Background: We aimed to analyze the epidemiology, clinical characteristics, and outcomes of malaria caused by Plasmodium vivax among military members of the Republic of Korea (ROK). Methods: We reviewed the medical records of patients diagnosed with P. vivax malaria in 16 military hospitals in the ROK between 2012–2021, excluding other types of malaria, as well as imported cases and those treated in civilian hospitals. Results: In total, 653 patients were treated for P. vivax malaria. Their mean age was 22.0 ± 3.8 years, and their mean body weight was 73.4 ± 10.8 kg. Hospitalization occurred in 92.0% (n = 601) of the cases, with 4.4% (n = 29) recurring. The mean administered dose was 20.7 ± 3.4 mg/kg for the chloroquine (CQ) base and 3.5 ± 1.2 mg/kg for the primaquine (PQ) base.Between 2012–2016 and 2017–2021, the mean patient body weight increased (72.9 ± 11.1 vs.74.3 ± 10.3 kg, P = 0.044). Correspondingly, the total administered doses of CQ (1,476.0 ± 144.0 vs. 1,515.1 ± 155.1 mg, P = 0.010) and PQ (242.6 ± 79.7 vs. 265.7 ± 92.3 mg, P < 0.001) were increased. However, there was no difference in the weight-based dosage of CQ (20.7 ± 3.6 vs. 20.7 ± 3.2 mg/kg, P = 0.580) or PQ (3.33 ± 1.1 vs. 3.64 ± 1.3 mg/kg, P = 0.256), nor in the percentage of patients who received sub-recommended doses. Among the 27 patients who experienced recurrence and had available initial treatment data, the proportion of those prescribed PQ (24 [88.9%] vs. 623 [99.5%], P = 0.001) and the mean PQ dose (2.75 ± 0.7 vs.3.50 ± 1.2 mg/kg, P = 0.003) were significantly lower in the recurrence group. Conclusion Over time, as the body weight of patients with P. vivax malaria in the ROK military has increased, the administered dosages of CQ and PQ have correspondingly risen.However, these dosages often remain suboptimal when compared to the body weightbased recommendations by the World Health Organization. Of particular concern is the continued administration of antimalarial drugs at suboptimal doses, which may contribute to an elevated risk of recurrence. Further education may therefore be beneficial to ensuring appropriate dosing for more effective malaria treatment.

Background: We aimed to analyze the epidemiology, clinical characteristics, and outcomes of malaria caused by Plasmodium vivax among military members of the Republic of Korea (ROK). Methods: We reviewed the medical records of patients diagnosed with P. vivax malaria in 16 military hospitals in the ROK between 2012–2021, excluding other types of malaria, as well as imported cases and those treated in civilian hospitals. Results: In total, 653 patients were treated for P. vivax malaria. Their mean age was 22.0 ± 3.8 years, and their mean body weight was 73.4 ± 10.8 kg. Hospitalization occurred in 92.0% (n = 601) of the cases, with 4.4% (n = 29) recurring. The mean administered dose was 20.7 ± 3.4 mg/kg for the chloroquine (CQ) base and 3.5 ± 1.2 mg/kg for the primaquine (PQ) base.Between 2012–2016 and 2017–2021, the mean patient body weight increased (72.9 ± 11.1 vs.74.3 ± 10.3 kg, P = 0.044). Correspondingly, the total administered doses of CQ (1,476.0 ± 144.0 vs. 1,515.1 ± 155.1 mg, P = 0.010) and PQ (242.6 ± 79.7 vs. 265.7 ± 92.3 mg, P < 0.001) were increased. However, there was no difference in the weight-based dosage of CQ (20.7 ± 3.6 vs. 20.7 ± 3.2 mg/kg, P = 0.580) or PQ (3.33 ± 1.1 vs. 3.64 ± 1.3 mg/kg, P = 0.256), nor in the percentage of patients who received sub-recommended doses. Among the 27 patients who experienced recurrence and had available initial treatment data, the proportion of those prescribed PQ (24 [88.9%] vs. 623 [99.5%], P = 0.001) and the mean PQ dose (2.75 ± 0.7 vs.3.50 ± 1.2 mg/kg, P = 0.003) were significantly lower in the recurrence group. Conclusion Over time, as the body weight of patients with P. vivax malaria in the ROK military has increased, the administered dosages of CQ and PQ have correspondingly risen.However, these dosages often remain suboptimal when compared to the body weightbased recommendations by the World Health Organization. Of particular concern is the continued administration of antimalarial drugs at suboptimal doses, which may contribute to an elevated risk of recurrence. Further education may therefore be beneficial to ensuring appropriate dosing for more effective malaria treatment.

