Acute interstitial nephritis with acute kidney injury after COVID-19 vaccination: a case report.

In the context of the massive spread of coronavirus disease 2019 (COVID-19), the development of a COVID-19 vaccine is urgently needed. The Pfizer-BioNTech COVID-19 vaccine has been widely applied across global populations. Herein, we report a case of acute interstitial nephritis with acute kidney injury in a young healthy subject after administration of the COVID-19 vaccine. A 20-year-old man was admitted with abdominal discomfort and nausea. He had received the Pfizer-BioNTech COVID-19 vaccine 6 days before. At 9 days after vaccination, his kidney function was decreased, with serum creatinine levels of 1.8 mg/dL. Even with supportive care with hydration, his kidney function worsened, and he underwent a kidney biopsy. The pathology findings revealed diffuse interstitial infiltration of inflammatory cells, predominantly comprising lymphocytes, with preservation of the glomerulus. No abnormal findings were noted by immunofluorescence or electron microscopy. Based on a diagnosis of drug-related acute interstitial nephritis, we treated the patient with high-dose prednisolone. After administration of prednisolone, kidney function slowly improved. A close linkage between COVID-19 vaccination and acute interstitial nephritis should be considered in the clinic, despite the low incidence.

Early Detection of Secondary Bladder Urothelial Carcinoma and Disseminated Bone Metastases with Normal Prostate-Specific Antigen Level after Pelvic Salvage Radiotherapy in Prostate Cancer.

This report describes the case of a 65-year-old man who presented with gross hematuria and a history of pelvic salvage radiotherapy for prostate cancer. Cystoscopy and transurethral resection of the bladder revealed urothelial carcinoma. Subsequently, disseminated bone metastases were detected with normal prostate-specific antigen (PSA) levels, and palliative radiotherapy and systemic chemotherapy were administered. Because gross hematuria can appear in both acute/chronic cystitis and bladder cancer in patients who have undergone pelvic radiotherapy for prostate cancer, close follow-up along with a detailed evaluation is needed. In addition, because prostate cancer disease progression with normal PSA levels may be associated with specific pathological findings, a detailed evaluation of symptoms and a careful review of pathologic reports are important.

SAMHD1-induced endosomal FAK signaling promotes human renal clear cell carcinoma metastasis by activating Rac1-mediated lamellipodia protrusion.

Human sterile α motif and HD domain-containing protein 1 (SAMHD1) has deoxyribonucleoside triphosphohydrolase (dNTPase) activity that allows it to defend against human immunodeficiency virus type I (HIV-1) infections and regulate the cell cycle. Although SAMHD1 mutations have been identified in various cancer types, their role in cancer is unclear. Here, we aimed to investigate the oncogenic role of SAMHD1 in human clear cell renal cell carcinoma (ccRCC), particularly as a core molecule promoting cancer cell migration. We found that SAMHD1 participated in endocytosis and lamellipodia formation. Mechanistically, SAMHD1 contributed to the formation of the endosomal complex by binding to cortactin. Thereafter, SAMHD1-stimulated endosomal focal adhesion kinase (FAK) signaling activated Rac1, which promoted lamellipodia formation on the plasma membrane and enhanced the motility of ccRCC cells. Finally, we observed a strong correlation between SAMHD1 expression and the activation of FAK and cortactin in tumor tissues obtained from patients with ccRCC. In brief, these findings reveal that SAMHD1 is an oncogene that plays a pivotal role in ccRCC cell migration through the endosomal FAK-Rac1 signaling pathway.

Biobanking for glomerular diseases: a study design and protocol for KOrea Renal biobank NEtwoRk System TOward NExt-generation analysis (KORNERSTONE).

