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Although the long-term use of topical glucocorticoids (TGC) may induce skin atrophy including striae distensae (SD), patients with atopic dermatitis (AD) appear to have lesser degree of skin atrophy than those with psoriasis (PSO). Periostin, encoded by POSTN, is involved in tissue remodelling processes of chronic AD lesions. This study was designed to investigate the difference in the occurrence of skin atrophy in patients with AD or PSO when treated with TGC and to elucidate the association between skin atrophy and periostin. Big data analysis using Korean Health Claims Database was performed to determine the prevalence of SD in AD and PSO patients. Blood and skin eosinophils count and dermal fibrosis between AD and PSO patients were compared, and immunohistochemistry for periostin and mRNA sequencing in the dermis were performed. Animal experiments using AD and PSO murine model were conducted. Big data analysis revealed that patients with AD have significantly lesser degree of SD than patients with PSO. The ratio of the dermal fibrous tissues and eosinophil counts were significantly higher in AD patients. In AD skin, periostin was more widely distributed in the entire dermis and POSTN mRNAs were significantly upregulated. Dermal thickness and fibrosis were significantly higher in AD mice even after TGC treatment. A significant positive correlation was observed between dermal fibrosis and tissue eosinophil counts. Lesser skin atrophy in AD patients even after long-term TGC application could be resulted from skin fibrosis caused by increased tissue eosinophils and periostin deposition.

This study aimed to investigate the predictive efficacy of shear-wave elastography, superb microvascular imaging (SMI), and CEUS for allograft rejection in kidney transplants without graft dysfunction.From January 2021 to November 2021, 72 consecutive patients who underwent both allograft biopsy and ultrasound were evaluated. Blood test results were obtained within a week of the ultrasound examinations, which were performed before the protocol biopsy. Resistive index (RI), tissue viscoelasticity, vascular index, and quantitative CEUS parameters were measured. Patients were divided based on biopsy results into the rejection and non-rejection groups.Among the 72 patients, 21 patients had pathological characteristics of acute rejection. RI of allograft was significantly higher in the rejection group (p = 0.007), compared to the non-rejection group. There were no significant between-group differences in vascular indices of SMI, mean elasticity, and mean viscosity. Meanwhile, among the parameters obtained by the time-intensity curve on CEUS, the cortical and medullary ratios of average contrast signal intensity, peak enhancement, wash-in area AUC, wash-in perfusion index, wash-out AUC, and wash-in and wash-out AUC were significantly different between the two groups (p0.05). In the receiver operating characteristic curve analysis for predicting allograft rejection, the AUC was 0.853 for the combination of six CEUS parameters, RI, and blood urea nitrogen.Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for diagnosing subclinical allograft rejection. Furthermore, the combination of CEUS parameters, RI, and blood urea nitrogen may be helpful for the early detection of renal allograft rejection.• Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for the diagnosis of subclinical allograft rejection. • On CEUS, the C/M ratios of MeanLin, PE, WiAUC, WiPI, WoAUC, and WiWoAUC are significantly lower in the rejection group; the combination of these showed reliable predictive performance for rejection. • The combination of CEUS parameters, RI, and BUN has a high predictive capability for subclinical allograft rejection.

Despite advances in medicine, mortality due to sepsis has not decreased. Pulsed electromagnetic field (PEMF) therapy is emerging as an alternative treatment in many inflammation-related diseases. However, there are few studies on the application of PEMF therapy to sepsis. In the current study, we examined the effect of PEMF therapy on a mouse model of lipopolysaccharide (LPS)-induced septic shock. Mice injected with LPS and treated with PEMF showed higher survival rates compared with the LPS group. The increased survival was correlated with decreased levels of pro-inflammatory cytokine mRNA expression and lower serum nitric oxide levels and nitric oxide synthase 2 mRNA expression in the liver compared with the LPS group. In the PEMF + LPS group, there was less organ damage in the liver, lungs, spleen, and kidneys compared to the LPS group. To identify potential gene targets of PEMF treatment, microarray analysis was performed, and the results showed that 136 genes were up-regulated, and 267 genes were down-regulated in the PEMF + LPS group compared to the LPS group. These results suggest that PEMF treatment can dramatically decrease septic shock through the reduction of pro-inflammatory cytokine gene expression. In a clinical setting, PEMF may provide a beneficial effect for patients with bacteria-induced sepsis and reduce septic shock-induced mortality.

The tumour microenvironment is a key regulators of tumour progression through the secretion of growth factors that activate epithelial-mesenchymal transition (EMT). Induction of EMT is a key step for transition from a benign state to a metastatic tumour. Adipose tissue forms a bulk portion of the breast cancer microenvironment, emerging evidence indicates the potential for adipocytes to influence tumour progression through the secretion of adipokines that can induce EMT. The molecular mechanisms underlying how adipocytes enhance breast cancer progression is largely unknown. We hypothesized that paracrine signalling by adipocytes can activate EMT and results in increased migration and invasion characteristics of breast cancer cells. We found that IL-6 secreted by adipocytes induce EMT in breast cancer cells. The effect of IL-6 expression on EMT is mediated through activation of the signal transducer and activated of transcription 3 (STAT3). Blocking of IL-6 signalling in breast cancer cells and adipocytes, decreased proliferation, migration and invasion capabilities and altered the expression of genes regulating EMT. Together, our results suggest that matured human adipocytes can enhance the aggressive behaviour of breast cancer cells and induce an EMT-phenotype through paracrine IL-6/STAT3 signalling.

