Expressions of glucose transporter genes are diversely attenuated and significantly associated with prostate cancer progression.

Prostate cancer is a health-threaten disease in men worldwide, however, lacking is the reliable biomarkers for patient management. Aberrant metabolic events including glucose metabolism are involved in prostate cancer progression. To examine the involvement of glucose metabolic pathways in prostate cancer, we analyzed the expression profiles of glucose transporter family genes using multiple RNA-seq datasets. Our results showed that three SLC2A family genes (SLC2A4/5/9) were significantly downregulated in primary prostate cancers compared to their benign compartments. These down-regulated expressions were inversely correlated with their gene promoter methylation and genome abnormalities. Among these three SLC2A genes, only SLC2A4 showed a significantly reverse correlation with all clinicopathological parameters, including TNM stage, disease relapse, Gleason score, disease-specific survival, and progression-free interval. In addition, the expression levels of these three genes were strongly correlated with anti-cancer immune cell filtration in primary prostate cancers. In a group of patients with early-onset prostate cancers, SLC2A4 also showed a strong negative correlation with multiple clinicopathological parameters, such as tumor mutation burden, biochemical relapse, pre-surgical PSA levels, and Gleason score but a positive correlation with progression-free interval after surgery. In metastatic castration-resistant prostate cancers (CRPC), SLC2A9 gene expression but not SLC2A4 or SLC2A5 genes showed a significant correlation with androgen receptor (AR) activity score and neuroendocrinal (NE) activity score. Meanwhile, SLC2A2/9/13 expression was significantly elevated in CRPC tumors with neuroendocrinal features compared to those without NE features. On the other hand, SLC2A10 and SlC2A12 gene expression were significantly reduced in NEPC tumors compared to CRPC tumors. Consistently, SLC2A10/12 expression levels were significantly reduced in castrated animals carrying the LuCaP35 xenograft models. Survival outcome analysis revealed that SLC2A4 expression in primary tumors is a favorable prognostic factor and SLC2A6 is a worse prognostic factor for disease-specific survival and progression-free survival in prostate cancer patients. In conclusion, our results suggest that SLC2A4/6 expressions are strong prognostic factors for prostate cancer progression and survival. The significance of SLC2A2/9/13 over-expression during NEPC progression needs more investigation.

Aberrant expression of multiple glycolytic enzyme genes is significantly associated with disease progression and survival outcomes in prostate cancers.

Prostate cancer is the leading cause of cancer death after lung cancer in men. Recent studies showed that aberrant metabolic pathways are involved in prostate cancer development and progression. In this study, we performed a systemic analysis of glycolytic enzyme gene expression using the TCGA-PRAD RNAseq dataset. Our analysis revealed that among 25 genes, only four genes (HK2/GPI/PFKL/PGAM5) were significantly upregulated while nine genes (HK1/GCK/PFKM/PFKP/ALDOC/PGK1/PGAM1/ENO2/PKM) were downregulated in primary prostate cancer tissues compared to benign compartments. Among these 13 altered genes, four genes (ENO2/ALDOC/GPI/GCK) exhibited strong diagnostic potential in distinguishing malignant and benign tissues. Meanwhile, GPI expression exerted as a prognostic factor of progression-free and disease-specific survival. PFKL and PGAM5 gene expressions were associated with AR signaling scores in castration-resistant patients, and AR-targeted therapy suppressed their expression. In LuCap35 xenograft tumors, PFKL and PGAM5 expression was significantly reduced after animal castration, confirming the AR dependency. Conversely, GCK/PKLR genes were significantly associated with neuroendocrinal progression, representing two novel neuroendocrinal biomarkers for prostate cancer. In conclusion, our results suggest that GPI expression is a strong prognostic factor for prostate cancer progression and survival while GCK/PKLR are two novel biomarkers of prostate cancer progression to neuroendocrinal status.

