Prostate-specific antigen bounce predicts for a favorable prognosis following brachytherapy: a meta-analysis.

PURPOSE: Controversy exists whether the prostate-specific antigen (PSA) bounce phenomenon following definitive radiation for prostate cancer has prognostic significance. Here, we perform a meta-analysis to determine the association between PSA bounce and biochemical control after brachytherapy alone. MATERIAL AND METHODS: We reviewed Medline, EMBASE, and CENTRAL citations through February 2012. Studies that recorded biochemical failure rates in bouncers and non-bouncers were included. Hazard ratios describing the impact of bounce on biochemical failure were extracted directly from the studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p \u3c 0.10 using Q test). RESULTS: The final analysis included 3011 patients over 6 studies treated with brachytherapy. Meta-analysis revealed that patients experiencing PSA bounce after brachytherapy, conferred a decreased risk of biochemical failure (random effects model HR = 0.42, 95% CI: 0.30-0.59; p \u3c 0.001). CONCLUSIONS: Our meta-analysis determined that PSA bounce predicts for improved biochemical control following brachytherapy. To our knowledge, this is the first study describing this effect

Protective Role of R-spondin1, an Intestinal Stem Cell Growth Factor, against Radiation-Induced Gastrointestinal Syndrome in Mice

BACKGROUND:Radiation-induced gastrointestinal syndrome (RIGS) results from a combination of direct cytocidal effects on intestinal crypt and endothelial cells and subsequent loss of the mucosal barrier, resulting in electrolyte imbalance, diarrhea, weight loss, infection and mortality. Because R-spondin1 (Rspo1) acts as a mitogenic factor for intestinal stem cells, we hypothesized that systemic administration of Rspo1 would amplify the intestinal crypt cells and accelerate the regeneration of the irradiated intestine, thereby, ameliorating RIGS. METHODS AND FINDINGS:Male C57Bl/6 mice received recombinant adenovirus expressing human R-spondin1 (AdRspo1) or E.coli Lacz (AdLacz), 1-3 days before whole body irradiation (WBI) or abdominal irradiation (AIR). Post-irradiation survival was assessed by Kaplan Meier analysis. RIGS was assessed by histological examination of intestine after hematoxilin and eosin staining, immunohistochemical staining of BrdU incorporation, Lgr5 and beta-catenin expression and TUNEL staining. The xylose absorption test (XAT) was performed to evaluate the functional integrity of the intestinal mucosal barrier. In order to examine the effect of R-spondin1 on tumor growth, AdRspo1 and AdLacZ was administered in the animals having palpable tumor and then exposed to AIR. There was a significant increase in survival in AdRspo1 cohorts compared to AdLacZ (p<0.003) controls, following WBI (10.4 Gy). Significant delay in tumor growth was observed after AIR in both cohorts AdRspo1 and AdLacZ but AdRspo1 treated animals showed improved survival compared to AdLacZ. Histological analysis and XAT demonstrated significant structural and functional regeneration of the intestine in irradiated animals following AdRspo1 treatment. Immunohistochemical analysis demonstrated an increase in Lgr5+ve crypt cells and the translocation of beta-catenin from the cytosol to nucleus and upregulation of beta-catenin target genes in AdRspo1-treated mice, as compared to AdLacz-treated mice. CONCLUSION:Rspo1 promoted radioprotection against RIGS and improved survival of mice exposed to WBI. The mechanism was likely related to induction of the Wnt-beta-catenin pathway and promotion of intestinal stem cell regeneration. Rspo1 has protective effect only on normal intestinal tissue but not in tumors after AIR and thereby may increase the therapeutic ratio of chemoradiation therapy in patients undergoing abdominal irradiation for GI malignancies

Human Urinary Epithelial Cells as a Source of Engraftable Hepatocyte-Like Cells Using Stem Cell Technology

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Long-term reduction of jaundice in gunn rats by nonviral liver-targeted delivery of sleeping beauty transposon