Breast cancer is the most common malignancy in women worldwide, with a developmental process spanning decades. The malignant cells recruit a variety of cells including fibroblasts, endothelial cells, immune cells, and adipocytes, creating the tumor microenvironment. The tumor microenvironment has emerged as active participants in breast cancer progression and response to treatment through autocrine and paracrine interaction with the malignant cells. Adipose tissue is abundant in the breast cancer microenvironment; interactions with cancer cells create cancer-associated adipocytes which produce a variety of adipokines that influence breast cancer initiation, metastasis, angiogenesis, and cachexia. Interleukin (IL)-6 has emerged as key compound significantly produced by breast cancer cells and adipocytes, with the potential of inducing proliferation, epithelial-mesenchymal phenotype, stem cell phenotype, angiogenesis, cachexia, and therapeutic resistance in breast cancer cells. Our aim is to present a brief knowledge of IL-6's role in breast cancer. This review summarizes our current understanding of the breast microenvironment, with emphasis on adipocytes as key players in breast cancer tumorigenesis. The effects of key adipocytes such as leptin, adipokines, TGF-b, and IL-6 are discussed. Finally, we discuss the role of IL-6 in various aspects of cancer progression.

Deregulation of Ca2+ signaling has been regarded as one of the key features of cancer progression. Lysine-deficient protein kinase 1 (WNK1), a major regulator of renal ion transport, regulates Ca2+ signaling through stimulating the phosphatidylinositol 4-kinase IIIα (PI4KIIIα) to activate Gαq-coupled receptor/PLC-β signaling. However, the contribution of WNK1-mediated Ca2+ signaling in the development of clear-cell renal-cell carcinoma (ccRCC) is yet unknown. We found that the canonical transient receptor potential channel (TRPC)6 was widely expressed in ccRCC tissues and functioned as a primary Ca2+ influx mechanism. We further identified that the expressions of WNK1, PI4KIIIα, TRPC6, and the nuclear factor of activated T cells cytoplasmic 1 (NFATc1) were elevated in the tumor tissues compared with the adjacent normal tissues. WNK1 expression was directly associated with the nuclear grade of ccRCC tissues. Functional experiments showed that WNK1 activated TRPC6-mediated Ca2+ influx and current by stimulating PI4KIIIα. Notably, the inhibition of WNK1-mediated TRPC6 activation and its downstream substrate calcineurin attenuated NFATc1 activation and the subsequent migration and proliferation of ccRCC. These findings revealed a novel perspective of WNK1 signaling in targeting the TRPC6-NFATc1 pathway as a therapeutic potential for renal-cell carcinoma.-Kim, J.-H., Hwang, K.-H., Eom, M., Kim, M., Park, E. Y., Jeong, Y., Park, K.-S., Cha, S.-K. WNK1 promotes renal tumor progression by activating TRPC6-NFAT pathway.

Delta neutrophil index (DNI), representing an elevated fraction of circulating immature granulocyte in acute infection, has been reported as a useful, predictable marker for mortality in patients with sepsis. We have hypothesized that an increased recipient DNI is associated with poor prognosis in cadaver donor kidney transplantation.We investigated patients undergoing kidney transplantation from cadaver donors from March 2013 to January 2018. Rejection was diagnosed by kidney biopsy with Banff classification and excluded subclinical rejection.In a total of 73 patients undergoing cadaver kidney transplantation, 25 (34.2%) patients were diagnosed with rejection based on the Banff classification. Among them, 11 patients were diagnosed with early rejection. The recipients' postoperative DNI (%) was different between patients with early rejection and patients without rejection (0.18 vs 1.21, P .001). In the univariate logistic regression analysis, cold ischemic time, donor preoperative last creatinine level, postoperative DNI level, and perioperative infection were predictive of early rejection. However, in a multivariate adjusted logistic regression test, only a high level of DNI (odds ratio 12.307, 95% confidence interval [CI] 1.22-129.82) was associated with early rejection. The C-statistic was 0.777 (95% CI 0.604-0.951, P = .004) for DNI. In multivariate Cox regression analysis, the donor's last creatinine level (hazard ratio 2.25, 95% CI 1.26-4.13) and preoperative DNI (hazard ratio 14.02 95% CI 2.62-75.26) were predictors of renal survival.Increased DNI in cadaver donor kidney transplantation recipients might be one of the predictive values of early kidney rejection and prognosis.

Store-operated calcium (Ca2+) entry (SOCE) is the principal Ca2+ entry route in non-excitable cells, including cancer cells. We previously demonstrated that Orai1 and STIM1, the molecular components of SOCE, are involved in tumorigenesis of clear cell renal cell carcinoma (CCRCC). However, a clinical relevance of Orai1 and STIM1 expression in CCRCC has been ill-defined. Here, we investigated the expression of Orai1 and STIM1 in CCRCC, and compared their expression with clinico-pathological parameters of CCRCC and the patients’ outcome. Immunohistochemical staining for Orai1 and STIM1 was performed on 126 formalin fixed paraffin embedded tissue of CCRCC and western blot analysis for Orai1 was performed on the available fresh tissue. The results were compared with generally well-established clinicopathologic prognostic factors in CCRCC and patient survival. Membrane protein Orai1 is expressed in the nuclei in CCRCC, whereas STIM1 shows the cytosolic expression pattern in immunohistochemical staining. Orai1 expression level is inversely correlated with CCRCC tumor grade, whereas STIM1 expression level is not associated with tumor grade. The higher Orai1 expression is significantly associated with lower Fuhrman nuclear grade, pathologic T stage, and TNM stage and with favorable prognosis. The expression level of STIM1 is not correlated with CCRCC grade and clinical outcomes. Orai1 expression in CCRCC is associated with tumor progression and with favorable prognostic factors. These results suggest that Orai1 is an attractive prognostic marker and therapeutic target for CCRCC., Graphical Abstract

