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Abstract Histone lysine-specific demethylase 1 (LSD1) has been implicated in the disease progression of several types of solid tumors. This study provides the first evidence showing that LSD1 overexpression occurred in 62.6% (224/358) of clear cell renal cell carcinomas (ccRCC). LSD1 expression was associated with the progression of ccRCC, as indicated by TNM stage (P =0.006), especially tumor stage (P =0.017) and lymph node metastasis (P =0.030). High LSD1 expression proved to be an independent prognostic factor for poor overall survival (P <0.001) and recurrence-free survival (P <0.001) of ccRCC patients. We further show that LSD1 inhibition by siRNA knockdown or using the small molecule inhibitor SP2509 suppressed the growth of ccRCC in vitro and in vivo. Mechanistically, inhibition of LSD1 decreased the H3K4 demethylation at the CDKN1A gene promoter, which was associated with P21 upregulation and cell cycle arrest at G1/S in ccRCC cells. Our findings provide new mechanistic insights into the role of LSD1 in ccRCC and suggest the therapeutic potential of LSD1 inhibitors in ccRCC treatment. Graphical abstract LSD1 mediates ccRCC cell proliferation: LSD1 is highly expressed in ccRCC samples and it suppresses H3K4 methylation, inducing ccRCC cell proliferation through p21 signaling dysfunction; inhibition of LSD1 restores H3K4 methylation, inducing G1/S cell-cycle arrest by increasing the level of check-point regulator p21. fx1 [ABSTRACT FROM AUTHOR]

Surface-enhanced Raman spectroscopy (SERS) involving expressed prostatic secretion (EPS) and serum was investigated; the objective was to determine if this approach could distinguish prostate cancer from benign prostatic hyperplasia. A total of 120 SERS spectra for EPS and 96 spectra for serum were gathered from patients within a prospective contemporary biopsy cohort. Significant differences in spectra between prostate cancer and benign prostatic hyperplasia were tentatively assigned to component changes in EPS and serum samples. Principal component analysis and linear discriminate analysis were utilized to evaluate the spectral data for EPS and serum, to build diagnostic algorithms. The leave-one-out cross-validation method was used to validate the diagnostic algorithms; it revealed diagnostic sensitivities of 75% and 60%, specificities of 75% and 76.5%, and accuracies of 75% and 68% for EPS and serum, respectively. The results suggest that EPS and serum SERS analysis could be a potential tool for prostate cancer detection. [ABSTRACT FROM AUTHOR]

Cell plasticity and neuroendocrine differentiation in prostate and lung adenocarcinomas are one of the major reasons for therapeutic resistance to targeted therapy. Whether and how metabolic changes contribute to this adenocarcinoma-to-neuroendocrine cell fate transition remains largely unclear. Here we show that neuroendocrine prostate or lung cancer cells possess mostly fragmented mitochondria with low membrane potential and rely on glycolysis for energy metabolism. We further show an important role of the cell fate determinant Numb in mitochondrial quality control via binding to Parkin and facilitating Parkin-mediated mitophagy. Deficiency in the Numb/Parkin pathway in prostate or lung adenocarcinomas causes a metabolic reprogramming featured with a significant increase in production of lactate acid, which subsequently leads to an upregulation of histone lactylation and transcription of neuroendocrine-associated genes. Collectively, the Numb/Parkin-directed mitochondrial fitness is a key metabolic switch and a promising therapeutic target on cancer cell plasticity through the regulation of histone lactylation. [Display omitted] • Cell fate determinant Numb binds to Parkin and promotes Parkin-mediated mitophagy • Impairment of mitochondrial quality control compels a metabolic-epigenetic switch • Histone lactylation leads to transcriptional surges of neuroendocrine genes • Defective Numb/Parkin axis drives a neuroendocrine cell fate in cancer cells Acquired therapeutic resistance to targeted therapy is a major clinical challenge in prostate and lung adenocarcinomas. He et al. find that the Numb/Parkin-directed mitochondrial fitness is a key metabolic switch on cancer cell plasticity and neuroendocrine differentiation, providing important insights into the mechanism of acquired resistance to targeted therapy. [ABSTRACT FROM AUTHOR]