Red blood cell membrane-coated functionalized Au nanocage as a biomimetic platform for improved MicroRNA delivery in hepatocellular carcinoma.

Dysregulation of microRNAs (miRNAs) expression is closely related to cancers and managing miRNA expression holds great promise for cancer therapy. However, their wide clinical application has been hampered by their poor stability, short half-life and non-specific biodistribution in vivo. Herein, a novel biomimetic platform designated as RHAuNCs-miRNA for improved miRNA delivery was prepared through wrapping miRNA-loaded functionalized Au nanocages (AuNCs) with red blood cell (RBC) membrane. RHAuNCs-miRNA not only successfully loaded miRNAs but also effectively protected them from enzymatic degradation. With good stability, RHAuNCs-miRNA had the characteristics of photothermal conversion and sustained release. Cellular uptake of RHAuNCs-miRNA by SMMC-7721 cells was in a time-dependent manner via clathrin- and caveolin-mediated endocytosis. The uptake of RHAuNCs-miRNAs was affected by cell types and improved by mild near infrared (NIR) laser irradiation. More importantly, RHAuNCs-miRNA exhibited a prolonged circulation time without the occurrence of accelerated blood clearance (ABC) in vivo, resulting in efficient delivery to tumor tissues. This study may demonstrate the great potential of RHAuNCs-miRNA for improved miRNAs delivery.

Jumonji domain-containing protein RIOX2 is overexpressed and associated with worse survival outcomes in prostate cancers.

Background: Histone demethylase RIOX2 was cloned as a c-Myc downstream gene involved in cell proliferation and has been implicated as an oncogenic factor in multiple tumor types. Its expression profiles and correlation with disease progression in prostate cancers are unknown. Methods: Transcriptomic profiles of Jumanji domain-containing protein genes were assessed using multiple public expression datasets generated from RNA-seq and cDNA microarray assays. RIOX2 protein expression was assessed using an immunohistochemistry approach on a tissue section array from benign and malignant prostate tissues. Gene expression profiles were analyzed using the bioinformatics software R package. Western blot assay examined androgen stimulation on RIOX2 protein expression in LNCaP cells. Results: Among 35 Jumanji domain-containing protein genes, 12 genes were significantly upregulated in prostate cancers compared to benign compartments. COX regression analysis identified that the ribosomal oxygenase 2 (RIOX2) gene was the only one significantly associated with disease-specific survival outcomes in prostate cancer patients. RIOX2 upregulation was confirmed at the protein levels using immunohistochemical assays on prostate cancer tissue sections. Meanwhile, RIOX2 upregulation was associated with clinicopathological features, including late-stage diseases, adverse Gleason scores, TP53 gene mutation, and disease-free status. In castration-resistant prostate cancers (CRPC), RIOX2 expression was positively correlated with AR signaling index but negatively correlated with the neuroendocrinal progression index. However, androgen treatment had no significant stimulatory effect on RIOX2 expression, indicating a parallel but not a causative effect of androgen signaling on RIOX2 gene expression. Further analysis discovered that RIOX2 expression was tightly correlated with its promoter hypomethylation and MYC gene expression, consistent with the notion that RIOX2 was a c-Myc target gene. Conclusion: The Jumanji domain-containing protein RIOX2 was significantly overexpressed in prostate cancer, possibly due to c-Myc upregulation. RIOX2 upregulation was identified as an independent prognostic factor for disease-specific survival.

Scaffold protein MAPK8IP2 expression is a robust prognostic factor in prostate cancer associated with AR signaling activity.

