Gestational alloimmune liver disease treated with exchange transfusion and intravenous immunoglobulin: A case study.

Gestational alloimmune liver disease (GALD) is a materno-fetal alloimmune disorder that targets the fetal liver and often causes neonatal liver failure. GALD most commonly presents as neonatal hemochromatosis (NH), which is a severe neonatal liver injury confirmed by extra-hepatic iron accumulation at various sites. With the discovery of the alloimmune mechanism of GALD, exchange transfusion and intravenous immunoglobulin (IVIG) administration are being used as novel treatments. Here, we present a rare case of an 11-day-old female infant who presented with marked hyperbilirubinemia. Laboratory findings showed significantly elevated direct and indirect bilirubin, high ferritin and alpha fetoprotein levels, high transferrin saturation, and severe coagulopathy. Abdominal magnetic resonance imaging revealed markedly reduced T2 signal intensity in the liver and pancreas compared to the spleen, suggesting iron deposition. The infant was diagnosed with NH and successfully treated with exchange transfusion and four doses of IVIG.

The Protective Effects of EMF-LTE against DNA Double-Strand Break Damage In Vitro and In Vivo.

With the rapid growth of the wireless communication industry, humans are extensively exposed to electromagnetic fields (EMF) comprised of radiofrequency (RF). The skin is considered the primary target of EMFs given its outermost location. Recent evidence suggests that extremely low frequency (ELF)-EMF can improve the efficacy of DNA repair in human cell-lines. However, the effects of EMF-RF on DNA damage remain unknown. Here, we investigated the impact of EMF-long term evolution (LTE, 1.762 GHz, 8 W/kg) irradiation on DNA double-strand break (DSB) using the murine melanoma cell line B16 and the human keratinocyte cell line HaCaT. EMF-LTE exposure alone did not affect cell viability or induce apoptosis or necrosis. In addition, DNA DSB damage, as determined by the neutral comet assay, was not induced by EMF-LTE irradiation. Of note, EMF-LTE exposure can attenuate the DNA DSB damage induced by physical and chemical DNA damaging agents (such as ionizing radiation (IR, 10 Gy) in HaCaT and B16 cells and bleomycin (BLM, 3 µM) in HaCaT cells and a human melanoma cell line MNT-1), suggesting that EMF-LTE promotes the repair of DNA DSB damage. The protective effect of EMF-LTE against DNA damage was further confirmed by attenuation of the DNA damage marker γ-H2AX after exposure to EMF-LTE in HaCaT and B16 cells. Most importantly, irradiation of EMF-LTE (1.76 GHz, 6 W/kg, 8 h/day) on mice in vivo for 4 weeks reduced the γ-H2AX level in the skin tissue, further supporting the protective effects of EMF-LTE against DNA DSB damage. Furthermore, p53, the master tumor-suppressor gene, was commonly upregulated by EMF-LTE irradiation in B16 and HaCaT cells. This finding suggests that p53 plays a role in the protective effect of EMF-LTE against DNA DSBs. Collectively, these results demonstrated that EMF-LTE might have a protective effect against DNA DSB damage in the skin, although further studies are necessary to understand its impact on human health.

Accuracy Verification of Spatio-Temporal and Kinematic Parameters for Gait Using Inertial Measurement Unit System.

Inertial measurement unit systems are wearable sensors that can measure the movement of a human in real-time with relatively little space and high portability. The purpose of this study was to investigate the accuracy of the inertial measurement unit (IMU) system for gait analysis by comparing it with measurements obtained using an optical motion capture (OMC) system. To compare the accuracies of these two different motion capture systems, the Spatio-temporal and kinematic parameters were measured in young adults during normal walking. Thirty healthy participants participated in the study. Data were collected while walking 5 strides on a 7 m walkway at a self-selected speed. Results of gait analysis showed that the Spatio-temporal (stride time, stride length, cadence, step length) and kinematic (knee joint peak to peak of movement) parameters were not significantly different in the participant. Spatio-temporal and kinematic parameters of the two systems were compared using the Bland-Altman method. The results obtained showed that the measurements of Spatio-temporal and kinematic parameters of gait by the two systems were similar, which suggested that IMU and OMC systems could be used interchangeably for gait measurements. Therefore, gait analysis performed using the wearable IMU system might efficiently provide gait measurements and enable accurate analysis.

