Phosphorylation of GluA1-Ser831 by CaMKII Activation in the Caudate and Putamen Is Required for Behavioral Sensitization After Challenge Nicotine in Rats

BackgroundPhosphorylation of the glutamate receptor (GluA1) subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor plays a crucial role in behavioral sensitization after exposure to psychostimulants. The present study determined the potential role of serine 831 (Ser831) phosphorylation in the GluA1 subunit of the caudate and putamen (CPu) in behavioral sensitization after challenge nicotine.MethodsChallenge nicotine (0.4 mg/kg) was administered subcutaneously (s.c.) after 7 days of repeated exposure to nicotine (0.4 mg/kg, s.c.) followed by 3 days of withdrawal in rats. Bilateral intra-CPu infusions of drugs were mainly performed to test this hypothesis.ResultsChallenge nicotine increased both phosphorylated (p)Ser831 immunoreactivity (IR) and pCa²⁺/calmodulin-dependentprotein kinases II (pCaMKII)-IR in the medium spiny neurons (MSNs) of the CPu. These increases were prevented by bilateral intra-CPu infusion of the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (0.5 nmol/side) and the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 (2 nmol/side). However, the dopamine D1 receptor (D1R) antagonist SCH23390 (7.5 nmol/side) prevented only pSer831-IR alone. Bilateral intra-CPu infusion of the Tat-GluA1_D peptide (25 pmol/side), which interferes with the binding of pCaMKII to GluA1-Ser831, decreased the challenge nicotine–induced increase in locomotor activity.ConclusionsThese findings suggest that the GluA1-Ser831 phosphorylation in the MSNs of the CPu is required for the challenge nicotine–induced behavioral sensitization in rats. CaMKII activation linked to mGluR5 and NMDA receptors, but not to D1R, is essential for inducing the CaMKII-Ser831 interaction.     

Tectorigenin, an isoflavone of Pueraria thunbergiana Benth., induces differentiation and apoptosis in human promyelocytic leukemia HL-60 cells

Cytotoxic effects of six isoflavonoids, tectorigenin, glycitein, tectoridin, glycitin, 6'-O-xylosyltectoridin, and 6'-O-xylosylglycitin isolated from the flower of Pueraria thunbergiana Benth. together with genistein, a known differentiation and apoptosis inducer, were examined. Among these isoflavonoids, tectorigenin and genistein exhibited cytotoxicity against various human cancer cells; glycitein showed only mild cytotoxicity. These results suggest that the isoflavone structure and 5-hydroxyl group are crucial for the cytotoxic properties and that glycosides are inactive. Moreover, tectorigenin induced differentiation of human promyelocytic leukemia HL-60 cells to granulocytes and monocytes/macrophages, and caused apoptotic changes of DNA in the cells, as did genistein. Tectorigenin also inhibited autophosphorylation of epidermal growth factor (EGF) receptor by EGF and decreased the expression of Bcl-2 protein, with less activity than genistein. From these results, tectorigenin may be a possible therapeutic agent for leukemia.     

Changes in Expenditures of the National Health Insurance of Korea during the COVID-19 Pandemic and the Financial Implications Thereof

As the number of coronavirus disease 2019 (COVID-19) patients increased rapidly, the Korean government decided to pay most of the related medical expenses with finances from the National Health Insurance (NHI). We aimed to document changes in NHI medical expenses during the COVID-19 pandemic period. We also sought to compare how Japan and Taiwan, neighboring countries with NHI systems, responded to COVID-19 and to discuss policy implications.     

Adoptive immunotherapy of metastatic breast cancer: present and future

Breast cancer is a systemic disease with a primarily local component. Besides surgical resection and irradiation of the locoregional tumor setting, central therapeutic aim is the elimination of disseminated micrometastatic tumor cells using cytostatic and/or hormonal treatment. Nevertheless, in the course of time a majority of patients suffer from systemic recurrence in the form of distant metastases. Intriguingly, in this connection, intratumoral cytotoxic T lymphocytes might serve as independent predictors of treatment efficacy and clinical outcome. Loss of immune balance (tumor dormancy) during intensive cross talk between T cells and tumor cells in the bone marrow microenvironment is suggested one reason for distant metastatic relapse. In this clinical context, further supportive therapies become increasingly attractive, taking immunological features of breast cancer cells into special account. The present review aims to dissect bone marrow-derived cellular antitumor immune responses and translational immunologic treatment options regarding their actual relevance to patients’ clinical benefit and their future directions in breast cancer management.     

Long-term outcomes of rigid ring versus De Vega annuloplasty for functional tricuspid regurgitation: A propensity score-matching analysis

ObjectiveThis study was conducted to compare the outcomes of rigid ring versus De Vega annuloplasty for the treatment of functional tricuspid regurgitation (TR).MethodsFrom 2003 to 2017, De Vega annuloplasty (group D) was used in 231 patients, and rigid ring annuloplasty (group R) was used in 204 patients for the treatment of functional TR during left-sided valve surgery. A propensity score-matching analysis was used to pair group D (n = 109) with group R (n = 109). The primary outcomes were long-term overall survival and cardiac death, and the secondary outcomes were tricuspid valve-related events and TR recurrence (TR moderate or severe). The follow-up data were complete in 99.6% (447 out of 449) of the patients with a follow-up duration of 102 months.ResultsThere were no differences in the overall survival and cardiac death between the propensity score-matched groups (P = .793 and P = .175, respectively) up to 14 years after surgery. Tricuspid valve-related events, including cardiac death, permanent pacemaker implantation, thromboembolism, bleeding and tricuspid valve reoperation were also similar between the 2 matched groups during the follow-up (P > .999). However, cumulative incidence of TR recurrence was significantly higher in group R than in group D (P = .007). Multivariate analysis indicated the annuloplasty method (De Vega) and preoperative TR grade as risk factors for late TR recurrence.ConclusionsIn functional TR, annuloplasty methods did not influence long-term overall survival, cardiac mortality, and tricuspid valve-related events. However, rigid ring annuloplasty showed less late TR recurrence. Rigid ring annuloplasty can be considered for the treatment of functional TR in terms of its better durability.