Mitogen-activated protein kinase-8-interacting protein 2 (MAPK8IP2) is a scaffold protein that modulates MAPK signal cascades. Although MAPK pathways were heavily implicated in prostate cancer progression, the regulation of MAPK8IP2 expression in prostate cancer is not yet reported. We assessed MAPK8IP2 gene expression in prostate cancer related to disease progression and patient survival outcomes. MAPK8IP2 expression was analyzed using multiple genome-wide gene expression datasets derived from The Cancer Genome Atlas (TCGA) RNA-sequence project and complementary DNA (cDNA) microarrays. Multivariable Cox regressions and log-rank tests were used to analyze the overall survival outcome and progression-free interval. MAPK8IP2 protein expression was evaluated using the immunohistochemistry approach. The quantitative PCR and Western blot methods analyzed androgen-stimulated MAPK8IP2 expression in LNCaP cells. In primary prostate cancer tissues, MAPK8IP2 mRNA expression levels were significantly higher than those in the case-matched benign prostatic tissues. Increased MAPK8IP2 expression was strongly correlated with late tumor stages, lymph node invasion, residual tumors after surgery, higher Gleason scores, and preoperational serum prostate-specific antigen (PSA) levels. MAPK8IP2 upregulation was significantly associated with worse overall survival outcomes and progression-free intervals. In castration-resistant prostate cancers, MAPK8IP2 expression strongly correlated with androgen receptor (AR) signaling activity. In cell culture-based experiments, MAPK8IP2 expression was stimulated by androgens in AR-positive prostate cancer cells. However, MAPK8IP2 expression was blocked by AR antagonists only in androgen-sensitive LNCaP but not castration-resistant C4-2B and 22RV1 cells. These results indicate that MAPK8IP2 is a robust prognostic factor and therapeutic biomarker for prostate cancer. The potential role of MAPK8IP2 in the castration-resistant progression is under further investigation.

The iron-modulating hormone hepcidin is upregulated and associated with poor survival outcomes in renal clear cell carcinoma.

Background: Reliable biomarkers are rare for renal cell carcinoma (RCC) treatment selection. We aimed to discover novel biomarkers for precision medicine. The iron-regulating hormone hepcidin (HAMP) was reportedly increased in RCC patient sera and tissues. However, its potential implication as a prognostic biomarker remains exclusive. Methods: Multiple RNA-seq and cDNA microarray datasets were utilized to analyze gene expression profiles. Hepcidin protein expression was assessed using an ELISA assay in cell culture models. Comparisons of gene expression profiles and patient survival outcomes were conducted using the R package bioinformatics software. Results: Five (HAMP, HBS, ISCA2, STEAP2, and STEAP3) out of 71 iron-modulating genes exhibited consistent changes along with tumor stage, lymph node invasion, distal metastasis, tumor cell grade, progression-free interval, overall survival, and disease-specific survival. Of which HAMP upregulation exerted as a superior factor (AUC = 0.911) over the other four genes in distinguishing ccRCC tissue from normal renal tissue. HAMP upregulation was tightly associated with its promoter hypomethylation and immune checkpoint factors (PDCD1, LAG3, TIGIT, and CTLA4). Interleukin-34 (IL34) treatment strongly enhanced hepcidin expression in renal cancer Caki-1 cells. Patients with higher levels of HAMP expression experienced worse survival outcomes. Conclusion: These data suggest that HAMP upregulation is a potent prognostic factor of poor survival outcomes and a novel immunotherapeutic biomarker for ccRCC patients.

Idarubicin combats abiraterone and enzalutamide resistance in prostate cells via targeting XPA protein.

Although second-generation therapies like abiraterone (ABI) and enzalutamide (ENZ) benefit patients with castration-resistant prostate cancer (CRPC), drug resistance frequently occurs, eventually resulting in therapy failure. In this study, we used two libraries, FDA-approved drug library and CRISP/Cas9 knockout (GeCKO) library to screen for drugs that overcome treatment resistance and to identify the potential drug-resistant genes involved in treatment resistance. Our screening results showed that the DNA-damaging agent idarubicin (IDA) overcame abiraterone and enzalutamide resistance in prostate cancer cells. IDA treatment inhibited the DNA repair protein XPA expression in a transcription-independent manner. Consistently, XPA knockout sensitized prostate cancer cells to abiraterone and enzalutamide treatment. In conclusion, IDA combats abiraterone and enzalutamide resistance by reducing XPA protein level in prostate cancer.

