NMR Profiling of Exhaled Breath Condensate Defines Different Metabolic Phenotypes of Non-Cystic Fibrosis Bronchiectasis

Nuclear-magnetic-resonance (NMR) profiling of exhaled breath condensate (EBC) provides insights into the pathophysiology of bronchiectasis by identifying specific biomarkers. We evaluated whether NMR-based metabolomics discriminates the EBC-derived metabolic phenotypes (“metabotypes”) of 41 patients with non-cystic fibrosis (nCF) bronchiectasis of various etiology [24 subjects with Primary Ciliary Dyskinesia (PCD); 17 patients with bronchiectasis not associated with PCD (nCF/nPCD)], who were compared to 17 healthy subjects (HS). NMR was used for EBC profiling, and Orthogonal Projections to Latent Structures with partial least-squares discriminant analysis (OPLS-DA) was used as a classifier. The results were validated by using the EBC from 17 PCD patients not included in the primary analysis. Different statistical models were built, which compared nCF/nPCD and HS, PCD and HS, all classes (nCF/nPCD-PCD-HS), and, finally, PCD and nCF/nPCD. In the PCD-nCF/nPCD model, four statistically significant metabolites were able to discriminate between the two groups, with only a minor reduction of the quality parameters. In particular, for nCF/nPCD, acetone/acetoin and methanol increased by 21% and 18%, respectively. In PCD patients, ethanol and lactate increased by 25% and 28%, respectively. They are all related to lung inflammation as methanol is found in the exhaled breath of lung cancer patients, acetone/acetoin produce toxic ROS that damage lung tissue in CF, and lactate is observed in acute inflammation. Interestingly, a high concentration of ethanol hampers cilia beating and can be associated with the genetic defect of PCD. Model validation with 17 PCD samples not included in the primary analysis correctly predicted all samples. Our results indicate that NMR of EBC discriminates nCF/nPCD and PCD bronchiectasis patients from HS, and patients with nCF/nPCD from those with PCD. The metabolites responsible for between-group separation identified specific metabotypes, which characterize bronchiectasis of a different etiology.     

Advanced Functional Structure‐Based Sensing and Imaging Strategies for Cancer Detection: Possibilities,Opportunities, Challenges,and Prospects

Cancer is the second most common cause of death in the world. The principal limitations thus far encountered in the clinical practice of probing cancer are diverse and include low sensitivity, time consumption, bulkiness, and cost. In this respect, nanomaterial (NM)‐based sensing techniques are recognized as a superior alternative to efficiently resolve such limitations. A better understanding of NM‐based sensing platforms is thus important so that these novel avenues can easily be explored for clinical applications. These platforms have the merits of high sensitivity, high specificity, rapid response, and easy‐to‐read signals. This review offers a comprehensive survey of NM‐based advanced cancer‐sensing techniques and will help the scientific community establish optimum sensing strategies based on an accurate assessment of the interactions between cancer biomarkers and NM‐based platforms.     

Mass Spectrometry-Based Proteomics for Pre-Eclampsia and Preterm Birth

Pregnancy-related complications such as pre-eclampsia and preterm birth now represent a notable burden of adverse health. Pre-eclampsia is a hypertensive disorder unique to pregnancy. It is an important cause of maternal death worldwide and a leading cause of fetal growth restriction and iatrogenic prematurity. Fifteen million infants are born preterm each year globally, but more than one million of those do not survive their first month of life. Currently there are no predictive tests available for diagnosis of these pregnancy-related complications and the biological mechanisms of the diseases have not been fully elucidated. Mass spectrometry-based proteomics have all the necessary attributes to provide the needed breakthrough in understanding the pathophysiology of complex human diseases thorough the discovery of biomarkers. The mass spectrometry methodologies employed in the studies for pregnancy-related complications are evaluated in this article. Top-down proteomic and peptidomic profiling by laser mass spectrometry, liquid chromatography or capillary electrophoresis coupled to mass spectrometry, and bottom-up quantitative proteomics and targeted proteomics by liquid chromatography mass spectrometry have been applied to elucidate protein biomarkers and biological mechanism of pregnancy-related complications. The proteomes of serum, urine, amniotic fluid, cervical-vaginal fluid, placental tissue, and cytotrophoblastic cells have all been investigated. Numerous biomarkers or biomarker candidates that could distinguish complicated pregnancies from healthy controls have been proposed. Nevertheless, questions as to the clinically utility and the capacity to elucidate the pathogenesis of the pre-eclampsia and preterm birth remain to be answered.     

Endoglin Targeting: Lessons Learned and Questions That Remain

Approximately 30 years ago, endoglin was identified as a transforming growth factor (TGF)-β coreceptor with a crucial role in developmental biology and tumor angiogenesis. Its selectively high expression on tumor vessels and its correlation with poor survival in cancer patients led to the exploration of endoglin as a therapeutic target for cancer. The endoglin neutralizing antibody TRC105 (Carotuximab^®, Tracon Pharmaceuticals (San Diego, CA, USA) was subsequently tested in a wide variety of preclinical cancer models before being tested in phase I-III clinical studies in cancer patients as both a monotherapy and in combination with other chemotherapeutic and anti-angiogenic therapies. The combined data of these studies have revealed new insights into the role of endoglin in angiogenesis and its expression and functional role on other cells in the tumor microenvironment. In this review, we will summarize the preclinical work, clinical trials and biomarker studies of TRC105 and explore what these studies have enabled us to learn and what questions remain unanswered.     

