Melatonin is well known to modulate the sleep–wake cycle. Accumulating evidence suggests that melatonin also has favorable effects such as anti-oxidant and anti-inflammatory properties in numerous disease models. It has been reported that melatonin has therapeutic effects against cisplatin-induced acute kidney injury (AKI). However, mechanisms underlying the therapeutic action of melatonin on the renal side-effects of cisplatin therapy remain poorly understood. In this study, we showed that melatonin treatment significantly ameliorates cisplatin-induced acute renal failure and histopathological alterations. Increased expression of tubular injury markers was largely reduced by melatonin. Melatonin treatment inhibited caspase-3 activation and apoptotic cell death. Moreover, protein levels of key components of the molecular machinery for necroptosis were decreased by melatonin. Melatonin also attenuated nuclear factor-κB activation and suppressed expression of pro-inflammatory cytokines. Consistent with in vivo findings, melatonin dose-dependently decreased apoptosis and necroptosis in cisplatin-treated mouse renal tubular epithelial cells. Collectively, our findings suggest that melatonin ameliorates cisplatin-induced acute renal failure and structural damages through dual suppression of apoptosis and necroptosis. These results reveal a novel mechanism underlying the therapeutic effect of melatonin against cisplatin-induced AKI and strengthen the idea that melatonin might be a promising therapeutic agent for the renal side-effects of cisplatin therapy.

Enhancer of zeste homolog 2 (EZH2) is a member of the Polycomb group proteins and a part of Polycomb repressive complex 2. EZH2 is important for transcriptional regulation through nucleosome modification and interaction with other transcription factors. Particularly, aberration of EZH2 has been implicated in oncogenesis and progression of various neoplasms. The objective of this study was to evaluate EZH2 expression in renal cell carcinoma (RCC), especially clear cell RCC (CRCC) and correlate the expression with prognostic factors. EZH2 expression was determined by immunohistochemical staining with additional Western blotting. High expression of EZH2 was significantly correlated with higher pT stage or more frequent distant metastases (P= 0.001 and 0.024, respectively). Survival analyses displayed that patients with high EZH2 expression had a significantly shorter disease‐free survival than those with low expression (P= 0.019). High expression of EZH2 tended to reduce the overall survival, however, differences did not reach statistical significance (P= 0.066). From our results, we propose that EZH2 is a useful prognostic marker for aggressive behavior of CRCC and may be applicable as a therapeutic target molecule.

Studies report beneficial effects of 3-hydroxybutyrate (3-OHB) on the treatment of type 2 diabetes and obesity, but the effects of 3-OHB on diabetic nephropathy have not been elucidated. This study was designed to investigate the efficacy and mechanism of 3-OHB against progression of diabetic nephropathy (DN). Mice (db/db) were fed normal chow, high-fat, or ketogenic diets (KD) containing precursors of 3-OHB. Hyperglycemia was determined based on random glucose level (≥250 mg/dL). Fasting blood glucose and body weights were measured once a week. Twenty four-hour urine albumin to creatinine ratio was determined 5 weeks after the differential diet. Energy expenditure was measured 9 weeks after the differential diet. Body weights were significantly lower in the KD group than those in other groups, but no significant differences in fasting blood glucose levels among three groups were observed. Urine albumin to creatinine ratio and serum blood urea nitrogen (BUN) to creatinine ratio in the KD group were significantly lower than in other groups. Histologic and quantitative analysis of mesangial area suggested that KD delayed the progression of DN phenotype in db/db mice. Metabolic cage analysis also revealed that KD increased energy expenditure in db/db mice. In vitro studies with proximal tubular cells revealed that 3-OHB stimulated autophagic flux. 3-OHB increased LC3 I to LC3 II ratio, phosphorylation of AMPK, beclin, p62 degradation, and NRF2 expression. Moreover, we found that 3-OHB attenuated high glucose-induced reactive oxygen species (ROS) levels in proximal tubular cells. In vivo study also confirmed increased LC3 and decreased ROS levels in the kidney of KD mice. In summary, this study shows in both in vivo and in vitro models that 3-OHB delays the progression of DN by augmenting autophagy and inhibiting oxidative stress.

