Using Effective Subnetworks to Predict Selected Properties of Gene Networks

BACKGROUND: Difficulties associated with implementing gene therapy are caused by the complexity of the underlying regulatory networks. The forms of interactions between the hundreds of genes, proteins, and metabolites in these networks are not known very accurately. An alternative approach is to limit consideration to genes on the network. Steady state measurements of these influence networks can be obtained from DNA microarray experiments. However, since they contain a large number of nodes, the computation of influence networks requires a prohibitively large set of microarray experiments. Furthermore, error estimates of the network make verifiable predictions impossible. METHODOLOGY/PRINCIPAL FINDINGS: Here, we propose an alternative approach. Rather than attempting to derive an accurate model of the network, we ask what questions can be addressed using lower dimensional, highly simplified models. More importantly, is it possible to use such robust features in applications? We first identify a small group of genes that can be used to affect changes in other nodes of the network. The reduced effective empirical subnetwork (EES) can be computed using steady state measurements on a small number of genetically perturbed systems. We show that the EES can be used to make predictions on expression profiles of other mutants, and to compute how to implement pre-specified changes in the steady state of the underlying biological process. These assertions are verified in a synthetic influence network. We also use previously published experimental data to compute the EES associated with an oxygen deprivation network of E.coli, and use it to predict gene expression levels on a double mutant. The predictions are significantly different from the experimental results for less than of genes. CONCLUSIONS/SIGNIFICANCE: The constraints imposed by gene expression levels of mutants can be used to address a selected set of questions about a gene network

A Robust Topology-Based Algorithm for Gene Expression Profiling

Early and accurate diagnoses of cancer can significantly improve the design of personalized therapy and enhance the success of therapeutic interventions. Histopathological approaches, which rely on microscopic examinations of malignant tissue, are not conducive to timely diagnoses. High throughput genomics offers a possible new classification of cancer subtypes. Unfortunately, most clustering algorithms have not been proven sufficiently robust. We propose a novel approach that relies on the use of statistical invariants and persistent homology, one of the most exciting recent developments in topology. It identifies a sufficient but compact set of genes for the analysis as well as a core group of tightly correlated patient samples for each subtype. Partitioning occurs hierarchically and allows for the identification of genetically similar subtypes. We analyzed the gene expression profiles of 202 tumors of the brain cancer glioblastoma multiforme (GBM) given at the Cancer Genome Atlas (TCGA) site. We identify core patient groups associated with the classical, mesenchymal, and proneural subtypes of GBM. In our analysis, the neural subtype consists of several small groups rather than a single component. A subtype prediction model is introduced which partitions tumors in a manner consistent with clustering algorithms but requires the genetic signature of only 59 genes.</jats:p

Utilisation of hospital-based specialist palliative care in patients with gynaecological cancer:Temporal trends, predictors and association with high-intensity end-of-life care

Objective: To examine hospital-based specialist palliative care (SPC) utilisation among patients with gynaecological cancer, including temporal trends, predictors and associations with high-intensity end-of-life care. Methods: We conducted a nationwide registry-based study for all patients dying from gynaecological cancer in Denmark during 2010–2016. We estimated the proportions of patients receiving SPC by year of death and used regression analyses to examine predictors of SPC utilisation. Use of high-intensity end-of-life care according to SPC utilisation was compared by regression analyses adjusting for type of gynaecological cancer, year of death, age, comorbidities, residential region, marital/cohabitation status, income level and migrant status. Results: Among 4502 patients dying from gynaecological cancer, the proportion of patients receiving SPC increased from 24.2% in 2010 to 50.7% in 2016. Young age, three or more comorbidities, residence outside the Capital Region and being immigrant/descendant were associated with increased SPC utilisation, whereas income, cancer type and stage were not. SPC was associated with lower high-intensity end-of-life care utilisation. Particularly, when compared with patients not receiving SPC, patients who accessed SPC &gt;30 days before death had 88% lower risk of intensive care unit admissions within 30 days before death (adjusted relative risk: 0.12 (95% CI: 0.06; 0.24)) and 96% lower risk of surgery within 14 days before death (adjusted relative risk: 0.04 (95% CI: 0.01; 0.31)). Conclusions: Among patients dying from gynaecological cancer, SPC utilisation increased over time and age, comorbidities, residential region and migrant status were associated with access to SPC. Furthermore, SPC was associated with lower use of high-intensity end-of-life care.</p