Effects of injuries to descending motor pathways on restoration of gait in patients with pontine hemorrhage.

BACKGROUND AND PURPOSE: Gait disturbance due to injuries of the descending motor pathway, including corticospinal tract (CST), corticoreticular pathway (CRP), and medial and lateral vestibulospinal tracts (VSTs), are commonly encountered disabling sequelae of pontine hemorrhage. We investigated relations between changes in the CST, CRP, and medial and lateral VST and corresponding changes in gait function in patients with pontine hemorrhage. METHOD: Nine consecutive stroke patients with pontine hemorrhage, and 6 age-matched normal subjects were recruited. Four patients were allocated to group A (can't walk independently) and 5 to group B (can walk independently). Diffusion tensor imaging (DTI) data were acquired twice at acute to subacute stage and chronic stage after stroke onset. Diffusion tensor tractography (DTT) was used to reconstruct CST, CRP, medial and lateral VST. RESULT: The CRP shows a significantly different between groups A and B in both initial and follow up DTT (p > 0.05). In contrast, CST, medial VST and lateral VST did not show a significant difference (p > 0.05). Regarding DTI parameters of CRPs in group A, percentages of patients with fractional anisotropy (FA) and mean diffusivity (MD) values more than two standard deviation from normal were higher by follow up DTI than by initial DTI, however, the CRPs in group B only showed increased abnormal range of MD. CONCLUSIONS: The CST does not play an essential role in recovery of independent walking and vestibulospinal tracts may not crucially affect recovery of independent walking in patients with pontine hemorrhage. In contrast, and intact CRP or changes of the CRP integrity appear to be related to the recovery of gait function.

The Tcf21 lineage constitutes the lung lipofibroblast population.

Transcription factor 21 (Tcf21) is a basic helix-loop-helix transcription factor required for mesenchymal development in several organs. Others have demonstrated that Tcf21 is expressed in embryonic lung mesenchyme and that loss of Tcf21 results in a pulmonary hypoplasia phenotype. Although recent single-cell transcriptome analysis has described multiple mesenchymal cell types in the lung, few have characterized the Tcf21 expressing population. To explore the Tcf21 mesenchymal lineage, we traced Tcf21-expressing cells during embryogenesis and in the adult. Our results showed that Tcf21 progenitor cells at embryonic day (E)11.5 generated a subpopulation of fibroblasts and lipofibroblasts and a limited number of smooth muscle cells. After E15.5, Tcf21 progenitor cells exclusively become lipofibroblasts and interstitial fibroblasts. Lipid metabolism genes were highly expressed in perinatal and adult Tcf21 lineage cells. Overexpression of Tcf21 in primary neonatal lung fibroblasts led to increases in intracellular neutral lipids, suggesting a regulatory role for Tcf21 in lipofibroblast function. Collectively, our results reveal that Tcf21 expression after E15.5 delineates the lipofibroblast and a population of interstitial fibroblasts. The Tcf21 inducible Cre mouse line provides a novel method for identifying and manipulating the lipofibroblast.

Hypervalent iodine-mediated Ritter-type amidation of terminal alkenes: The synthesis of isoxazoline and pyrazoline cores.

Hypervalent iodine-mediated olefin functionalization provides a rapid gateway towards accessing both various heterocyclic cores and functional groups. In this regard, we have developed a Ritter-type alkene functionalization utilizing a PhI(OAc)2 ((diacetoxyiodo)benzene, PIDA)/Lewis acid combination in order to access isoxazoline and pyrazoline cores. Based on allyl ketone oximes and allyl ketone tosylhydrazones, we have developed an alkene oxyamidation and amido-amidation protocol en route to accessing both isoxazoline and pyrazoline cores. Additionally, acetonitrile serves as both the solvent and an amine source in the presence of this PIDA/Lewis acid combination. This operationally straightforward and metal-free protocol provides an easy access to isoxazoline and pyrazoline derivatives.

Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage.

