[MRI/TRUS cognitive fusion combined with 12-core systematic transperineal prostate biopsy for the diagnosis of clinically significant prostate cancer: A report of 208 cases].

OBJECTIVE: To investigate the detection rate and complications of magnetic resonance imaging / transrectal ultrasonography (MRI/TRUS) cognitive fusion combined with 12-core systematic transperineal prostate biopsy (TPPB) in the diagnosis of clinically significant PCa (CS-PCa). METHODS: This retrospective study included 208 patients undergoing first-time MRI/TRUS cognitive fusion combined with 12-core systematic TPPB from June 2015 to May 2019. The patients, aged 54－85 (67.6 ± 7.8) years, all received digital rectal examination, PSA detection, TRUS and prostate multiparametric MRI (mpMRI) before biopsy. We analyzed the mpMRI images, identified and marked the suspected signal areas, repeated TRUS for further observation of the prostate, conducted cognitive fusion based on the mpMRI images and determined the target before 12-core systematic TPPB and subjecting the samples obtained to pathological examination. RESULTS: Of the 208 patients, 112 were diagnosed with CS-PCa (no case with tPSA < 4 µg/L, 21 cases with 4 µg/L ≤ tPSA < 10 µg/L, 47 cases with 10 µg/L ≤ tPSA < 20 µg/L, 40 cases with 20 µg/L ≤ tPSA < 100 µg/L, and 4 cases with tPSA ≥ 100 µg/L), 85 with BPH, 8 with chronic prostatitis, 2 with atypical prostatic hyperplasia, and 1 with prostatic intraepithelial neoplasia. Systemic inflammatory response syndrome occurred in 3 and gross hematuria and/or bloody stool in 12 cases after biopsy, which were all cured by anti-infection and hemostasis treatment. CONCLUSIONS: MRI/TRUS cognitive fusion combined with 12-core systematic transperineal prostate biopsy can improve the detection rate of the initial diagnosis of clinically significant PCa with a low incidence of controllable complications.

Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation.

Single Ig IL-1R-related molecule (SIGIRR, also called IL-1R8 or Toll/IL-1R [TIR]8), a negative regulator for Toll/IL-1R signaling, plays critical roles in innate immunity and various diseases in mammals. However, the occurrence of this molecule in ancient vertebrates and its function in liver homeostasis and disorders remain poorly understood. In this study, we identified a SIGIRR homology from zebrafish (Danio rerio [DrSIGIRR]) by using a number of conserved structural and functional hallmarks to its mammalian counterparts. DrSIGIRR was highly expressed in the liver. Ablation of DrSIGIRR by lentivirus-delivered small interfering RNA in the liver significantly enhanced hepatic inflammation in response to polyinosinic-polycytidylic acid [poly(I:C)] stimulation, as shown by the upregulation of inflammatory cytokines and increased histological disorders. In contrast, depletion of TIR domain-containing adaptor inducing IFN-ß (TRIF) or administration of TRIF signaling inhibitor extremely abrogated the poly(I:C)-induced hepatic inflammation. Aided by the zebrafish embryo model, overexpression of DrSIGIRR in vivo significantly inhibited the poly(I:C)- and TRIF-induced NF-κB activations; however, knockdown of DrSIGIRR promoted such activations. Furthermore, pull-down and Duolink in situ proximity ligation assay assays showed that DrSIGIRR can interact with the TRIF protein. Results suggest that DrSIGIRR plays an inhibitory role in TRIF-mediated inflammatory reactions by competitive recruitment of the TRIF adaptor protein from its TLR3/TLR22 receptor. To our knowledge, this study is the first to report a functional SIGIRR homolog that existed in a lower vertebrate. This molecule is essential to establish liver homeostasis under inflammatory stimuli. Overall, the results will enrich the current knowledge about SIGIRR-mediated immunity and disorders in the liver.

Safety and efficacy of multilevel vertebroplasty for painful osteolytic spinal metastases: a single-centre experience.