An Evaluation of Parylene Thin Films to Prevent Encrustation for a Urinary Bladder Pressure MEMS Sensor System

Recent developments in urological implants have focused on preventive strategies to mitigate encrustation and biofilm formation. Parylene, a conformal, pinhole-free polymer coating, has gained attention due to its high biocompatibility and chemical resistance, excellent barrier properties, and low friction coefficient. This study aims to evaluate the effectiveness of parylene C in comparison to a parylene VT4 grade coating in preventing encrustation on a urinary bladder pressure MEMS sensor system. Additionally, silicon oxide (SiOx) applied as a finish coating was investigated for further improvements. An in vitro encrustation system mimicking natural urine flow was used to quantify the formation of urinary stones. These stones were subsequently analyzed using Fourier transform infrared spectrometry (FTIR). Encrustation results were then discussed in relation to coating surface chemical properties. Parylene C and VT4 grades demonstrated a very low encrustation mass, making them attractive options for encrustation prevention. The best performance was achieved after the addition of a hydrophilic SiOx finish coating on parylene VT4 grade. Parylene-based encapsulation proved to be an outstanding solution to prevent encrustation for urological implants

Deposit of Red Blood Cells at low concentrations in evaporating droplets: central edge growth and potential applications

Evaporation of blood droplets and diluted blood samples is a topic of intensive research, as it is seen as a possible low-cost tool for diagnosis. So far, samples with volume fraction down to a few percents of Red Blood Cells (RBCs) have been studied, and those were reportedly dominated by a ``coffee-ring'' deposit. In this study, samples with lower volume fractions have been used in order to study the growth of the evaporative deposit from sessile droplets more in details. We observed that blood samples and salt solutions with less than 1\% volume fraction of RBCs are dominated by a central deposit. We characterized the growth process of this central deposit by evaporating elongated drops, and determined that it is consistent with the Kardar-Parisi-Zhang process in the presence of quenched disorder. Our results showed a sensitivity of this deposit size to the fibrinogen concentration and shape of the RBCs, meaning that this parameter could be used to develop a new and cost-effective clinical marker for inflammation and RBC deformation.Comment: 27 pages, 11 Figure

Organic matter decomposition and greenhouse gas production in thermokarst lake taliks on the Baldwin Peninsula, Alaska

In the continuous permafrost zone, thermokarst processes are altering and accelerating as the climate changes. Surface subsidence is accelerating and thermokarst lakes are draining, while gullies are expanding and thaw slumps are widening. On the Baldwin Peninsula in West Alaska, such processes are evident and have direct consequences for the local environment as well as the city of Kotzebue. Furthermore, these landscape dynamics have far-reaching effects on biogeochemical cycles, as microbial activity in thawed sediments of thermokarst landforms decomposes organic matter and releases greenhouse gases, further contributing to global warming. To investigate these processes, sediment cores were collected in March 2024 along two transects that extend from upland areas through thermokarst disturbances into the near-shore zone of the Kotzebue Sound. Taliks were identified and sampled in two thermokarst lakes, a semi-drained lake, and a drained lake basin. These unfrozen sediments are of particular interest concerning organic matter decomposition and greenhouse gas production. A one-year long incubation experiment coupled with pre- and post-incubation n-alkane biomarker analyses on the sediments, aims to decipher organic matter patterns and potentials. First findings from this laboratory work will be presented at the 15th DACH Permafrost Conference

PRO B: evaluating the effect of an alarm-based patient-reported outcome monitoring compared with usual care in metastatic breast cancer patients—study protocol for a randomised controlled trial