Purpose: Vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been the standard of care for advanced and metastatic clear cell renal cell carcinoma (ccRCC). However, the therapeutic effect of TKI monotherapy remains unsatisfactory given the high rates of acquired resistance to TKI therapy despite favorable initial tumor response. Materials and Methods: To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset. Sunitinib-resistant RCC cell lines were established and used to test their malignant behaviors of TKI resistance through in vitro and in vivo studies. Immunohistochemistry was conducted to compare expression between the tumor and normal kidney and verify expression of pathway-related proteins. Results: Integrated differential gene expression analysis revealed increased interferon-induced transmembrane protein 3 (IFITM3) expression in post-TKI samples. IFITM3 expression was increased in ccRCC compared with the normal kidney. TKI-resistant RCC cells showed high expression of IFITM3 compared with TKI-sensitive cells and displayed aggressive biologic features such as higher proliferative ability, clonogenic survival, migration, and invasion while being treated with sunitinib. These aggressive features were suppressed by the inhibition of IFITM3 expression and promoted by IFITM3 overexpression, and these findings were confirmed in a xenograft model. IFITM3-mediated TKI resistance was associated with the activation of TRAF6 and MAPK/AP-1 pathways. Conclusions These results demonstrate IFITM3-mediated activation of the TRAF6/MAPK/AP-1 pathways as a mechanism of acquired TKI resistance, and suggest IFITM3 as a new target for TKI-resistant ccRCC.

Background: We aimed to analyze the epidemiology, clinical characteristics, and outcomes of malaria caused by Plasmodium vivax among military members of the Republic of Korea (ROK). Methods: We reviewed the medical records of patients diagnosed with P. vivax malaria in 16 military hospitals in the ROK between 2012–2021, excluding other types of malaria, as well as imported cases and those treated in civilian hospitals. Results: In total, 653 patients were treated for P. vivax malaria. Their mean age was 22.0 ± 3.8 years, and their mean body weight was 73.4 ± 10.8 kg. Hospitalization occurred in 92.0% (n = 601) of the cases, with 4.4% (n = 29) recurring. The mean administered dose was 20.7 ± 3.4 mg/kg for the chloroquine (CQ) base and 3.5 ± 1.2 mg/kg for the primaquine (PQ) base.Between 2012–2016 and 2017–2021, the mean patient body weight increased (72.9 ± 11.1 vs.74.3 ± 10.3 kg, P = 0.044). Correspondingly, the total administered doses of CQ (1,476.0 ± 144.0 vs. 1,515.1 ± 155.1 mg, P = 0.010) and PQ (242.6 ± 79.7 vs. 265.7 ± 92.3 mg, P < 0.001) were increased. However, there was no difference in the weight-based dosage of CQ (20.7 ± 3.6 vs. 20.7 ± 3.2 mg/kg, P = 0.580) or PQ (3.33 ± 1.1 vs. 3.64 ± 1.3 mg/kg, P = 0.256), nor in the percentage of patients who received sub-recommended doses. Among the 27 patients who experienced recurrence and had available initial treatment data, the proportion of those prescribed PQ (24 [88.9%] vs. 623 [99.5%], P = 0.001) and the mean PQ dose (2.75 ± 0.7 vs.3.50 ± 1.2 mg/kg, P = 0.003) were significantly lower in the recurrence group. Conclusion Over time, as the body weight of patients with P. vivax malaria in the ROK military has increased, the administered dosages of CQ and PQ have correspondingly risen.However, these dosages often remain suboptimal when compared to the body weightbased recommendations by the World Health Organization. Of particular concern is the continued administration of antimalarial drugs at suboptimal doses, which may contribute to an elevated risk of recurrence. Further education may therefore be beneficial to ensuring appropriate dosing for more effective malaria treatment.

