Laparoscopic versus robotic TAPP/TEP inguinal hernia repair: a multicenter, propensity score weighted study.

PURPOSE: The objective of this retrospective study was to assess safety and comparative clinical effectiveness of laparoscopic inguinal hernia repair (LIHR) and robot-assisted inguinal hernia repair (RIHR) from multi-institutional experience in Taiwan. METHODS: Medical records from a total of eight hospitals were retrospectively collected and analyzed. Patients primarily diagnosed of inguinal hernia, recurrent inguinal hernia or incarceration groin hernia patients who either underwent laparoscopic or robot-assisted inguinal hernia repair between January 2018 and December 2022 were included in the study. Baseline characteristics, intra-operative and post-operative results were analyzed. To compare two cohorts, overlap weighting was employed to balance the significant inter-group differences. We also conducted subgroup analyses by state of a hernia (primary or recurrent/incarceration) and laterality (unilateral or bilateral) that indicated complexity of surgery. RESULTS: A total of 1,080 patients who underwent minimally invasive inguinal hernia repair from 8 hospitals across Taiwan were collected. Following the application of inclusion criteria, there were 279 patients received RIHR and 763 patients received LIHR. In the baseline analysis, RIHR was more often performed in recurrent/incarceration (RIHR 18.6% vs LIHR 10.3%, p = 0.001) and bilateral cases (RIHR 81.4 vs LIHR 58.3, p < 0.001). Suturing was dominant mesh fixation method in RIHR (RIHR 81% vs LIHR 35.8%, p < 0.001). More overweight patients were treated with RIHR (RIHR 58.8% vs LIHR 48.9%, p = 0.006). After overlap weighting, there were no significant difference in intraoperative and post-operative complications between RIHR and LIHR. Reoperation and prescription rates of pain medication (opioid) were significantly lower in RIHR than LIHR in overall group comparison (reoperation: RIHR 0% vs. LIHR 2.9%, p = 0.016) (Opioid prescription: RIHR 3.34 mg vs LIHR 10.82 mg, p = 0.001) while operation time was significantly longer in RIHR (OR time: RIHR 155.27 min vs LIHR 95.30 min, p < 0.001). CONCLUSIONS: This real-world experience suggested that RIHR is a safe, and feasible option with comparable intra-operative and post-operative outcomes to LHIR. In our study, RIHR showed technical advantages in more complicated hernia cases with yielding to lower reoperation rates, and less opioid use.

Inhibition of the androgen receptor induces a novel tumor promoter, ZBTB46, for prostate cancer metastasis.

Current therapeutic regimens for prostate cancer focus on targeting androgen receptor (AR) signaling. However, the AR is a key factor in luminal epithelium differentiation and was shown to have a role as a tumor suppressor. Thus, its inhibition may activate oncogenic pathways that contribute to metastatic castration-resistant prostate cancer (CRPC). Herein, we report a novel tumor promoter, ZBTB46, which is negatively regulated by AR signaling via microRNA (miR)-1-mediated downregulation. ZBTB46 is associated with malignant prostate cancer and is essential for metastasis. Its overexpression can overcome the antitumor effects of miR-1 and promote androgen-independent proliferation. We demonstrated that ZBTB46 can transcriptionally regulate SNAI1, a key epithelial-to-mesenchymal transition (EMT) driver, which could contribute to induction of the EMT after androgen-deprivation therapy and metastasis. Our findings are supportive of the model that disruption of AR's function may predispose prostate cancer to progress to metastatic CRPC.

TCF7 is suppressed by the androgen receptor via microRNA-1-mediated downregulation and is involved in the development of resistance to androgen deprivation in prostate cancer.