The metabolic program is altered during macrophage activation and influences macrophage polarization. Glutaminolysis promotes accumulation of α-ketoglutarate (αKG), leading to Jumonji domain-containing protein D3 (Jmjd3)-dependent demethylation at H3K27me3 during M2 polarization of macrophages. However, it remains unclear how αKG accumulation is regulated during M2 polarization of macrophages. This study shows that SENP1-Sirt3 signaling controls glutaminolysis, leading to αKG accumulation during IL-4-stimulated M2 polarization. Activation of the SENP1-Sirt3 axis augments M2 macrophage polarization through the accumulation of αKG via glutaminolysis. We also identify glutamate dehydrogenase 1 (GLUD1) as an acetylated protein in mitochondria. The SENP1-Sirt3 axis deacetylates GLUD1 and increases its activity in glutaminolysis to promote αKG production, leading to M2 polarization of macrophages. Therefore, SENP1-Sirt3 signaling plays a critical role in αKG accumulation via glutaminolysis to promote M2 polarization. [Display omitted] • IL-4 activates SENP1-Sirt3 axis to augment M2 macrophage polarization • SENP1-Sirt3 axis controls αKG accumulation via glutaminolysis in M2 polarization • SENP1-Sirt3 axis deacetylates and activates GLUD1 in glutaminolysis Zhou et al. find that IL-4 activates SENP1-Sirt3 signaling in mitochondria to deacetylate glutamate dehydrogenase 1 (GLUD1) to promote glutaminolysis and α-ketoglutarate (αKG) production leading to macrophage M2 polarization. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate a method for predicting renal function recoverability after the relief of obstructive uropathy using 1H NMR-based metabonomics. Design and methods: This study included 16 bilateral ureteral obstruction (BUO) patients and 9 unilateral ureteral obstruction (UUO) patients. The obstructions in all of the patients were successfully relieved after treatment. Urine samples at different time points before and after treatment were obtained, and their 1H NMR spectra were recorded and analyzed using multivariate statistical techniques combined with quantitative statistical analyses. Results: A distinctive pattern in the metabolite profile of urine samples from preoperation and early and late stages after treatment was observed, which was in good agreement with the clinical chemistry analyses. Some important systemic perturbations in endogenous metabolites were correlated with different recoverability stages of renal function after obstruction relief. In addition, the OPLS-DA model of BUO patients could help predict the recovery of renal function of UUO patients. Conclusion: The results suggest that 1H NMR-based metabonomics can be used to evaluate the recoverability of renal function after obstruction relief. Our results suggest that 1H NMR-based metabonomics may help stratify patients according to disease stages, provide prognostic information, and be useful for postoperative surveillance. [Copyright &y& Elsevier]