Background The utilization of expanded-criteria donors (ECDs) has increased to overcome donor shortages. Unfortunately, the discard rate has also increased, especially in ECDs with acute kidney injury (AKI). We evaluated the outcomes of kidney transplantation in ECDs and standard-criteria donors (SCDs) with and without AKI. Methods We reviewed the medical records of patients who underwent kidney transplantation. We used the AKI definition published by the Kidney Disease: Improving Global Outcomes group and reviewed the demographic characteristics of donors and recipients. We analyzed transplantation outcomes. Results Twenty-seven patients underwent kidney transplantation from ECDs with AKI ( n = 6) or without AKI ( n = 5) and SCDs with AKI ( n = 6) or without AKI ( n = 10). Initial creatinine and estimated glomerular filtration rate (eGFR) were not significantly different between the groups. The incidence of delayed graft function was highest in ECDs with AKI ( n = 3; 36.4%), but this was not a significantly difference. There was no difference in the last creatinine and eGFR in ECDs with AKI (1.32 mg/dL, 58.7 mL/min/1.73 m 2 ), ECDs without AKI (1.67 mg/dL, 44.2 mL/min/1.73 m 2 ), SCDs with AKI (0.94 mg/dL, 81.5 mL/min/1.73 m 2 ) and SCDs without AKI (0.97 mg/dL, 81.8 mL/min/1.73 m 2 ). Conclusions As the donor pool is extended to ECDs, young transplant surgeons may increasingly face decisions regarding ECDs with AKI or allocation failure. There is no consensus regarding discard criteria. However, if the donor showed initially normal creatinine levels or if dual-kidney transplantation can be performed, young transplant surgeons should not hesitate to use ECDs with AKI or allocation failure.

While the etiology of sarcoidosis remains uncertain, mycobacteria have been suggested as a causative infectious agent. To investigate the causal relationship between mycobacteria and sarcoidosis, we performed a reverse blot hybridization assay (REBA) to identify mycobacteria from the skin samples of nine patients with sarcoidosis. Six of the nine samples were shown to be positive for mycobacteria by REBA, including Mycobacterium tuberculosis and non-tuberculous mycobacteria. This is the first study to identify mycobacteria from the skin samples of sarcoidosis patients using REBA, and our results could strengthen the etiologic association between mycobacteria and sarcoidosis.

The tumour microenvironment is a key regulators of tumour progression through the secretion of growth factors that activate epithelial-mesenchymal transition (EMT). Induction of EMT is a key step for transition from a benign state to a metastatic tumour. Adipose tissue forms a bulk portion of the breast cancer microenvironment, emerging evidence indicates the potential for adipocytes to influence tumour progression through the secretion of adipokines that can induce EMT. The molecular mechanisms underlying how adipocytes enhance breast cancer progression is largely unknown. We hypothesized that paracrine signalling by adipocytes can activate EMT and results in increased migration and invasion characteristics of breast cancer cells. We found that IL-6 secreted by adipocytes induce EMT in breast cancer cells. The effect of IL-6 expression on EMT is mediated through activation of the signal transducer and activated of transcription 3 (STAT3). Blocking of IL-6 signalling in breast cancer cells and adipocytes, decreased proliferation, migration and invasion capabilities and altered the expression of genes regulating EMT. Together, our results suggest that matured human adipocytes can enhance the aggressive behaviour of breast cancer cells and induce an EMT-phenotype through paracrine IL-6/STAT3 signalling.

Purpose It is well known that testicular germ cell tumors arise with increased frequency in patients with cryptorchidism. In addition, intratubular germ cell neoplasia (ITGCN) is a precursor lesion to testicular germ cell tumor. Approximately 50% of patients with ITGCN will develop an invasive of testicular germ cell tumors within 5 years. Therefore, we evaluated that the incidence of ITGCN in postpubertal cryptorchidism. Materials and Methods Between January 2002 and August 2012, orchiectomy specimens from 31 postpubertalpatients (aged 12 or over) with cryptorchid testis were reviewed. The specimens were evaluated for ITGCN using immunohistochemical stains of placental-like alkaline phosphatase and Oct 3/4 with routine hematoxylin-eosin stain. Additionally, the degree of spermatogenesis was assessed using the Johnsen score. Results Mean age was 34 years (range, 17 to 74 years) at surgery. All patients were diagnosed as unilateral cryptorchidism. One patient (3.2%) of 20-year-old had ITGCN in surgical specimen with all positive markers. Histological assessment of spermatogenesis showed that mean Johnsen score was 3.42 (range, 1 to 9). Majority of patients (27 of 31) presented impaired spermatogenesis with low Johnsen score lesser than 5. Conclusions Considering the risk of malignancy and low spermatogenesis, we should perform immunohistochemical stains and discuss preventative orchiectomy for the postpubertal cryptorchidism.

Kidney transplantation is the preferred treatment in end stage renal disease for autosomal dominant polycystic kidney disease (ADPKD) patients. Removal of the native kidney is not usually recommended for ADPKD patients during a transplantation proce- dure because the operation time may be prolonged or the risk of bleeding may be higher. Therefore, native kidney removal is indicated for patients with chronic pain by enlarged kidney, frequent complications from cysts, such as infection or bleeding, and renal tumor development. Here, we report a case of a patient whose native kidneys were removed during a kidney trans- plantation procedure, and multifocal adenomas were identified in the removed kidneys after the procedure.

Summary Background The Methylaminolevulinate-photodynamic therapy (MAL-PDT) has been reported to be effective in treating actinic keratosis (AK). Fluorescent images taken after topical MAL application have been used to diagnose cancerous lesions. Objectives We evaluated therapeutic efficacy of MAL-PDT for multiple AK and defined value of fluorescent images in evaluating treatment response. We also investigated photorejuvenation effects of PDT. Methods Ten patients with multiple AK were enrolled. We did histological confirmation of the lesion by biopsy. After 3 h of MAL cream occlusion, red light was illuminated with 37 J/cm2 on 0, 4, 16, and 20 weeks. At each visit, lesions were counted by inspection and fluorescent images were taken under ultraviolet A light. We repeated skin biopsy in 16 weeks. Results All patients showed significant improvement after three sessions of PDT. The average remission rate was 85.96%. Overall, patients showed significant improvement in photoaging such as erythema, coarse wrinkles, and skin roughness. Histological examination also showed improvement. There was meaningful agreement between lesion count by fluorescent imaging and inspection (coefficient = 0.9). Conclusions PDT was found to be effective, well-tolerated, cosmetically acceptable for AK treatment and photorejuvenation, both clinically and histologically. In addition, fluorescent images taken after MAL application aided in evaluation of treatment response as well as diagnosis.