We present the case of a 71-year-old man who was diagnosed with amoebic encephalitis caused by Balamuthia mandrillaris. He had rheumatic arthritis for 30 years and had undergone continuous treatment with immunosuppressants. First, he complained of partial spasm from the left thigh to the left upper limb. Magnetic resonance imaging revealed multifocal enhancing nodules in the cortical and subcortical area of both cerebral hemispheres, which were suggestive of brain metastases. However, the patient developed fever with stuporous mentality and an open biopsy was performed immediately. Microscopically, numerous amoebic trophozoites, measuring 20 to 25 µm in size, with nuclei containing one to four nucleoli and some scattered cysts having a double-layered wall were noted in the background of hemorrhagic necrosis. Based on the microscopic findings, amoebic encephalitis caused by Balamuthia mandrillaris was diagnosed. The patient died on the 10th day after being admitted at the hospital. The diagnosis of amoebic encephalitis in the early stage is difficult for clinicians. Moreover, most cases undergo rapid deterioration, resulting in fatal consequences. In this report, we present the first case of B. mandrillaris amoebic encephalitis with fatal progression in a Korean patient.

Laparoscopic cholecystectomy is a widely used treatment method for most cholelithiasis and is a relatively safe procedure. Foreign body granulomatous reaction to bile or gallstone spillage during laparoscopic cholecystectomy has rarely been reported. We report a case of bile granuloma after laparoscopic cholecystectomy, which mimicked peritoneal seeding. A 59-year-old Korean man presented with right upper quadrant pain. He underwent laparoscopic cholecystectomy for acute cholecystitis with cholelithiasis. Pathologic examination revealed an incidental adenocarcinoma invading the lamina propria with acute cholecystitis and cholelithiasis. After 3 months, follow-up abdominal computed tomography revealed a subhepatic nodule, which showed hypermetabolism on positron emission tomography-computed tomography. Suspecting localized peritoneal seeding, wedge resection of the liver, wedge resection of the transverse colon, and omentectomy were performed. Pathologic examination of the resected specimens revealed multiple bile granulomas. Awareness of bile granuloma mimicking malignancy is noteworthy for patient management to reduce unnecessary procedure during postoperative surveillance.

Histologic grade is the most important predictor of the clinical outcome of non-muscle invasive (Ta, T1) papillary urothelial carcinoma (NMIPUCa), but its ambiguous criteria diminish its power to predict recurrence/progression for individual patients. We attempted to find an objective and reproducible histologic predictor of NMIPUCa that correlates well with the clinical outcome. A total of 296 PUCas were collected from the Departments of Surgical Pathology of 11 institutions in South Korea. The clinical outcome was grouped into no event (NE), recurrence (R), and progression (P) categories. All 25 histological parameters were numerically redefined. The clinical pathology of each case was reviewed individually by 11 pathologists from 11 institutions based on the 2004 WHO criteria and afterwards blindly evaluated by two participants, based on our proposed parameters. Univariate and multivariate logistic regression analyses were performed using the R software package. The level of mitoses was the most reliable parameter for predicting the clinical outcome. We propose a four-tiered grading system based on mitotic count (> 10/10 high-power fields), nuclear pleomorphism (smallest-to-largest ratio of tumor nuclei >20), presence of divergent histology, and capillary proliferation (> 20 capillary lumina per papillary core). The level of mitoses at the initial bladder biopsy and transurethral resection (TUR) specimen appeared to be an independent predictor of the Ta PUCa outcome. Other parameters include the number of mitoses, nuclear pleomorphism, divergent histology, and capillary proliferation within the fibrovascular core. These findings may improve selection of patients for a therapeutic strategy as compared to previous grading systems.