TMEM158 expression is negatively regulated by AR signaling and associated with favorite survival outcomes in prostate cancers.

Background: Membrane protein TMEM158 was initially reported as a Ras-induced gene during senescence and has been implicated as either an oncogenic factor or tumor suppressor, depending on tumor types. It is unknown if TMEM158 expression is altered in prostate cancers. Methods: Multiple public gene expression datasets from RNA-seq and cDNA microarray assays were utilized to analyze candidate gene expression profiles. TMEM158 protein expression was assessed using an immunohistochemistry approach on a tissue section array from benign and malignant prostate tissues. Comparisons of gene expression profiles were conducted using the bioinformatics software R package. Results: COX regression-based screening identified the membrane protein TMEM158 gene as negatively associated with disease-specific and progression-free survival in prostate cancer patients. Gene expression at the mRNA and protein levels revealed that TMEM158 expression was significantly reduced in malignant tissues compared to benign compartments. Meanwhile, TMEM158 downregulation was strongly correlated with advanced clinicopathological features, including late-stage diseases, lymph node invasion, higher PSA levels, residual tumors after surgery, and adverse Gleason scores. In castration-resistant prostate cancers, TMEM158 expression was negatively correlated with AR signaling activity but positively correlated with neuroendocrinal progression index. Consistently, in cell culture models, androgen treatment reduced TMEM158 expression, while androgen deprivation led to upregulation of TMEM158 expression. Correlation analysis showed a tight correlation of TMEM158 expression with the level of R-Ras gene expression, which was also significantly downregulated in prostate cancers. Tumor immune infiltration profiling analysis discovered a strong association of TMEM158 expression with NK cell and Mast cell enrichment. Conclusion: The membrane protein TMEM158 is significantly downregulated in prostate cancer and is tightly associated with disease progression, anti-tumor immune infiltration, and patient survival outcome.

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective.

Prostate cancer is a major health issue in western countries and is the second leading cause of cancer death in American men. Prostate cancer depends on the androgen receptor (AR), a transcriptional factor critical for prostate cancer growth and progression. Castration by surgery or medical treatment reduces androgen levels, resulting in prostatic atrophy and prostate cancer regression. Thus, metastatic prostate cancers are initially managed with androgen deprivation therapy. Unfortunately, prostate cancers rapidly relapse after castration therapy and progress to a disease stage called castration-resistant prostate cancer (CRPC). Currently, clinical treatment for CRPCs is focused on suppressing AR activity with antagonists like Enzalutamide or by reducing androgen production with Abiraterone. In clinical practice, these treatments fail to yield a curative benefit in CRPC patients in part due to AR gene mutations or splicing variations, resulting in AR reactivation. It is conceivable that eliminating the AR protein in prostate cancer cells is a promising solution to provide a potential curative outcome. Multiple strategies have emerged, and several potent agents that reduce AR protein levels were reported to eliminate xenograft tumor growth in preclinical models via distinct mechanisms, including proteasome-mediated degradation, heat-shock protein inhibition, AR splicing suppression, blockage of AR nuclear localization, AR N-terminal suppression. A few small chemical compounds are undergoing clinical trials combined with existing AR antagonists. AR protein elimination by enhanced protein or mRNA degradation is a realistic solution for avoiding AR reactivation during androgen deprivation therapy in prostate cancers.

Sleep Quality Improvement Enhances Neuropsychological Recovery and Reduces Blood Aß42/40 Ratio in Patients with Mild-Moderate Cognitive Impairment.

