Idiosyncratic drug toxicities (IDTs) pose a significant challenge; they are marked by life-threatening adverse reactions that emerge aftermarket release and are influenced by intricate genetic and ...environmental variations. Recent genome-wide association studies have highlighted a strong correlation between specific human leukocyte antigen (HLA) polymorphisms and IDT onset. This review provides an overview of current research on HLA-mediated drug toxicities. In the last six years, HLA-transgenic (Tg) mice have been instrumental in advancing our understanding of these underlying mechanisms, uncovering systemic immune reactions that replicate human drug-induced immune stimulation. Additionally, the potential role of immune tolerance in shaping individual differences in adverse effects highlights its relevance to the interplay between HLA polymorphisms and IDTs. Although HLA-Tg mice offer valuable insights into systemic immune reactions, further exploration is essential to decipher the intricate interactions that lead to organ-specific adverse effects, especially in organs such as the skin or liver. Navigating the intricate interplay of HLA, which may potentially trigger intracellular immune responses, this review emphasizes the need for a holistic approach that integrates findings from both animal models and molecular/cellular investigations. The overarching goal is to enhance our comprehensive understanding of HLA-mediated IDTs and identify factors shaping individual variations in drug reactions. This review aims to facilitate the development of strategies to prevent severe adverse effects, address existing knowledge gaps, and provide guidance for future research initiatives in the field of HLA-mediated IDTs.
Most cancer cells rely on glycolysis to generate ATP, even when oxygen is available. However, merely inhibiting the glycolysis is insufficient for the eradication of cancer cells. One main reason for ...this is that cancer cells have the potential to adapt their metabolism to their environmental conditions. In this study, we investigated how cancer cells modify their intracellular metabolism when glycolysis is suppressed, using PANC-1 pancreatic cancer cells and two other solid tumor cell lines, A549 and HeLa. Our study revealed that glycolytically suppressed cells upregulated mitochondrial function and relied on oxidative phosphorylation (OXPHOS) to obtain the ATP necessary for their survival. Dynamic changes in intracellular metabolic profiles were also observed, reflected by the reduced levels of TCA cycle intermediates and elevated levels of most amino acids. Glutamine and glutamate were important for this metabolic reprogramming, as these were largely consumed by influx into the TCA cycle when the glycolytic pathway was suppressed. During the reprogramming process, activated autophagy was involved in modulating mitochondrial function. We conclude that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.
The incidence of neurodegenerative diseases has shown an increasing trend. These conditions typically cause progressive functional disability. Identification of robust biomarkers of neurodegenerative ...diseases is a key imperative to facilitate early identification of the pathological features and to foster a better understanding of the pathogenetic mechanisms of individual diseases. Diffusion tensor imaging (DTI) is the most widely used diffusion MRI technique for assessment of neurodegenerative diseases. The DTI parameters are promising biomarkers for evaluation of microstructural changes; however, some limitations of DTI restrict its wider clinical use. New diffusion MRI techniques, such as diffusion kurtosis imaging (DKI), bi‐tensor DTI, and neurite orientation density and dispersion imaging (NODDI) have been demonstrated to provide value addition to DTI for evaluation of neurodegenerative diseases. In this review article, we summarize the key technical aspects and provide an overview of the current state of knowledge regarding the role of DKI, bi‐tensor DTI, and NODDI as biomarkers of microstructural changes in representative neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.
Level of Evidence
5
Technical Efficacy Stage
2 J. MAGN. RESON. IMAGING 2020;52:1620–1636.
Purpose
The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method was developed to evaluate the brain’s glymphatic function or interstitial fluid dynamics. This study aimed ...to evaluate the reproducibility of the DTI-ALPS method and the effect of modifications in the imaging method and data evaluation.
Materials and methods
Seven healthy volunteers were enrolled in this study. Image acquisition was performed for this test–retest study using a fixed imaging sequence and modified imaging methods which included the placement of region of interest (ROI), imaging plane, head position, averaging, number of motion-proving gradients, echo time (TE), and a different scanner. The ALPS-index values were evaluated for the change of conditions listed above.
Results
This test–retest study by a fixed imaging sequence showed very high reproducibility (intraclass coefficient = 0.828) for the ALPS-index value. The bilateral ROI placement showed higher reproducibility. The number of averaging and the difference of the scanner did not influence the ALPS-index values. However, modification of the imaging plane and head position impaired reproducibility, and the number of motion-proving gradients affected the ALPS-index value. The ALPS-index values from 12-axis DTI and 3-axis diffusion-weighted image (DWI) showed good correlation (
r
= 0.86). Also, a shorter TE resulted in a larger value of the ALPS-index.
Conclusion
ALPS index was robust under the fixed imaging method even when different scanners were used. ALPS index was influenced by the imaging plane, the number of motion-proving gradient axes, and TE in the imaging sequence. These factors should be uniformed in the planning ALPS method studies. The possibility to develop a 3-axis DWI-ALPS method using three axes of the motion-proving gradient was also suggested.
White matter bundle segmentation using diffusion magnetic resonance imaging fiber tractography enables detailed evaluation of individual white matter tracts three-dimensionally, and plays a crucial ...role in studying human brain anatomy, function, development, and diseases. Manual extraction of streamlines utilizing a combination of the inclusion and exclusion of regions of interest can be considered the current gold standard for extracting white matter bundles from whole-brain tractograms. However, this is a time-consuming and operator-dependent process with limited reproducibility. Several automated approaches using different strategies to reconstruct the white matter tracts have been proposed to address the issues of time, labor, and reproducibility. In this review, we discuss few of the most well-validated approaches that automate white matter bundle segmentation with an end-to-end pipeline, including TRActs Constrained by UnderLying Anatomy (TRACULA), Automated Fiber Quantification, and TractSeg.