Endometrial carcinomas arising in a bicornuate uterus are rare, only five case of which have been previously reported. We present a case of endometrial cancer arising in a bicornuate uterus, occurring in a 65-year-old woman. Unlike previously reported cases, our case showed mixed endometrial adenocarcinoma and undifferentiated carcinoma in one horn and focal adenocarcinoma in the other. Adequate tissue sampling of both horns is necessary for accurate diagnosis of malignancy in patients with a bicornuate uterus. Physicians should be aware of the possibility of this abnormality in cases when endometrial cancer is suspected but histology fails to confirm.

Background: Increasing evidence suggests that vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) 1 signaling may play an important role in the progression of pathological angiogenesis that occurs in many tumors, including renal cell carcinoma (RCC). Therapeutic targeting directed against VEGF and VEGFR-2 has been proven to be successful for metastatic clear cell RCC (CCRCC). However, the expression of VEGFR-1 and its association with prognostic parameters of CCRCC in the tumorigenesis of renal cancer remains unclear. Therefore, we examined the expression of VEGFR-1 and its prognostic significance in CCRCC. Methods: Immunohistochemical staining for VEGFR-1 was performed on 126 formalin-fixed paraffin-embedded CCRCC tissue samples. Six of these cases were available for Western blot analyses. The results were compared with various clinicopathologic parameters of CCRCC and patients’ survival. Results: VEGFR-1 expression was detected in 59 cases (46.8%) of CCRCC. Higher VEGFR-1 expression was significantly correlated with a lower Fuhrman nuclear grade and the absence of renal pelvis invasion, although it was not related to patients’ survival. Western blot analyses showed higher VEGFR-1 expression in low grade tumors. Conclusion: VEGFR-1 expression may be associated with favorable prognostic factors, particularly a lower Fuhrman nuclear grade in CCRCC.

Simian virus 40 (SV40) is a polyomavirus that originates from the rhesus macaque and was discovered in 1960 as a contaminant of human polio vaccines produced in monkey cells.1 Recently, there has been considerable interest in the identification of SV40 in human tumors, including malignant mesothelioma (MM) and other rare tumors such as osteosarcoma, ependymoma, and choroid plexus tumors.2-6 Subsequently, it has been found that SV40 may play an important role in the etiology of these tumors.2-6 However, SV40 was not detected in malignant lymphomas in Korean patients.7 Oncogenesis driven by SV40 is mediated by the large tumor antigen (T-Ag) oncoprotein, which is capable of transforming different types of cells in the absence of other viral genes.8,9 T-Ag induces DNA synthesis in host cells and prolongs the onset of the S-phase through the inhibition of tumor suppressor proteins p53 and Rb.8 MM is a rare and extremely aggressive neoplasm that arises from the serosal surfaces of pleural, peritoneal, and pericardial cavities and is very likely associated with amphibole asbestos exposure.10,11 In recent years, the incidence of MM has been gradually increasing in concert with industrial development and increased exposure to asbestos.12 However, only a small number of people who have been exposed to asbestos during their lifetime will develop MM.11 This suggests that SV40 may act as an independent carcinogenic agent or as a cofactor of asbestos to augment the risk of MM.13 Studies investigating the relation of SV40 to MM have been inconsistent and differ by geographical location.6 The incidence of MM varies according to geographic location, and the highest incidence rates are reported from Australia, Belgium, and Great Britain.14 In Korea, the incidence of MM is very low compared with other developed countries, with only about one case per million in the last decade.14,15 However, the incidence is recently increasing. Korea has a higher proportion of females (33.8%) among MM cases compared with other nations such as Canada (15.4%) or Italy (27.6%), and most of the patients are diagnosed when they are in their 50s, which is younger compared to cases in other countries.15 Although the majority of MM patients have had occupational (36.8%) and/or environmental (20.4%) asbestos exposure, the remaining patients (42.8%) had no known asbestos exposure.15 The role of SV40 in the oncogenesis of MM following asbestos exposure has not yet been studied in a Korean population. The purpose of this study is to identify SV40 DNA and protein in tissues extracted from MM from a Korean population using quantitative polymerase chain reaction (PCR) and immunohistochemical staining.

Lung cancer is a major cause of cancer-related death worldwide. It is believed that obesity-related malignancies such as breast, endometrial, colorectal, and kidney carcinomas have lower plasma level and/or tissue expression of adiponectin receptors. However, the association between adiponectin receptors and lung cancer, a non obesity-related malignancy, is still unknown. We evaluated the tissue expression of adiponectin receptor (AdipoR) 1 and AdipoR2 in 83 cases of non-small cell lung carcinoma (NSCLC) and matched non-neoplastic lung tissues by immunohistochemistry and real-time polymerase chain reaction (PCR). Clinicopathological data, including smoking history, smoker's bronchiolitis, emphysema, lymph node metastasis, and T-stage were collected and evaluated. Expression of immunohistochemically stained AdipoR1 and AdipoR2 was observed in all samples of non-neoplastic lung tissues. Both receptors showed higher mRNA expression in non-neoplastic than neoplastic tissues (p < 0.05). In NSCLC tissues, AdipoR1 immunohistochemical expression was not observed in most of patients with squamous cell carcinoma and current smoking history (31/42, p = 0.04 and 25/29, p = 0.003, respectively). Additionally, AdipoR1 mRNA expression was significantly lower in patients with lymph node metastasis (p = 0.05). Meanwhile, AdipoR2 immunohistochemical stain expression was inversely correlated with T-stage (p = 0.05) and AdipoR2 mRNA expression was significantly lower in patients with smoker's bronchiolitis (p = 0.01) and emphysema (p = 0.03). Patients with expression of AdipoR1 had longer overall survival. AdipoR2 expression was not correlated with patients' survival. In conclusion, we suggest that expression of AdipoR1 is indicative of favorable prognosis and may be used as prognostic marker in NSCLC.