Prostate cancer most frequently metastasizes to bone, resulting in abnormal bone metabolism and the release of components into the blood stream. Here, we evaluated the capacity of convolutional neural networks (CNNs) to use Raman data for screening of prostate cancer bone metastases. We used label-free surface-enhanced Raman spectroscopy (SERS) to collect 1281 serum Raman spectra from 427 patients with prostate cancer, and then we constructed a CNN based on LetNet-5 to recognize prostate cancer patients with bone metastases. We then used 5-fold cross-validation method to train and test the CNN model and evaluated its actual performance. Our CNN model for bone metastases detection revealed a mean training accuracy of 99.51% ± 0.23%, mean testing accuracy of 81.70% ± 2.83%, mean testing sensitivity of 80.63% ± 5.07%, and mean testing specificity of 82.82% ± 2.94%. Prostate cancer (PCA) most frequently metastasizes to bone, resulting in abnormal bone metabolism and release of components into the blood stream. We used label free surface-enhanced Raman spectroscopy (SERS) to analyze the components changes in blood and then developed a deep learning method (convolutional neural networks) to extract features of Raman spectra and recognize PCA patients of bone metastases. In the future, larger datasets will improve the model for rapid and automated BM screening to supplement PCA bone scans. Unlabelled Image • Prostate cancer most frequently metastasizes to bone, resulting in abnormal bone metabolism and releasing of components into the blood stream. Surface-enhanced Raman spectroscopy (SERS) has emerged as a powerful technique for blood components analysis. It is a good point to translate SERS to clinical practice. • The subject size is relative large; a total of 427 patients are included in this study. • Convolutional neural networks (CNN) are firstly utilized to analyze Raman spectra and develop a practical classification model. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study is to investigate the effect and mechanism of acidic fibroblast growth factor (aFGF) on treating refractory wound of diabetic rats. SD rats were randomly divided into control group, diabetes group, and aFGF group. Ulcer skin tissues of three groups of rats were respectively collected on days 7 and 14 after establishment of ulcer model for biochemical test, pathological section and immunohistochemistry to comprehensively evaluate the treatment effect of aFGF on diabetic ulcer. The results showed that aFGF could significantly increase capillaries and fibroblast amounts of ulcer tissues, enhance the expression of TGF-β and PCNA proliferation proteins, and thus improved diabetic ulcer tissues. The preliminary mechanism that aFGF helps to promote healing of diabetic ulcer is possibly associated with that aFGF stimulated ulcer skins to secrete TGF-β and PCNA proteins and promoted proliferation of capillaries and fibroblasts. [Copyright &y& Elsevier]

Most prostate cancer (PCa)-related deaths are caused by progression to bone metastasis. Recently, the importance of extracellular vesicles (EVs) in pre-metastatic niche formation has been reported. However, whether and how tumor-derived EVs interact with bone marrow macrophages (BMMs) to release EV-delivered microRNAs to promote osteolysis and induce pre-metastatic niche formation for PCa bone metastasis remain unclear. Our in vitro and in vivo functional and mechanistic assays revealed that EV-mediated release of miR-378a-3p from tumor cells was upregulated in bone-metastatic PCa, maintaining low intracellular miR-378a-3p concentration to promote proliferation and MAOA-mediated epithelial-to-mesenchymal transition. Moreover, miR-378a-3p enrichment in tumor-derived EVs was induced by hnRNPA2B1 (a transfer chaperone) overexpression. After tumor-derived EVs were taken in by BMMs, enriched miR-378a-3p promoted osteolytic progression by inhibiting Dyrk1a to improve Nfatc1 (an osteolysis-related transcription factor) nuclear translocation, to activate the expression of downstream target gene Angptl2. As a feedback, increased Angptl2 secretion into the tumor environment promoted PCa progression. In conclusion, tumor-derived miR-378a-3p-containing EVs play a significant role in PCa bone metastasis by activating the Dyrk1a/Nfatc1/Angptl2 axis in BMMs to induce osteolytic progression, making miR-378a-3p a potential predictor of metastatic PCa. Reducing the release of miR-378a-3p-containing EVs or inhibiting the recruitment of miR-378a-3p into EVs can be a therapeutic strategy against PCa metastasis. [ABSTRACT FROM AUTHOR]

• For the first time, neural networks were applied to denoise in spatial heterodyne spectroscopy, and significant results were achieved. • Four corresponding network models were constructed for denoising different brightness and noise levels. • The denoising ability of DnCNN in spatial heterodyne interferograms were comprehensively evaluated. • The reasonable selection of four neural network schemes were discussed. Spatial heterodyne spectroscopy is a hyperspectral remote sensing technology. With the continuous improvement of signal detection accuracy, new methods are urgently needed to further reduce the interference of noise on the information contained in spatial heterodyne interferograms. Convolutional neural networks, as an emerging field, have achieved good results in image denoising in recent years. This paper applies convolutional neural networks to the field of spatial heterodyne spectroscopy, constructs and trains four deep convolutional neural network models for denoising spatial heterodyne interferograms under different brightness and Gaussian noise conditions, and compares their performance with other algorithms. The results show that deep convolutional neural networks have significant advantages in denoising spatial heterodyne interferograms. Finally, a comparison of four neural networks was conducted to explore how to reasonably select network models. This work provides new ideas and effective solutions for reducing the interference of noise on spatial heterodyne spectral information and improving signal detection accuracy. [ABSTRACT FROM AUTHOR]