BACKGROUND: Resistance to androgen deprivation therapy (ADT) represents a key step in the malignant progression of prostate cancer, and mutation to androgen receptor (AR) is one major driver to an androgen-independent phenotype. However, alternative oncogenic pathways that bypass AR signaling have emerged as an important mechanism promoting resistance to ADT. It is known that AR activation can prevent the interaction between ß-catenin and T cell factor/lymphoid enhancer-binding factor (TCF/LEF) family, inhibiting the Wnt signaling pathway. The aim of this study was to determine the role of transcription factor 7 (TCF7), a transcription factor best known as a Wnt effector that forms a complex with ß-catenin, in the development of advanced prostate cancer. We further investigated the molecular mechanisms by which TCF7 is induced when AR signaling is inactivated. METHODS: A novel AR signaling pathway that induces microRNA-1 (miR-1) to suppress metastatic prostate cancer was recently demonstrated (AR-miR-1 signaling axis), and its regulation of Wnt signaling was explored in the current study. Clinical data sets were analyzed for potential targets of AR-miR-1 signaling in the TCF/LEF family, and tissue samples were utilized to validate the relationship. The molecular mechanism and biological functions were demonstrated in prostate cancer cell lines and a mouse xenograft model. RESULTS: We demonstrated a molecular mechanism of AR signaling suppressing TCF7 partly through miR-1-mediated downregulation. TCF7 exhibited oncogenic properties and compromised the tumor-suppressive effects of miR-1. Our results also showed that overexpression of TCF7 or disruption of miR-1 function promoted androgen-independent proliferation. CONCLUSIONS: We demonstrated that the AR-miR-1 axis negatively regulates the novel oncogenic factor, TCF7. Dysregulation of TCF7 promoted a survival advantage and resistance to androgen deprivation, suggesting its therapeutic potential for castration-resistant prostate cancer.

KLF4 functions as an activator of the androgen receptor through reciprocal feedback.

In prostate cancer, Krüppel-like factor 4 (KLF4) depletion occurs frequently, suggesting a role as suppressor tumor. KLF4 is a transcription factor associated with androgen receptor (AR) expression; however, its cellular functions and signaling regulation mechanism remain largely unknown. In this study, we demonstrated that activated AR binds to the KLF4 promoter and enhances KLF4 expression, which reciprocally targets the AR promoter, thus sustaining KLF4 activity. Ectopic KLF4 expression in androgen-independent prostate cancer cells induced AR expression and decreased cell proliferation, invasion and bone metastasis. We previously showed that increased microRNA (miR)-1 expression is associated with reduced bone metastasis of prostate cancer cells. Here we observed that KLF4 targets the primary miR-1-2 stem-loop promoter and stimulates miR-1 expression. In clinical prostate cancer specimens, KLF4 levels were positively correlated with miR-1 and AR levels. These data suggest that the loss of KLF4 expression is one mechanistic link between aggressive prostate cancer progression and low canonical AR output through miR-1 inactivation.

Anti-inflammatory effects of Lactobacillus brevis K65 on RAW 264.7 cells and in mice with dextran sulphate sodium-induced ulcerative colitis.

Lactic acid bacteria (LAB) with anti-inflammatory effects may be beneficial to the prevention or treatment for inflammation-related diseases, such as inflammatory bowel diseases. In an in vitro assay, heat-killed Lactobacillus brevis K65 (K65) reduced lipopolysaccharide-induced production of nitric oxide, tumour necrosis factor (TNF)-α and prostaglandin E2 in RAW 264.7 cells. In RAW 264.7 cells stably expressing an ind=ucible nitric oxide synthase (iNOS) reporter, viable K65 showed greater inhibition of iNOS production than its heat-killed form. In order to further examine the in vivo anti-inflammatory effect of K65, viable K65 was orally administered to BALB/c mice before and during the period of dextran sulphate sodium (DSS)-induced ulcerative colitis (UC). K65 improved UC symptoms, including reduced the levels of the pro-inflammatory cytokines, TNF-α, interleukin (IL)-6 and IL-1ß, and lowered the activity of myeloperoxidase. Furthermore, K65 inhibited TNF-α, cyclo-oxygenase 2, forkhead box P3, and Toll-like receptor 4 mRNA expression in the colonic tissue of DSS-induced UC mice. Taken together, K65, a LAB with in vitro anti-inflammatory activity showed preventive effects on mice with DSS-induced UC by lowering the expression of inflammatory molecules.

Evaluation of the potential anti-allergic effects of heat-inactivated Lactobacillus paracasei V0151 in vitro, ex vivo, and in vivo.

The efficacy of Lactobacillus paracasei V0151 (V0151), isolated from the faeces of a child, to modulate immune responses was investigated. In RAW 264.7 cells expressing an inducible nitric oxide synthase (iNOS)-directed luciferase gene, heat-inactivated V0151 stimulated iNOS expression followed by nitric oxide production. V0151 significantly elevated interferon gamma, interleukin (IL)-10, tumour necrosis factor alpha, and IL-1ß production in human peripheral blood mononuclear cells. In splenocytes isolated from ovalbumin (OVA)-sensitised BALB/c mice treated with OVA and V0151 at different bacterium-to-cell ratios (1:1, 10:1, and 20:1) for 96 h, IL-2, IL-4, IL-5, and IL-13 production was dose-dependently downregulated, whereas IL-12 was dose-dependently upregulated. Collectively, our findings indicate that V0151 might regulate pro-inflammatory factors in macrophages and splenocytes. Furthermore, the T helper 1/T helper 2 (Th1/Th2) balance was also skewed toward Th1 dominance through the elevation of Th1 cytokine production.