OBJECTIVE: To retrospectively assess the safety and efficacy of percutaneous vertebroplasty (PVP) for painful osteolytic spinal metastases when treating more than three vertebrae per session. METHODS: A total of 153 patients with painful osteolytic spinal metastases underwent PVP. Group A patients (n = 93) underwent PVP at up to three vertebral levels per session. Group B patients (n = 60) underwent PVP at more than three levels in one session. Pain, quality of life (QoL), and mobility were assessed before and after PVP. Minor and major complications were systematically assessed. RESULTS: Both groups experienced significant pain relief and QoL improvement after the intervention (p < 0.001). Mobility improvement was observed in both groups, despite worse mobility status before PVP in group B compared with group A. There was no significant difference between the two groups throughout the follow-up period in overall pain relief and improvement in QoL and mobility. There was also no significant difference between groups in minor and major complications. CONCLUSIONS: Multilevel vertebroplasty is safe and effective for the treatment of multiple osteolytic spinal metastases. Multilevel PVP relieves pain and improves QoL and mobility. KEY POINTS: • Percutaneous vertebroplasty is safe and effective for painful osteolytic spinal metastases. • Multilevel vertebroplasty does not cause more complications than single-level vertebroplasty. • Multiple spinal metastases patients may regain functional independence after multilevel vertebroplasty.

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis.

Why different species are predisposed to different tumor spectra is not well understood. In particular, whether the physical location of tumor suppressor genes relative to one another influences tumor predisposition is unknown. Renal cancer presents a unique opportunity to explore this question. Renal cell carcinoma (RCC) of clear-cell type (ccRCC), the most common type, begins with an intragenic mutation in the von Hippel-Lindau (VHL) gene and loss of 3p (where VHL is located). Chromosome 3p harbors several additional tumor suppressor genes, including BRCA1-associated protein-1 (BAP1). In the mouse, Vhl is on a different chromosome than Bap1. Thus, whereas loss of 3p in humans simultaneously deletes one copy of BAP1, loss of heterozygosity in the corresponding Vhl region in the mouse would not affect Bap1. To test the role of BAP1 in ccRCC development, we generated mice deficient for either Vhl or Vhl together with one allele of Bap1 in nephron progenitor cells. Six2-Cre;Vhl(F/F);Bap1(F/+) mice developed ccRCC, but Six2-Cre;Vhl(F/F) mice did not. Kidneys from Six2-Cre;Vhl(F/F);Bap1(F/+) mice resembled kidneys from humans with VHL syndrome, containing multiple lesions spanning from benign cysts to cystic and solid RCC. Although the tumors were small, they showed nuclear atypia and exhibited features of human ccRCC. These results provide an explanation for why VHL heterozygous humans, but not mice, develop ccRCC. They also explain why a mouse model of ccRCC has been lacking. More broadly, our data suggest that differences in tumor predisposition across species may be explained, at least in part, by differences in the location of two-hit tumor suppressor genes across the genome.

Combination radiofrequency ablation and percutaneous osteoplasty for palliative treatment of painful extraspinal bone metastasis: a single-center experience.

PURPOSE: To evaluate combined radiofrequency (RF) ablation and percutaneous osteoplasty (POP) in patients with painful extraspinal bone metastases. MATERIALS AND METHODS: In a retrospective study, 38 patients with 54 extraspinal bone metastases (ilium, n = 24; acetabulum, n = 21; femur, n = 7; ischium, n = 1; tibia, n = 1) were treated with RF ablation and POP. All patients had pain refractory to analgesic medication with intensity > 3 on a visual analog scale (VAS). Changes in quality of life were evaluated based on pain relief (VAS score), function on a Karnofsky performance scale, and analgesic dose before and immediately after the procedure and during follow-up. VAS score was the primary outcome, and the others were secondary outcomes. RESULTS: Technical success was achieved in 37 patients (97.4%). Mean VAS score declined significantly from 7.1 ± 1.5 before treatment to 2.2 ± 2.0 at 24 hours after treatment (P < .05), 1.6 ± 1.8 at 3 months after treatment (P < .05), and 1.3 ± 1.8 at 6 months after treatment (P < .05). Pain relief immediately after the procedure was reported by 35 patients (92.1%); pain regressed completely in 7 (18.4%) patients. After 6 months, narcotic analgesia had been suspended in 32 of 33 patients (97.0%). Pain was controlled by nonsteroidal antiinflammatory drugs in 8 patients (24.2%), and no analgesia was necessary in 24 patients (72.7%). Mean Karnofsky performance scale score after treatment was higher than before treatment (P < .05). The major complication rate was 2.6% (1 of 38 patients), with one case of vasovagal shock. The minor complication rate was 23.7% (9 of 38 patients). CONCLUSIONS: RF ablation with POP is effective for pain relief and functional recovery in patients with painful extraspinal bone metastases and can significantly improve quality of life.