Podocyte, the gatekeeper of the glomerular filtration barrier, is a primary target for growth factor and Ca

Klotho is a type-1 membrane protein predominantly produced in the kidney, the extracellular domain of which is secreted into the systemic circulation. Membranous and secreted Klotho protect organs, including the kidney, but whether and how Klotho directly protects the glomerular filter is unknown. Here, we report that secreted Klotho suppressed transient receptor potential channel 6 (TRPC6)-mediated Ca2+ influx in cultured mouse podocytes by inhibiting phosphoinositide 3-kinase-dependent exocytosis of the channel. Furthermore, soluble Klotho reduced ATP-stimulated actin cytoskeletal remodeling and transepithelial albumin leakage in these cells. Overexpression of TRPC6 by gene delivery in mice induced albuminuria, and exogenous administration of Klotho ameliorated the albuminuria. Notably, immunofluorescence and in situ hybridization revealed Klotho expression in podocytes of mouse and human kidney. Heterozygous Klotho-deficient CKD mice had aggravated albuminuria compared with that in wild-type CKD mice with a similar degree of hypertension and reduced clearance function. Finally, disrupting the integrity of glomerular filter by saline infusion-mediated extracellular fluid volume expansion increased urinary Klotho excretion. These results reveal a potential novel function of Klotho in protecting the glomerular filter, and may offer a new therapeutic strategy for treatment of proteinuria.

Fibroadenoma (FA) and phyllodes tumor (PT) are common stromal tumors in the female breast that originate from the intralobular stroma.1,2 PT occurs approximately 10-20 years after the occurrence of FA. Because the recurrence rates for PT are higher than those of FA, it is classified as a borderline malignant tumor.3 Although PT is a type of breast stromal tumor, it is often difficult to distinguish it from FA because these tumors are histologically similar. In previous research, we applied a cDNA microarray method and reported that Ras homolog enriched in brain (RHEB), histone deacetylase 1 (HDAC1), and WEE1 homolog (WEE1) are expressed at a two-fold higher level in FA than in normal breast tissues.4 RHEB is associated with tuberous sclerosis, a human genetic disease, and RHEB plays an important role in cell growth and cell-cycle control.5,6 HDAC1 is associated with the expression and function of estrogen receptor-α (ER-α), and it has been considered an important factor in breast tumor progression, cell proliferation, invasiveness, and prognosis.7-10 WEE1 functions as a potent tumor suppressor.11 Although numerous genetic studies of breast cancer have been published, few have specifically addressed the genes expressed in these stromal tumors and no studies have reported differences in the expression of these proteins in FA and PT.4,12 Therefore, this study aimed to examine the expression of the RHEB, HDAC1, and WEE1 proteins and to compare the differences in their expression in FA and PT.

Aim: Toll-like receptor 4 (TLR-4) is the major receptor used for recognition of specific gram negative bacteria by the host immune system. The role of TLR-4 has been revealed in preterm parturition. This study aims to demonstrate the immunohistochemical expression of TLR-4 with regard to histological layers and anatomical regions of the human fetal membranes. Material and Methods: Fetal membranes were obtained from the uterine fundus and low segment. Immunohistochemical staining for TLR-4 and hematoxylin and eosin stain were performed. Results: The chorion expressed significantly higher levels of TLR-4 than the amnion (P = 0.001). There was no difference in the expression of TLR-4 between the uterine fundus and the uterine low segment (P = 0.942). There was no significant difference in TLR-4 expression according to the presence of histological chorioamnionitis (P = 0.444). TLR-4 expression decreased significantly with the progression of gestation (P = 0.002). Conclusions: The level of expression of TLR-4 did not differ according to anatomic location, but did differ according to the histological layer of the human fetal membranes and gestational age. These results suggest that TLR-4 may be involved in preterm parturition.

Tuberculosis remains a major problem for much of the world. Tuberculous lymphadenitis is the most common type of extrapulmonary tuberculosis, although a difficult invasive procedure is required for its diagnosis. We evaluated the usefulness of the whole-blood interferon-gamma release assay (IGRA) for diagnosis of tuberculous lymphadenitis. From January 2008 to October 2010, 108 patients underwent lymph node biopsy and the IGRA concurrently in Wonju Christian Hospital, Yonsei University Wonju College of Medicine. Among the patients, 27 were diagnosed with tuberculous lymphadenitis and 81 were diagnosed with non-tuberculous lymphadenitis. The diagnostic performances of the IGRA were evaluated. The median patient age was 33 years (interquartile range [IQR] 23.5 to 48 years), and 28 (25.9%) patients were male. No patient was administered immunosuppressive agents such as high-dose steroids or underwent chemotherapy within 90 days before the IGRA test. The IGRA was positive in 25 of 27 patients with tuberculous lymphadenitis and in 13 of 81 patients with non-tuberculous lymphadenopathy. Therefore, the sensitivity of IGRA was 92.6% (95% CI, 82.0 to 100), and the specificity was 80.2% (95% CI, 71.4 to 89.1). In the patients with positive IGRA results, the INF-γ concentration was significantly higher in the patients with tuberculous lymphadenitis compared to that in the patients without tuberculous lymphadenitis (15.58 [IQR 6.87 to 45.10] IU/mL versus 0.97 [IQR 0.65 to 2.41] IU/mL, p < 0.001). In conclusion, the IGRA is helpful for the diagnosis of tuberculous lymphadenitis.