BACKGROUNDS: Glomerular diseases, a set of debilitating and complex disease entities, are related to mortality and morbidity. To gain insight into pathophysiology and novel treatment targets of glomerular disease, various types of biospecimens linked to deep clinical phenotyping including clinical information, digital pathology, and well-defined outcomes are required. We provide the rationale and design of the KOrea Renal biobank NEtwoRk System TOward Next-generation analysis (KORNERSTONE). METHODS: The KORNERSTONE, which has been initiated by Korea Centres for Disease Control and Prevention, is designed as a multi-centre, prospective cohort study and biobank for glomerular diseases. Clinical data, questionnaires will be collected at the time of kidney biopsy and subsequently every 1 year after kidney biopsy. All of the clinical data will be extracted from the electrical health record and automatically uploaded to the web-based database. High-quality digital pathologies are obtained and connected in the database. Various types of biospecimens are collected at baseline and during follow-up: serum, urine, buffy coat, stool, glomerular complementary DNA (cDNA), tubulointerstitial cDNA. All data and biospecimens are processed and stored in a standardised manner. The primary outcomes are mortality and end-stage renal disease. The secondary outcomes will be deterioration renal function, remission of proteinuria, cardiovascular events and quality of life. DISCUSSION: Ethical approval has been obtained from the institutional review board of each participating centre and ethics oversight committee. The KORNERSTONE is designed to deliver pioneer insights into glomerular diseases. The study design allows comprehensive, integrated and high-quality data collection on baseline laboratory findings, clinical outcomes including administrative data and digital pathologic images. This may provide various biospecimens and information to many researchers, establish the rationale for future more individualised treatment strategies for glomerular diseases. TRIAL REGISTRATION: NCT03929887 .

Survival and Prognosis of Patients with Pilocytic Astrocytoma: A Single-Center Study.

BACKGROUND: Pilocytic astrocytoma (PA) is a brain tumor that is relatively more common in children and young adults. METHODS: We retrospectively reviewed the medical records of patients with PA treated at a single center between 1988 and 2018. RESULTS: We included 31 subjects with PA. The median age at diagnosis was 13.4 years, and the median follow-up duration was 9.9 years. The total PA group had a 10-year disease-specific survival (DSS) rate of 92.6% [95% confidence interval (CI), 82.6-100] and 10-year progression-free survival (PFS) rate of 52.8% (95% CI, 32.0-73.6). In patients aged <20 years, tumors were more likely to be located in sites in which gross total tumor resection (GTR) was impossible. No statistically significant difference in 10-year DSS was found between the GTR (100%) and non-GTR (89.7%; 95% CI, 76.2-100; p=0.374) groups. However, a statistically significant difference in 10-year PFS was found between the GTR (100%) and non-GTR groups (30.7%; 95% CI, 8.6-52.8; p=0.012). In the non-GTR group, no statistically significant difference in 10-year DSS was found between the patients who received immediate additional chemotherapy and/or radiotherapy (Add-Tx group, 92.9%; 95% CI, 79.4-100) and the non-Add-Tx group (83.3%; 95% CI, 53.5-100; p=0.577). No statistically significant difference in 10-year PFS was found between the Add-Tx group (28.9%; 95% CI, 1.7-56.1) and non-Add-Tx group (33.3%; 95% CI, 0-70.9; p=0.706). CONCLUSION: The PFS of the patients with PA in our study depended only on the degree of surgical excision associated with tumor location. This study is limited by its small number of patients and retrospective nature. A multicenter and prospective study is necessary to confirm these findings.

Differences in Pathologic Features and Graft Outcomes of Rejection on Kidney Transplant.

