The Impact of the Microbiome on Resistance to Cancer Treatment with Chemotherapeutic Agents and Immunotherapy

Understanding the mechanisms of resistance to therapy in human cancer cells has become a multifaceted limiting factor to achieving optimal cures in cancer patients. Besides genetic and epigenetic alterations, enhanced DNA damage repair activity, deregulation of cell death, overexpression of transmembrane transporters, and complex interactions within the tumor microenvironment, other mechanisms of cancer treatment resistance have been recently proposed. In this review, we will summarize the preclinical and clinical studies highlighting the critical role of the microbiome in the efficacy of cancer treatment, concerning mainly chemotherapy and immunotherapy with immune checkpoint inhibitors. In addition to involvement in drug metabolism and immune surveillance, the production of microbiota-derived metabolites might represent the link between gut/intratumoral bacteria and response to anticancer therapies. Importantly, an emerging trend of using microbiota modulation by probiotics and fecal microbiota transplantation (FMT) to overcome cancer treatment resistance will be also discussed.     

Mitochondrial Processing Peptidases—Structure,Function and the Role in Human Diseases

Mitochondrial proteins are encoded by both nuclear and mitochondrial DNA. While some of the essential subunits of the oxidative phosphorylation (OXPHOS) complexes responsible for cellular ATP production are synthesized directly in the mitochondria, most mitochondrial proteins are first translated in the cytosol and then imported into the organelle using a sophisticated transport system. These proteins are directed mainly by targeting presequences at their N-termini. These presequences need to be cleaved to allow the proper folding and assembly of the pre-proteins into functional protein complexes. In the mitochondria, the presequences are removed by several processing peptidases, including the mitochondrial processing peptidase (MPP), the inner membrane processing peptidase (IMP), the inter-membrane processing peptidase (MIP), and the mitochondrial rhomboid protease (Pcp1/PARL). Their proper functioning is essential for mitochondrial homeostasis as the disruption of any of them is lethal in yeast and severely impacts the lifespan and survival in humans. In this review, we focus on characterizing the structure, function, and substrate specificities of mitochondrial processing peptidases, as well as the connection of their malfunctions to severe human diseases.     

Arsenic in atmospheric deposition at the Czech-Polish border: two sampling campaigns 20 years apart

Arsenic (As) occurs in atmospheric deposition both in soluble and insoluble forms, mainly bound to fine aerosol particles (less than 2.5 microm). Interception deposition (i.e. fog, dew and ice accretion) represents a specific type of atmospheric deposition, which has been much more contaminated with As than bulk deposition. This study compares the As amount and its binding forms in bulk and interception deposition in the winters of 1984-1986 and 2003-2005 in the Orlické hory mountains (Adlergebirge) near the Czech-Polish border; sampled and analysed by the same methodology. The As concentrations in ice accretions decreased 16 times over the twenty year period (from 50 microg L(-1) to 3 microg L(-1)), while the pH values increased by 0.8 units. As concentrations in snow decreased from 15 microg L(-1) in 1984-1986 to <2 microg L(-1) in 2003-2005. This decline mirrored the considerable decrease in industrial emissions in Central Europe. Higher acidity of interception deposition (about 1 pH unit) in comparison with the bulk deposition was observed in both sampling periods. The quantity of bulk deposition (snowfall) also influenced the As concentration in interception deposition. Dry periods resulted in higher As-amounts in interception deposition due to limited washing of atmospheric aerosol particles by wet deposition. The As concentration and stability in atmospheric deposition are important for the study of subsequent As-migration and/or accumulation in soil -- groundwater -- surface water.     

XPS studies of perovskites surface instability caused by Ar+ ion and electron bombardment and metal deposition

X-ray Photoelectron Spectroscopy (XPS) was used to study the influence of low energy Ar⁺ ion bombardment, electron bombardment and Pt deposition on the SrTiO₃ (STO) single crystal electronic structure. Atomic composition changes were found and attributed to chemical reconstruction of the STO surface. A clear correlation between the presence of conducting, low Ti oxidation states in valence band and core level changes was detected. A strong effect caused by electron irradiation was ascribed to the electroreduction process. The influence of lanthanum doping on surface instability of STO was also discussed. The La doped sample (STO: 3,75% La) was found to be modified upon Pt metal deposition to a higher degree than pure STO crystal.     

Bupropion and desipramine increase dopamine transporter mRNA expression in the ventral tegmental area/substantia nigra of rat brain

The homeobox gene Otx2 is a mouse cognate of the Drosophila orthodenticle gene, which is required for development of the brain, rostral to rhombomere three. We have investigated the mechanisms involved in this neural function and specifically the requirement for Otx2 in the visceral endoderm and the neuroectoderm using chimeric analysis in mice and explant recombination assay. Analyses of chimeric embryos composed of more than 90% of Otx2-/- ES cells identified an essential function for Otx2 in the visceral endoderm for induction of the forebrain and midbrain. The chimeric studies also demonstrated that an anterior neural plate can form without expressing Otx2. However, in the absence of Otx2, expression of important regulatory genes, such as Hesx1/Rpx, Six3, Pax2, Wnt1 and En, fail to be initiated or maintained in the neural plate. Using explant-recombination assay, we could further demonstrate that Otx2 is required in the neuroectodem for expression of En. Altogether, these results demonstrate that Otx2 is first required in the visceral endoderm for the induction, and subsequently in the neuroectoderm for the specification of forebrain and midbrain territories.     