Among the various disorders that manifest with gait disturbance, cognitive impairment, and urinary incontinence in the elderly population, idiopathic normal pressure hydrocephalus (iNPH) is becoming ...of great importance. The first edition of these guidelines for management of iNPH was published in 2004, and the second edition in 2012, to provide a series of timely, evidence-based recommendations related to iNPH. Since the last edition, clinical awareness of iNPH has risen dramatically, and clinical and basic research efforts on iNPH have increased significantly. This third edition of the guidelines was made to share these ideas with the international community and to promote international research on iNPH. The revision of the guidelines was undertaken by a multidisciplinary expert working group of the Japanese Society of Normal Pressure Hydrocephalus in conjunction with the Japanese Ministry of Health, Labour and Welfare research project. This revision proposes a new classification for NPH. The category of iNPH is clearly distinguished from NPH with congenital/developmental and acquired etiologies. Additionally, the essential role of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) in the imaging diagnosis and decision for further management of iNPH is discussed in this edition. We created an algorithm for diagnosis and decision for shunt management. Diagnosis by biomarkers that distinguish prognosis has been also initiated. Therefore, diagnosis and treatment of iNPH have entered a new phase. We hope that this third edition of the guidelines will help patients, their families, and healthcare professionals involved in treating iNPH.
Abstract
Despite progress in the use of hyperthermia in clinical practice, the thermosensitivity of cancer cells is poorly understood. In a previous study, we found that sensitivity to hyperthermia ...varied between ovarian and uterine cancer cell lines. Upon hyperthermia, glycolytic enzymes decreased in hyperthermia-resistant SKOV3 cells. However, the mechanisms of glycolysis inhibition and their relationship with thermoresistance remain to be explored. In this study, metabolomic analysis indicated the downregulation of glycolytic metabolites in SKOV3 cells after hyperthermia. Proteomic and pathway analyses predicted that the ubiquitin pathway was explicitly activated in resistant SKOV3 cells, compared with hyperthermia-sensitive A2780 cells, and STUB1, a ubiquitin ligase, potentially targeted PKM, a glycolytic rate-limiting enzyme. PKM is degraded via ubiquitination upon hyperthermia. Although glycolysis is inactivated by hyperthermia, ATP production is maintained. We observed that oxygen consumption and mitochondrial membrane potential were activated in SKOV3 cells but suppressed in A2780 cells. The activation of mitochondria could compensate for the loss of ATP production due to the suppression of glycolysis by hyperthermia. Although the physiological significance has not yet been elucidated, our results demonstrated that metabolomic adaptation from the Warburg effect to mitochondrial oxidative phosphorylation could contribute to thermoresistance in ovarian and uterine cancer cells.
A
bstract
In the DsTau experiment at the CERN SPS (NA65), an independent and direct way to measure tau neutrino production following high energy proton interactions was proposed. As the main source ...of tau neutrinos is a decay of
D
s
mesons, produced in proton-nucleus interactions, the project aims at measuring a differential cross section of this reaction. The experimental method is based on a use of high resolution emulsion detectors for effective registration of events with short lived particle decays. Here we present the motivation of the study, details of the experimental technique, and the first results of the analysis of the data collected during test runs, which prove feasibility of the full scale study of the process in future.
•Flucloxacillin alone did not induce liver injury in HLA-B*57:01 transgenic mice.•Flucloxacillin conjugation with human serum albumin appeared to be dependent on incubation time.•Conjugation of ...flucloxacillin and human serum albumin stimulates effector memory CD8+ T cells in the draining lymph node in HLA-B*57:01 transgenic mice.
Flucloxacillin (FLX) induces adverse liver reactions, which has been reported to be related to human leukocyte antigen (HLA)-B*57:01. In a previous study, abacavir-induced hypersensitivity was induced in HLA-B*57:01-transgenic mice (B*57:01-Tg), originally constructed by our group (Susukida et al., 2021). In this study, B*57:01-Tg mice were used to reproduce FLX-induced liver injury. However, treatment of B*57:01-Tg mice with FLX alone did not increase serum ALT levels. Immune-deficient B*57:01-Tg/PD-1-/-mice were produced by mating B*57:01-Tg with PD-1-/- mice. The immune response of B*57:01-Tg/PD-1-/- mice was further modulated by co-administration of CpG-oligodeoxynucleotides and anti-CD4 mAb. Nevertheless, immune regulation in B*57:01-Tg mice did not contribute to the onset of FLX-induced liver injury or immune activation. Moreover, we generated an FLX-human serum albumin (HSA) conjugate and showed that FLX covalently bound to HSA in a time-dependent manner. The FLX-HSA conjugate was administered to the B*57:01-Tg mice. The immune response was investigated using flow cytometry, revealing the phenotype of CD44highCD62Llow in CD8+ T cells (TEM cells). Administration of the FLX-HSA conjugate resulted in an HLA-B*57:01 restricted immune response as shown by the stimulation of TEM cells in the draining lymph nodes. In conclusion, administration of FLX alone to B*57:01-Tg mice did not induce liver injury or immune activation. Immune system sensitivity does not play a decisive role in this process. The conjugation of FLX and HSA results in specific TEM cell stimulation, which suggests that HLA-B*57:01 drives a stronger interaction with CD8+ T cells. These results suggest that patients carrying HLA-B*57:01 could be more susceptible to a conjugate of FLX and albumin and drive CD8+ T cell activation, which may be a vital risk factor for FLX-induced liver injury. In addition, the application of the FLX-HSA adduct may be an effective method for the construction of FLX-induced idiosyncratic liver injury in mice.
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