Safety and efficacy of percutaneous vertebroplasty and interventional tumor removal for metastatic spinal tumors and malignant vertebral compression fractures.

OBJECTIVE: The purpose of this study was to determine the safety and efficacy of percutaneous vertebroplasty and interventional tumor removal in the management of metastatic spinal tumors and malignant vertebral compression fractures. SUBJECTS AND METHODS: Thirty-one patients with metastatic spinal tumors and malignant vertebral compression fractures were treated with percutaneous vertebroplasty and interventional tumor removal. Insertion of a 14-gauge needle and guidewire into the vertebral body was followed by sequential dilation of the track with working cannulae until the last cannula reached the anterior portions of the pedicle. Interventional tumor removal was performed with marrow nucleus rongeurs, and 5-10 mL of cement was injected into the treated vertebra. Outcome data (visual analog scale score, Oswestry disability index score, and Karnofsky performance scale score) were collected preoperatively; 1 week and 1, 3, and 6 months after the procedure; and every 6 months thereafter until death. RESULTS: The overall clinical assessment at the last follow-up evaluation showed that pain was completely resolved in 23 patients, decreased in six patients, and unimproved in two patients, yielding a pain relief rate of 94%. The average preoperative visual analog scale score was 7.2, which decreased to 2.4 at 1 month, 1.9 at 6 months, and 1.6 at 1 year and was maintained at 1.3 at the follow-up evaluations performed after more than 1 year. Statistically significant improvement in Oswestry disability index and Karnofsky performance scale scores was also seen between the preoperative evaluation and every follow-up assessment postoperatively (p<0.001). CONCLUSION: Percutaneous vertebroplasty and interventional tumor removal are safe, effective, and minimally invasive palliative therapies for reducing pain and improving function in patients with metastatic spinal tumors and malignant vertebral compression fractures.

Interventional tumor removal: a new technique for malignant spinal tumor and malignant vertebral compression fractures without epidural involvement.

BACKGROUND: Percutaneous vertebroplasty (PVP) is associated with incomplete pain relief and vertebral instability due to cement leakages. PURPOSE: To evaluate the feasibility of a new method of PVP, radiofrequency ablation (RFA) and interventional tumor removal (ITR) for malignant spinal tumor and malignant vertebral compression fractures without epidural involvement. MATERIAL AND METHODS: Twelve patients were treated with PVP, RFA, and ITR. A 14 G needle and a guidewire were inserted into the vertebral body, followed by sequential dilatation of the tract with the working cannula until the last working cannula reached the anterior portions of the pedicle. Thereafter, tumors were ablated with a radiofrequency probe, and ITR was performed with a marrow nucleus rongeurs. Then, cement was injected into the extirpated vertebral body. The data were collected and follow-up was performed after 1, 3, and 6 months, and thereafter every 6 months postoperatively. RESULTS: PVP, RFA, and ITR were technically successful in all patients. The average preoperative pain visual analog scale (VAS) score was 7.0 ± 1.0, which decreased to 2.1 ± 1.2 at 1 month, to 1.6 ± 1.4 at 6 months, to 1.8 ± 1.7 at 1 year, and was maintained at 1.3 ± 1.1 at >1-year follow-up. A total of 92% patients (11/12) obtained excellent and good pain relief with improvement of quality of life. Seven patients continued with follow-up healthcare, and five patients died of the underlying disease. CONCLUSION: PVP, RFA, and ITR may be a feasible approach for malignant spinal tumor and malignant vertebral compression fractures without epidural involvement.

