Transgenerational and intergenerational effects of early childhood famine exposure in the cohort of offspring of Leningrad Siege survivors

Famine exposure during early life development can affect disease risk in late-life period, yet, transmission of phenotypic features from famine-exposed individuals to the next generations has not been well characterized. The purpose of our case–control study was to investigate the association of parental starvation in the perinatal period and the period of early childhood with the phenotypic features observed in two generations of descendants of Leningrad siege survivors. We examined 54 children and 30 grandchildren of 58 besieged Leningrad residents who suffered from starvation in early childhood and prenatal age during the Second World War. Controls from the population-based national epidemiological ESSE-RF study (n = 175) were matched on sex, age and body mass index (BMI). Phenotypes of controls and descendants (both generations, children and grandchildren separately) were compared, taking into account multiple testing. Comparison of two generations descendants with corresponding control groups revealed significantly higher creatinine and lower glomerular filtration rate (GFR), both in meta-analysis and in independent analyses. The mean values of GFR for all groups were within the normal range (GFR less than 60 mL/min/1.73 m2 was recorded in 2 controls and no one in DLSS). Additionally, independent of the creatinine level, differences in the eating pattern were detected: insufficient fish and excessive red meat consumption were significantly more frequent in the children of the Leningrad siege survivors compared with controls. Blood pressure, blood lipids and glucose did not differ between the groups. Parental famine exposure in early childhood may contribute to a decrease in kidney filtration capacity and altered eating pattern in the offspring of famine-exposed individuals.</p

Orally administered oxygen nanobubbles enhance tumor response to sonodynamic therapy

Suspensions of oxygen-filled bubbles are under active investigation as potential means of relieving tissue hypoxia. Intravenous administration of large quantities of bubbles is, however, undesirable. Previous work by the authors has demonstrated that tumor oxygen levels can be increased following oral administration of phospholipid stabilized oxygen nanobubbles. The aim of this study was to determine whether this would enhance the efficacy of sonodynamic therapy (SDT), which is known to be inhibited in hypoxic tissue. Experiments were conducted in a murine model of pancreatic cancer. Animals were treated with SDT (intratumoural injection of 1 mM Rose Bengal followed by exposure to 1 MHz ultrasound, 0.1 kHz pulse repetition frequency, 30% duty cycle, 3.5 W cm−2 for 3.5 minutes) either with or without a prior gavage of oxygen bubbles. A statistically significant reduction in the rate of tumor growth was observed in the groups receiving oxygen nanobubbles either 5 or 20 minutes before SDT. Separate measurements of tumor oxygen using a fiber optic probe and expression of hypoxia inducible factor (HIF)1α following tumor excision, confirmed the change in tumor oxygen levels. These findings offer a potentially promising new approach to relieving tissue hypoxia in order to facilitate cancer therapy

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Investigation of the mechanisms of oxygen delivery and cell death in oxygen-enhanced sonodynamic therapy

Sonodynamic therapy, which is usually defined as ultrasound-mediated activation of certain drugs, is of substantial interest in the field of oncology. However, currently there is no consensus on the mechanisms of its action, and elucidating them would assist in the transition of sonodynamic therapy into clinical practice. There is a discrepancy between the observed low quantities of reactive oxygen species produced by drugs combined with ultrasound and the substantial in vivo effects seen in a number of studies; in addition, for oxygen-enhanced sonodynamic therapy, there is also a mismatch between the low dose of oxygen transported by the carrier agents and the observed improvements in therapy outcomes. The overall goal of this thesis was to investigate these discrepancies. Hypotheses were proposed to explain both mismatches, and new setups and experiments were designed to test them, resulting in a better understanding of oxygen-enhanced sonodynamic therapy mechanisms

Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment

The emergence of drug resistant Mycobacterium tuberculosis (MTB) strains has become a global public health problem, while, at the same time, there has been development of new antimicrobial agents. The main goals of this study were to determine new variants associated with drug resistance in MTB and to observe which polymorphisms emerge in MTB genomes after anti-tuberculosis treatment. We performed whole-genome sequencing of 152 MTB isolates including 70 isolates as 32 series of pre- and post-treatment MTB. Based on genotypes and phenotypic drug susceptibility, we conducted phylogenetic convergence-based genome-wide association study (GWAS) with streptomycin-, isoniazid-, rifampicin-, ethambutol-, fluoroquinolones-, and aminoglycosides-resistant MTB against susceptible ones. GWAS revealed statistically significant associations of SNPs within Rv2820c, cyp123 and indels in Rv1269c, Rv1907c, Rv1883c, Rv2407, Rv3785 genes with resistant MTB phenotypes. Comparisons of serial isolates showed that treatment induced different patterns of intra-host evolution. We found indels within Rv1435c and ppsA that were not lineage-specific. In addition, Beijing-specific polymorphisms within Rv0036c, Rv0678, Rv3433c, and dop genes were detected in post-treatment isolates. The appearance of Rv3785 frameshift insertion in 2 post-treatment strains compared to pre-treatment was also observed. We propose that the insertion within Rv3785, which was a GWAS hit, might affect cell wall biosynthesis and probably mediates a compensatory mechanism in response to treatment. These results may shed light on the mechanisms of MTB adaptation to chemotherapy and drug resistance formation

Highly Sensitive Measurement of Horseradish Peroxidase Using Surface-Enhanced Raman Scattering of 2,3-Diaminophenazine

The development of various enzyme-linked immunosorbent assays (ELISAs) coupled with surface-enhanced Raman scattering (SERS) detection is a growing area in analytical chemistry due to their potentially high sensitivity. A SERS-based ELISA with horseradish peroxidase (HRP) as an enzymatic label, an o-phenylenediamine (oPD) substrate, and a 2,3-diaminophenazine (DAP) enzymatic product was one of the first examples of such a system. However, the full capabilities of this long-known approach have yet to be revealed. The current study addresses a previously unrecognized problem of SERS detection stage performance. Using silver nanoparticles and model mixtures of oPD and DAP, the effects of the pH, the concentration of the aggregating agent, and the particle surface chloride stabilizer were extensively evaluated. At the optimal mildly acidic pH of 3, a 0.93 to 1 M citrate buffer, and AgNPs stabilized with 20 mM chloride, a two orders of magnitude advantage in the limits of detection (LODs) for SERS compared to colorimetry was demonstrated for both DAP and HRP. The resulting LOD for HRP of 0.067 pmol/L (1.3 amol per assay) underscores that the developed approach is a highly sensitive technique. We suppose that this improved detection system could become a useful tool for the development of SERS-based ELISA protocols

Controlled LCST Behavior and Structure Formation of Alternating Amphiphilic Copolymers in Water

Amphiphilic polymers show a rich self-assembly behavior in aqueous solutions. In experimental investigations statistical copolymer or block copolymer architectures are usually investigated, because of their ease of synthesis or their structural analogy to surfactants. A copolymer structure that links the two architectures are alternating copolymers, which are easily accessible by polycondensation reactions. Using alternating hydrophilic and hydrophobic building blocks with varying length allows a systematic variation between statistical and multi-block architectures. We synthesized alternating amphiphilic copolymers as polyesters using hydrophobic dicarboxylic acids (C4 – C20) and hydrophilic polyethylene glycol (PEG) units (EG3 – EG1000). Copolymers with long EG units were made accessible with the help of a newly developed esterification process. The solution properties of the amphiphilic copolymers feature a lower critical solution temperature (LCST) behavior in water, which can be systematically varied over a wide range from 3 – 83°C by adjusting the lengths of the Cn- and EGm–units. We find that the transition temperature depends linearly on the hydrophobic unit length Cm and logarithmically on the hydrophilic length EGn. In the one-phase region the PEG copolymer coils are more compact compared to the respective PEG homopolymers due to hydrophobic interactions between the hydrophobic units leading to loop formation. For shorter PEG-units the copolymers form micellar structures consisting only of a few copolymer chains. The micellar cores consist of hydrophobic regions containing only a few dicarboxylic acid units, embedded in a PEG-rich and water-poor matrix. The cores are surrounded by a rather diluted corona of PEG chains. Further decreasing the PEG unit length leads to the formation of highly swollen gels consisting of networks of interconnected micelles. These can self-assemble to form highly ordered liquid crystalline cubic phases. The study demonstrates how the structure of alternating amphiphilic copolymers can be systematically varied to adjust thermal solution properties such as the LCST over a wide range, as well as the self-assembly properties varying between single chain, micelle, gels and highly ordered lyotropic liquid crystals