Studies have suggested that chronic social stress specifically downregulates endothelial tight junction protein expression in the nucleus accumbens (NAc), thus increasing blood-brain barrier (BBB) ...permeability and promoting depression-like behaviors. However, the molecular mechanism underlying the reduction in tight junction protein, particularly in the NAc, is largely uncharacterized.
We performed comparative metabolomic profiling of the nucleus accumbens, prefrontal cortex, and hippocampus of social defeat–stressed mice to identify the molecular events that mediate BBB breakdown.
We identified the levels of cyclic adenosine monophosphate (cAMP) that were specifically reduced in the NAc and positively correlated with the degree of social avoidance. Replenishing cAMP in the NAc was sufficient to improve BBB integrity and depression-like behaviors. We further found that cAMP levels were markedly decreased in neurons of the NAc, rather than in endothelial cells, astrocytes, or microglia. RNA-sequencing data showed that adenylate cyclase 5 (Adcy5), an enzyme responsible for the synthesis of cAMP from adenosine triphosphate (ATP), was predominantly expressed in the NAc; it also resided exclusively in neurons. Endogenous modulation of cAMP synthesis in neurons through the knockdown of Adcy5 in the NAc regulated the sensitivity to social stress. Moreover, deficient neuronal cAMP production in the NAc decreased the expression of reelin, while supplementary injection of exogenous reelin into the NAc promoted BBB integrity and ameliorated depression-like behaviors.
Chronic social stress diminished cAMP synthesis in neurons, thus damaging BBB integrity in the NAc and promoting stress vulnerability. These results characterize neuron-produced cAMP in the NAc as a biological mechanism of neurovascular pathology in social stress.
SLC7A11 controls the uptake of extracellular cystine in exchange for glutamate at a ratio of 1:1, and it is overexpressed in a variety of tumours. Accumulating evidence has shown that the expression ...of SLC7A11 is fine-tuned at multiple levels, and plays diverse functional and pharmacological roles in tumours, such as cellular redox homeostasis, cell growth and death, and cell metabolism. Many reports have suggested that the inhibition of SLC7A11 expression and activity is favourable for tumour therapy; thus, SLC7A11 is regarded as a potential therapeutic target. However, emerging evidence also suggests that on some occasions, the inhibition of SLC7A11 is beneficial to the survival of cancer cells, and confers the development of drug resistance. In this review, we first briefly introduce the biological properties of SLC7A11, including its structure and physiological functions, and further summarise its regulatory network and potential regulators. Then, focusing on its role in cancer, we describe the relationships of SLC7A11 with tumourigenesis, survival, proliferation, metastasis, and therapeutic resistance in more detail. Finally, since SLC7A11 has been linked to cancer through multiple approaches, we propose that its contribution and regulatory mechanism require further elucidation. Thus, more personalised therapeutic strategies should be adapted when targeting SLC7A11.
Survivin (encoded by the gene BIRC5) plays an important role in the carcinogenesis of bladder cancer. Identifying miRNAs that target Survivin in the setting of bladder cancer will help to develop ...Survivin-based therapies for bladder cancer.
The expression levels of miR-138-5p and Survivin protein were measured in 12 resected bladder cancer specimens. The correlation between miR-138-5p and Survivin was further examined by evaluating Survivin expression in human bladder cancer cell lines that either overexpressed or knocked down miR-138-5p. A luciferase reporter assay was performed to test the direct binding of miR-138-5p to the target gene BIRC5. We also investigated the biological role of miR-138-5p targeting to Survivin in bladder cancer cell lines both in vivo and in vitro.
In this study, we found that the Survivin protein was either absent or weakly expressed in normal adjacent tissues and consistently up-regulated in bladder cancer tissues; however, the mRNA levels did not vary as much, suggesting that a post-transcriptional mechanism was involved. Because microRNAs are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for microRNAs that could potentially target BIRC5 in the setting of bladder cancer. We identified 2 specific targeting sites for miR-138-5p in the 3' untranslated region (3'-UTR) of BIRC5. We further identified an inverse correlation between miR-138-5p and Survivin protein levels in bladder cancer tissue samples. By overexpressing or knocking down miR-138-5p in bladder cancer cells, we experimentally confirmed that miR-138-5p directly recognizes the 3'-UTR of the BIRC5 transcript and regulates Survivin expression. Furthermore, the biological consequences of the targeting of BIRC5 by miR-138-5p were examined in vitro via cell proliferation and invasion assays and in vivo using a mouse xenograft tumor model. We demonstrated that BIRC5 repression by miR-138-5p suppressed the proliferative and invasive characteristics of bladder cancer cells and that miR-138-5p exerted an anti-tumor effect by negatively regulating BIRC5 in a xenograft mouse model.
