Technical and Regulatory Considerations for Taking Liquid Biopsy to the Clinic: Validation of the JAX PlasmaMonitor

The standard of care in oncology has been genomic profiling of tumor tissue biopsies for the treatment and management of disease, which can prove to be quite challenging in terms of cost, invasiveness of procedure, and potential risk for the patient. As the number of available drugs in oncology continues to increase, so too does the demand for technologies and testing applications that can identify genomic alterations targetable by these new therapies. Liquid biopsies that use a blood draw from the diseased patient may offset the many disadvantages of the invasive procedure. However, as with any new technology or finding in the clinical field, the clinical utility of an analytical test such as that of the liquid biopsy has to be established. Here, we review the clinical testing space for liquid biopsy offerings and elucidate the technical and regulatory considerations to develop such an assay, using our recently validated PlasmaMonito

Genomic Profiling of Two Histologically Distinct Rare Urothelial Cancers in a Clinical Setting to Identify Potential Therapeutic Options for Treatment and Management of Disease.

Molecular profiling of urothelial cancers for therapeutic and prognostic potential has been very limited due to the absence of cancer-specific targeted therapies. We describe here 2 clinical cases with a histological diagnosis of an invasive sarcomatoid and a poorly differentiated carcinoma favoring urothelial with some neuroendocrine differentiation, two of the rarer types of urothelial cancers, which were evaluated for mutations in 212 genes for single-nucleotide variants and copy-number variants and 53 genes for fusions associated with solid tumors. In both cases, we identified variants in 2 genes, Case Rep Oncol 2018 Mar 27; 11(1):196-205

Expedition 357 Preliminary Report: Atlantis Massif Serpentinization and Life

International Ocean Discovery Program (IODP) Expedition 357 successfully cored an east–west transect across the southern wall of Atlantis Massif on the western flank of the Mid-Atlantic Ridge to study the links between serpentinization processes and microbial activity in the shallow subsurface of highly altered ultramafic and mafic sequences that have been uplifted to the seafloor along a major detachment fault zone. The primary goals of this expedition were to (1) examine the role of serpentinization in driving hydrothermal systems, sustaining microbial communities, and sequestering carbon; (2) characterize the tectonomagmatic processes that lead to lithospheric heterogeneities and detachment faulting; and (3) assess how abiotic and biotic processes change with variations in rock type and progressive exposure on the seafloor. To accomplish these objectives, we developed a coring and sampling strategy based around the use of seabed rock drills—the first time that such systems have been used in the scientific ocean drilling programs. This technology was chosen in hopes of achieving high recovery of the carbonate cap sequences and intact contact and deformation relationships. The expedition plans also included several engineering developments to assess geochemical parameters during drilling; sample bottom water before and after drilling; supply synthetic tracers during drilling for contamination assessment; gather downhole electrical resistivity and magnetic susceptibility logs for assessing fractures, fluid flow, and extent of serpentinization; and seal boreholes to provide opportunities for future experiments. Seventeen holes were drilled at nine sites across Atlantis Massif, with two sites on the eastern end of the southern wall (Sites M0068 and M0075), three sites in the central section of the southern wall north of the Lost City hydrothermal field (Sites M0069, M0072, and M0076), two sites on the western end (Sites M0071 and M0073), and two sites north of the southern wall in the direction of the central dome of the massif and Integrated Ocean Drilling Program Site U1309 (Sites M0070 and M0074). Use of seabed rock drills enabled collection of more than 57 m of core, with borehole penetration ranging from 1.3 to 16.44 meters below seafloor and core recoveries as high as 75% of total penetration. This high level of recovery of shallow mantle sequences is unprecedented in the history of ocean drilling. The cores recovered along the southern wall of Atlantis Massif have highly heterogeneous lithologies, types of alteration, and degrees of deformation. The ultramafic rocks are dominated by harzburgites with intervals of dunite and minor pyroxenite veins, as well as gabbroic rocks occurring as melt impregnations and veins, all of which provide information about early magmatic processes and the magmatic evolution in the southernmost portion of Atlantis Massif. Dolerite dikes and basaltic rocks represent the latest stage of magmatic activity. Overall, the ultramafic rocks recovered during Expedition 357 revealed a high degree of serpentinization, as well as metasomatic talc-amphibole-chlorite overprinting and local rodingitization. Metasomatism postdates an early phase of serpentinization but predates late-stage intrusion and alteration of dolerite dikes and the extrusion of basalt. The intensity of alteration is generally lower in the gabbroic and doleritic rocks. Chilled margins in dolerite intruded into talc-amphibole-chlorite schists are observed at the most eastern Site M0075. Deformation in Expedition 357 cores is variable and dominated by brecciation and formation of localized shear zones; the degree of carbonate veining was lower than anticipated. All types of variably altered and deformed ultramafic and mafic rocks occur as components in sedimentary breccias and as fault scarp rubble. The sedimentary cap rocks include basaltic breccias with a carbonate sand matrix and/or fossiliferous carbonate. Fresh glass on basaltic components was observed in some of the breccias. The expedition also successfully applied new technologies, namely (1) extensively using an in situ sensor package and water sampling system on the seabed drills for evaluating real-time dissolved oxygen and methane, pH, oxidation-reduction potential, temperature, and conductivity during drilling; (2) deploying a borehole plug system for sealing seabed drill boreholes at four sites to allow access for future sampling; and (3) proving that tracers can be delivered into drilling fluids when using seabed drills. The rock drill sensor packages and water sampling enabled detection of elevated dissolved methane and hydrogen concentrations during and/or after drilling, with “hot spots” of hydrogen observed over Sites M0068–M0072 and methane over Sites M0070–M0072. Shipboard determination of contamination tracer delivery confirmed appropriate sample handling procedures for microbiological and geochemical analyses, which will aid all subsequent microbiological investigations that are part of the science party sampling plans, as well as verify this new tracer delivery technology for seabed drill rigs. Shipboard investigation of biomass density in select samples revealed relatively low and variable cell densities, and enrichment experiments set up shipboard reveal growth. Thus, we anticipate achieving many of the deep biosphere–related objectives of the expedition through continued scientific investigation in the coming years. Finally, although not an objective of the expedition, we were serendipitously able to generate a high-resolution (20 m per pixel) multibeam bathymetry map across the entire Atlantis Massif and the nearby fracture zone, Mid-Atlantic Ridge, and eastern conjugate, taking advantage of weather and operational downtime. This will assist science party members in evaluating and interpreting tectonic and mass-wasting processes at Atlantis Massif