Oxalate nephropathy is commonly caused by ethylene glycol, vitamin C, and foods like star fruit that contain a lot of oxalate. Peanuts also have high oxalate contents. However, case reports of peanut-induced oxalate nephropathy are not common. Here, we describe a case of peanut-induced acute oxalate nephropathy with acute kidney injury and intend to demonstrate the conditions under which peanut-induced oxalate nephropathy is likely to occur.

Waldenstrom's macroglobulinemia (WM) is lymphoplasmacytoid malignancy that affects B lymphocytes. Cutaneous involvement of WM is rare, but various cutaneous manifestations have been reported. These findings are due to various pathological processes including direct invasion of tumor cells into the skin, deposition of paraproteins, hyperviscosity syndrome, and cryoglobulinemia. A 64-year-old man presented with a 10-day history of pruritic erythematous papules and plaques on his trunk and elbows. The clinical features were suspicious for eczematous dermatitis. However, treatments such as oral antihistamines, topical steroids, ultraviolet light therapy and immunomodulators (dapsone and cyclosporine) were minimally effective. The patient's hemoglobin decreased gradually, and he was referred to the department of hematology. Serum electrophoresis exhibited a monoclonal peak in the β1 region. The diagnosis of WM was established based on a bone marrow biopsy that revealed 80% lymphoplasma cellularity, staining positive for CD20 and CD79a. However, there was no direct infiltration of tumor cells or immunoglobulin deposition on the skin biopsy. After the patient started rituximab, cyclophosphamide and dexamethasone therapy, anemia and neutropenia gradually improved. His pruritus also markedly subsided. Although there was no evidence of infiltration of WM in the skin lesions, they were thought to be strongly associated with monoclonal gammopathy. This dermatologic feature has not been documented as a nonspecific cutaneous manifestation of WM or monoclonal gammopathy. To clarify the association between intensely pruritic papules/plaques and WM, more reports and further studies could be needed.

Background and Objectives To determine the best routinely available molecular methodology for assessing thymidylate synthase (TS) as a prognostic marker in colorectal adenocarcinoma, TS was examined at the protein, mRNA, and DNA levels. Direct comparison of these routinely available assays has not been systematically studied across a large colon cancer patient cohort with long-term follow-up. Methods We studied 150 surgically resected colorectal adenocarcinoma patients who received postoperative 5-Fluorouracil (5-FU) chemotherapy. TS immuunohistochemistry and real-time quantitative RT-PCR and PCR genotyping on patient-matched tumor and normal tissues were performed. Results Surprisingly, mRNA values in normal tissue varied from 0.11 to 62.0 and significantly correlated with mRNA values of matched tumor tissues. Although higher tumor/normal ratios of mRNA expression trended toward poorer patient survival, neither this nor TS immunohistochemistry results were statistically significant predictors. TS tumor genotype was generally concordant with matched normal tissues. Further, the 2R/3R genotype of 5′-TSER was significantly correlated with poorer patient survival (P = 0.0249) and was also an independent prognostic marker on multivariate analysis. Conclusion TS genotyping on paraffin-embedded fixed tissues proved to be the most useful method for prediction of outcome of 5-FU treatment in patients with colorectal adenocarcinoma. J. Surg. Oncol. 2009;100:546–552. © 2009 Wiley-Liss, Inc.

We present the first report of ovarian dysgerminoma in Cowden syndrome, presenting in a 7-year-old girl. In her second decade, a hamartomatous soft tissue extremity mass and diffuse gastrointestinal hamartomatous polyposis with pathologic features suggestive of either juvenile, Peutz-Jeghers, or Cowden polyps were identified, along with diffuse esophageal glycogenic acanthosis and skin manifestations. During regular thyroid cancer surveillance under the provisional diagnosis of Cowden syndrome, papillary thyroid carcinoma and benign follicular nodules were diagnosed at age 23. PTEN mutational analysis revealed a novel germline nonsense point mutation of Q219X. Loss of PTEN heterozygosity was also present in the ovarian dysgerminoma. Parental mutation testing and phenotype screening were negative. The correct classification of Cowden syndrome is difficult because of its protean manifestations and overlapping phenotypes with other genetic and noninherited pathologies, particularly regarding various gastrointestinal polyposis syndromes. Despite the challenges, correct classification is critical to patient care because of the associated cancer predispositions and necessary surveillance programs. This is the first report of Cowden syndrome presenting with ovarian dysgerminoma, which implicates PTEN in the molecular pathogenesis of dysgerminoma and adds it to the phenotypic manifestations of Cowden syndrome.

Although fibroadenoma is one of the most common types of benign breast tumor, genes specific to the tumor have not been identified. Microarrays were used to identify differentially expressed genes between fibroadenoma and infiltrating ductal carcinoma. The comparative expression of one of the identified genes, RAS homolog enriched in the brain (RHEB), was further explored using reverse transcriptase-polymerase chain reaction (RT-PCR). Microarray analysis was performed on tissue samples from five patients with fibroadenoma. In the fibroadenoma samples, the genes HDAC1, ROS1, TNFRSF10A, WASP2, TYRP1, WEE1, and RHEB were expressed at levels more than twofold higher than in the normal tissues. RT-PCR for RHEB indicated increased expression of RHEB in fibroadenoma compared to breast cancer. When studied with real-time PCR, the average RHEB/beta-actin ratio in fibroadenoma samples was 1.99, 2.46-fold greater than the average RHEB/beta-actin ratio in breast carcinoma of 0.81 (P < 0.01). Immunohistochemistry and PCR followed by microdissection shows increased expression of RHEB in epithelial cells compared to the stromal cells of fibroadenoma. Therefore, RHEB could be used cytopathologically to distinguish fibroadenoma from malignant breast carcinomas as a secondary diagnostic tool.