Comparison of percutaneous vertebroplasty with and without interventional tumour removal for malignant vertebral compression fractures with symptoms of neurological compression.

OBJECTIVE: To compare the efficacy of percutaneous vertebroplasty (PVP) with and without interventional tumor removal (ITR) on malignant vertebral compression fractures and symptoms of neurological compression. MATERIALS AND METHODS: A total of 52 patients with malignant vertebral compression fractures and symptoms of neurological compression were selected for PVP and ITR (n = 24, group A) or PVP alone (n = 28, group B). A 14-G needle and a guidewire were inserted into the vertebral body, followed by sequential dilatation of the tract with the working cannula until the last working cannula reached the distal pedicle of the vertebral arch. ITR was performed with marrow nucleus rongeurs. Then, 5-10 mL cement was injected into the extirpated vertebral body. RESULTS: PVP procedures with and without ITR were successful in all patients, except for one patient in group A. The clinical assessment obtained at the initial and final follow-up indicated that the rates of full recovery and improved neurological compression symptoms were significantly higher in group A than in group B (P < 0.05). CONCLUSION: Treatment of malignant vertebral compression fractures with symptoms of neurological compression with PVP and ITR resulted in better intermediate-term clinical results in terms of improved neurological compression symptoms than the currently recommended approach of PVP. KEY POINTS: • Percutaneous vertebroplasty (PVP) is now widely used for vertebral collapse due to malignancy • PVP can be coupled with interventional tumour removal (ITR) • PVP coupled with ITR provided better clinical results for neurological compression • PVP coupled with ITR provided better pain relief • PVP and ITR can remove tumour and helps prevent polymethyl methacrylate leakage.

Discovery of the DIGIRR gene from teleost fish: a novel Toll-IL-1 receptor family member serving as a negative regulator of IL-1 signaling.

Toll-IL-1R (TIR) family members play crucial roles in a variety of defense, inflammatory, injury, and stress responses. Although they have been widely investigated in mammals, little is known about TIRs in ancient vertebrates. In this study, we report a novel double Ig IL-1R related molecule (DIGIRR) from three model fish (Tetraodon nigroviridis, Gasterosteus aculeatus, and Takifugu rubripes), adding a previously unknown homolog to the TIR family. This DIGIRR molecule contains two Ig-like domains in the extracellular region, one Arg-Tyr-mutated TIR domain in the intracellular region, and a unique subcellular distribution within the Golgi apparatus. These characteristics distinguish DIGIRR from other known family members. In vitro injection of DIGIRR into zebrafish embryos dramatically inhibited LPS-induced and IL-1ß-induced NF-κB activation. Moreover, in vivo knockdown of DIGIRR by small interfering RNA significantly promoted the expression of IL-1ß-stimulated proinflammatory cytokines (IL-6 and IL-1ß) in DIGIRR-silenced liver and kidney tissues and in leukocytes. These results strongly suggest that DIGIRR is an important negative regulator of LPS-mediated and IL-1ß-mediated signaling pathways and inflammatory responses. The Arg-Tyr-mutated site disrupted the signal transduction ability of DIGIRR TIR. Evolutionally, we propose a hypothesis that DIGIRR and single Ig IL-1R related molecule (SIGIRR) might originate from a common ancient IL-1R-like molecule that lost one (in DIGIRR) or two (in SIGIRR) extracellular Ig-like domains and intracellular Ser and Arg-Tyr amino acids. DIGIRR might be an evolutionary "transitional molecule" between IL-1R and SIGIRR, representing a shift from a potent receptor to a negative regulator. These results help define the evolutionary history of TIR family members and their associated signaling pathways and mechanisms.

Molecular Characterization and Functional Analysis of Leucine Zipper Transcription Factor Like 1 in Zebrafish (Danio rerio).