Asialoglycoprotein receptor (ASGPR)-mediated endocytosis has been used to target genes to hepatocytes in vivo. However, the level and duration of transgene expression have been low because of lysosomal translocation and degradation of the DNA and lack of its integration into the host genome. In this study we packaged the DNA of interest in proteoliposomes containing the fusogenic galactose-terminated F-glycoprotein of the Sendai virus (FPL) for targeted delivery to hepatocytes. After the FPL binds to ASGPR on the hepatocyte surface, fusogenic activity of the F-protein delivers the DNA into the cytosol, bypassing the endosomal pathway. For transgene integration we designed plasmids containing one transcription unit expressing the Sleeping Beauty transposase (SB) and another expressing human uridinediphosphoglucuronate glucuronosyltransferase-1A1 (pSB-hUGT1A1). The latter was flanked by inverted/direct repeats that are substrates of SB. In cell culture, FPL-mediated delivery of the E. coli β-galactosidase gene (LacZ) resulted in transduction of ASGPR-positive cells (rat hepatocytes or Hepa1 cell line), but not of ASGPR-negative 293 cells. Intravenous injection of the FPL-entrapped pSB-hUGT1A1 (4-8 μg/day, 1-4 doses) into UGT1A1-deficient hyperbilirubinemic Gunn rats (model of Crigler-Najjar syndrome type 1) resulted in hUGT1A1 expression in 5%-10% of hepatocytes, but not in other cell types. Serum bilirubin levels declined by 30% ± 4% in 2 weeks and remained at that level throughout the 7-month study duration. With histidine containing FPL, serum bilirubin was reduced by 40% ± 5%, and bilirubin glucuronides were excreted into bile. No antibodies were detectable in the recipient rats against the F-protein or human UGT1A1. Conclusion: FPL is an efficient hepatocyte-targeted gene delivery platform in vivo that warrants further exploration toward clinical application

Construction of liver tissue in vivo with preparative partial hepatic irradiation and growth stimulus: investigations of less invasive techniques and progenitor cells

The selective proliferation of transplanted hepatocytes with a growth stimulus, such as partial hepatectomy or hepatocyte growth factor, concomitant with hepatic irradiation (HIR), which can suppress proliferation of host hepatocytes, has been reported. We have conducted experiments that focused on less invasive and clinically applicable techniques and progenitor cells. First, dipeptidyl-peptidase IV-F344 or jaundiced Gunn rats underwent partial HIR (only 30% of whole liver) and portal vein branch ligation (PVBL) of one lobe, followed by intrasplenic hepatocyte transplantation at 1 × 10(7). Second, after partial HIR and PVBL, two types of progenitor cells were transplanted (i.e., small hepatocytes (SHs) or adipose-derived mesenchymal stem cells. Sixteen weeks after transplantation, the donor cells constituted > 70% of the hepatocytes of the irradiated lobe, showing connexin 32, phosphoenolpyruvate carboxykinase-1, and glycogen storage. Moreover, the serum bilirubin level had decreased significantly in the jaundiced Gunn rats and remained at this level throughout the 24 wk experimental period. The SHs grew more quickly than the hepatocytes. After 8 wk, around 40% of the host hepatocytes had been replaced by transplanted SHs. Although the donor adipose-derived mesenchymal cells were engrafted after 8 wk, their proliferation was not observed. HIR, combined with PVBL, can be given to a selective liver lobe and is a less-invasive but effective method for proliferation of transplanted hepatocytes. Even a smaller number of SHs can construct liver tissue with their prevailing proliferative ability

Resolution of hepatic fibrosis after ZFN-mediated gene editing in the PiZ mouse model of human α1-antitrypsin deficiency

BACKGROUND: α1-antitrypsin deficiency is most commonly caused by a mutation in exon-7 of SERPINA1 (SA1-ATZ), resulting in hepatocellular accumulation of a misfolded variant (ATZ). Human SA1-ATZ-transgenic (PiZ) mice exhibit hepatocellular ATZ accumulation and liver fibrosis. We hypothesized that disrupting the SA1-ATZ transgene in PiZ mice by in vivo genome editing would confer a proliferative advantage to the genome-edited hepatocytes, enabling them to repopulate the liver. METHODS: To create a targeted DNA break in exon-7 of the SA1-ATZ transgene, we generated 2 recombinant adeno-associated viruses (rAAV) expressing a zinc-finger nuclease pair (rAAV-ZFN), and another rAAV for gene correction by targeted insertion (rAAV-TI). PiZ mice were injected i.v. with rAAV-TI alone or the rAAV-ZFNs at a low (7.5×1010vg/mouse, LD) or a high dose (1.5×1011vg/mouse, HD), with or without rAAV-TI. Two weeks and 6 months after treatment, livers were harvested for molecular, histological, and biochemical analyses. RESULTS: Two weeks after treatment, deep sequencing of the hepatic SA1-ATZ transgene pool showed 6%±3% or 15%±4% nonhomologous end joining in mice receiving LD or HD rAAV-ZFN, respectively, which increased to 36%±12% and 36%±12%, respectively, 6 months after treatment. Two weeks postinjection of rAAV-TI with LD or HD of rAAV-ZFN, repair by targeted insertion occurred in 0.10%±0.09% and 0.25%±0.14% of SA1-ATZ transgenes, respectively, which increased to 5.2%±5.0% and 33%±13%, respectively, 6 months after treatment. Six months after rAAV-ZFN administration, there was a marked clearance of ATZ globules from hepatocytes, and resolution of liver fibrosis, along with reduction of hepatic TAZ/WWTR1, hedgehog ligands, Gli2, a TIMP, and collagen content. CONCLUSIONS: ZFN-mediated SA1-ATZ transgene disruption provides a proliferative advantage to ATZ-depleted hepatocytes, enabling them to repopulate the liver and reverse hepatic fibrosis