Taken together, our findings provide the first clues regarding the role of miR-138-5p as a tumor suppressor in bladder cancer by inhibiting BIRC5 translation.
Background
Response prediction is necessary for renal cell carcinoma (RCC) tumors. We aim to evaluate parameters derived from
68
Ga-PSMA-11 PET/CT images for prediction of pathological ...VEGFR-2/PDGFR-β expression of primary RCC tumors.
Methods
Forty-eight RCC patients were retrospectively enrolled with preoperative
68
Ga-PSMA-11 PET/CT scan and surgical specimen. Radiological parameters including tumor diameter, mean CT value, and maximal standard uptake value (SUV
max
) were derived from PET/CT images and pathological VEGFR-2/PDGFR-β/PSMA expression were identified with immunohistochemistry. Mann–Whitney
U
test was performed for continuous variables and the chi-square test for categorical variables. ROC was used for determining the effectiveness of preoperative parameters in differentiating VEGFR-2/PDGFR-β expression. Univariate and multivariate logistic regression analyses were performed for significant parameters to predict VEGFR-2 & PDGFR-β co-expression.
Results
Of the 48 tumors, 25 (52.1%) harbored positive VEGFR-2 expression, 28 (58.3%) harbored positive PDGFR-β expression, and 24 (50%) were both VEGFR-2 positive and PDGFR-β positive. SUV
max
significantly differed by subgroups of VEGFR-2/PDGFR-β expression (both
P
< 0.001). SUV
max
demonstrated superior performance for differentiating VEGFR-2 & PDGFR-β co-expression (positive vs. negative), with area under the curve 0.87 (95% CI 0.78–0.96,
P
< 0.001), sensitivity 93% and specificity 78%. Moreover, SUV
max
was identified as the significant predictor for VEGFR-2 & PDGFR-β co-expression (odds ratio 4.01, 95% CI 1.99–8.08,
P
< 0.001). Concordant with radiological findings with
68
Ga-PSMA-11 PET/CT, pathological PSMA staining intensity was significantly higher in both VEGFR-2-positive tumor and PDGFR-β-positive tumor (
P
= 0.009 and
P
< 0.001, respectively).
Conclusion
68
Ga-PSMA-11 PET/CT could effectively identify pathological VEGFR-2/PDGFR-β expression of primary RCC tumors, which may help with selection of mRCC patients suitable for TKIs treatment.
Nephrotoxicity is the dose-limiting factor of cisplatin treatment. Magnesium isoglycyrrhizinate (MgIG) has been reported to ameliorate renal ischemia–reperfusion injury. This study aimed to ...investigate the protective effect and possible mechanisms of MgIG against cisplatin-induced nephrotoxicity from the perspective of cellular pharmacokinetics. We found that cisplatin predominantly accumulated in mitochondria of renal tubular epithelial cells, and the amount of binding with mitochondrial DNA (mtDNA) was more than twice that with nuclear DNA (nDNA). MgIG significantly lowered the accumulation of cisplatin in mitochondria and, in particular, the degree of target-binding to mtDNA. MgIG notably ameliorated cisplatin-induced changes in mitochondrial membrane potential, morphology, function, and cell viability, while the magnesium donor drugs failed to work. In a mouse model, MgIG significantly alleviated cisplatin-caused renal dysfunction, pathological changes of renal tubules, mitochondrial ultrastructure variations, and disturbed energy metabolism. Both in vitro and in vivo data showed that MgIG recovered the reduction of NAD+-related substances and NAD+-dependent deacetylase sirtuin-3 (SIRT3) level caused by cisplatin. Furthermore, SIRT3 knockdown weakened the protective effect of MgIG on mitochondria, while SIRT3 agonist protected HK-2 cells from cisplatin and specifically reduced platinum-binding activity with mtDNA. In conclusion, MgIG reduces the target-binding amount of platinum to mtDNA and exerts a protective effect on cisplatin-induced renal injury through SIRT3, which may provide a new strategy for the treatment of cisplatin-induced nephrotoxicity.