Platinum drugs are a mainstay of anticancer chemotherapy. Nevertheless, tumors often display inherent or acquired resistance to platinum-based treatments, prompting the search for new compounds that do not exhibit cross-resistance with current therapies. Phenanthriplatin, cis-diamminephenanthridinechloroplatinum(II), is a potent monofunctional platinum complex that displays a spectrum of activity distinct from those of the clinically approved platinum drugs. Inhibition of RNA polymerases by phenanthriplatin lesions has been implicated in its mechanism of action. The present study evaluates the ability of phenanthriplatin lesions to inhibit DNA replication, a function disrupted by traditional platinum drugs. Phenanthriplatin lesions effectively inhibit DNA polymerases ν, ζ, and κ and the Klenow fragment. In contrast to results obtained with DNA damaged by cisplatin, all of these polymerases were capable of inserting a base opposite a phenanthriplatin lesion, but only Pol η, an enzyme efficient in translesion synthesis, was able to fully bypass the adduct, albeit with low efficiency. X-ray structural characterization of Pol η complexed with site-specifically platinated DNA at both the insertion and +1 extension steps reveals that phenanthriplatin on DNA interacts with and inhibits Pol η in a manner distinct from that of cisplatin-DNA adducts. Unlike cisplatin and oxaliplatin, the efficacies of which are influenced by Pol η expression, phenanthriplatin is highly toxic to both Pol η+ and Pol η- cells. Given that increased expression of Pol η is a known mechanism by which cells resist cisplatin treatment, phenanthriplatin may be valuable in the treatment of cancers that are, or can easily become, resistant to cisplatin.

Prophylactic versus Early Rescue Surfactant Treatment in Preterm Infants Born at Less than 30 Weeks Gestation or with Birth Weight Less than or Equal 1,250 Grams.

Prophylactic surfactant is known to be effective to reduce chronic lung disease in preterm infants compared with rescue surfactant treatment. In Korea, early prophylactic surfactant therapy was introduced in 2011. However, recently, the increased utilization of antenatal steroids and early stabilization through continuous positive airway pressure (CPAP) in the delivery room may have changed the risks and benefits of prophylactic surfactant therapy of infants at high risk of respiratory distress syndrome (RDS). We compared the effects and safety of prophylactic surfactant therapy (within 30 minutes after birth) and early selective surfactant therapy (within 3 hours after birth) in preterm infants born at < 30 weeks gestation or with birth weight ≤ 1,250 g. The clinical data of 193 infants in period 1 (from 2008 to 2010, early selective surfactant therapy group) were collected retrospectively; those of 191 infants in period 2 (from 2012 to 2014, prophylactic surfactant therapy group) were collected prospectively. Compared to period 1, the rate of intubation and surfactant use were significantly increased in period 2. The use of multiple doses of surfactant in period 2 was significantly increased compared with period 1. Despite more invasive and aggressive management in period 2, there was no difference in the duration of mechanical ventilation, the incidence of bronchopulmonary dysplasia (BPD) or death, and the risk of other adverse neonatal outcomes between the 2 groups. In conclusion, the benefit of prophylactic surfactant therapy in infants treated under current practices is no longer clear compared to early selective surfactant therapy.

Neural correlates of spatial and nonspatial attention determined using intracranial electroencephalographic signals in humans.

Few studies have directly compared the neural correlates of spatial attention (i.e., attention to a particular location) and nonspatial attention (i.e., attention to a feature in the visual scene) using well-controlled tasks. Here, we investigated the neural correlates of spatial and nonspatial attention in humans using intracranial electroencephalography. The topography and number of electrodes showing significant event-related desynchronization (ERD) or event-related synchronization (ERS) in different frequency bands were studied in 13 epileptic patients. Performance was not significantly different between the two conditions. In both conditions, ERD in the low-frequency bands and ERS in the high-frequency bands were present bilaterally in the parietal cortex (prominently on the right hemisphere) and frontal regions. In addition to these common changes, spatial attention involved right-lateralized activity that was maximal in the right superior parietal lobule (SPL), whereas nonspatial attention involved wider brain networks including the bilateral parietal, frontal, and temporal regions, but still had maximal activity in the right parietal lobe. Within the parietal lobe, spatial attention involved ERD or ERS in the right SPL, whereas nonspatial attention involved ERD or ERS in the right inferior parietal lobule. These findings reveal that common as well as different brain networks are engaged in spatial and nonspatial attention. Hum Brain Mapp 37:3041-3054, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Nucleotide Binding Preference of the Monofunctional Platinum Anticancer-Agent Phenanthriplatin.