Leucine zipper transcription factor like 1 (LZTFL1) is a member of the Bardet-Biedl syndrome gene family. LZTFL1-null mice show the phenotype of obesity, retinal degeneration, and abnormal cilia development. Functionally, LZTFL1 serves as a tumor suppressor and a negative regulator in the hedgehog signaling pathways. The biological function of mammalian LZTFL1 is partially addressed, but data on other model organisms are limited. Zebrafish (Danio rerio) is widely considered as a powerful model to understand the functions of genes implicated in obesity, disease, and cancer. In this study, LZTFL1 homologs were identified in zebrafish (zebrafish LZTFL1). The full-length cDNA of zebrafish LZTFL1 contained 897 bps encoding 298 amino acids. Zebrafish LZTFL1 displayed conserved domains of coil-coil and leucine zipper domain. PCR results showed that zebrafish LZTFL1 was widely distributed in various tissues. Western blot analysis further revealed that zebrafish LZTFL1 was detected to be ectopically expressed in HeLa cells with correct molecular weight. Fluorescence images showed as well that zebrafish LZTFL1 was localized in the cytoplasm. Furthermore, luciferase reporter assay indicated zebrafish LZTFL1 served as a negative regulator in the hedgehog signaling pathway. These data supported that zebrafish was a good model for understanding the biological roles of LZTFL1.

Percutaneous sacroplasty for sacral metastatic tumors under fluoroscopic guidance only.

Percutaneous sacroplasty is a safe and effective procedure for sacral insufficient fractures under CT or fluoroscopic guidance; although, few reports exist about sacral metastatic tumors. We designed a pilot study to treat intractable pain caused by a sacral metastatic tumor with sacroplasty. A 62-year-old man and a 38-year-old woman with medically intractable pain due to metastatic tumors of S1 from lymphoma and lung cancer, respectively, underwent percutaneous sacroplasty. Over the course of the follow-up period, the two patients experienced substantial and immediate pain relief that persisted over a 3-month and beyond. The woman had deposition of PMMA (polymethyl methacrylate) in the needle track, but did not experience significant symptoms. No other peri-procedural complications were observed for either patient.

Prospective evaluation of transabdominal percutaneous lumbar discectomy for L5-S1 disc herniation: initial clinical experience.

OBJECT: Anterior approaches to the lumbosacral spine have become an increasingly common procedure in spine surgery, but transabdominal percutaneous lumbar discectomy (TPLD) performed anteriorly under fluoroscopic guidance is challenging. In this study the authors describe the TPLD and evaluate its safety and early clinical results in the management of L5-S1 disc herniation. METHODS: Between January 2005 and June 2007, 30 consecutive patients with L5-S1 disc herniation were treated with L5-S1 TPLD. All procedures were performed with the patient in a state of local anesthesia. After bowel preparation, the hypogastrium was compressed to move the intestinal canal away from the puncture site. The TPLD was then performed with fluoroscopic guidance to remove herniated disc material. Patients were evaluated prospectively using the visual analog scale (VAS) and the Oswestry Disability Index (ODI) during

Percutaneous vertebroplasty in the treatment of malignant vertebral compression fractures with epidural involvement.

Purpose: To evaluate the safety and the clinical efficacy of percutaneous vertebroplasty (PVP) in treating malignant spinal tumors and malignant vertebral compression fractures with epidural involvement. Materials and methods: 43 patients with spinal metastatic tumors and malignant vertebral compression fractures with epidural involvement were treated using PVP. American Spinal Injury Association (ASIA) impairment scale results at presentation were used to divide patients into 2 groups. Patients in group A had no symptoms of neurological compression (n = 25); and patients in group B had symptoms of neurological compression (n = 28). A 13G bone puncture needle was placed across the pedicle of the fractured vertebra, and polymethyl methacrylate (PMMA) was injected into the fractured vertebral body under fluoroscopic control. Patients were seen in follow-up at 1, 3, and 6 months after the procedure and every six months thereafter. Results: PVP was technically successful and well-tolerated in all patients. Clinical assessment at the final follow-up found complete pain relief (n = 19) or good pain relief (n = 14) in 33 patients (62.3%, 95% CI: 49%, 76%). ASIA impairment scale assessment at the final follow-up demonstrated symptoms of neurologic compression in 31 patients and no symptoms of neurologic compression in 22 patients. Symptoms of neurologic compression were found in five group A patients and eight group B patients. Conclusions: PVP was a safe and moderately effective procedure in the treatment of malignant vertebral compression fractures with epidural involvement.