Objective: Docetaxel has been shown to be an effective chemotherapy agent when combined with androgen deprivation therapy for hormone sensitive metastatic prostate cancer (CaP). Since very high risk CaP has a high rate of occult metastatic disease and early recurrence, we hypothesize that patients with very high risk locally advanced CaP may benefit from docetaxel-based neoadjuvant chemohormonal therapy (NCHT). Thus, we conducted a retrospective study to identify the outcome of these patients treated with NCHT followed by radical prostatectomy (RP).Patients and Methods: We retrospectively analyzed data from 177 consecutive patients who had very high risk locally advanced CaP between March 2014 and July 2017. Patients received 3 different therapies: (i) 60 men in NCHT group, (ii) 73 men in neoadjuvant hormonal therapy (NHT) group, and (iii) 44 men received immediate RP without neoadjuvant therapy (No-NT group). Surgical outcomes were analyzed and survival differences were compared by the Kaplan-Meier method.Results: The NCHT group had statistically significant higher preoperative Prostate-Specific Antigen (PSA) (P < 0.002), higher Gleason score (P < 0.002), and more advanced clinical stage (P < 0.001) than other groups. After RP, 81% (42/52) of patients in NCHT group, 73% (51/70) of patients in NHT group, and 48% (21/44) of patients in No-NT group achieved an undetectable PSA (P < 0.001). A total of 14% (6/42) patients achieving a postoperative undetectable PSA experienced biochemical recurrence in the NCHT group, with median biochemical progression-free survival (bPFS) time of 19 months; 47% (24/51) experienced biochemical recurrence in the NHT group, with median bPFS time of 13 months; 81% (17/21) experienced biochemical recurrence in the No-NT group, with median bPFS time of 9 months (P < 0.001). The median follow-up time of 3 groups was 12.5 months in the NCHT group, 18.3 months in the NHT group, and 22.8 months in the No-NT group (P = 0.01).Conclusion: Despite having poorer prognostic factors, the NCHT group had better bPFS time after surgery compared to NHT and No-NT groups. Randomized controlled investigations are needed to validate these results and further follow-up is required for survival endpoints. [ABSTRACT FROM AUTHOR]

Lineage plasticity causes therapeutic resistance; however, it remains unclear how the fate conversion and phenotype switching of cancer-associated fibroblasts (CAFs) are implicated in disease relapse. Here, we show that androgen deprivation therapy (ADT)-induced SPP1+ myofibroblastic CAFs (myCAFs) are critical stromal constituents that drive the development of castration-resistant prostate cancer (CRPC). Our results reveal that SPP1+ myCAFs arise from the inflammatory CAFs in hormone-sensitive PCa; therefore, they represent two functional states of an otherwise ontogenically identical cell type. Antiandrogen treatment unleashes TGF-β signaling, resulting in SOX4-SWI/SNF-dependent CAF phenotype switching. SPP1+ myCAFs in turn render PCa refractory to ADT via an SPP1-ERK paracrine mechanism. Importantly, these sub-myCAFs are associated with inferior therapeutic outcomes, providing the rationale for inhibiting polarization or paracrine mechanisms to circumvent castration resistance. Collectively, our results highlight that therapy-induced phenotypic switching of CAFs is coupled with disease progression and that targeting this stromal component may restrain CRPC. [Display omitted] • CRPC-related SPP1+ myCAFs resist ADT via paracrine activation of ERK signaling • AR inhibition unleashes TGF-β signaling to convert iCAFs into SPP1+ myCAFs • Targeting therapy-induced CAF conversion may enhance the effect of ADT on CRPC Wang et al. show that the polarization of cancer-associated fibroblasts (CAFs) is shaped collaboratively by the tumor microenvironment (TME) and target therapy. AR inhibition unleashes TGF-β signaling to convert inflammatory CAFs into SPP1+ myofibroblastic CAFs and targeting of CAF polarization or paracrine mechanisms may restrain castration resistant in prostate cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) incidence and mortality have rapidly increased in China. Notably, unique epidemiological characteristics of PCa are found in the Chinese PCa population, including a low but rising incidence and an inferior but improving disease prognosis. Consequently, the current treatment landscape of PCa in China demonstrates distinct features. Establishing a more thorough understanding of the characteristics of Chinese patients may help provide novel insights into potential treatment strategies for PCa patients. Herein, we review the epidemiological status and differences in treatment modalities of Chinese PCa patients. In addition, we discuss the underlying socioeconomic and biological factors that contribute to such diversity and further propose directions for future efforts in optimizing the PCa treatment in China. [ABSTRACT FROM AUTHOR]