Purpose
Prostate-specific membrane antigen (PSMA) positron emission tomography (PSMA-PET) is an ideal tool for staging and restaging of prostate cancer (PCa). This study was designed to investigate ...the prognostic role of preoperative
68
Ga-PSMA-11 PET/CT in predicting pathological upgrading from multiparametric magnetic resonance imaging–targeted biopsy (mpMRI-TB) to final radical prostatectomy (RP) specimens in patients with localized PCa.
Methods
A total of 67 biopsy-confirmed localized PCa patients with mpMRI and
68
Ga-PSMA-11 PET/CT prior to RP were included. Clinical and imaging characteristics derived from mpMRI and PET/CT were compared in patients with or without pathological upgrading. Predictors for pathological upgrading were evaluated by using univariate and multivariable analyses. A prediction model was developed based on the identified parameters and validated using internal validation.
Results
Pathological upgrading from mpMRI-TB to final RP specimens occurred in 38.8% (26/67) of the patients. Multivariable logistic regression analysis showed SUV
max
(OR: 1.223, 95% CI 1.068–1.399,
p
= 0.003); highest tumor grade at mpMRI-TB, ISUP grade group (ISUP GG) 1 vs. 4 (OR: 0.11, 95% CI 0.000–0.452,
p
= 0.018) and ISUP GG 2 vs. 4 (OR: 0.16, 95% CI 0.001–0.252,
p
= 0.003); and multifocality on PET/CT (OR: 9.821, 95% CI 1.438–67.085,
p
= 0.02) were independent risk factors for pathological upgrading. Our developed prediction model based on the identified parameter showed good calibration at internal validation (mean absolute error = 0.033).
Conclusion
68
Ga-PSMA-11 PET/CT was found to be an ideal biomarker for the prediction of pathological upgrading from mpMRI-TB to RP, especially for patients with lower tumor grade at mpMRI-TB.
Purpose
This study was designed to investigate the prognostic role of preoperative
68
Ga-PSMA-11 PET/CT in predicting biochemical recurrence (BCR) of localized prostate cancer (PCa) after radical ...prostatectomy (RP).
Methods
A total of 77 biopsy-confirmed PCa patients with
68
Ga-PSMA-11 PET/CT prior to RP were included. A PSMA-ligand PET/CT-based risk model with SUV
max
, maximum diameter of the index tumor and T stage was developed for prediction of 2-year BCR using Cox regression analysis. Also, the efficacy of the developed risk model was compared with European Association of Urology risk stratification (D’Amico) and the Cancer of the Prostate Risk Assessment (CAPRA) score. C-index and calibration plot were used to assess discrimination and calibration with internal validation.
Results
With a median follow-up of 25 months, 23 (29.9%) patients experienced BCR within 2 years after RP. Patients experienced BCR had a significant higher PSA at diagnosis (p<0.001), a higher ISUP grade of biopsy (p=0.044), as well as a higher ISUP grade (p=0.001), a higher possibility of T3 diseases (p=0.001) and positive margin (p=0.008) on postoperative pathology. SUV
max
, maximum diameter of the index tumor and T stage on preoperative PSMA-ligand PET/CT were significantly associated with BCR (all p<0.01). PSMA-ligand PET/CT-based risk model had a superior discrimination (c-index 78.5%) and good calibration at internal validation. The efficacy of this model in predicting 2-year BCR after RP was better, compared with CAPRA (c-index 66.3%) and D’Amico (c-index 66.2%). The addition of the PSMA-ligand PET/CT-derived variables also improved the efficacy of the existing models in predicting 2-year BCR (C-index of 78.9% for modified CAPRA and 79.3% for modified D’Amico, respectively).
Conclusion
A PSMA-ligand PET/CT-based risk model showed good efficacy in predicting 2-year BCR after RP, which needed to be validated by further prospective studies.