The role of pre- and post-SRS systemic therapy in patients with NSCLC brain metastases

Purpose: We report our experience with stereotactic radiosurgery (SRS) for NSCLC brain metastases. We then assess the prognostic value of pre- and post-SRS systemic therapy (PrSST and PoSST) and evaluate the timing of PoSST.Methods: In this retrospective study, we analyzed 96 patients with lung cancer and ECOG PS ≤ 3 who underwent SRS during 2007-2013. Recorded factors included SRS treatment parameters, systemic status of disease (SDS) at time of SRS, and the use of PrSST and PoSST. SDS was designated as pulmonary disease or extrapulmonary disease. For analysis, the SRS-PoSST interval (SPI) was divided into ≤30 days and &gt;30 days. Univariate and multivariate analyses were performed.Results: 85 patients with NSCLC were included in this analysis. 48% received PrSST and 48% received PoSST. 57% of patients had pulmonary disease while 40% had extrapulmonary disease. 46% of patients had synchronous metastases. At a median follow-up of 6 months, the median survival was 6.4 months and the actuarial overall survival at 3, 6, 12, and 36 months was 80%, 52%, 31%, and 6%. Extrapulmonary disease (p = 0.008) negatively predicted for survival while the receipt of any systemic therapy (p = 0.050) or PoSST alone (p = 0.039) positively predicted for survival. In patients receiving PoSST, an SPI &gt;30 days positively predicted for survival (HR 0.28, 95% CI 0.13-0.62, p = 0.002) regardless of SDS.Conclusion: Our results indicate the prognostic importance of systemic therapy and specifically PoSST. Additionally, delaying the initiation of PoSST to &gt;30 days seems beneficial. This finding was potentially influenced by neurotoxicity after SRS. Further investigation is warranted to define the optimal SPI.</p

Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury

WNT/β-catenin signalling is crucial for intestinal homoeostasis. The intestinal epithelium and stroma are the major source of WNT ligands but their origin and role in intestinal stem cell (ISC) and epithelial repair remains unknown. Macrophages are a major constituent of the intestinal stroma. Here, we analyse the role of macrophage-derived WNT in intestinal repair in mice by inhibiting their release using a macrophage-restricted ablation of Porcupine, a gene essential for WNT synthesis. Such Porcn-depleted mice have normal intestinal morphology but are hypersensitive to radiation injury in the intestine compared with wild-type (WT) littermates. Porcn-null mice are rescued from radiation lethality by treatment with WT but not Porcn-null bone marrow macrophage-conditioned medium (CM). Depletion of extracellular vesicles (EV) from the macrophage CM removes WNT function and its ability to rescue ISCs from radiation lethality. Therefore macrophage-derived EV-packaged WNTs are essential for regenerative response of intestine against radiation

The role of pre- and post-SRS systemic therapy in patients with NSCLC brain metastases

Purpose: We report our experience with stereotactic radiosurgery (SRS) for NSCLC brain metastases. We then assess the prognostic value of pre- and post-SRS systemic therapy (PrSST and PoSST) and evaluate the timing of PoSST.Methods: In this retrospective study, we analyzed 96 patients with lung cancer and ECOG PS ≤ 3 who underwent SRS during 2007-2013. Recorded factors included SRS treatment parameters, systemic status of disease (SDS) at time of SRS, and the use of PrSST and PoSST. SDS was designated as pulmonary disease or extrapulmonary disease. For analysis, the SRS-PoSST interval (SPI) was divided into ≤30 days and &gt;30 days. Univariate and multivariate analyses were performed.Results: 85 patients with NSCLC were included in this analysis. 48% received PrSST and 48% received PoSST. 57% of patients had pulmonary disease while 40% had extrapulmonary disease. 46% of patients had synchronous metastases. At a median follow-up of 6 months, the median survival was 6.4 months and the actuarial overall survival at 3, 6, 12, and 36 months was 80%, 52%, 31%, and 6%. Extrapulmonary disease (p = 0.008) negatively predicted for survival while the receipt of any systemic therapy (p = 0.050) or PoSST alone (p = 0.039) positively predicted for survival. In patients receiving PoSST, an SPI &gt;30 days positively predicted for survival (HR 0.28, 95% CI 0.13-0.62, p = 0.002) regardless of SDS.Conclusion: Our results indicate the prognostic importance of systemic therapy and specifically PoSST. Additionally, delaying the initiation of PoSST to &gt;30 days seems beneficial. This finding was potentially influenced by neurotoxicity after SRS. Further investigation is warranted to define the optimal SPI