Background: Despite the progress of research and treatment for breast cancer, still up to 30% of the patients afflicted will develop distant disease. Elongation of survival and maintaining the quality of life (QoL) become pivotal issues guiding the treatment decisions. One possible approach to optimise survival and QoL is the use of patient-reported outcomes (PROs) to timely identify acute disease-related burden. We present the protocol of a trial that investigates the effect of real-time PRO data captured with electronic mobile devices on QoL in female breast cancer patients with metastatic disease. Methods: This study is a randomised, controlled trial with 1:1 randomisation between two arms. A total of 1000 patients will be recruited in 40 selected breast cancer centres. Patients in the intervention arm receive a weekly request via an app to complete the PRO survey. Symptoms will be assessed by study-specific optimised short forms based on the EORTC QLQ-C30 domains using items from the EORTC CAT item banks. In case of deteriorating PRO scores, an alarm is sent to the treating study centre as well as to the PRO B study office. Following the alarm, the treating breast cancer centre is required to contact the patient to inquire about the reported symptoms and to intervene, if necessary. The intervention is not specified and depends on the clinical need determined by the treating physician. Patients in the control arm are prompted by the app every 3 months to participate in the PRO survey, but their response will not trigger an alarm. The primary outcome is the fatigue level 6 months after enrolment. Secondary endpoints include among others hospitalisations, use of rescue services and overall QoL. Discussion: Within the PRO B intervention group, we expect lower fatigue levels 6 months after intervention start, higher levels of QoL, less unplanned hospitalisations and less emergency room visits compared to controls. In case of positive results, our approach would allow a fast and easy transfer into clinical practice due to the use of the already nationwide existing IT infrastructure of the German Cancer Society and the independent certification institute OnkoZert

Somatic Mutation Profiles of MSI and MSS Colorectal Cancer Identified by Whole Exome Next Generation Sequencing and Bioinformatics Analysis

BACKGROUND: Colorectal cancer (CRC) is with approximately 1 million cases the third most common cancer worldwide. Extensive research is ongoing to decipher the underlying genetic patterns with the hope to improve early cancer diagnosis and treatment. In this direction, the recent progress in next generation sequencing technologies has revolutionized the field of cancer genomics. However, one caveat of these studies remains the large amount of genetic variations identified and their interpretation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the first work on whole exome NGS of primary colon cancers. We performed 454 whole exome pyrosequencing of tumor as well as adjacent not affected normal colonic tissue from microsatellite stable (MSS) and microsatellite instable (MSI) colon cancer patients and identified more than 50,000 small nucleotide variations for each tissue. According to predictions based on MSS and MSI pathomechanisms we identified eight times more somatic non-synonymous variations in MSI cancers than in MSS and we were able to reproduce the result in four additional CRCs. Our bioinformatics filtering approach narrowed down the rate of most significant mutations to 359 for MSI and 45 for MSS CRCs with predicted altered protein functions. In both CRCs, MSI and MSS, we found somatic mutations in the intracellular kinase domain of bone morphogenetic protein receptor 1A, BMPR1A, a gene where so far germline mutations are associated with juvenile polyposis syndrome, and show that the mutations functionally impair the protein function. CONCLUSIONS/SIGNIFICANCE: We conclude that with deep sequencing of tumor exomes one may be able to predict the microsatellite status of CRC and in addition identify potentially clinically relevant mutations

Tracking the international spread of SARS-CoV-2 lineages B.1.1.7 and B.1.351/501Y-V2

Publisher Copyright: © 2021 O'Toole Á et al.Late in 2020, two genetically-distinct clusters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with mutations of biological concern were reported, one in the United Kingdom and one in South Africa. Using a combination of data from routine surveillance, genomic sequencing and international travel we track the international dispersal of lineages B.1.1.7 and B.1.351 (variant 501Y-V2). We account for potential biases in genomic surveillance efforts by including passenger volumes from location of where the lineage was first reported, London and South Africa respectively. Using the software tool grinch (global report investigating novel coronavirus haplotypes), we track the international spread of lineages of concern with automated daily reports, Further, we have built a custom tracking website (cov-lineages.org/global_report.html) which hosts this daily report and will continue to include novel SARS-CoV-2 lineages of concern as they are detected.Peer reviewe

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.</p