Transforming growth factor-ß promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway.

Transforming growth factor-ß (TGFß) is enriched in the bone matrix and serves as a key factor in promoting bone metastasis in cancer. In addition, TGFß signaling activates mammalian target of rapamycin (mTOR) functions, which is important for the malignant progression. Here, we demonstrate that TGFß regulates the level of microRNA-96 (miR-96) through Smad-dependent transcription and that miR-96 promotes the bone metastasis in prostate cancer. The enhanced effects in cellular growth and invasiveness suggest that miR-96 functions as an oncomir/and metastamir. Supporting this idea, we identified a downstream target of the TGFß-miR-96 signaling pathway to be AKT1S1 mRNA, whose translated protein is a negative regulator of mTOR kinase. Our findings provide a novel mechanism accounting for the TGFß signaling and bone metastasis.

Technical refinement of mini-laparoscopic hernia repair in infants and children.

BACKGROUND: In large, long-term series of laparoscopic pediatric groin hernia repairs, the recurrence rate is commonly higher compared with the open herniotomy. Thus, we refined our laparoscopic technique from a simple hernia sac ligation into combined posterior wall repair for pediatric groin hernias. METHODS: Between March 2010 and March 2013, 41 consecutive infants and children with primary inguinal hernia were treated surgically with our refined mini-laparoscopic hernia technique. The mean patient age was 4.5 years. Before hernia repair, there were synchronous bilateral hernias in 4 (9.7 %), left inguinal hernias in 14 (34.2 %) and right inguinal hernias in 23 (56.1 %). The mini-laparoscopic hernia repair was carried out with three 3.5 mm trocar ports including 3 mm telescope and 3 mm instruments. RESULTS: Totally 61 repairs were performed. The mean follow-up period was 12 months. The mean operation time was 45 min. None of the repaired groin hernias had a recurrence or procedure-related complication during the period of follow-up. None of them experienced a chronic pain postoperatively. To date there was no scrotal or testicular complication detected by regular ultrasonographic follow-up. CONCLUSIONS: Our refined laparoscopic technique is a safe and effective method in the management of groin hernias in infants and children with a minimal early recurrence rate.

The corpus-predominant gastritis index may serve as an early marker of Helicobacter pylori-infected patients at risk of gastric cancer.

BACKGROUND: To eradicate Helicobacter pylori before the occurrence of precancerous changes is important to prevent gastric carcinogenesis. AIM: To validate whether the corpus-predominant gastritis index (CGI) can serve as an early marker to identify the H. pylori-infected patients at risk of gastric carcinogenesis. METHODS: This study enrolled 188 subjects, including 43 noncardiac gastric cancer patients, 63 of their first-degree relatives and 82 sex- and age-matched duodenal ulcer patients as controls. All received endoscopy to provide topographic gastric specimens to test for H. pylori infection and its related histological features, translated into the operative link on gastritis assessment (OLGA), operative link on gastric intestinal metaplasia assessment (OLGIM) stages, and the presence of CGI. Spasmolytic polypeptide-expressing metaplasia (SPEM) was assessed by immunohistochemistry staining of trefoil factor 2. RESULTS: Gastric cancer patients had higher prevalence of CGI and OLGIM stage II-IV, but not OLGA stage II-IV, than the controls (P = 0.001, OR = 3.4[95% CI: 1.4-8.1] for CGI; OR = 5.0[95% CI: 2.0-12.8] for OLGIM). In patients with the combined presence of CGI and OLGIM stage II-IV, the risk of gastric cancer increased to 9.8 (P < 0.001). The first-degree relatives of the gastric cancer patients had a higher rate of the presence of CGI, but not OLGA or OLGIM stage II-IV than the duodenal ulcer controls (P = 0.001). Of the first-degree relatives, the presence of CGI increased the risk of SPEM (P = 0.003, OR = 5.5[95% CI: 1.8-17.0]). CONCLUSION: The corpus-predominant gastritis index, which is highly correlated to SPEM, may serve as an early marker to identify the H. pylori-infected patients at a higher risk of gastric cancer.

Interleukin 10 and residual kidney function are associated with risk of vascular calcification in patients undergoing peritoneal dialysis.