The monofunctional platinum anticancer agent phenanthriplatin generates covalent adducts with the purine bases guanine and adenine. Preferential nucleotide binding was investigated by using a polymerase stop assay and linear DNA amplification with a 163-base pair DNA double helix. Similarly to cisplatin, phenanthriplatin forms the majority of adducts at guanosine residues, but significant differences in both the number and position of platination sites emerge when comparing results for the two complexes. Notably, the monofunctional complex generates a greater number of polymerase-halting lesions at adenosine residues than does cisplatin. Studies with 9-methyladenine reveal that, under abiological conditions, phenanthriplatin binds to the N(1) or N(7) position of 9-methyladenine in approximately equimolar amounts. By contrast, comparable reactions with 9-methylguanine afforded only the N(7) -bound species. Both of the 9-methyladenine linkage isomers (N(1) and N(7) ) exist as two diastereomeric species, arising from hindered rotation of the aromatic ligands about their respective platinum-nitrogen bonds. Eyring analysis of rate constants extracted from variable-temperature NMR spectroscopic data revealed that the activation energies for ligand rotation in the N(1) -bound platinum complex and the N(7) -linkage isomers are comparable. Finally, a kinetic analysis indicated that phenanthriplatin reacts more rapidly, by a factor of eight, with 9-methylguanine than with 9-methyladenine, suggesting that the distribution of lesions formed on double-stranded DNA is kinetically controlled. In addition, implications for the potent anticancer activity of phenanthriplatin are discussed herein.

Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug.

Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1, REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide-coglycolide)-b-poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L-specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.

Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile.

Monofunctional platinum(II) complexes of general formula cis-[Pt(NH(3))(2)(N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N-heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N-heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis-[Pt(NH(3))(2)(phenanthridine)Cl]NO(3), which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5'-deoxyguanosine monophosphate than to N-acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links.

Preserved Hippocampal Glucose Metabolism on 18F-FDG PET after Transplantation of Human Umbilical Cord Blood-derived Mesenchymal Stem Cells in Chronic Epileptic Rats.

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) may be a promising modality for treating medial temporal lobe epilepsy. (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a noninvasive method for monitoring in vivo glucose metabolism. We evaluated the efficacy of hUCB-MSCs transplantation in chronic epileptic rats using FDG-PET. Rats with recurrent seizures were randomly assigned into three groups: the stem cell treatment (SCT) group received hUCB-MSCs transplantation into the right hippocampus, the sham control (ShC) group received same procedure with saline, and the positive control (PC) group consisted of treatment-negative epileptic rats. Normal rats received hUCB-MSCs transplantation acted as the negative control (NC). FDG-PET was performed at pre-treatment baseline and 1- and 8-week posttreatment. Hippocampal volume was evaluated and histological examination was done. In the SCT group, bilateral hippocampi at 8-week after transplantation showed significantly higher glucose metabolism (0.990 ± 0.032) than the ShC (0.873 ± 0.087; P < 0.001) and PC groups (0.858 ± 0.093; P < 0.001). Histological examination resulted that the transplanted hUCB-MSCs survived in the ipsilateral hippocampus and migrated to the contralateral hippocampus but did not differentiate. In spite of successful engraftment, seizure frequency among the groups was not significantly different. Transplanted hUCB-MSCs can engraft and migrate, thereby partially restoring bilateral hippocampal glucose metabolism. The results suggest encouraging effect of hUCB-MSCs on restoring epileptic networks.

Copper-peptide complex structure and reactivity when found in conserved His-X(aa)-His sequences.