Background and objectives: Alzheimer's disease is a progressive brain degeneration and is associated with a high prevalence of sleep disorders. Amyloid ß peptide-42/40 (Aß42/40) and Tau-pT181 are the core biomarkers in cerebrospinal fluid and blood. Accumulated data from studies in mouse models and humans demonstrated an aberrant elevation of these biomarkers due to sleep disturbance, especially sleep-disordered breathing (SDB). However, it is not clear if sleep quality improvement reduces the blood levels of Ab42/40 ratio and Tau-pT181 in Alzheimer's disease patients. Materials and Methods: In this prospective study, a longitudinal analysis was conducted on 64 patients with mild-moderate cognition impairment (MCI) due to Alzheimer's disease accompanied by SDB. Another 33 MCI cases without sleep-disordered breathing were included as the control group. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) score system. Neuropsychological assessments were conducted using the Montreal Cognitive Assessment (MoCA), Geriatric Depression Scale (GDS), Clinical Dementia Rating (CDR), 24-h Hamilton Rating Scale for Depression (HRSD-24), and Hamilton Anxiety Rating Scale (HAMA) scoring systems. Aß42, Aß40, and Tau-pT181 protein levels in blood specimens were measured using ELISA assays. All patients received donepezil treatment for Alzheimer's disease. SDB was managed with continuous pressure ventilation. Results: A significant correlation was found among PSQI, HRSD-24, HAMA, Aß42/40 ratio, and Tau-pT181 level in all cases. In addition, a very strong and negative correlation was discovered between education level and dementia onset age. Compared to patients without SDB (33 non-SD cases), patients with SDB (64 SD cases) showed a significantly lower HRSD-24 score and a higher Aß42/40 ratio Tau-pT181 level. Sleep treatment for patients with SDB significantly improved all neuropsychological scores, Aß42/40 ratio, and Tau-pT181 levels. However, 11 patients did not completely recover from a sleep disorder (PSQI > 5 post-treatment). In this subgroup of patients, although HAMA score and Tau-pT181 levels were significantly reduced, MoCA and HRSD-24 scores, as well as Aß42/40 ratio, were not significantly improved. ROC analysis found that the blood Aß42/40 ratio held the highest significance in predicting sleep disorder occurrence. Conclusions: This is the first clinical study on sleep quality improvement in Alzheimer's disease patients. Sleep quality score was associated with patient depression and anxiety scores, as well as Aß42/40 ratio and Tau-pT181 levels. A complete recovery is critical for fully improving all neuropsychological assessments, Aß42/40 ratio, and Tau-pT181 levels. Blood Aß42/40 ratio is a feasible prognostic factor for predicting sleep quality.

PAQR6 Upregulation Is Associated with AR Signaling and Unfavorite Prognosis in Prostate Cancers.

Progesterone-induced rapid non-genomic signaling events have been confirmed through several membrane progesterone receptors (mPR). Some mPRs were reported to correlate with cancer progression and patient prognosis. In this study, we conducted a comprehensive analysis of all progesterone receptor (PGR)-related genes in prostate cancer tissues and examined the correlations of their expression levels with disease progression and patient survival outcomes. We utilized multiple RNA-seq and cDNA microarray datasets to analyze gene expression profiles and performed logistics aggression and Kaplan-Meier survival analysis after stratifying patients based on tumor stages and Gleason scores. We also used NCBI GEO datasets to examine gene expression patterns in individual cell types of the prostate gland and to determine the androgen-induced alteration of gene expression. Spearman coefficient analysis was conducted to access the correlation of target gene expression with treatment responses and disease progression status. The classic PGR was mainly expressed in stromal cells and progestin and adipoQ receptor (PAQR) genes were the predominant genes in prostate epithelial cells. Progesterone receptor membrane component-1 (PGRMC1) was significantly higher than PGRMC2 in all prostate cell types. In prostate cancer tissues, PAQR6 expression was significantly upregulated, while all other genes were largely downregulated compared to normal prostate tissues. Although both PAQR6 upregulation and PAQR5 downregulation were significantly correlated with tumor pathological stages, only PAQR6 upregulation was associated with Gleason score, free-prostate-specific antigen (fPSA)/total-PSA (tPSA) ratio, and patient overall survival outcomes. In addition, PAQR6 upregulation and PGR/PGRMC1 downregulation were significantly associated with a quick relapse. Conversely, in neuroendocrinal prostate cancer (NEPC) tissues, PAQR6 expression was significantly lower, but PAQR7/8 expression was higher than castration-resistant prostate cancer (CRPC) tissues. PAQR8 expression was positively correlated with androgen receptor (AR) score and AR-V7 expression levels but inversely correlated with NEPC score in metastatic CRPC tumors. This study provides detailed expression profiles of membrane progesterone receptor genes in primary cancer, CRPC, and NEPC tissues. PAQR6 upregulation in primary cancer tissues is a novel prognostic biomarker for disease progression, overall, and progression-free survival in prostate cancers. PAQR8 expression in CRPC tissues is a biomarker for AR activation.