AIMS: Vascular calcification is a common complication among dialysis patients and its pathogenesis involves a variety of factors. The roles of pro-inflammatory cytokines and residual kidney function (RKF) in peritoneal dialysis (PD) patients with vascular calcification have not been investigated. MATERIALS AND METHODS: 157 stable PD patients were enrolled. All patients had plain X-ray film examination including chest (posterior-anterior view, CXR) and pelvis. Vascular calcification was interpreted as calcified deposit over aortic arch and linear calcification of pelvic arteries. Relevant biochemical data, pro-inflammatory markers, and PD-related factors were measured and collected. RESULTS: Vascular calcification prevalence in CXRs was higher than that in pelvis films (38.2% vs. 22.3%, p < 0.05). Patients with vascular calcification in CXR had higher incidence of calcification in pelvis films (p < 0.05). Only a minor portion (14.6%) had two calcification sites. Regression analysis revealed that age, PD duration, body mass index, and RKF were independent factors associated with vascular calcification in CXR. Age, diabetes, IL-10 and RKF were factors associated in pelvis films. Factors independently related to vascular calcification in both films were age, duration, diabetes, IL-10, and RKF. CONCLUSIONS: Besides traditional risk factors, IL-10 and RKF were important factors associated with vascular calcification in PD patients.

Preparative chromatography of flavonoids and saponins in Gynostemma pentaphyllum and their antiproliferation effect on hepatoma cell.

A preparative column chromatographic method was developed to isolate flavonoids and saponins from Gynostemma pentaphyllum, a Chinese Medicinal herb, and evaluate their antiproliferation effect on hepatoma cell Hep3B, with the standards rutin and ginsenoside Rb(3) being used for comparison. Initially the powdered G. pentaphyllum was extracted with ethanol, followed by eluting flavonoids and saponins with ethanol-water (30:70, v/v) and 100% ethanol, respectively, in an open-column containing 5 g of Cosmosil 75C(18)-OPN, and then subjected to HPLC-MS analysis. The flavonoid fraction was mainly composed of quercetin- and kaempferol-glycosides, while in saponin fraction, both ginsenoside Rb(3) and ginsenoside Rd dominated. Both fractions were more effective against Hep3B cells than the standards rutin and ginsenoside Rb(3), with the cell cycle being arrested at G0/G1 phase for all the treatments. Additionally, the inhibition effect followed a dose-dependent increase for all the sample treatments. The result of this study may be used as a basis for possible phytopreparations in the future with G. pentaphyllum as raw material.

Simultaneous acute nephrosis and hepatitis in secondary syphilis.

Simultaneous occurrence of acute nephrosis and hepatitis in secondary syphilis is rare. We report a 24-year-old man who presented with sudden onset of nephrotic syndrome, acute hepatitis, and skin lesions associated with secondary syphilis. A renal biopsy demonstrated electron-dense deposits located in the subepithelial, mesangial and intramembranous areas under electron microscopy. Light microscopy revealed a mild increase in mesangial matrix with normal glomerular cellularity. Immunofluorescent examination showed granular deposition of IgG and IgA along the glomerular capillary basement membrane without deposits of complements. These morphological changes differed from those reported previously. All, the heavy proteinuria, disturbances of liver function, and skin lesions resolved after 4-week treatment.

Enhancement of CD4+ T-cell help reverses the doxorubicin-induced suppression of antigen-specific immune responses in vaccinated mice.

Multimodality treatments that combine conventional cancer therapies with antigen-specific immunotherapy have emerged as promising approaches for the control of cancer. In the current study, we have explored the effect of doxorubicin on the antigen-specific immune responses generated in mice vaccinated with calreticulin (CRT)/E6 and/or Ii-PADRE DNA. We observed that pretreatment with doxorubicin suppressed the E6-specific CD8+ T-cell immune responses generated by CRT/E6 DNA vaccination in vaccinated mice. In contrast, pretreatment with doxorubicin enhanced the PADRE-specific CD4+ T-cell immune responses generated by Ii-PADRE DNA vaccination. Furthermore, coadministration of Ii-PADRE DNA could not only reverse the suppression, but also enhanced the E6-specific CD8+ T-cell responses in CRT/E6-vaccinated mice pretreated with doxorubicin. Finally, treatment with doxorubicin followed by CRT/E6 combined with Ii-PADRE DNA vaccination led to enhanced antitumor effects and prolonged survival in TC-1 tumor-bearing mice. The clinical implications of the current study are discussed.

