Metabolomic Profiling of Plasma from Melioidosis Patients Using UHPLC-QTOF MS Reveals Novel Biomarkers for Diagnosis

To identify potential biomarkers for improving diagnosis of melioidosis, we compared plasma metabolome profiles of melioidosis patients compared to patients with other bacteremia and controls without active infection, using ultra-high-performance liquid chromatography-electrospray ionization-quadruple time-of-flight mass spectrometry. Principal component analysis (PCA) showed that the metabolomic profiles of melioidosis patients are distinguishable from bacteremia patients and controls. Using multivariate and univariate analysis, 12 significant metabolites from four lipid classes, acylcarnitine (n = 6), lysophosphatidylethanolamine (LysoPE) (n = 3), sphingomyelins (SM) (n = 2) and phosphatidylcholine (PC) (n = 1), with significantly higher levels in melioidosis patients than bacteremia patients and controls, were identified. Ten of the 12 metabolites showed area-under-receiver operating characteristic curve (AUC) >0.80 when compared both between melioidosis and bacteremia patients, and between melioidosis patients and controls. SM(d18:2/16:0) possessed the largest AUC when compared, both between melioidosis and bacteremia patients (AUC 0.998, sensitivity 100% and specificity 91.7%), and between melioidosis patients and controls (AUC 1.000, sensitivity 96.7% and specificity 100%). Our results indicate that metabolome profiling might serve as a promising approach for diagnosis of melioidosis using patient plasma, with SM(d18:2/16:0) representing a potential biomarker. Since the 12 metabolites were related to various pathways for energy and lipid metabolism, further studies may reveal their possible role in the pathogenesis and host response in melioidosis.     

Tripalmitin–Sodium Dodecyl Sulfate Emulsion Droplet Liquid vs. Solid State Impacts in vitro Digestive Lipolysis

Questions remain as to the impact of lipid structure, including crystallinity, on digestibility and metabolic response. This study was undertaken to determine the impact of triacylglycerol crystallinity on digestibility using undercooled (liquid emulsion, LE) and crystalline (solid emulsion, SE) particles exposed to an in vitro model simulating upper gastrointestinal tract (GIT) digestive conditions. By hot microfluidization, 10 wt% tripalmitin oil‐in‐water emulsions (D_3,2 ~ 0.115 nm) with 0.9 wt% sodium dodecyl sulfate (SDS) were prepared. SE demonstrated complex melting behavior, was predominantly in the beta polymorph, and consisted of a heterogeneous mixture of anisometric particles. In vitro duodenal lipolysis was more extensive for the spherically shaped LE droplets vs. SE (P < 0.05), despite the fact that exposure to simulated gastric conditions (at pH 2, but not at pH 7) induced partial crystallization. Therefore, lipid droplet physical state impacted and was impacted by exposure to gastrointestinal conditions, with differences observed in fatty acid digestive release and implications for lipid absorption.     

Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.     

In Situ X-ray Diffraction and Young's Modulus Measurement during Heat Treatment of High-Alumina Cement Castables

In situ Young's modulus measurements and synchrotron radiation-energy dispersive diffraction have been used to study changes in high-alumina castables subjected to heat treatment from room temperature to 1600°C. Particular attention was paid to the hydrate conversion process and the effects of high temperature.     

In vivo study of hybrid biomaterial scaffold bioactive glass–chitosan after incorporation of Ciprofloxacin

The present study aimed to evaluate the effect of bioactive glass as well as the presence of Ciprofloxacin drug (%Cip) into bioactive glass–chitosan composite on the in vivo behavior of these scaffolds. These scaffolds were implanted in the femoral condyl of an ovariectomized rat. The serum and organs (liver and kidney) of the under investigated rats were analyzed. Also the physicochemical properties of the prepared implants were assessed using Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) before and after implantation (at different periods of implantation). Biochemical and histological analyses of the under investigated rats proved the biocompatibility of the prepared scaffolds. The hydroxyapatite like layer was significantly precipitated on the surface of BG–CH scaffold than BG–CH–20Cip. In this same period, FT-IR of BG–CH shows complete disappearance of Si–O–Si. Their characteristics bands were replaced by P–O group arisen form bone apatite bands. Physicochemical results show progressive degradation of BG–CH and BG–CH–20Cip that occurred at the same time as replacement of the implant by an apatite layer. However, the bioresorbability and bioactivity of BG–CH are faster than those of BG–CH–20Cip. Therefore, the incorporation of the Ciprofloxacin in the BG–CH induces a retarding effect on the formation of the hydroxyapatite, and consequently on the ossification, without any side effects on the liver–kidney.     

Vitamin D and Death by Sunshine

Exposure to sunlight is the major cause of skin cancer. Ultraviolet radiation (UV) from the sun causes damage to DNA by direct absorption and can cause skin cell death. UV also causes production of reactive oxygen species that may interact with DNA to indirectly cause oxidative DNA damage. UV increases accumulation of p53 in skin cells, which upregulates repair genes but promotes death of irreparably damaged cells. A benefit of sunlight is vitamin D, which is formed following exposure of 7-dehydrocholesterol in skin cells to UV. The relatively inert vitamin D is metabolized to various biologically active compounds, including 1,25-dihydroxyvitamin D3. Therapeutic use of vitamin D compounds has proven beneficial in several cancer types, but more recently these compounds have been shown to prevent UV-induced cell death and DNA damage in human skin cells. Here, we discuss the effects of vitamin D compounds in skin cells that have been exposed to UV. Specifically, we examine the various signaling pathways involved in the vitamin D-induced protection of skin cells from UV.     