BACKGROUND: Rejection is still a barrier to long-term allograft survival, but there are not many reports of clinical outcomes according to rejection types. The purpose of this study was to investigate differences in pathologic features and graft outcomes of rejection on kidney transplant (KT). MATERIALS AND METHODS: We retrospectively analyzed 139 kidney transplant recipients diagnosed to rejection by allograft biopsy results between 2006 and 2018. We divided kidney transplant recipients into 3 groups as follows: T cell-mediated rejection (TCMR), antibody-mediated rejection, and mixed rejection. We investigated clinical characteristics, pathologic findings, death-censored graft survival rates, and patient survival rates among the 3 groups. RESULTS: Mean follow-up duration was 113.5 (SD, 80.6) months. The mixed rejection group was the youngest significantly. There were no significant differences of the proportion of sex, KT type, KT number, number of HLA mismatches, induction immunosuppressant, and maintenance immunosuppressant among the 3 groups. In pathologic findings, microvascular inflammation and C4d were significantly different among the 3 groups. Death-censored graft survival of mixed rejection was the least. In multivariate analysis, recipient age, TCMR, and positive C4d were the risk factors associated with graft failure. However, patient survival rates showed no significant differences among the 3 groups. CONCLUSIONS: Our study showed that mixed rejection had poor prognosis in comparison with TCMR and antibody-mediated rejection groups, and TCMR and positive C4d were the most important risk factors for graft survival. Therefore, constant monitoring through allograft biopsy and early treatment for rejection are very important in post-transplant clinical outcomes.

Amoebic Encephalitis Caused by Balamuthia mandrillaris.

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.

Bile Granuloma Mimicking Peritoneal Seeding: A Case Report.

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.

Long-term prognosis of BK virus-associated nephropathy in kidney transplant recipients.

BACKGROUND: The long-term prognosis of BK virus-associated nephropathy (BKVAN) in kidney transplant recipients (KTRs) is uncertain. We evaluated the long-term prognosis in KTRs with BKVAN and the clinical significance of BKVAN on post-transplant clinical outcome. METHODS: We retrospectively analyzed the medical records of 582 patients who underwent kidney transplant (KT) between 2001 and 2014. We divided the patients into a BKVAN group (15 patients) diagnosed by allograft biopsy and a control group (356 patients). RESULTS: The incidence of BKVAN was 4.0%, and the mean follow-up duration was 93.1 ± 52.3 months. Median time from KT to BKVAN diagnosis was 5.9 months (interquartile range [IQR], 4.4-8.7). In the BKVAN group, 9 (60.0%) KTRs with combined acute rejection progressed to graft failure, and the median time from BKVAN diagnosis to graft failure was 36.2 months (IQR, 9.7-65.5). Death-censored graft survival rate and patient survival rate in the BKVAN group were significantly lower than those in the control group. BKVAN and rejection were independent risk factors for graft failure. In the subgroup analysis, death-censored graft survival rate of KTRs with BKVAN with acute rejection was significantly worst in comparison with similar patients without BKVAN regardless of acute rejection (P < 0.001). CONCLUSION: The long-term prognosis of BKVAN with acute rejection was very poor because of graft failure caused by inadequate treatment for acute rejection considering BKVAN. Therefore, we should carefully monitor the allograft status of KTRs through regular surveillance tests after treatment for BKVAN with acute rejection.

Diagnostic Accuracy of Combined Acetylcholinesterase Histochemistry and Calretinin Immunohistochemistry of Rectal Biopsy Specimens in Hirschsprung's Disease.

BACKGROUND: Acetylcholinesterase (AchE) histochemistry has been established as an accurate diagnostic tool for Hirschsprung's disease (HD). In addition, calretinin immunohistochemistry is also reported as a reliable and adjunctive method to diagnose HD. We investigated the diagnostic value of combined AchE histochemistry and calretinin immunohistochemistry in rectal suction biopsies from HD and non-HD patients. METHODS: We retrospectively reviewed 99 rectal suction biopsy specimens including 4 repeat biopsies from 95 patients (34 HD and 61 non-HD). Each specimen was evaluated with hematoxylin-eosin, AchE histochemistry, and calretinin immunohistochemistry. RESULTS: Of 95 patients, only 21 (22.1%) showed some ganglion cells. All 61 non-HD cases revealed no abnormal AchE-positive fibers. Of 34 HD patients, 32 exhibited abnormal AchE fibers, but 2 showed no stained fibers. None of the tissues from the HD patients exhibited calretinin immunoreactivity. Test sensitivity and specificity of AchE histochemistry alone were 93.5% and 100.0%, respectively, while calretinin immunohistochemistry were 100.0% and 85.2%, respectively. CONCLUSIONS: AchE histochemistry is a good diagnostic method for HD, if feasible, and a combination of AchE histochemistry and calretinin immunohistochemistry will help increase the accuracy of the diagnosis of HD.