Oxygen-activating copper proteins may possess His-X(aa)-His chelating sequences at their active sites and additionally exhibit imidiazole group δN vs εN tautomeric preferences. As shown here, such variations strongly affect copper ion's coordination geometry, redox behavior, and oxidative reactivity. Copper(I) complexes bound to either δ-HGH or ε-HGH tripeptides were synthesized and characterized. Structural investigations using X-ray absorption spectroscopy, density functional theory calculations, and solution conductivity measurements reveal that δ-HGH forms the Cu(I) dimer complex [{Cu(I)(δ-HGH)}2](2+) (1) while ε-HGH binds Cu(I) to give the monomeric complex [Cu(I)(ε-HGH)](+) (2). Only 2 exhibits any reactivity, forming a strong CO adduct, [Cu(I)(ε-HGH)(CO)](+), with properties closely matching those of the copper monooxygenase PHM. Also, 2 is reactive toward O2 or H2O2, giving a new type of O2-adduct or Cu(II)-OOH complex, respectively.

Role of low- and high-frequency oscillations in the human hippocampus for encoding environmental novelty during a spatial navigation task.

The hippocampus plays a key role in the encoding and retrieval of information related to novel environments during spatial navigation. However, the neural basis for these processes in the human hippocampus remains unknown because it is difficult to directly measure neural signals in the human hippocampus. This study investigated hippocampal neural oscillations involved in encoding novel environments during spatial navigation in a virtual environment. Seven epileptic patients with implanted intracranial hippocampal depth electrodes performed three sessions of virtual environment navigation. Each session consisted of a navigation task and a location-recall task. The navigation task consisted of eight blocks, and in each block, the participant navigated to the location of four different objects and was instructed to remember the location of the objects. After the eight blocks were completed, a location-recall task was performed for each of the four objects. Intracranial electroencephalography data were monitored during the navigation tasks. Theta (5-8 Hz) and delta (1-4 Hz) oscillations were lower in the first block (novel environment) than in the eighth block (familiar environment) of the navigation task, and significantly increased from block one to block eight. By contrast, low-gamma (31-50 Hz) oscillations were higher in the first block than in the eighth block of the navigation task, and significantly decreased from block one to block eight. Comparison of sessions with high recall performance (low error between identified and actual object location) and low recall performance revealed that high-gamma (51-100 Hz) oscillations significantly decreased from block one to block eight only in sessions with high recall performance. These findings suggest that delta, theta, and low-gamma oscillations were associated with encoding of environmental novelty and high-gamma oscillations were important for the successful encoding of environmental novelty.

Crocin suppresses LPS-stimulated expression of inducible nitric oxide synthase by upregulation of heme oxygenase-1 via calcium/calmodulin-dependent protein kinase 4.

Crocin is a water-soluble carotenoid pigment that is primarily used in various cuisines as a seasoning and coloring agent, as well as in traditional medicines for the treatment of edema, fever, and hepatic disorder. In this study, we demonstrated that crocin markedly induces the expression of heme oxygenase-1 (HO-1) which leads to an anti-inflammatory response. Crocin inhibited inducible nitric oxide synthase (iNOS) expression and nitric oxide production via downregulation of nuclear factor kappa B activity in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. These effects were abrogated by blocking of HO-1 expression or activity. Crocin also induced Ca(2+) mobilization from intracellular pools and phosphorylation of Ca(2+)/calmodulin-dependent protein kinase 4 (CAMK4). CAMK4 knockdown and kinase-dead mutant inhibited crocin-mediated HO-1 expression, Nrf2 activation, and phosphorylation of Akt, indicating that HO-1 expression is mediated by CAMK4 and that Akt is a downstream mediator of CAMK4 in crocin signaling. Moreover, crocin-mediated suppression of iNOS expression was blocked by CAMK4 inhibition. Overall, these results suggest that crocin suppresses LPS-stimulated expression of iNOS by inducing HO-1 expression via Ca(2+)/calmodulin-CAMK4-PI3K/Akt-Nrf2 signaling cascades. Our findings provide a novel molecular mechanism for the inhibitory effects of crocin against endotoxin-mediated inflammation.

Successful treatment of recurrent focal segmental glomerulosclerosis with a low dose rituximab in a kidney transplant recipient.