Alternol triggers immunogenic cell death via reactive oxygen species generation.

Alternol is a naturally occurring compound that exerts antitumor activity in several cancers. However, whether Alternol induces antitumor immune response remains unknown. In this study, we investigated whether Alternol induced immunogenic cell death (ICD) in prostate cancer cells. Alternol triggered ICD in prostate cancer cells, as evidenced by the release of damage-associated molecular patterns (DAMPs) (i.e., calreticulin, CALR; high mobility group protein B1, HMGB1; and adenosine triphosphate, ATP) and pro-inflammatory cytokine (i.e., interleukin [IL]-1α, IL-1ß, IL-6, and IL-8) expression. Alternol facilitated tumor-associated antigen uptake and cross-presentation, CD8 + T-cell priming, and T-cell infiltration in tumor-draining lymph nodes (LNs) and tumors. The presence of Alternol fostered antitumor immune response in vivo, resulting in delayed tumor growth and prolonged survival. Moreover, inhibition of reactive oxygen species (ROS) generation blocked Alternol-induced upregulation of pre-inflammation cytokines, endoplasmic reticulum (ER) stress, and consequent antitumor immune response. Overall, our data indicate that Alternol triggers ICD in prostate cancer cells, which is mediated by ROS generation.

Hepcidin Downregulation Correlates With Disease Aggressiveness And Immune Infiltration in Liver Cancers.

BACKGROUND: Hepcidin is a polypeptide hormone mainly produced by hepatocytes to modulate systemic iron balance. A drastic downregulation of the hepcidin gene was found in liver cancers. However, there is a paucity of information about the clinical significance of hepcidin gene downregulation in liver cancers. METHODS: Hepcidin expression profiles were assessed using multiple public datasets via several bioinformatics platforms. Clinical and pathological information was utilized to stratify patients for comparison. Patient survival outcomes were evaluated using the Kaplan-Meier plotter, a meta-analysis tool. Tumor immune infiltration was analyzed using the single sample gene set enrichment analysis (ssGSEA) approach on the Cancer Genome Atlas (TCGA) dataset. Hepcidin antagonist Fursultiamine was used to treat liver cancer HepG2 and Huh7 cells together with Sorafenib. RESULTS: Hepcidin gene was predominantly expressed in benign liver tissues but drastically decreased in liver cancer tissues. Hepcidin reduction in liver cancers correlated with risk factors like non-alcoholic fatty liver disease (NAFLD) and liver fibrosis, as well as cancer grade and tumor stage. Hepcidin downregulation was associated with a rapid cancer progression and worse disease-specific survival, especially in patients of the White race without alcohol consumption history. Hepcidin expression in liver cancer tissues positively correlated with the bone morphogenetic protein-6 (BPM6)/interleukin-6 (IL6) cytokines and cytotoxic immune infiltration. Blocking hepcidin action with its antagonist Fursultiamine moderately reduced Sorafenib-induced apoptotic cell death in HepG2 and Huh7 cells. CONCLUSION: Hepcidin downregulation in liver cancers correlated with liver cancer risk factors, cancer aggressiveness, cytotoxic immune cell infiltration, and patient survival outcomes. BMP6/IL6 pathway insufficiency is a potential cause of hepcidin downregulation in liver cancers.