Effect of hydrodynamics on dynamics of phase separation in polystyrene/poly(vinyl methyl ether) blend

Polystyrene/poly(vinyl methyl ether) (PS/PVME) phase diagram was assessed by rheological tools and by on-line microscopy observations both under quiescent and shear flow conditions. Shear flow was found to induce both mixing and demixing of the mixture depending on the amplitude of the imposed shear rate. Viscoelastic properties of PS/PVME blends were also measured under steady shear flow near the phase separation temperature. At lower shear rate, flow enhances concentration fluctuation and induces phase segregation. At high shear rate, flow suppresses fluctuations and the polymer mixture keeps its miscible state. Several rheological signatures of phase transition were found. In steady shear flow, a secondary plateau in viscosity was observed when the temperature was close to T_s whereas, at the start-up shear flow, transient shear stress showed a second overshoot after a few minutes of shearing.     

UV resonance Raman probe of heme-bound imidazole established by 15N-labeling of hemoglobin

Recent studies of Cu, Zn superoxide dismutase, and of zinc-finger peptides have established that histidine ligands can be detected in ultraviolet resonance Raman (UVRR) spectra, following NH/D exchange of the imidazole. UVRR spectroscopy therefore offers promise for monitoring histidine ligation in heme proteins. In this work, we characterize heme-bound histidine UVRR bands for N-acetyl-microperoxidase-8 (MP-8) and microperoxidase-11 (MP-11), and also for hemoglobin (Hb). The Hb UVRR spectra are dominated by tyrosine and tryptophan contributions, but a band appears at 1340 cm⁻¹ in D₂O solution, which is assigned to a mode of Fe-bound imidazole. This band shifted 24 cm⁻¹ in protein which was labeled with ¹⁵N via expression of the Hb gene in E. coli grown on ¹⁵NH₄⁺. In MP-11, the position of this band is insensitive to ligation or oxidation state changes, but it is 2 cm⁻¹ lower in deoxyHb than in the CO adduct. This shift may reflect mechanical forces on the proximal histidine in the T state, and/or changes in its H-bonding.     

The Role of Gut Microbiota in Overcoming Resistance to Checkpoint Inhibitors in Cancer Patients: Mechanisms and Challenges

The introduction of immune checkpoint inhibitors has constituted a major revolution in the treatment of patients with cancer. In contrast with the traditional cytotoxic therapies that directly kill tumor cells, this treatment modality enhances the ability of the host’s immune system to recognize and target cancerous cells. While immune checkpoint inhibitors have been effective across multiple cancer types, overcoming resistance remains a key area of ongoing research. The gut microbiota and its role in cancer immunosurveillance have recently become a major field of study. Gut microbiota has been shown to have direct and systemic effects on cancer pathogenesis and hosts anti-tumor immune response. Many studies have also shown that the host microbiota profile plays an essential role in the response to immunotherapy, especially immune checkpoint inhibitors. As such, modulating this microbial environment has offered a potential path to overcome the resistance to immune checkpoint inhibitors. In this review, we will talk about the role of microbiota in cancer pathogenesis and immune-system activity. We will also discuss preclinical and clinical studies that have increased our understanding about the roles and the mechanisms through which microbiota influences the response to treatment with immune checkpoint inhibitors.     

Tributary confluences are dynamic thermal refuges for a juvenile salmonid in a warming river network

As rivers warm, cold‐water fish species may alleviate thermal stress by moving into localized thermal refuges such as cold‐water plumes created by cool tributary inflows. We quantified use of two tributary confluence plumes by juvenile steelhead, Oncorhynchus mykiss, throughout the summer, including how trout positioned themselves in relation to temperature within confluence plumes. At two confluences, Cedar and Elder creeks, along the South Fork Eel River, California, USA, we monitored temperatures using in situ logger grids throughout summer 2016. Fish were counted within confluences via snorkel surveys five times a day on 5 days at each site. We found diel and seasonal dependence on confluence use by steelhead, especially at the Cedar Creek confluence, where mainstem temperatures exceeded 28°C. At this site, fish moved into the confluence on the warmest days and warmest times of the day. Fish observed within the Cedar Creek confluence plume were most common in locations between 20–22°C, rather than the coldest locations (14.5°C). At Elder Creek, where mainstem temperatures remained below 24°C, there was little relationship between mainstem temperature and steelhead presence in the confluence plume. At both sites, steelhead distribution within plumes was influenced by spatial variation of temperature and mean temperature in surveyed grid cells. Our results show that cool tributaries flowing into warmer mainstem reaches (over 24°C) likely create important thermal refuges for juvenile steelhead. As mainstem rivers warm with climate change, cool‐water tributary inputs may become more important for sustaining cold‐water salmonids near the southern end of their range.