Role of IL-2 secreted by PADRE-specific CD4+ T cells in enhancing E7-specific CD8+ T-cell immune responses.

CD4(+) T helper cells are known to play an integral role in the generation of CD8(+) T-cell immune responses. We have previously shown that co-administration of DNA vaccines containing E6 or E7 protein of human papillomavirus 16 (HPV-16) combined with DNA encoding invariant (Ii) chain in which class II-associated Ii peptide (CLIP) region is replaced with the CD4(+) T helper epitope, PADRE (Pan-DR-epitope) (Ii-PADRE DNA) enhanced HPV antigen-specific CD8(+) T-cell immune responses in vaccinated mice. In the current study, we investigated the enhancement of HPV E7-specific CD8(+) T-cell immune responses by PADRE-specific CD4(+) T cells. We showed that intradermal administration of Ii-PADRE DNA at the same location as E7-expressing DNA is necessary to generate strong E7-specific CD8(+) T-cell immune responses. We also showed that PADRE-specific CD4(+) T cells generated by Ii-PADRE DNA vaccination expressed Th1 cytokine profile. Furthermore, our in vitro study demonstrated that PADRE-specific CD4(+) T cells stimulated with PADRE-loaded dendritic cells secrete IL-2 that leads to the proliferation of E7-specific CD8(+) T cells. Thus, our data suggest that activated PADRE-specific CD4(+) T helper cells may be required at the vicinity of E7-specific CD8(+) T cells where they secrete IL-2, which enhances the E7-specific CD8(+) T-cell immune responses generated by DNA vaccination.

The experience of biliary tract complications after liver transplantation.

AIM: To report the morbidity and mortality of patients who undergo liver transplantation with or without T-tube implantation after choledochocholedochostomy as well as to discuss management of biliary complications. PATIENTS AND METHODS: We performed a retrospective review of 104 liver transplantations from August 2001 to February 2006, including 51 patients who underwent choledochocholedochostomy with a T-tube (group A) and 53, without a T-tube (group B). We compared the clinical characteristics, operative methods, biliary complications, morbidity, mortality, and management of complications. RESULTS: Between the two groups, there were no significant differences in clinical characteristics, including sex, age, and indication for liver transplantation (hepatitis B virus, hepatitis C virus, alcoholic liver cirrhosis, or hepatocellular carcinoma), Child-Pugh classification, Model for End-stage Liver Disease score, and operative macroscopic/microscopic findings. Additionally, there was no significant difference in biliary complications. Among these 104 patients, 14 (13.5%) developed biliary complications: seven anastomotic strictures, two intrahepatic duct strictures, two anastomotic stricture combined intrahepatic duct stricture, one bile leakage, one bile leakage combined with anastomotic stricture, and one external biliary compression. Nine patients with anastomotic stricture underwent endoscopy with a stent, which was successful only in two patients. The other six patients underwent choledochojejunostomy with excellent results. CONCLUSIONS: This study showed choledochocholedochostomy with or without a T-tube after liver transplantation did not influence the biliary complications. The biliary complications of anastomotic stricture after liver transplantation can be managed by endoscopy with a stent. If endoscopy fails, surgical intervention should be considered immediately.

The effect of scheduled forced wheel activity on body weight in male F344 rats undergoing chronic circadian desynchronization.

OBJECTIVE: To examine whether scheduled forced wheel activity counteracts the increased body weight gain in rats undergoing chronic circadian desynchronization induced by repeated 12-h shifts in the light-dark cycle. DESIGN: Four age- and body weight-matched groups of adult male F344 rats were subjected to 12-h intermittent forced wheel activity daily (2.2 km/day). Each group had the following schedule for 13 weeks: a fixed schedule of a daily 12:12-h light-dark cycle and activity training (WF); a fixed light-dark cycle and 12-h shifts twice a week in activity training (WS); 12-h shifts twice a week in the light-dark cycle and a fixed schedule of activity training (LSWF); and 12-h shifts twice a week in both the light-dark cycle and activity training (LSWS). Two additional age- and body weight-matched sedentary rat groups were selected from our database: one was maintained on a fixed light-dark cycle (LC) and the other was subjected to 12-h shifts twice a week in the light-dark cycle (LS). RESULTS: The four rat groups that were exercised showed different response patterns of the daily body temperature rhythm to different combinations of forced activity and lighting schedules. Their food intake was more than that of the two sedentary rat groups, but their body weight was comparable with that of the LC rats and less than that of the LS rats during the forced activity period. The LSWS rats were heavier than the WF and WS rats in the first and second months of the experimental treatment, but their body weight was comparable with that of the WS and WF rats in the third month. CONCLUSION: Forced activity was effective in reducing the body weight gain in chronic circadian desynchronization that was induced by repeated shifts in the light-dark cycle, although such an effect might become significant only after some time.