Intravesical instillation is the main therapy for bladder cancer and interstitial cystitis. However, most drug solutions are eliminated from bladder after the first voiding of urine. To solve this ...problem, we proposed a floating hydrogel with self-generating micro-bubbles as a new delivery system. It floated in urine, avoiding the urinary obstruction and bladder irritation that ordinary hydrogels caused. In this study, we abandoned traditional gas-producing method like chemical decomposition of NaHCO₃, and used the foamability of Poloxamer 407 (P407) instead. Through simple shaking (just like shaking SonoVue for contrast-enhanced ultrasound in clinical), the P407 solution will "lock" many micro-bubbles and float in urine as quickly and steadily as other gas producing materials. In vivo release experiments showed that drug was released continually from hydrogel for 10 h during the erosion process. Thus, the residence time of drug in bladder was prolonged and drug efficacy was improved. In vivo efficacy study using rabbit acute bladder injury model showed that prolonged drug residence time in bladder increased the efficiency of heparin in the protection of bladder mucosal permeability. Therefore, our floating hydrogel system with self-generating micro-bubbles was single-component, simply prepared and efficacy enhancing, successfully exempting users from worries on safety and clinical efficiency from bench to bedside.
To compare robot-assisted simple enucleation with renal arterial cold perfusion (RACP-RASE) and RASE alone in complex renal tumors with regard to perioperative, functional and oncologic outcomes by ...propensity score-matched analysis.
Data from 351 patients who underwent RACP-RASE or RASE for complex renal tumors were recorded between September 2014 and December 2017. Propensity score-matched analysis was performed on age, sex, BMI, ECOG score, tumor side and size, preoperative estimated glomerular filtration rate (eGFR), RENAL score and PADUA score.
The study included 31 RACP-RASE and 320 RASE procedures. RENAL score and PADUA score were higher and tumor diameter was greater under RACP-RASE than RASE. After matching, the two groups were similar in estimated blood loss (208.3 vs 230.7 ml; p = 0.696) and ischemic time (34.8 vs 32.8 min; p = 0.342). The RACP-RASE group had significantly longer operative time than the RASE group (264.1 ± 55.7 vs 206.9 ± 64.0 min, p = 0.001). There was no difference in the incidence of postoperative complications between the two groups (13.8% vs 24.1%; p = 0.315), as was the overall incidence of positive surgical margins (3.4 vs 0%; p = 1.000). The changes in eGFR significantly differed between the two groups at 3 months (p = 0.018) and 12 months (p = 0.038). More patients in the RASE group were CKD upstaged (p = 0.043). At multivariable analysis, preoperative eGFR and the type of procedure were significant predictive factors for a change of more than 10% in eGFR at 3 months postoperatively. There was no local recurrence or distant metastasis during follow-up.
RACP-RASE is an effective and safe technique for complex renal tumors that can provide appropriate temporary arterial occlusion and renal hypothermic perfusion. Renal arterial cold perfusion may be helpful in protecting renal function in RASE as compared with warm ischemia.
To evaluate the perioperative outcomes of zero ischemia radiofrequency ablation-assisted tumor enucleation.
Patients undergoing zero ischemia radiofrequency ablation-assisted tumor enucleation were ...retrospectively identified from July 2008 to March 2013. The tumor was enucleated after RFA treatment. R.E.N.A.L., PADUA and centrality index (C-index) score systems were used to assess each tumor case. We analyzed the correlation of perioperative outcomes with these scores. Postoperative complications were graded with Clavien-Dindo system. Multivariate logistic regression analyses were used to assess risk of complications.
Among 182 patients assessed, median tumor size, estimated blood loss, hospital stay and operative time were 3.2 cm (IQR 2.8-3.4), 80 ml (IQR 50-120), 7 days (IQR 6-8) and 100 min (IQR 90-120), respectively. All three scoring systems were strongly correlated with estimated blood loss, hospital stay and operative time. We found 3 (1.6%) intraoperative and 23 (12.6%, 13 7.1% Grade 1 and 10 5.5% Grade 2 & 3a) postoperative complications. The median follow-up was 55.5 months (IQR 45-70). Additionally, the complexities of R.E.N.A.L., PADUA and C-index scores were significantly correlated with complication grades (P < 0.001; P < 0.001; P < 0.001; respectively). As the representative, R.E.N.A.L. score was an independent predictive factor for postoperative complications and patients with a high complexity had an over 24-fold higher risk compared to those with a low complexity (OR 24.360, 95% CI 4.412-134.493, P < 0.001).
Zero ischemia radiofrequency ablation-assisted tumor enucleation is considered an effective nephron-sparing treatment. Scoring systems could be useful for predicting perioperative outcomes of radiofrequency ablation-assisted tumor enucleation.
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