A significant number of studies suggest that coffee consumption reduces cancer risk. This beneficial effect is usually ascribed to the presence of polyphenolic antioxidants and anti-inflammatory ...agents, including caffeine, cafestol, kahweol, and chlorogenic acids. To summarize recent literature on this subject, we performed a bibliographic search in PubMed and Embase over the period January 2005 to December 2020 to identify cohort studies and meta-analysis (with data collection ensuring quality of selected reports) that could provide quantitative data on the relationship between coffee consumption and common cancers. The totality of eligible scientific articles supports the evidence that coffee intake is inversely associated with risk of hepatocellular cancer and, to a slight extent, risk of breast cancer among postmenopausal women. As to the association with other organs, including the esophagus, pancreas, colorectum, kidneys, bladder, ovaries, and prostate, the results are less clear as reports reveal conflicting results or statistically nonsignificant data. Therefore, this overview does not provide broad-based conclusions. Important uncertainties include general study design, inhomogeneous patient sampling, different statistical analysis (deliberate), misreporting of socioeconomic status, education, coffee-brewing methods, consumption of caffeinated or decaffeinated coffee, smoking habits, and alcohol intake. Clearly, more epidemiologic research needs to be conducted before solid science-based recommendations can be made with regard to coffee consumption.
The extremely harsh conditions, in which the detectors will have to operate during the High Luminosity phase of the Large Hadron Collider at CERN, set stringent requirements on the properties of the ...scintillators which can be used. Among different scintillating materials under study, inorganic crystals such as LuAG:Ce and YAG:Ce represent good candidates for such application. A detailed investigation of the radiation hardness of LuAG:Ce and YAG:Ce crystal samples (1 ×1 ×1 cm 3 cubes) produced by Crytur is presented in this study. Given their potential in many calorimeter designs, YAG:Ce samples with high aspect ratio ( 1 ×1 ×14 cm 3 ) have also been tested. Optical and scintillating properties of the samples were studied before and after irradiation with different sources and at different intensities. Irradiation with gamma-rays to the doses of 1 and 100 kGy and with 24 GeV protons up to an integrated fluence of 10 14 cm -2 were performed at CERN. The scintillating properties of the crystals, as emission and excitation spectra and light yield remained unchanged after irradiation and only small levels of induced absorption were observed. The results obtained in this test confirm the potential of LuAG:Ce and YAG:Ce crystals as good candidates for calorimetry applications in future high energy physics experiments.
Friends and Foes in Alzheimer’s Disease Pauwels, Ernest K.J.; Boer, Gerard J.
Medical principles and practice,
12/2023, Letnik:
32, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Alzheimer’s disease (AD) is a disabling neurodegenerative disease. The prognosis is poor, and currently there are no proven effective therapies. Most likely, the etiology is related to cerebral ...inflammatory processes that cause neuronal damage, resulting in dysfunction and apoptosis of nerve cells. Pathogens that evoke a neuroinflammatory response, collectively activate astrocytes and microglia, which contributes to the secretion of pro-inflammatory cytokines. This leads to the deposit of clustered fragments of beta-amyloid and misfolded tau proteins which do not elicit an adequate immune reaction. Apart from the function of astrocytes and microglia, molecular entities such as TREM2, SYK, C22, and C33 play a role in the physiopathology of AD. Furthermore, bacteria and viruses may trigger an overactive inflammatory response in the brain. Pathogens like Helicobacter pylori, Chlamydia pneumonia, and Porphyromonas gingivalis (known for low-grade infection in the oral cavity) can release gingipains, which are enzymes that can damage and destroy neurons. Chronic infection with Borrelia burgdorferi (the causative agent of Lyme disease) can co-localize with tau tangles and amyloid deposits. As for viral infections, herpes simplex virus 1, cytomegalovirus, and Epstein-Barr virus can play a role in the pathogenesis of AD. Present investigations have resulted in the development of antibodies that can clear the brain of beta-amyloid plaques. Trials with humanized aducanumab, lecanemab, and donanemab revealed limited success in AD patients. However, AD should be considered as a continuum in which the initial preclinical phase may take 10 or even 20 years. It is generally thought that this phase offers a window for efficacious treatment. Therefore, research is also focused on the identification of biomarkers for early AD detection. In this respect, the plasma measurement of neurofilament light chain in patients treated with hydromethylthionine mesylate may well open a new way to prevent the formation of tau tangles and represents the first treatment for AD at its roots.
In 2020, more than 9 million patients suffering from Parkinson’s disease (PD) were reported worldwide, and studies predict that the burden of this disease will grow substantially in industrial ...countries. In the last decade, there has been a better understanding of this neurodegenerative disorder, clinically characterized by motor disturbances, impaired balance, coordination, memory difficulties, and behavioral changes. Various preclinical investigations and studies on human postmortem brains suggest that local oxidative stress and inflammation promote misfolding and aggregation of alpha-synuclein within Lewy bodies and cause nerve cell damage. Parallel to these investigations, the familial contribution to the disease became evident from studies on genome-wide association in which specific genetic defects were linked to neuritic alpha-synuclein pathology. As for treatment, currently available pharmacological and surgical interventions may improve the quality of life but do not stop the progress of neurodegeneration. However, numerous preclinical studies have provided insights into the pathogenesis of PD. Their results provide a solid base for clinical trials and further developments. In this review, we discuss the pathogenesis, the prospects, and challenges of synolytic therapy, CRISPR, gene editing, and gene- and cell-based therapy. We also throw light on the recent observation that targeted physiotherapy may help improve the gait and other motor impairments.