Control of mesothelin-expressing ovarian cancer using adoptive transfer of mesothelin peptide-specific CD8+ T cells.

Cancer immunotherapy targeting mesothelin represents a potentially plausible approach for the control of ovarian cancer as most ovarian cancers express high levels of mesothelin. In the current study, we created a mesothelin-positive luciferase-expressing ovarian cancer model, MOSEC/luc. This luciferase-expressing tumor model allowed us to quantitate tumor distribution and tumor load in tumor-challenged mice using a non-invasive bioluminescence imaging system. In addition, we identified an H-2D(b)-restricted mesothelin peptide-specific cytotoxic T-lymphocyte (CTL) epitope (amino acid (aa) 406-414) that was endogenously processed and presented by MOSEC/luc tumor cells. We showed that adoptive transfer of mesothelin peptide (aa406-414)-specific CD8(+) T cells led to the control of MOSEC/luc tumor cells. The MOSEC/luc tumor model and the newly identified H-2D(b)-restricted murine mesothelin-specific CTL epitope (aa406-414) will be very useful for the development of immunotherapy for ovarian cancer as well as for the development of quantitative CD8(+) T cell-mediated immunological assays.

Amyloid-producing odontogenic tumor and its immunohistochemical characterization in a Shih Tzu dog.

A 10-year-old, male, Shih-Tzu dog presented with swelling of the right lower jaw caused by a mass arising from the right mandibular gingiva. Radiographic examination revealed bone lysis of the right wing of the mandible. Histopathologically, the growth was characterized by indistinctly lobulated nests, islands, and strands of proliferating odontogenic and squamous epithelial cells, intermingled in close association with large numbers of irregular extracellular deposits of amyloid and amorphous calcified substance. Immunohistochemically, both epithelial components stained strongly positive for cytokeratin (AE1/AE3); the squamous epithelial cells also reacted strongly with neuron-specific enolase (NSE) and S-100 protein, whereas the odontogenic epithelial cells displayed weak immunoreactivity to NSE and partial reactivity to S-100 protein. The amyloid deposits were AE1/AE3-negative. The growth was diagnosed as an amyloid-producing odontogenic tumor.

Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice.

Vaccinia virus has been shown to efficiently infect tumor cells. Therefore, vaccinia virus represents a potentially safe and effective antitumor agent against ovarian cancer. Here, we assessed the ability of vaccinia virus to preferentially infect and control both human and murine ovarian tumors in vivo. We used the non-invasive luminescence imaging system to monitor the infection and suppression of ovarian tumors by vaccinia in live mice. Our data indicated that vaccinia was able to effectively infect and kill both human and murine ovarian tumors. Vaccinia virus administered to mice intraperitoneally was specifically targeted to the murine or human ovarian tumors and led to antitumor responses. These findings suggest that vaccinia virus is capable of selectively targeting and controlling ovarian tumors. Thus, intraperitoneal injection with vaccinia virus may provide a potentially effective strategy for treating advanced-stage ovarian cancers.

RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene.

TRC8/RNF139 and von Hippel-Lindau (VHL) both encode E3 ubiquitin (Ub) ligases mutated in clear-cell renal carcinomas (ccRCC). VHL, inactivated in nearly 70% of ccRCCs, is a tumor suppressor encoding the targeting subunit for a Ub ligase complex that downregulates hypoxia-inducible factor-alpha. TRC8/RNF139 is a putative tumor suppressor containing a sterol-sensing domain and a RING-H2 motif essential for Ub ligase activity. Here we report that human kidney cells are growth inhibited by TRC8. Inhibition is manifested by G2/M arrest, decreased DNA synthesis and increased apoptosis and is dependent upon the Ub ligase activity of the RING domain. Tumor formation in a nude mouse model is inhibited by TRC8 in a RING-dependent manner. Expression of TRC8 represses genes involved in cholesterol and fatty acid biosynthesis that are transcriptionally regulated by the sterol response element binding proteins (SREBPs). Expression of activated SREBP-1a partially restores the growth of TRC8-inhibited cells. These data suggest that TRC8 modulation of SREBP activity comprises a novel regulatory link between growth control and the cholesterol/lipid homeostasis pathway.