The Orphan Nuclear Receptor Gene NR0B2 Is a Favorite Prognosis Factor Modulated by Multiple Cellular Signal Pathways in Human Liver Cancers.

BACKGROUND: Liver cancer is a leading cause of cancer death worldwide, and novel prognostic factor is needed for early detection and therapeutic responsiveness monitoring. The orphan nuclear receptor NR0B2 was reported to suppress liver cancer development in a mouse model, and its expression levels were reduced in liver cancer tissues and cell lines due to hypermethylation within its promoter region. However, it is not clear if NR0B2 expression is associated with cancer survival or disease progression and how NR0B2 gene expression is regulated at the molecular level. METHODS: Multiple cancer databases were utilized to explore NR0B2 gene expression profiles crossing a variety of human cancers, including liver cancers, on several publicly assessable bioinformatics platforms. NR0B2 gene expression with or without kinase inhibitor treatment was analyzed using the qPCR technique, and NR0B2 protein expression was assessed in western blot assays. Two human hepatocellular carcinoma cell lines HepG2 and Huh7, were used in these experiments. NR0B2 gene activation was evaluated using NR0B2 promoter-driven luciferase reporter assays. RESULTS: NR0B2 gene is predominantly expressed in liver tissue crossing human major organs or tissues, but it is significantly downregulated in liver cancers. NR0B2 expression is mostly downregulated in most common cancers but also upregulated in a few intestinal cancers. NR0B2 gene expression significantly correlated with patient overall survival status in multiple human malignancies, including lung, kidney, breast, urinary bladder, thyroid, colon, and head-neck cancers, as well as liposarcoma and B-cell lymphoma. In liver cancer patients, higher NR0B2 expression is associated with favorite relapse-free and progression-free survival, especially in Asian male patients with viral infection history. In addition, NR0B2 expression negatively correlated with immune infiltration and PIK3CA and PIK3CG gene expression in liver cancer tissues. In HepG2 and Huh7 cells, NR0B2 expression at the transcription level was drastically reduced after MAPK inhibition but was significantly enhanced after PI3K inhibition. CONCLUSION: NR0B2 gene expression is altered mainly in most human malignancies and significantly reduced in liver cancers. NR0B2 is a prognosis factor for patient survival in liver cancers. MAPK and PI3K oppositely modulate NR0B2 expression, and NR0B2 gene upregulation might serve as a therapeutic responsiveness factor in anti-PI3K therapy for liver cancer.

Antisolvent engineering on low-temperature processed CsPbI3 inorganic perovskites for improved performances of solar cells.

CsPbI3 inorganic perovskites with ideal bandgap and much enhanced thermal stability compared with organic-inorganic hybrid perovskites, have attracted much interest in the field of solar cells. The performances of solar cells highly depend on the quality of perovskite films, yet the research on fabrication methods of inorganic perovskites is far below that of organic-inorganic hybrid counterparts. Antisolvent engineering is a widely used method in controlling the morphology and crystallinity of organic-inorganic hybrid perovskites. Its effect varies with parameters such as the physicochemical properties of antisolvents and the compositions of perovskite precursors. Specially, there lacks a comprehensive study comparing different antisolvents used in low-temperature processed CsPbI3 from dimethylammonium-based precursors. In this work, we used three different antisolvents to control the growth of CsPbI3 films in a low-temperature (<200 °C) processed procedure and systematically compared the properties of resultant films. The green antisolvent ethyl acetate (EA) engineered CsPbI3 films exhibit improved morphology and crystallinity as well as reduced defects, compared with the counterparts processed without antisolvent or those with widely employed toxic antisolvents toluene and chlorobenzene. The EA antisolvent engineering results in efficient CsPbI3 perovskite solar cells with a champion power conversion efficiency of 8.8%. Our work thus provides a green and viable way to prepare high quality CsPbI3 perovskite films for optoelectronic applications.