Dielectric properties and phase transition in SrBi2Nb2O9–SrBi2Ta2O9 solid solution

Structural and dielectric properties of SrBi₂(Nb_1?xTa_x)₂O₉ solid solution, (SBNT), with x = 0.0, 0.1, 0.2, 0.3, 0.5, 0.7, 1.0 were investigated. Crystal structure at room temperature was analyzed by X-ray diffraction study. SBNT exhibits an Aurivillius structure and the c lattice constant decreases with increasing concentration of Ta in the solution. The studies of real (?′) and imaginary (?″) parts of permittivity as a function of temperature (20–500 °C) and frequency (0.1–100 kHz) were carried out, as well. The anomalies of ?′(T) and ?″(T) associated with phase transition from the tetragonal paraelectric phase (P_T) to the orthorhombic ferroelectric phase (F_O) were observed. They are strongly dependent on the Ta content in the solution. The grain structure and chemical composition were examined by a scanning electron microscope (SEM), with an energy dispersion spectrometer (EDS). The EDS analysis indicated a homogeneous distribution of all elements of ceramics within the grains.     

The role of CD8 and CD4 T cells in intestinal allograft rejection: a comparison of monoclonal antibody-treated and knockout mice

Studies were performed to determine the effects of PTH and related compounds on phosphatidylcholine (PC) hydrolysis in UMR-106 cells and the pathway by which the PTH effects occurred. The responses were compared with those of phorbol 12,13-dibutyrate (PDBu). Both bovine PTH-(1-34) [bPTH-(1-34)] and PDBu stimulated PC hydrolysis within 10 min. Significant effects were elicited by concentrations of 0.3-1 nM bPTH-(1-34) and 5 nM PDBu. Dose-dependent increases were seen at higher concentrations of both compounds, however, the response to bPTH-(1-34) was reduced at 30 nM. Bovine or human PTH-(1-34) and human PTH-related peptide-(1-34) [hPTHrP-(1-34)] were equipotent in their effects, whereas bovine [Nle(8,18)Tyr34]PTH-(3-34) amide [bPTH-(3-34)] and hPTH-(1-31) amide [hPTH-(1-31)] were less potent than bPTH-(1-34). bPTH-(3-34) did not antagonize the effects of bPTH-(1-34). Down-regulation of protein kinase C isozymes by 24-h treatment with PDBu completely prevented the stimulatory effect of PDBu on PC hydrolysis, but did not significantly affect the stimulatory effect of bPTH-(1-34). Both bPTH-(1-34) and PDBu stimulated transphosphatidylation of PC, indicating a phospholipase D-stimulated mechanism. The results suggest that in the UMR-106 cell line PTH can stimulate activation of PLD by a mechanism other than through protein kinase C.     

New applications of pHluorin—measuring intracellular pH of prototrophic yeasts and determining changes in the buffering capacity of strains with affected potassium homeostasis

pHluorin is a pH‐sensitive variant of green fluorescent protein for measuring intracellular pH (pH_in) in living cells. We constructed a new pHluorin plasmid with the dominant selection marker KanMX. This plasmid allows pH measurements in cells without auxotrophic mutations and/or grown in chemically indefinite media. We observed differing values of pH_in for three prototrophic wild‐types. The new construct was also used to determine the pH_in in strains differing in the activity of the plasma membrane Pma1 H⁺‐ATPase and the influence of glucose on pH_in. We describe in detail pHluorin measurements performed in a microplate reader, which require much less hands‐on time and much lower cell culture volumes compared to standard cuvettes measurements. We also utilized pHluorin in a new method of measuring the buffering capacity of yeast cell cytosol in vivo, shown to be ca. 52 mM /pH for wild‐type yeast and moderately decreased in mutants with affected potassium transport. Copyright © 2010 John Wiley & Sons, Ltd.     

Performance of “ductless” personalized ventilation in conjunction with displacement ventilation: Impact of intake height

The importance of the intake positioning height above the floor level on the performance of “ductless” personalized ventilation (“ductless” PV) in conjunction with displacement ventilation (DV) was examined with regard to the quality of inhaled air and of the thermal comfort provided. A typical office room with two workstations positioned one behind the other was arranged in a full-scale room. Each workstation consisted of a table with an installed “ductless” PV system, PC, desk lamp and seated breathing thermal manikin. The “ductless” PV system sucked the clean and cool displacement air supplied over the floor at four different heights, i.e. 2, 5, 10 and 20 cm and transported it direct to the breathing level. Moreover, two displacement airflow rates were used with a supply temperature adjusted in order to maintain an exhaust air temperature of 26 °C. Two pollution sources, namely air exhaled by one of the manikins and passive pollution on the table in front of the same manikin were simulated by constant dosing of tracer gases. The results show that the positioning of a “ductless” PV intake height up to 0.2 m above the floor will not significantly influence the quality of inhaled air and thermal comfort.