In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homologous end joining (NHEJ). DNA damage is detected by PARP proteins that ...facilitate this repair, both in normal cells and in cancer cells. Cells containing BRCA1/2 mutations have an HRR-deficient repair mechanism which may result in unrepaired one-ended double-strand breaks and stalled replication forks, considered as the most lethal cell damage. Here, we review the state of the art of the role of Poly (ADP-ribose) polymerase (PARP) inhibitors as a precision-targeted anticancer drug in BRCA1/2-mutated female breast cancer. Although knowledge is incomplete, it is assumed that the main role of the archetype PARP1 in the cell nucleus is to detect and adhere to single-strand breaks. This mediates possible damage repair, after which cells may continue replication; this process is called synthetic lethality. As for PARP clinical monotherapy, progression-free survival has been observed using the FDA- and EMA-approved drugs olaparib and talazoparib. In the case of combined drug therapy, a synergy has been demonstrated between veliparib and platinum drugs. Information regarding adverse effects is limited, but hematological effects have been described. However, there is need for multicenter trials, preferably conducted without commercial guidance and funding. Some of the available trials reported resistance to PARP inhibitors. In this review, we also describe the various causes of resistance to PARP inhibitors and research indicating how resistance can be overcome.
The aggregation and deposition of the amyloid-β peptide (Aβ) in the brain has been linked with neuronal death, which progresses in the diagnostic and pathological signs of Alzheimer’s disease (AD). ...The transition of an unstructured monomeric peptide into self-assembled and more structured aggregates is the crucial conversion from what appears to be a harmless polypeptide into a malignant form that causes synaptotoxicity and neuronal cell death. Despite efforts to identify the toxic form of Aβ, the development of effective treatments for AD is still limited by the highly transient and dynamic nature of interconverting forms of Aβ. The variability within the in vivo “pool” of different Aβ peptides is another complicating factor. Here we review the dynamical interplay between various components that influence the heterogeneous Aβ system, from intramolecular Aβ flexibility to intermolecular dynamics between various Aβ alloforms and external factors. The complex dynamics of Aβ contributes to the causative role of Aβ in the pathogenesis of AD.
The purpose of this study was to investigate the contribution of stereopsis to the processing of observed manipulative actions. To this end, we first combined the factors "stimulus type" (action, ...static control, and dynamic control), "stereopsis" (present, absent) and "viewpoint" (frontal, lateral) into a single design. Four sites in premotor, retro-insular (2) and parietal cortex operated specifically when actions were viewed stereoscopically and frontally. A second experiment clarified that the stereo-action-specific regions were driven by actions moving out of the frontoparallel plane, an effect amplified by frontal viewing in premotor cortex. Analysis of single voxels and their discriminatory power showed that the representation of action in the stereo-action-specific areas was more accurate when stereopsis was active. Further analyses showed that the 4 stereo-action-specific sites form a closed network converging onto the premotor node, which connects to parietal and occipitotemporal regions outside the network. Several of the specific sites are known to process vestibular signals, suggesting that the network combines observed actions in peripersonal space with gravitational signals. These findings have wider implications for the function of premotor cortex and the role of stereopsis in human behavior.
Molecular imaging techniques are increasingly being used as valuable tools in the drug development process. Radionuclide-based imaging modalities such as single-photon emission computed tomography ...(SPECT) and positron emission tomography (PET) have proven to be useful in phases ranging from preclinical development to the initial stages of clinical testing. The high sensitivity of these imaging modalities makes them particularly suited for exploratory investigational new drug (IND) studies as they have the potential to characterize
in vivo pharmacokinetics and biodistribution of the compounds using only a fraction of the intended therapeutic dose (microdosing). This information obtained at an early stage of clinical testing results in a better selection among promising drug candidates, thereby increasing the success rate of agents entering clinical trials and the overall efficiency of the process. In this article, we will review the potential applications of SPECT imaging in the drug development process with an emphasis on its applications in exploratory IND studies.
Undoped and Ce3+-doped Lu3Al5O12 (LuAG) fibers were grown to evaluate their potential use in new particle physics experiments, such as dual-readout calorimeters. The choice of grown crystals was made ...to detect scintillation (doped LuAG) and Cherenkov radiation (undoped LuAG). Growth conditions for obtaining fibers with improved quality were found based on measurements of attenuation length of the fibers and cathodoluminescence measurements. The effect of annealing on attenuation length for LuAG and LuAG:Ce was also studied. In addition, we also evaluated a possibility to substitute LuAG by the cheaper mixed and (Lu,Y)3Al5O12 (LuYAG:Ce) fibers.
•Undoped and Ce-doped LuAG fibers were grown by micro-pulling down technique.•Substitution of Lu3+ by Y3+ in (Lu1−xYx)3Al5O12 fibers improve Ce distribution.•Annealing of Ce-doped LuAG fibers improve the light propagation through the fibers.•Attenuation length over 1m can be achieved in LuAG:Ce after thermal annealing.
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