TFE3/PI3K/Akt/mTOR Axis in Renal Cell Carcinoma Affects Tumor Microenvironment.

The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin (mTOR) and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. Data from this study indicate that TFE3 plays a role in the PI3K/Akt pathway in RCC. The results of this study suggest that PI3K/Akt inhibitors may aid in the treatment of patients with RCC by affecting the tumor microenvironment.

A rice seed-specific glycine-rich protein OsDOR1 interacts with GID1 to repress GA signaling and regulates seed dormancy.

Seed dormancy is an important agronomic trait under the control of complex genetic and environmental interactions, which have not been yet comprehensively understood. From the field screening of rice mutant library generated by a Ds transposable element, we identified a pre-harvest sprouting (PHS) mutant dor1. This mutant has a single insertion of Ds element at the second exon of OsDOR1 (LOC_Os03g20770), which encodes a novel seed-specific glycine-rich protein. This gene successfully complemented the PHS phenotype of dor1 mutant and its ectopic expression enhanced seed dormancy. Here, we demonstrated that OsDOR1 protein binds to the GA receptor protein, OsGID1 in rice protoplasts, and interrupts with the formation OsGID1-OsSLR1 complex in yeast cells. Co-expression of OsDOR1 with OsGID1 in rice protoplasts attenuated the GA-dependent degradation of OsSLR1, the key repressor of GA signaling. We showed the endogenous OsSLR1 protein level in the dor1 mutant seeds is significantly lower than that of wild type. The dor1 mutant featured a hypersensitive GA-response of α-amylase gene expression during seed germination. Based on these findings, we suggest that OsDOR1 is a novel negative player of GA signaling operated in the maintenance of seed dormancy. Our findings provide a novel source of PHS resistance.

mTOR Inhibition Increases Transcription Factor E3 (TFE3) Activity and Modulates Programmed Death-Ligand 1 (PD-L1) Expression in Translocation Renal Cell Carcinoma.

The efficacy of programmed death ligand (PD-L)-1/PD-1 checkpoint blockade in renal cell carcinoma (RCC) remains unknown. The effects of mTOR inhibitors are uncertain, and patients may develop resistance to them. The limited understanding of cancer cell-intrinsic mTOR-mediated pathways remains a challenge in developing effective treatments. Whether transcription factor (TF)-E3 regulates PD-L1 expression and the tumor microenvironment was investigated, and the effects of an mammalian target of rapamycin (mTOR) inhibitor on translocation RCC were explored. TFE3 was overexpressed in clear cell RCC cell lines, and PD-L1 expression was analyzed by Western blot analysis. PD-L1 activity in translocation RCC was analyzed in relation to TFE3 expression via TFE3 knockdown and treatment with an mTOR inhibitor. The results were correlated with the gene expression profile, evaluated using digital multiplex analysis. TFE3 and PD-L1 expression were positively correlated in RCC cells. TFE3 overexpression was associated with the expression of PD-L1 in RCC. Furthermore, mTOR inhibition was associated with enhanced PD-L1 expression via TFE3 activation in translocation RCC. These data support the feasibility of combination therapy based on mTOR inhibition and PD-L1 blockade as a novel strategy for the treatment of patients with translocation RCC.

The OsERF115/AP2EREBP110 Transcription Factor Is Involved in the Multiple Stress Tolerance to Heat and Drought in Rice Plants.

The AP2/EREBP family transcription factors play important roles in a wide range of stress tolerance and hormone signaling. In this study, a heat-inducible rice ERF gene was isolated and functionally characterized. The OsERF115/AP2EREBP110 was categorized to Group-IIIc of the rice AP2/EREBP family and strongly induced by heat and drought treatment. The OsERF115/AP2EREBP110 protein targeted to nuclei and suppressed the ABA-induced transcriptional activation of Rab16A promoter in rice protoplasts. Overexpression of OsERF115/AP2EREBP110 enhanced thermotolerance of seeds and vegetative growth stage plants. The OsERF115/AP2EREBP110 overexpressing (OE) plants exhibited higher proline level and increased expression of a proline biosynthesis P5CS1 gene. Phenotyping of water use dynamics of the individual plant indicates that the OsERF115/AP2EREBP110-OE plant exhibited better water saving traits under heat and drought combined stress. Our combined results suggest the potential use of OsERF115/AP2EREBP110 as a candidate gene for genetic engineering approaches to develop heat and drought stress-tolerant crops.