PAQR5 Expression Is Suppressed by TGFß1 and Associated With a Poor Survival Outcome in Renal Clear Cell Carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) was sex-hormone responsive, and clinical trials using progesterone significantly reduced the incidence of distal metastasis after radical nephrectomy. Recently membrane-bound progesterone receptors (mPRs) were discovered to mediate the non-genomic effect of progesterone. Aberrant expressions of these mPRs were reported in human breast, ovarian, urinary bladder, brain, uterine, and prostate cancers. However, their expression profiles in RCC are yet to be assessed. METHODS: Multiple datasets from RNA sequencing (RNA-seq), cDNA microarray, and proteomic analysis were used to compare gene expression between cancerous and normal kidney tissues. Immunohistochemistry was conducted to examine protein expression in kidney tissues. Promoter methylation levels were assessed for correlation analysis with gene expression. RESULTS: Of the seven membrane-bound progesterone receptor genes, the progestin and adipoQ receptor-5 (PAQR5) gene is predominantly expressed in normal kidney tissue but was significantly downregulated in RCC tissues. PAQR5 downregulation correlated with tumor stage, cancer grade, lymph node invasion, and distal metastasis only in clear cell RCC (ccRCC) tissues. PAQR5 downregulation was associated with an increased promoter DNA methylation and a poor survival outcome in ccRCC patients. In addition, PAQR5 expression inversely correlated with transforming growth factor beta-1 (TGFB1) expression, and TGFß1 treatment significantly reduced PAQR5 gene expression. CONCLUSION: PAQR5 is a novel prognostic biomarker in ccRCC and is negatively regulated by the TGFß1 pathway.

Alternol/Alteronol: Potent Anti-cancer Compounds With Multiple Mechanistic Actions.

Alternol and its oxidate isomer Alteronol are small compounds isolated from the fermentation of a mutant fungus obtained from Taxus brevifolia bark. Preclinical studies showed their potent anti-cancer activities, including attenuating cellular survival pathways, altering protein levels of cell cycle regulators, activating xanthine dehydrogenase to cause accumulation of cellular reactive oxygen species and disrupting cell metabolism by disturbing four Krebs cycle enzymes specifically in malignant cells while having no significant effect on benign cells. In cancer cell culture models, Alternol or Alteronol exert their anti-cancer effect by inducing cell cycle arrest and triggering apoptotic cell death. In mice xenograft models, Alternol or Alteronol potently suppresses tumor growth with no obvious toxicity to the host with a wide therapeutic index over 30-fold. In conclusion, Alternol or Alteronol possess a great potential and feasibility to be developed as an effective anti-tumor therapeutic.

Natural compound Alternol as a novel therapeutic for prostate cancer treatment.

Alternol is a monomeric compound purified from the fermentation of a microbial strain obtained from the bark of the yew tree. Recent studies have confirmed that it has specific anti-prostate cancer efficacy in vitro and in vivo. In in vitro cell culture experiments Alternol inhibits prostate cancer cell proliferation by causing cell cycle arrest, reduces the expression of Bcl-2 and other pro-survival proteins, increases the level of radical oxygen species by activating xanthine dehydrogenase, blunts mitochondrial aerobic respiration and ATP production, and triggers autophagy flux. However, there is no significant adverse effect on benign prostatic cells. Animal experiments demonstrated that Alternol significantly inhibits the growth of prostate cancer xenografts without obvious adverse effect on normal tissues and organs. Therefore, Alternol is expected to be developed as a new anti-prostate cancer therapy.