Lztfl1/BBS17 controls energy homeostasis by regulating the leptin signaling in the hypothalamic neurons.

Leptin receptor (LepRb) signaling pathway in the hypothalamus of the forebrain controls food intake and energy expenditure in response to an altered energy state. Defects in the LepRb signaling pathway can result in leptin-resistance and obesity. Leucine zipper transcription factor like 1 (Lztfl1)/BBS17 is a member of the Bardet-Biedl syndrome (BBS) gene family. Human BBS patients have a wide range of pathologies including obesity. The cellular and molecular mechanisms underlying Lztfl1-regulated obesity are unknown. Here, we generated Lztfl1f/f mouse model in which Lztfl1 can be deleted globally and in tissue-specific manner. Global Lztfl1 deficiency resulted in pleiotropic phenotypes including obesity. Lztfl1-/- mice are hyperphagic and showed similar energy expenditure as WT littermates. The obese phenotype of Lztfl1-/- mice is caused by the loss of Lztfl1 in the brain but not in the adipocytes. Lztfl1-/- mice are leptin-resistant. Inactivation of Lztfl1 abolished phosphorylation of Stat3 in the LepRb signaling pathway in the hypothalamus upon leptin stimulation. Deletion of Lztfl1 had no effect on LepRb membrane localization. Furthermore, we observed that Lztfl1-/- mouse embryonic fibroblasts (MEFs) have significantly longer cilia than WT MEFs. We identified several proteins that potentially interact with Lztfl1. As these proteins are known to be involved in regulation of actin/cytoskeleton dynamics, we suggest that Lztfl1 may regulate leptin signaling and ciliary structure via these proteins. Our study identified Lztfl1 as a novel player in the LepRb signaling pathway in the hypothalamus that controls energy homeostasis.

An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors.

By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, TH1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. IS is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors.Significance: We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis. Cancer Discov; 8(9); 1142-55. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.

Percutaneous vertebroplasty and interventional tumor removal for malignant vertebral compression fractures and/or spinal metastatic tumor with epidural involvement: a prospective pilot study.

OBJECTIVE: The aim of this study was to compare the efficacy of percutaneous vertebroplasty (PVP) and interventional tumor removal (ITR), with PVP alone for malignant vertebral compression fractures and/or spinal metastatic tumor with epidural involvement. PATIENTS AND METHODS: A total of 124 patients were selected for PVP and ITR (n = 71, group A) and PVP alone (n = 53, group B). A 14 G needle and guide wire were inserted into the vertebral body, followed by sequential dilatation of the tract until the last cannula reached the anterior portion of the pedicle. Tumors were then ablated with a radiofrequency probe. ITR was performed with marrow nucleus rongeurs, and then cement was injected into the extirpated vertebra. Outcomes were collected preoperatively and at 1, 3 and 6 months and every subsequent 6 months. RESULTS: The rates of pain relief and increased mobility at the last follow-up were higher in group A than those in group B (P < 0.05). There were significant differences in visual analog scale (VAS) score and Oswestry disability index (ODI) score at 1, 3 and 6 months, 1 year and >1 year in group A than in group B (P < 0.05). The rates of paraplegia recovery and vertebral stability in group A were higher than those in group B (P < 0.05). CONCLUSION: PVP and ITR proved to be an effective approach for patients with malignant vertebral compression fractures and/or spinal metastatic tumor and provided distinct advantages in pain relief, function recovery and vertebral stability that are comparable to that obtained with PVP alone.

Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade.

Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutations, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. Bap1-deficient tumors were of high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histologic grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCCs arise from Bowman capsule cells.Significance: Determinants of tumor grade and aggressiveness across cancer types are poorly understood. Using ccRCC as a model, we show that Bap1 and Pbrm1 loss drives tumor grade. Furthermore, we show that the conversion from low grade to high grade can be promoted by activation of mTORC1. Cancer Discov; 7(8); 900-17. ©2017 AACR.See related commentary by Leung and Kim, p. 802This article is highlighted in the In This Issue feature, p. 783.

[Effect of biminne on vascular permeability of nasal mucosa in allergic rhinitis rats].

OBJECTIVE: To investigate whether the effect of Biminne on allergic rhinitis (AR) was through improving vascular permeability of nasal mucosa. METHODS: Rat's model in Biminne-treated group and model group was induced by intraperitoneal injection of ovalbumin (OVA) and aluminum hydroxide gel suspension Biminne-treated rats were orally given Biminne suspension from the 8th day to the 17th day. On the 18th day, Evan's blue dye (EBD) in the nasal perfusate was detected to assess the vascular permeability. RESULTS: EBD concentration was higher in the model rats than that in the normal rats, and lower in the Biminne-treated rats than that in the model rats (both P < 0.01). CONCLUSION: Biminne could improve vascular permeability of nasal mucosa in sensitized rats, which may be the mechanism of its clinical effect on AR.

Molecular characterization and functional analysis of IRF3 in tilapia (Oreochromis niloticus).

Interferon regulatory factor 3 (IRF3) plays a key role in interferon (IFN) response and binding to the IFN stimulatory response elements (ISREs) within the promoter of IFN and IFN-stimulated genes followed by virus infection. In the current study, we discovered one IRF3 homologue in tilapia genome and analyzed the characterizations and functions of tilapia IRF3. Tilapia IRF3 contains 1368 bp with an ORF of 455 aa. Structurally, tilapia IRF3 protein typically shares the conserved characterizations with other species' IRF3 homologues, displaying conserved DNA-binding domain, IRF association domain, serine-rich C terminal domain, and tryptophan residue cluster. Phylogenetic analysis illustrated that tilapia IRF3 belongs to the IRF3 subfamily. Real-time PCR revealed a broad expression pattern of tilapia IRF3 in various tissues. Subcellular localization analysis showed that tilapia IRF3 mainly resides in the cytoplasm, Western blot demonstrated that IRF3 was distributed in the cytoplasmic fraction. Functionally, IRF3 was found to be transcriptionally up-regulated by the poly I:C stimulation. Moreover, reporter assay elucidated that tilapia IRF3 serves as a regulator in mediating IFN response by increasing the activity of IFN-ß and ISRE-containing promoter. These data supported the view that tilapia IRF3 is a potential molecule in IFN immune defense system against viral infection.

Identification and functional analysis of interferon regulatory factor 3 in Lateolabrax maculatus.

The interferon (IFN) regulatory factor 3 (IRF3) is a member of the IFN regulatory transcription factor family, which binds to the IFN-stimulated response element (ISRE) within the promoter of IFN genes and IFN-stimulated genes. In this study, the IRF3 cDNA of sea perch Lateolabrax maculatus (SpIRF3) was identified, which contained 1781 bp with an open reading frame of 1398 bp that coded a 465 amino acid protein. The SpIRF3 protein shared conserved characterizations with its homologues and displayed the conserved DNA-binding domain, IRF association domain, serine-rich C-terminal domain, and tryptophan residue cluster. Phylogenetic analysis illustrated that SpIRF3 belonged to the IRF3 subfamily. Subcellular localization analysis showed that SpIRF3 mainly resided in the cytoplasm without stimuli but translocated into nuclei in the presence of poly I:C. Real-time PCR data indicated that SpIRF3 was transcriptionally up-regulated by poly I:C stimulation in various organs. Moreover, reporter assay revealed that SpIRF3 functioned as a modulator in triggering the IFN response by inducing the activity of IFN and ISRE-containing promoter. These data revealed that SpIRF3 was a potential molecule in the IFN immune defense system against viral infection.