The Rice Abscisic Acid-Responsive RING Finger E3 Ligase OsRF1 Targets OsPP2C09 for Degradation and Confers Drought and Salinity Tolerance in Rice.

Drought and salinity are major important factors that restrain growth and productivity of rice. In plants, many really interesting new gene (RING) finger proteins have been reported to enhance drought and salt tolerance. However, their mode of action and interacting substrates are largely unknown. Here, we identified a new small RING-H2 type E3 ligase OsRF1, which is involved in the ABA and stress responses of rice. OsRF1 transcripts were highly induced by ABA, salt, or drought treatment. Upregulation of OsRF1 in transgenic rice conferred drought and salt tolerance and increased endogenous ABA levels. Consistent with this, faster transcriptional activation of key ABA biosynthetic genes, ZEP, NCED3, and ABA4, was observed in OsRF1-OE plants compared with wild type in response to drought stress. Yeast two-hybrid assay, BiFC, and co-immunoprecipitation analysis identified clade A PP2C proteins as direct interacting partners with OsRF1. In vitro ubiquitination assay indicated that OsRF1 exhibited E3 ligase activity, and that it targeted OsPP2C09 protein for ubiquitination and degradation. Cell-free degradation assay further showed that the OsPP2C09 protein is more rapidly degraded by ABA in the OsRF1-OE rice than in the wild type. The combined results suggested that OsRF1 is a positive player of stress responses by modulating protein stability of clade A PP2C proteins, negative regulators of ABA signaling.

Bisifusarium Delphinoides, an Emerging Opportunistic Pathogen in a Burn Patient with Diabetes Mellitus.

An 82-year-old man with diabetes was admitted to the emergency department with a third-degree burn on his left leg. The deep swab specimen from his left leg was cultured on Sabouraud dextrose agar without cycloheximide and incubated at 25 °C for 5 days. On the basis of morphological characteristics and multigene phylogenetic analyses of the internal transcribed spacer region of ribosomal DNA and partial fragments of beta-tubulin and translation elongation factor 1-alpha, the causal agent of fungal skin infection was identified as Bisifusarium delphinoides, which was newly introduced by accommodating a Fusarium dimerum species complex. Thus, we describe here the first case of skin infection caused by B. delphinoides on a burn patient with diabetes mellitus based on morphological observation and molecular analysis.

Comparison of Radiological and Histological Findings of Lung Parenchyma in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

PURPOSE: The present study investigated chest computed tomography (CT) patterns and lung histological features, as well as the consistency between radiological and histological features among patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic GPA (EGPA). MATERIALS AND METHODS: The medical records of 74 antineutrophil cytoplasmic antibody-associated vasculitis (AAV) patients with radiological lung parenchymal lesions were reviewed along with the histological results for 28 of them. Chest CT patterns were divided according 12 items mostly suggested by radiologists and histological features were divided according to necrotising granuloma, necrotising vasculitis, eosinophilic infiltration, and hemosiderin laden macrophages as defined by a pathologist. RESULTS: The mean age was 57.1 years (22 men). The most common clinical manifestation other than lung manifestation was renal manifestation (62.2%), and the most common chest CT pattern was lung involvement of vasculitis (35.1%). In MPA patients, the major histological features were hemosiderin-laden macrophages in the alveolar space and vasculitis. In GPA patients, the major histological features were necrotizing vasculitis and necrotizing granuloma, while in EGPA patients, the major histological feature was only necrotising vasculitis. The consistency rate in GPA patients was the highest (100%), followed by that in MPA patients (66.7%) and EGPA patients (50.0%). CONCLUSION: When lung involvement of AAV is suspected on chest CT, lung biopsy should be recommended for the proper classification of AAV, due to the discordance rate between radiological and histological findings in MPA and EGPA patients, but not GPA patients.

Management of epidermal cysts arising from scar tissues: A retrospective clinical study.