Foam cells in human glomeruli can be encountered in various renal diseases including focal segmental glomerulosclerosis and diabetic nephropathy. Although foam cells are key participants in atherosclerosis, surprisingly little is known about their pathogenicity in the kidney. We review our understanding (or lack thereof) of foam cells in the kidney, as well as insights gained in studies of foam cells and macrophages involved in atherosclerosis to suggest areas of investigation that will allow better characterization of the role of these cells in renal disease. There is a general dearth of animal models of disease with renal foam cell accumulation, limiting progress in our understanding of the pathobiology of these cells. Recent genetic modifications of hyperlipidemic mice have resulted in some new disease models with renal foam cell accumulation. Recent studies have challenged older paradigms by findings that indicate that many tissue macrophages are derived from cells permanently residing in the tissue from birth rather than circulating monocytes. Renal foam cells remain an enigma. Extrapolating from studies of atherosclerosis suggests that therapeutics targeting mitochondrial reactive oxygen species production, or modulating cholesterol and lipoprotein uptake or egress from these cells, may prove beneficial for kidney diseases in which foam cells are present.

Cases of acute myocardial infarction (AMI) that occur during pregnancy or postpartum are rarely reported. Ergot derivatives are known to induce the spasmodic contraction of coronary arteries. Administration of ergot derivatives can cause AMI, even in normal healthy people. In several reported cases, ergot derivatives triggered severe AMI during the postpartum period. Here, we report the case of a forty-year-old woman who was successfully impregnated by artificial fertilization and died after treatment with ergot derivatives. The autopsy revealed AMI with severe coronary atherosclerosis. This is the first case that reports aggravation of pre-existent severe coronary atherosclerosis after postpartum infusion of ergot derivatives.

Background/Purpose: The etiology of meconium obstruction without cystic fibrosis is unclear. Interstitial cells of Cajal (ICC) function as pacemakers in gut motility and may play a role in the pathophysiology of the disease. Methods: The ICC were examined by immunohistochemical staining with anti-c-kit antibody in the bowel walls of 6 neonates who had meconium obstruction without cystic fibrosis, and the results were compared with specimens from normal neonates (n 2). Results: Six patients underwent ileostomy between 2 and 15 days after birth, and 5 of them presented with microcolon. Ganglion cells were present in the ileum and colon. Whereas ICC were evenly distributed in the control specimens, they were not seen at the time of ileostomy in the colons of 2 patients, and the other 4 showed scanty distribution in muscle layers. However, ileum showed normal distribution of ICC in all patients. The ileostomies were closed between 39 and 104 days of age, and the ICC distribution was changed to a normal pattern in the colons of all 6 patients. Their bowel movements were restored to normal after closure. Conclusion: The findings of this study suggest that delayed maturity of ICC may be a cause of meconium obstruction without cystic fibrosis.

The differentiation of malignant mesotheliomas and benign mesothelial proliferations is crucial in determining patient care and prognosis. But, this distinction can be extremely difficult, particularly in small biopsies. Recently, insulin-like growth factor II mRNA-binding protein 3 (IMP3) and glucose transporter 1 (GLUT-1) have been reported as specific and sensitive markers in the distinction of mesotheliomas from benign mesothelial proliferations. The purpose of this study is to evaluate the utility of IMP3, GLUT-1, and epithelial membrane antigen (EMA) immunohistochemistry for distinguishing mesotheliomas from benign mesothelial proliferations. Immunoexpression of IMP3, GLUT-1, and EMA was evaluated in 88 malignant mesotheliomas, 35 adenomatoid tumors, and 20 benign lung tissues with reactive mesothelial cells. The sensitivity for IMP3, GLUT-1, and EMA was 37%, 21%, and 41%, respectively. The specificity for IMP3, GLUT-1, and EMA was 100%. When IMP3, GLUT1, and EMA combined, the sensitivity was 66% for IMP3/EMA staining, 53% for GLUT-1/EMA staining, and 45% for IMP3/GLUT-1. Use of IMP3 and EMA together is more helpful to distinguish malignant mesotheliomas from benign mesothelial proliferations than the use of IMP3 or EMA alone.

The Methylaminolevulinate-photodynamic therapy (MAL-PDT) has been reported to be effective in treating actinic keratosis (AK). Fluorescent images taken after topical MAL application have been used to diagnose cancerous lesions.We evaluated therapeutic efficacy of MAL-PDT for multiple AK and defined value of fluorescent images in evaluating treatment response. We also investigated photorejuvenation effects of PDT.Ten patients with multiple AK were enrolled. We did histological confirmation of the lesion by biopsy. After 3 h of MAL cream occlusion, red light was illuminated with 37 J/cm(2) on 0, 4, 16, and 20 weeks. At each visit, lesions were counted by inspection and fluorescent images were taken under ultraviolet A light. We repeated skin biopsy in 16 weeks.All patients showed significant improvement after three sessions of PDT. The average remission rate was 85.96%. Overall, patients showed significant improvement in photoaging such as erythema, coarse wrinkles, and skin roughness. Histological examination also showed improvement. There was meaningful agreement between lesion count by fluorescent imaging and inspection (coefficient = 0.9).PDT was found to be effective, well-tolerated, cosmetically acceptable for AK treatment and photorejuvenation, both clinically and histologically. In addition, fluorescent images taken after MAL application aided in evaluation of treatment response as well as diagnosis.