Differential Expression of Chemokine and Matrix Re-Modelling Genes Is Associated with Contrasting Schistosome-Induced Hepatopathology in Murine Models

The pathological outcomes of schistosomiasis are largely dependent on the molecular and cellular mechanisms of the host immune response. In this study, we investigated the contribution of variations in host gene expression to the contrasting hepatic pathology observed between two inbred mouse strains following Schistosoma japonicum infection. Whole genome microarray analysis was employed in conjunction with histological and immunohistochemical analysis to define and compare the hepatic gene expression profiles and cellular composition associated with the hepatopathology observed in S. japonicum-infected BALB/c and CBA mice. We show that the transcriptional profiles differ significantly between the two mouse strains with high statistical confidence. We identified specific genes correlating with the more severe pathology associated with CBA mice, as well as genes which may confer the milder degree of pathology associated with BALB/c mice. In BALB/c mice, neutrophil genes exhibited striking increases in expression, which coincided with the significantly greater accumulation of neutrophils at granulomatous regions seen in histological sections of hepatic tissue. In contrast, up-regulated expression of the eosinophil chemokine CCL24 in CBA mice paralleled the cellular influx of eosinophils to the hepatic granulomas. Additionally, there was greater down-regulation of genes involved in metabolic processes in CBA mice, reflecting the more pronounced hepatic damage in these mice. Profibrotic genes showed similar levels of expression in both mouse strains, as did genes associated with Th1 and Th2 responses. However, imbalances in expression of matrix metalloproteinases (e.g. MMP12, MMP13) and tissue inhibitors of metalloproteinases (TIMP1) may contribute to the contrasting pathology observed in the two strains. Overall, these results provide a more complete picture of the molecular and cellular mechanisms which govern the pathological outcome of hepatic schistosomiasis. This improved understanding of the immunopathogenesis in the murine model schistosomiasis provides the basis for a better appreciation of the complexities associated with chronic human schistosomiasis

Endemic Dengue Associated with the Co-Circulation of Multiple Viral Lineages and Localized Density-Dependent Transmission