Few reports have described epidermal cysts (ECs) arising from scar tissues, and the standard course of treatment has not been established. We aimed to report the findings of a Korean patient series with ECs arising from scar tissues, to describe patient management in the context of previous publications, and to present a simple algorithm for managing ECs arising from scar tissues.We managed 6 patients with ECs arising from scar tissues, and retrospectively reviewed their demographic and clinical data.The scars were located on the anterior chest wall (n = 3), shoulder (n = 1), forehead (n = 1), and ear lobule (n = 1). Two patients with anterior chest wall scars, 1 with a shoulder scar, and 1 with an ear lobule scar had keloid scars, whereas the other patients had hypertrophic scars. The scar sizes ranged from 2 × 1 cm to 9 × 7 cm. The EC sizes ranged from 0.2 × 0.2 cm to 2 × 1.5 cm. Three patients underwent total scar revisions with complete EC excisions, 2 underwent partial scar tissue excisions with complete EC excisions, and 1 had laser therapy for the scar and EC. No complications occurred, and all patients' final outcomes were satisfactory during the mean follow-up period of 14.8 months.We successfully managed the patients with ECs arising from scar tissues. We recommend that surgeons and patients first decide whether the ECs and scar tissue should be completely removed. Moreover, consideration should be given to the options chosen for the management of ECs. Finally, postoperative scar care is necessary to prevent hypertrophic and keloid scar recurrences.

Perirenal capsule and scrotal involvement in immunoglobulin G4-related kidney disease: case-based review.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic, immune-mediated-, systemic disease that is characterized by IgG4 plasma cell infiltration with fibrotic changes in various organs. The most affected organs are pancreas and salivary glands. Kidney can be rarely involved, and is usually represented as a renal mass and organomegaly. Usually, elevated levels of serum IgG4 more than 135 mg/dl with organ-specific features and biopsy results showing enriched infiltration of IgG4-positive plasma cells are needed to diagnose the disease. However, we experienced two unusual cases of IgG4-RD involving kidney. IgG4-related kidney disease (IgG4-RKD) was first reported as an extra pancreatic feature of autoimmune pancreatitis(AIP) in 2004. Herein, we describe two cases of such unique presentation of IgG4RKD and a literature review focusing on clinicopathologic features of IgG4RKD. Our cases are distinct in the fact that IgG4RD invades unusual organs such as perinephric capsule or scrotum. We reported the patient who showed extinct perirenal capsule invasion with multi-organ involvement including exocrine glands in comparison to previous IgG4RKD that often involved in renal parenchyma and renal pelvis lesions. And the other patient had scrotal invasion with multifocal renal parenchymes. Referring to the features observed in these two cases, we could propose that as every organ can be related to IgG4RD, we propose clinicians to confirm the disease using imaging, serologic, and pathologic studies. We also reviewed previous reports of IgG4-RKD and summarized diverse imaging findings and pathologic features.

The functional relevance of diffusion tensor imaging in comparison to conventional MRI in patients with cervical compressive myelopathy.

OBJECTIVE: To determine the functional relevance of diffusion tensor imaging (DTI) metrics and conventional MRI (signal intensity change in T2, compression ratio) by measuring the correlation of these parameters with clinical outcome measured by the modified Japanese Orthopedic Association (mJOA) score. MATERIALS AND METHODS: A total of 20 cervical myelopathy (CM) patients participated in this prospective cohort study. The severities of CM were assessed using the mJOA score. Conventional MRIs (T2-weighted images) measuring the signal changes of spinal cords and the degree of compression at the lesion level and DTI metrics [fractional anisotropy (FA), apparent diffusion coefficient (ADC)] at each lesion and below each lesion (C7/T1) level were acquired using a 3-T Achieva MRI. These parameters were correlated with the mJOA scores to determine the functional relevance. RESULTS: Ninety percent of CM patients showed signal changes and 30 % of patients noted a more than 40% canal compression ratio in conventional MRIs at the lesion level; however, these findings were not correlated with the mJOA score (p < 0.05). In contrast, FA values on DTI showed high sensitivity to CM (100%), which was well correlated with the mJOA score (p = 0.034, r = 0.475) below the lesion level (C7/T1). CONCLUSIONS: This study showed a meaningful symptomatic correlation between mJOA scores and FA values below the lesion levels in CM patients. It could give us more understanding of the pathological changes in spinal cords matched with various clinical findings in CM patients than the results from conventional MRI.