes during maturation, being higher at early neuronal stages with respect to adult neurons. Here we investigate the possibility that [Cl−]i could modulate the sequential expression of specific GABAARs subtypes in primary cerebellar neurons. We show that [Cl−]i regulates the expression of α3-1 and δ-containing GABAA receptors, responsible for phasic and tonic inhibition, respectively. Our findings highlight the role of [Cl−]i in tuning the strength of GABAergic responses by acting as an intracellular messenger

Multiple Chronic Conditions: Prevalence, Health Consequences, and Implications for Quality, Care Management, and Costs

Persons with multiple chronic conditions are a large and growing segment of the US population. However, little is known about how chronic conditions cluster, and the ramifications of having specific combinations of chronic conditions. Clinical guidelines and disease management programs focus on single conditions, and clinical research often excludes persons with multiple chronic conditions. Understanding how conditions in combination impact the burden of disease and the costs and quality of care received is critical to improving care for the 1 in 5 Americans with multiple chronic conditions. This Medline review of publications examining somatic chronic conditions co-occurring with 1 or more additional specific chronic illness between January 2000 and March 2007 summarizes the state of our understanding of the prevalence and health challenges of multiple chronic conditions and the implications for quality, care management, and costs

Maternal Infection with Trypanosoma cruzi and Congenital Chagas Disease Induce a Trend to a Type 1 Polarization of Infant Immune Responses to Vaccines

Vaccines are of crucial importance to prevent morbidity and mortality due to infectious diseases in childhood. A modulation of the fetal/neonatal immune system (considered immature) toward Th1 or Th2 dominance could modify responses to vaccines administered in early life. T. cruzi is the agent of Chagas' disease, in Latin America currently infecting about 2 million women at fertile ages who are susceptible to transmitting the parasite to their fetus. In previous studies we showed that T. cruzi-infected mothers can induce a pro-inflammatory environment in their uninfected neonates (M+B−), whereas congenitally infected newborns (M+B+) are able to develop a pro-Th1 parasite-specific T cell response. In the present study, we analysed the cellular and/or antibody responses to Bacillus Calmette Guerin (BCG), hepatitis B birus (HBV), diphtheria and tetanus vaccines in 6- to 7-month-old infants living in Bolivia. M+B− infants produced more IFN-γ in response to BCG, whereas M+B+ infants developed a stronger IFN-γ response to hepatitis B, diphtheria and tetanus vaccines and enhanced antibody production to HBs antigen. These results show that both maternal infection with T. cruzi and congenital Chagas disease do not interfere with responses to BCG, hepatitis B, diphtheria and tetanus vaccines in the neonatal period and that T. cruzi infection in early life tends to favour type 1 immune responses to vaccinal antigens

Age-dependent effects of protein restriction on dopamine release

FUNDING AND DISCLOSURE This work was supported by the Biotechnology and Biological Sciences Research Council [grant # BB/M007391/1 to J.E.M.], the European Commission [grant # GA 631404 to J.E.M.], The Leverhulme Trust [grant # RPG-2017-417 to J.E.M.] and the Tromsø Research Foundation [grant # 19-SG-JMcC to J. E. M.). The authors declare no conflict of interest. ACKNOWLEDGEMENTS The authors would like to acknowledge the help and support from the staff of the Division of Biomedical Services, Preclinical Research Facility, University of Leicester, for technical support and the care of experimental animals.Peer reviewedPublisher PD

Clinical significance of serological biomarkers and neuropsychological performances in patients with temporal lobe epilepsy

<p>Abstract</p> <p>Background</p> <p>Temporal lobe epilepsy (TLE) is a common form of focal epilepsy. Serum biomarkers to predict cognitive performance in TLE patients without psychiatric comorbidities and the link with gray matter (GM) atrophy have not been fully explored.</p> <p>Methods</p> <p>Thirty-four patients with TLE and 34 sex - and age-matched controls were enrolled for standardized cognitive tests, neuroimaging studies as well as measurements of serum levels of heat shock protein 70 (HSP70), S100ß protein (S100ßP), neuronal specific enolase (NSE), plasma nuclear and mitochondrial DNA levels.</p> <p>Results</p> <p>Compared with the controls, the patients with TLE had poorer cognitive performances and higher HSP70 and S100ßP levels (<it>p </it>< 0.01). The patients with higher frequencies of seizures had higher levels of HSP70, NSE and S100ßP (<it>p </it>< 0.01). Serum HSP70 level correlated positively with duration of epilepsy (σ = 0.413, <it>p </it>< 0.01), and inversely with memory scores in the late registration (σ = −0.276, <it>p </it>= 0.01) and early recall score (σ = −0.304, <it>p </it>= 0.007). Compared with the controls, gray matter atrophy in the hippocampal and parahippocampal areas, putamen, thalamus and supplementary motor areas were found in the patient group. The HSP70 levels showed an inverse correlation with hippocampal volume (R square = 0.22, <it>p </it>= 0.007) after controlling for the effect of age.</p> <p>Conclusions</p> <p>Our results suggest that serum biomarkers were predictive of higher frequencies of seizures in the TLE group. HSP70 may be considered to be a stress biomarker in patients with TLE in that it correlated inversely with memory scores and hippocampal volume. In addition, the symmetric extratemporal atrophic patterns may be related to damage of neuronal networks and epileptogenesis in TLE.</p