The differentiation of malignant mesotheliomas and benign mesothelial proliferations is crucial in determining patient care and prognosis. But, this distinction can be extremely difficult, particularly in small biopsies. Recently, insulin-like growth factor II mRNA-binding protein 3 (IMP3) and glucose transporter 1 (GLUT-1) have been reported as specific and sensitive markers in the distinction of mesotheliomas from benign mesothelial proliferations. The purpose of this study is to evaluate the utility of IMP3, GLUT-1, and epithelial membrane antigen (EMA) immunohistochemistry for distinguishing mesotheliomas from benign mesothelial proliferations. Immunoexpression of IMP3, GLUT-1, and EMA was evaluated in 88 malignant mesotheliomas, 35 adenomatoid tumors, and 20 benign lung tissues with reactive mesothelial cells. The sensitivity for IMP3, GLUT-1, and EMA was 37%, 21%, and 41%, respectively. The specificity for IMP3, GLUT-1, and EMA was 100%. When IMP3, GLUT1, and EMA combined, the sensitivity was 66% for IMP3/EMA staining, 53% for GLUT-1/EMA staining, and 45% for IMP3/GLUT-1. Use of IMP3 and EMA together is more helpful to distinguish malignant mesotheliomas from benign mesothelial proliferations than the use of IMP3 or EMA alone.

The intracellular Ca(2+) regulation has been implicated in tumorigenesis and tumor progression. Notably, store-operated Ca(2+) entry (SOCE) is a major Ca(2+) entry mechanism in non-excitable cells, being involved in cell proliferation and migration in several types of cancer. However, the expression and biological role of SOCE have not been investigated in clear cell renal cell carcinoma (ccRCC). Here, we demonstrate that Orai1 and STIM1, not Orai3, are crucial components of SOCE in the progression of ccRCC. The expression levels of Orai1 in tumor tissues were significantly higher than those in the adjacent normal parenchymal tissues. In addition, native SOCE was blunted by inhibiting SOCE or by silencing Orai1 and STIM1. Pharmacological blockade or knockdown of Orai1 or STIM1 also significantly inhibited RCC cell migration and proliferative capability. Taken together, Orai1 is highly expressed in ccRCC tissues illuminating that Orai1-mediated SOCE may play an important role in ccRCC development. Indeed, Orai1 and STIM1 constitute a native SOCE pathway in ccRCC by promoting cell proliferation and migration.

PURPOSE ROS1 is an oncogene, expressed primarily in glioblastomas of the brain that has been hypothesized to mediate the effects of early stage tumor progression. In addition, it was reported that ROS1 expression was observed in diverse cancer tissue or cell lines and ROS1 is associated with the development of several tumors. However, ROS1 expression has not been studied in breast cancer to date. Therefore, we investigated ROS1 expression at the protein and gene level to compare expression patterns and to verify the association with prognostic factors in invasive ductal carcinoma (IDC) of the breast. MATERIALS AND METHODS Tissue samples from 203 patients were used. Forty-six cases were available for fresh tissue. We performed immunohistochemical staining and real-time polymerase chain reaction (PCR). RESULTS ROS1 expression was significantly lower in proportion to higher histologic grade, higher mitotic counts, lower estrogen receptor expression, and a higher Ki-67 proliferation index, although ROS1 expression was not significantly associated with the survival rate. The result of real-time PCR revealed similar trends, however not statistically significant. CONCLUSION Higher ROS1 expression may be associated with favorable prognostic factors of IDC and its expression in IDC is related to the proliferation of tumor cells.

Klotho functions as a tumor suppressor predominantly expressed in renal tubular cells, the origin of clear cell renal cell carcinoma (ccRCC). Altered expression and/or activity of growth factor receptor have been implicated in ccRCC development. Although Klotho suppresses a tumor progression through growth factor receptor signaling including insulin-like growth factor-1 receptor (IGF-1R), the role of Klotho acting on IGF-1R in ccRCC and its clinical relevance remains obscure. Here, we show that Klotho is favorable prognostic factor for ccRCC and exerts tumor suppressive role for ccRCC through inhibiting IGF-1R signaling. Our data shows the following key findings. First, in tumor tissues, the level of Klotho and IGF-1R expression are low or high, respectively, compared to that of adjacent non-neoplastic parenchyma. Second, the Klotho expression is clearly low in higher grade of ccRCC and is closely associated with clinical outcomes in tumor progression. Third, Klotho suppresses IGF-1-stimulated cell proliferation and migration by inhibiting PI3K/Akt pathway. These results provide compelling evidence supporting that Klotho acting on IGF-1R signaling functions as tumor suppressor in ccRCC and suggest that Klotho is a potential carcinostatis substance for ccRCC.

Arsenic is a terribly poisonous material. There have been many reports of arsine poisoning in workers, and a few have discussed acute kidney injury by arsine. But literatures which investigated the pathologic findings are uncommon, and especially, the ones describing ultrastructural findings are rare. Here, we report an incident of acute arsine poisoning complicated by acute kidney injury and suggest the characteristics of the renal pathology in arsine-induced renal injury, especially the ultrastructural findings.

Most breast cancers express estrogen receptor α (ER-α), which is important for the diagnosis, treatment, and prognosis of the disease. However, ER-α is not expressed in more than one-third of breast cancer cases at diagnosis,1,2 which was attributed to histone deacetylation and chromatin inactivation by DNA methylation. Histone deacetylase 1 (HDAC1) is associated with the expression and function of ER and has been considered a very important factor in breast tumor progression and prognosis.3-6 An increase in HDAC1 mRNA has been reported in breast cancer cases without lymph node metastasis and with smaller tumor size, lower histologic grade, negative human epidermal growth factor receptor 2 (HER-2), and positive ER and progesterone receptor (PR) expression; the HDAC1 expression level, therefore, has been considered a good prognostic indicator in breast cancer.4 However, HDAC1 has also been reported to be associated with invasive growth and a poor prognosis.5,6 To date, few studies of HDAC1 expression in breast cancer have been performed, and the prognostic significance of HDAC1 for breast cancer has not been well defined. Therefore, we examined HDAC1 expression in invasive ductal carcinoma (IDC), the most common type of breast cancer, and aimed to verify the prognostic significance of HDAC1 expression in IDC. In this study, the expression pattern of HDAC1 at the protein and mRNA level was examined, and compared to diverse prognostic factors in IDC and the survival rates of patients to confirm the prognostic value of HDAC1 expression in IDC.