Recurrence of focal segmental glomerulosclerosis (FSGS) is a major therapeutic challenge in kidney transplantation (KT). Although intensive plasmapheresis and high-dose rituximab have been introduced to treat recurrent FSGS, the most effective dosage and regimen of rituximab have not been determined. Herein we reported the first case of successful treatment of recurrent FSGS with a low-dose rituximab. The patient showed marked proteinuria (3.5 g/d) and oliguria 2 d after KT. Two courses of plasmapheresis and immunoglobulin were applied to the patient, however, nephrotic range proteinuria persisted and creatinine level increased to 3.56 mg/dL. Five months post-transplant, the patient received injection with only one dose of rituximab 100 mg, without further plasmapheresis, which resulted in immediate reduction of serum creatinine and full remission of proteinuria during the following 18 months. This case suggested that recurrent FSGS, which frequently relapses after plasmapheresis, could be treated successfully with a low-dose rituximab even without plasmapheresis.

Nationwide assessment of illicit drug consumption patterns in South Korea using wastewater-based epidemiology during the COVID-19 pandemic (2020-2022).

Illicit drugs have become a crucial global social issue, with South Korea experiencing a continuous increase in the number of offenders and drug smuggling. This study employed wastewater-based epidemiology to investigate consumption patterns of 8 illicit drugs and their 7 metabolites during the COVID-19 pandemic (2020-2022) in South Korea. Ten compouds were detected in the wastewater influent. Methamphetamine (METH) was prevalent in samples, followed by amphetamine and ecstasy (MDMA). Interestingly, MDMA and ketamine (KET), which were not detected in previous Korean studies conducted before COVID-19 pandemic, were detected in this study. METH exhibited the highest consumption rates, decreasing from 16.6 to 12.4 mg/day/1000 people between 2020 and 2022, while MDMA increased over the three years (mean: 1.16, 1.24, and 1.62 mg/day/1000 people in 2020, 2021, and 2022, respectively) (p < 0.05). Significant correlations were identified between regional income levels and the consumption rates of METH (p < 0.01), MDMA (p < 0.01), and KET (p < 0.05). Furthermore, METH and MDMA consumption rates in cities were positively correlated with the number of drug offenders arrested and local clubs in those cities. The findings of this study provide valuable insights into shaping regulatory policies related to illicit drugs and future studies.

Effect of a monofunctional phenanthriplatin-DNA adduct on RNA polymerase II transcriptional fidelity and translesion synthesis.

Transcription inhibition by platinum anticancer drugs is an important component of their mechanism of action. Phenanthriplatin, a cisplatin derivative containing phenanthridine in place of one of the chloride ligands, forms highly potent monofunctional adducts on DNA having a structure and spectrum of anticancer activity distinct from those of the parent drug. Understanding the functional consequences of DNA damage by phenanthriplatin for the normal functions of RNA polymerase II (Pol II), the major cellular transcription machinery component, is an important step toward elucidating its mechanism of action. In this study, we present the first systematic mechanistic investigation that addresses how a site-specific phenanthriplatin-DNA d(G) monofunctional adduct affects the Pol II elongation and transcriptional fidelity checkpoint steps. Pol II processing of the phenanthriplatin lesion differs significantly from that of the canonical cisplatin-DNA 1,2-d(GpG) intrastrand cross-link. A majority of Pol II elongation complexes stall after successful addition of CTP opposite the phenanthriplatin-dG adduct in an error-free manner, with specificity for CTP incorporation being essentially the same as for undamaged dG on the template. A small portion of Pol II undergoes slow, error-prone bypass of the phenanthriplatin-dG lesion, which resembles DNA polymerases that similarly switch from high-fidelity replicative DNA processing (error-free) to low-fidelity translesion DNA synthesis (error-prone) at DNA damage sites. These results provide the first insights into how the Pol II transcription machinery processes the most abundant DNA lesion of the monofunctional phenanthriplatin anticancer drug candidate and enrich our general understanding of Pol II transcription fidelity maintenance, lesion bypass, and transcription-derived mutagenesis. Because of the current interest in monofunctional, DNA-damaging metallodrugs, these results are of likely relevance to a broad spectrum of next-generation anticancer agents being developed by the medicinal inorganic chemistry community.

A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy.

Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.