Purpose: To predict Gleason grade group (GG) upgrade in biopsy Gleason grade group 1 (GG1) prostate cancer (CaP) patients using surface-enhanced Raman spectroscopy (SERS).Materials and Methods: Preoperative serum samples of patients with biopsy GG1 and subsequent radical prostatectomy were analyzed using SERS. The role of clinical variables and distinctive SERS spectra in the prediction of GG upgrade were evaluated. Principal component analysis and linear discriminant analysis (PCA-LDA) were used to manage spectral data and develop diagnostic algorithms.Results: A total of 342 preoperative serum SERS spectra from 114 patients were obtained. SERS detected a higher level of circulating free nucleic acid bases and a lower level of lipids in patients with GG upgrade to GG3 and higher, presenting as SERS spectral peaks of 728 cm-1 and 1,655 cm-1, respectively. Both spectral peaks were independent predictors of GG upgrade and their addition to clinical predictors of PSA and positive core percent significantly improved predictive power of the logistic regression model with area under curve improved from 0.65 to 0.80 (P = 0.0045). Meanwhile, PCA-LDA diagnostic model based on serum SERS spectra showed a high accuracy of 91.2% in predicted groups and remained stable with a sensitivity, specificity, and accuracy of 65%, 97.3%, 86.0%, respectively when validated by leave-one-out cross-validation method.Conclusions: By analyzing preoperative serum samples, SERS combined with PCA-LDA model could be a promising tool for prediction of Gleason GG upgrade in biopsy GG1 CaP and assist in treatment decision-making in clinical practice. [ABSTRACT FROM AUTHOR]

The cyclic adenosine monophosphate (cAMP)-activated protein kinase A (PKA) pathway is profoundly implicated in Prostate cancer (PCa) progression. Previously, we showed that PRKAR2B, the type II-beta regulatory subunit of PKA, is highly expressed in castration-resistant prostate cancer (CRPC) and can induce epithelial-mesenchymal transition by activating Wnt/β-catenin signaling in PCa cells. However, the molecular mechanism of dysregulated PRKAR2B expression pattern is still largely unknown. In this study, we found that the mutation, copy number alteration, and methylation status of PRKAR2B gene have no correlation with its expression level in PCa. Then, we identified two microRNAs (miR-200b-3p and miR-200c-3p) to be critical regulators of PRKAR2B expression in PCa. Notably, miR-200b-3p and miR-200c-3p expression were significantly downregulated in metastatic CRPC and negatively correlated with the expression level of PRKAR2B in PCa tissues. Moreover, we characterized X-Box Binding Protein 1 (XBP1) as a key transcription factor responsible for PRKAR2B expression in PCa. Importantly, miR-200b-3p/200c-3p or XBP1 knockdown inhibited PCa cell proliferation and promoted cell apoptosis and these inhibitory roles could be largely restored by PRKAR2B, suggesting that PRKAR2B is a functional mediator of miR-200b-3p, miR-200c-3p, and XBP1 in PCa. Collectively, our study firstly identified miR-200b-3p/200c-3p and XBP1 as the critical upstream regulators of PRKAR2B in PCa and provided novel insights to PRKAR2B-driven PCa progression. [ABSTRACT FROM AUTHOR]