Inhibition of Cathepsin S Induces Mitochondrial ROS That Sensitizes TRAIL-Mediated Apoptosis Through p53-Mediated Downregulation of Bcl-2 and c-FLIP.

AIMS: Cathepsin S is highly expressed in various cancer cells, and it has protumoral effects, including promotion of migration, invasion, and neovascularization. In this study, we show that inhibition of cathepsin S could sensitize cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. RESULTS: An inhibitor of cathepsin S (Z-FL-COCHO; ZFL) markedly induced apoptosis in human renal cancer cells treated with TRAIL. In contrast, combined treatment with ZFL and TRAIL had no effect on normal cells. ZFL downregulated Bcl-2 expression at the transcriptional level in a p53-dependent manner, and overexpression of Bcl-2 also markedly blocked apoptosis induced by combined treatment with ZFL and TRAIL. In addition, ZFL induced downregulation of c-FLIP, and overexpression of c-FLIP blocked the apoptosis induced by ZFL plus TRAIL. Moreover, ZFL increased the expression of Cbl, an E3 ligase of c-FLIP, in a p53-dependent manner, and knockdown of Cbl markedly prevented c-FLIP downregulation and the apoptosis induced by ZFL plus TRAIL. Interestingly, ZFL induced p53 expression via production of mitochondrial reactive oxygen species (ROS). We also demonstrated that downregulation of cathepsin S by small interfering RNA sensitized TRAIL-mediated apoptosis in Caki cells. INNOVATION: These results reveal the importance of cathepsin S on resistance against TRAIL, and inhibition of cathepsin S activity plays a crucial role in TRAIL-mediated cell death of cancer cells. CONCLUSION: Our results indicated that inhibition of cathepsin S stimulates TRAIL-induced apoptosis through downregulation of Bcl-2 and Cbl-mediated c-FLIP by ROS-mediated p53 expression. Antioxid. Redox Signal. 27, 215-233.

IMP3, a Promising Prognostic Marker in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) has been reported as a prognostic biomarker in various cancers. To validate IMP3 as a prognostic biomarker in renal cell carcinoma (RCC), we investigated the expression of IMP3, p53, and Ki-67, and their associations with clinicopathologic outcomes. METHODS: We studied 148 clear cell RCCs (CCRCCs) from patients who underwent radical nephrectomy. The expression levels of IMP3, p53, and Ki-67 were assessed by immunohistochemical staining and the clinical and pathologic parameters were retrospectively reviewed. RESULTS: Twenty-nine percent of CCRCCs expressed IMP3. Forty-one percent of IMP3-immunopositive tumors developed metastases, while only 11.4% of IMP3-negative tumors developed metastases (p<.001). A Kaplan-Meier curve showed that patients with IMP3-immunopositive tumors had lower metastasis-free survival and cancer-specific survival than did those with IMP3-immunonegative tumors (p<.001 and p<.001, respectively). Expression of high Ki-67 proliferation index was also associated with a higher metastatic rate. In the multivariate Cox regression analysis, pT stage and IMP3-positivity were independently associated with disease-specific survival. CONCLUSIONS: IMP3 is an independent prognostic biomarker for patients with CCRCC to predict metastasis and poor outcome.

Anthocyanins from black soybean seed coat enhance wound healing.