Dengue is one of the most important infectious diseases of humans and has spread throughout much of the tropical and subtropical world. Despite this widespread dispersal, the determinants of dengue transmission in endemic populations are not well understood, although essential for virus control. To address this issue we performed a phylogeographic analysis of 751 complete genome sequences of dengue 1 virus (DENV-1) sampled from both rural (Dong Thap) and urban (Ho Chi Minh City) populations in southern Viet Nam during the period 2003–2008. We show that DENV-1 in Viet Nam exhibits strong spatial clustering, with likely importation from Cambodia on multiple occasions. Notably, multiple lineages of DENV-1 co-circulated in Ho Chi Minh City. That these lineages emerged at approximately the same time and dispersed over similar spatial regions suggests that they are of broadly equivalent fitness. We also observed an important relationship between the density of the human host population and the dispersion rate of dengue, such that DENV-1 tends to move from urban to rural populations, and that densely populated regions within Ho Chi Minh City act as major transmission foci. Despite these fluid dynamics, the dispersion rates of DENV-1 are relatively low, particularly in Ho Chi Minh City where the virus moves less than an average of 20 km/year. These low rates suggest a major role for mosquito-mediated dispersal, such that DENV-1 does not need to move great distances to infect a new host when there are abundant susceptibles, and imply that control measures should be directed toward the most densely populated urban environments

A long-period transiting substellar companion in the super-Jupiters to brown dwarfs mass regime and a prototypical warm-Jupiter detected by TESS

We report on the confirmation and follow-up characterization of two long-period transiting substellar companions on low-eccentricity orbits around TIC 4672985 and TOI-2529, whose transit events were detected by the TESS space mission. Ground-based photometric and spectroscopic follow up from different facilities, confirmed the substellar nature of TIC 4672985 b, a massive gas giant, in the transition between the super-Jupiters and brown-dwarfs mass regime. From the joint analysis we derived the following orbital parameters: P = 69.0480+0.0004−0.0005 d, Mp = 12.74+1.01−1.01 MJ, Rp =1.026+0.065−0.067 RJ and e = 0.018+0.004−0.004 . In addition, the RV time series revealed a significant trend at the ∼ 350 m s−1 yr−1level, which is indicative of the presence of a massive outer companion in the system. TIC 4672985 b is a unique example of a transiting substellar companion with a mass above the deuterium-burning limit, located beyond 0.1 AU and in a nearly circular orbit. These planetary properties are difficult to reproduce from canonical planet formation and evolution models. For TOI-2529 b, we obtained the following orbital parameters: P = 64.5949+0.0003−0.0003 d, Mp =2.340+0.197−0.195 MJ, Rp = 1.030+0.050−0.050 RJ and e = 0.021+0.024−0.015 , making this object a new example of a growing population of transiting warm giant planets

Impact of inactivity and exercise on the vasculature in humans

The effects of inactivity and exercise training on established and novel cardiovascular risk factors are relatively modest and do not account for the impact of inactivity and exercise on vascular risk. We examine evidence that inactivity and exercise have direct effects on both vasculature function and structure in humans. Physical deconditioning is associated with enhanced vasoconstrictor tone and has profound and rapid effects on arterial remodelling in both large and smaller arteries. Evidence for an effect of deconditioning on vasodilator function is less consistent. Studies of the impact of exercise training suggest that both functional and structural remodelling adaptations occur and that the magnitude and time-course of these changes depends upon training duration and intensity and the vessel beds involved. Inactivity and exercise have direct “vascular deconditioning and conditioning” effects which likely modify cardiovascular risk

Predicting attitudinal and behavioral responses to COVID-19 pandemic using machine learning

At the beginning of 2020, COVID-19 became a global problem. Despite all the efforts to emphasize the relevance of preventive measures, not everyone adhered to them. Thus, learning more about the characteristics determining attitudinal and behavioral responses to the pandemic is crucial to improving future interventions. In this study, we applied machine learning on the multinational data collected by the International Collaboration on the Social and Moral Psychology of COVID-19 (N = 51,404) to test the predictive efficacy of constructs from social, moral, cognitive, and personality psychology, as well as socio-demographic factors, in the attitudinal and behavioral responses to the pandemic. The results point to several valuable insights. Internalized moral identity provided the most consistent predictive contribution—individuals perceiving moral traits as central to their self-concept reported higher adherence to preventive measures. Similar results were found for morality as cooperation, symbolized moral identity, self-control, open-mindedness, and collective narcissism, while the inverse relationship was evident for the endorsement of conspiracy theories. However, we also found a non-neglible variability in the explained variance and predictive contributions with respect to macro-level factors such as the pandemic stage or cultural region. Overall, the results underscore the importance of morality-related and contextual factors in understanding adherence to public health recommendations during the pandemic.Peer reviewe