Health benefits of orally administered anti-IL-10 antibody in milk-fed dairy calves

The primary objective of this randomized controlled trial was to determine whether anti-IL-10 egg yolk antibodies fed upon arrival to a calf ranch would lower the prevalence of Cryptosporidium parvum shedding in naturally challenged preweaned dairy calves. The secondary objectives included measuring the effect of anti-IL-10 antibodies on calf health, performance, and shedding of less common diarrheal pathogens. A total of 133 calves, enrolled at 24 to 72 h of age, received a daily dose of 0.96 g of egg yolk powder with anti-IL-10 antibodies (MAB, n = 71) or without anti-IL-10 antibodies (MEP, n = 62) split between 2 feedings for the first 11 d on feed at a calf ranch. Daily health evaluations were completed for 15 d after arrival and on d 56. Digital weights were collected at enrollment and d 56, and hipometer weights were collected at enrollment and d 7 and 56. Packed cell volume and serum total protein concentration were measured at enrollment and on d 7 and 14. Fecal pH was measured at enrollment and on d 5 and 14, and fecal pathogen (C. parvum, coronavirus, rotavirus, and Salmonella spp.) shedding was assessed at d 5 and 14. Continuous outcomes were compared between groups using a Student's t-test or Wilcoxon rank sum test. Fecal pathogen shedding at d 14, respiratory disease at d 56, and antibiotic usage were compared using relative risk (RR) and chi-squared test. Fecal pH (median and interquartile range) on d 14 was 6.65 (6.39–6.99) and 6.52 (5.97–6.81) for MAB and MEP, respectively. On d 56, the risk of respiratory disease was lower for MAB compared with MEP (RR = 0.40; confidence interval = 0.16–0.99). The risk for antibiotic treatment was lower for MAB- compared with MEP-treated calves (RR = 0.38; confidence interval = 0.17–0.88). The risk of shedding rotavirus was higher in MAB (RR = 1.38; confidence interval = 1.10–1.81) calves. After multivariable analyses, hipometer weights (least squares means ± standard error) were 1.7 ± 0.8 kg greater on d 56 in MAB compared with MEP; however, ADG was 0.04 ± 0.02 kg/d lower in MAB calves. Total health score, diarrhea days, average respiratory score, packed cell volume, and serum total protein were not affected by feeding anti-IL-10 egg antibodies. In summary, feeding anti-IL-10 antibodies was associated with increased fecal pH, reduced risk of respiratory disease later in the preweaning period, and decreased antibiotic usage despite higher rotavirus infection. These findings might be associated with improved mucosal immunity, enhanced host defenses, or reduced susceptibility and warrant further investigation.     

Early CSF Biomarkers and Late Functional Outcomes in Spinal Cord Injury. A Pilot Study

Although, biomarkers are regarded as an important tool for monitoring injury severity and treatment efficacy, and for predicting clinical evolution in many neurological diseases and disorders including spinal cord injury, there is still a lack of reliable biomarkers for the assessment of clinical course and patient outcome. In this study, a biological dataset of 60 cytokines/chemokines, growth factorsm and intracellular and extracellular matrix proteins, analyzed in CSF within 24 h of injury, was used for correlation analysis with the clinical dataset of the same patients. A heat map was generated of positive and negative correlations between biomarkers and clinical rating scale scores at discharge, and between biomarkers and changes in clinical scores during the observation period. Using very stringent statistical criteria, we found 10 molecules which correlated with clinical scores at discharge, and five molecules, which correlated with changes in clinical scores. The proposed methodology may be useful for generating hypotheses regarding “predictive” and “treatment effectiveness” biomarkers, thereby suggesting potential candidates for disease-modifying therapies using a “bed-to-bench” approach.     

Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes–Considerations for Future Studies

To discover novel high-penetrant risk loci for hereditary colorectal cancer (hCRC) and polyposis syndromes many whole-exome and whole-genome sequencing (WES/WGS) studies have been performed. Remarkably, these studies resulted in only a few novel high-penetrant risk genes. Given this observation, the possibility and strategy to identify high-penetrant risk genes for hCRC and polyposis needs reconsideration. Therefore, we reviewed the study design of WES/WGS-based hCRC and polyposis gene discovery studies (n = 37) and provide recommendations to optimize discovery and validation strategies. The group of genetically unresolved patients is phenotypically heterogeneous, and likely composed of distinct molecular subtypes. This knowledge advocates for the screening of a homogeneous, stringently preselected discovery cohort and obtaining multi-level evidence for variant pathogenicity. This evidence can be collected by characterizing the molecular landscape of tumors from individuals with the same affected gene or by functional validation in cell-based models. Together, the combined approach of a phenotype-driven, tumor-based candidate gene search might elucidate the potential contribution of novel genetic predispositions in genetically unresolved hCRC and polyposis.