Background: We aimed to analyze the epidemiology, clinical characteristics, and outcomes of malaria caused by Plasmodium vivax among military members of the Republic of Korea (ROK). Methods: We reviewed the medical records of patients diagnosed with P. vivax malaria in 16 military hospitals in the ROK between 2012–2021, excluding other types of malaria, as well as imported cases and those treated in civilian hospitals. Results: In total, 653 patients were treated for P. vivax malaria. Their mean age was 22.0 ± 3.8 years, and their mean body weight was 73.4 ± 10.8 kg. Hospitalization occurred in 92.0% (n = 601) of the cases, with 4.4% (n = 29) recurring. The mean administered dose was 20.7 ± 3.4 mg/kg for the chloroquine (CQ) base and 3.5 ± 1.2 mg/kg for the primaquine (PQ) base.Between 2012–2016 and 2017–2021, the mean patient body weight increased (72.9 ± 11.1 vs.74.3 ± 10.3 kg, P = 0.044). Correspondingly, the total administered doses of CQ (1,476.0 ± 144.0 vs. 1,515.1 ± 155.1 mg, P = 0.010) and PQ (242.6 ± 79.7 vs. 265.7 ± 92.3 mg, P < 0.001) were increased. However, there was no difference in the weight-based dosage of CQ (20.7 ± 3.6 vs. 20.7 ± 3.2 mg/kg, P = 0.580) or PQ (3.33 ± 1.1 vs. 3.64 ± 1.3 mg/kg, P = 0.256), nor in the percentage of patients who received sub-recommended doses. Among the 27 patients who experienced recurrence and had available initial treatment data, the proportion of those prescribed PQ (24 [88.9%] vs. 623 [99.5%], P = 0.001) and the mean PQ dose (2.75 ± 0.7 vs.3.50 ± 1.2 mg/kg, P = 0.003) were significantly lower in the recurrence group. Conclusion Over time, as the body weight of patients with P. vivax malaria in the ROK military has increased, the administered dosages of CQ and PQ have correspondingly risen.However, these dosages often remain suboptimal when compared to the body weightbased recommendations by the World Health Organization. Of particular concern is the continued administration of antimalarial drugs at suboptimal doses, which may contribute to an elevated risk of recurrence. Further education may therefore be beneficial to ensuring appropriate dosing for more effective malaria treatment.

Purpose: Prognostic Index for Natural Killer Lymphoma (PINK) is the most widely accepted prognostic model for patients withextranodal natural killer/T-cell lymphoma (ENKTL) treated with non-anthracycline–based therapy. We aimed to evaluate the prognostic implications of serum β-2 microglobulin (β2M) in the context of PINK and proposed a new prognostic model. Materials and Methods: A total of 138 patients who were newly diagnosed with ENKTL and treated with non-anthracycline-based chemotherapy were identified. The cut-off value of high serum β2M was calculated by maximal-chi square methods (4.1 mg/L). A new prognostic model incorporating serum β2M into PINK was proposed and validated in an independent validation cohort (n=88). Results: The patients’ median age was 53.5 years (range, 19 to 80 years). Patients with high serum β2M levels had significantly worse overall survival (OS) and progression-free survival (PFS). In multivariate analysis, high serum β2M was an independent adverse prognostic factor for OS. A new PINK-B (Prognostic Index for Natural Killer Lymphoma-serum β-2 microglobulin) model stratifiedpatients into three groups with distinct OS and PFS in the training cohort (3-year OS, 84.1% [95% confidence interval, 75.1 to 94.2], 46.8% [36.1 to 60.8] and 17.6% [6.3 to 49.2] for the low-, intermediate, and high-risk groups, respectively; 3-year PFS, 70.6% [59.4 to 83.8], 35.9% [25.9 to 49.8], and 7.35% [1.1 to 46.7] for the low-, intermediate-, and high-risk groups, respectively). The PINK-B model was further validated in an independent cohort. Conclusion Serum β2M is an independent prognostic factor for ENKTL patients. The new serum β2M-based prognostic model may be useful for identifying ultra-high-risk patients, and it can easily be adopted into daily clinical practice.

Purpose: Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism. Materials and Methods: To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared. A TKI-resistant renal cancer cell line was established by long-term treatment with sunitinib. Results: Among differentially expressed genes in the discovery cohort, increased PD-L1 expression in post-treatment tissues was noted in four patients. Pathway analysis showed that PD-L1 expression was positively correlated with the mammalian target of rapamycin (mTOR) signaling pathway. The TKI-resistant renal cancer cells showed increased expression of PD-L1 and mTOR signaling proteins and demonstrated aggressive tumoral behaviour. Treatment with mTOR inhibitors down-regulated PD-L1 expression and suppressed aggressive tumoral behaviour, which was reversed with stimulation of the mTOR pathway. Conclusion These results showed that PD-L1 expression may be increased in a subset of VEGFR-TKI–resistant mCCRCC patients via the mTOR pathway.

According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis.Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.