Anthocyanins are known to have antioxidant and antiinflammatory effects. We hypothesized that anthocyanins would enhance wound healing in Sprague-Dawley rats. The purpose of this study was to evaluate our hypothesis and investigate the mechanism of wound healing enhancement. The cytoprotective effect of an immortalized epidermal keratinocyte cell line (HaCaT) and human neonatal dermal fibroblasts in response to various concentrations of anthocyanins was determined. Vascular endothelial growth factor (VEGF) and thrombospondin 1 (TSP1) of HaCaT were measured by Western blot analysis. Anthocyanins were applied to the wounds in rats, and the healing ratio was calculated. Tissue VEGF, TSP1, CD31, nuclear factor-κB, and phosphorylation of IκBα were measured. The viability of the HaCaT cell line and human neonatal dermal fibroblasts increased under cytotoxicity by H2O2 in the anthocyanin-treated groups. The VEGF in the anthocyanin-treated groups increased, whereas TSP1 decreased. Wounds in the experimental groups healed faster, and VEGF and CD31 increased in the experimental groups, whereas TSP1 decreased. Anthocyanins inhibited the translocation of nuclear factor-κB (p65) from cytosol to nucleus and also prevented the phosphorylation of IκBα. Anthocyanins enhance wound healing through a cytoprotective effect, enhancement of angiogenesis, and an antiinflammatory effect.

Expression of EZH2 in renal cell carcinoma as a novel prognostic marker.

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.

Proteomic analysis of psoriatic skin tissue for identification of differentially expressed proteins: up-regulation of GSTP1, SFN and PRDX2 in psoriatic skin.

Psoriasis is a chronic inflammatory skin disease, characterized by a combination of abnormal proliferation of keratinocytes, immunology and vascular proliferation. Proteomic analyses have revealed some clues regarding the pathogenesis of psoriasis. In the present study, we conducted an investigation of different proteomes of psoriatic lesional skin, and compared them with those of normal and non-lesional psoriatic skin. We performed 2-D gel electrophoresis, liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and database searches. Expression of proteins were evaluated by immunoblot and immunohistochemistry analyses. Our data showed differential expression of 74 and 145 protein spots in non-lesional and lesional psoriatic skin, respectively. Eleven of 36 proteins, which were identified by LC-MS/MS, were categorized as apoptosis-regulating proteins. Other protein spots were categorized as proteins with involvement in the negative regulation of apoptosis, defense response-related proteins and inflammatory response. Of particular interest, increased expression of glutathione S transferase 1 (GSTP1) and peroxiredoxin 2 (PRDX2), which are involved in the Redox balance system, and SFN, which is involved in the cellular proliferation system, was observed in psoriatic lesional skin. Localization of GSTP1 and SFN was observed above the middle layer of the epidermis in psoriatic skin lesions. Expression of PRDX2 was clearly observed below the middle layer of the epidermis in chronic type psoriatic skin lesions. Taken together, 36 identified proteins were associated with biological regulation, including regulation of cell death, defense response, inflammatory response and reactive oxygen species (ROS) regulation. PRDX2 and GSTP1 may play roles in compensating mechanisms for reduction of ROS stress, and SFN may play roles in prevention of cancer development in proliferating cells through G2/M cell cycle arrest upon accidental DNA damage within psoriatic skin lesions.

Increased expression of connexin43 on the aortic valve in the hypercholesterolemic rabbit model.

BACKGROUND: Aortic valve sclerosis is associated with increased risk of cardiovascular death and myocardial infarction. However, the relevance of connexin43 in aortic valve sclerosis remains unclear. We hypothesized that the mechanism regulating aortic valve sclerosis is associated with the alteration of cell-to-cell communication. METHODS: Twenty male New Zealand rabbits were divided into two groups. Group 1 (n = 10) were fed a normal chow diet, while those in group 2 (n = 10) received a diet containing 1% cholesterol for 12 weeks. After utanizing the animals, the aortic valves were excised for analysis. RESULTS: Myofibroblasts and macrophages were more highly expressed in the cholesterol diet group. Osteopontin and connexin43 were found to concentrate within the endothelial layer on the aortic side of the valve leaflets in the cholesterol diet group. A real-time polymerase chain reaction revealed increased connexin43 and osteopontin mRNA levels in the hypercholesterolemic aortic valves. CONCLUSIONS: The present study demonstrates that hypercholesterolemia increases the expression of connexin43 in the rabbit aortic valve. The results suggest that alterations in gap junctional intercellular communication via connexin43 gap junctions may play a role in the development of aortic valve sclerosis.