Identification of tumor-antigen signatures and immune subtypes for messenger RNA vaccine selection in advanced clear cell renal cell carcinoma.

BACKGROUND: Advanced clear cell renal cell carcinoma still lacks reliable diagnostic and prognostic biomarkers. Recently, tumor vaccines targeting specific molecules have been proposed as a promising treatment in mitigating tumor progression, which was rekindled under the background of the COVID-19 pandemic. However, the application of messenger RNA vaccine against advanced clear cell renal cell carcinoma antigens remains stagnant, and no subgroup of patients deemed suitable for vaccination has been extensively studied or validated. Our study aims to explore novel advanced clear cell renal cell carcinoma antigen signatures to select suitable patients for vaccination. METHODS: Gene expression profiles of advanced clear cell renal cell carcinoma samples and their corresponding clinical data were retrieved from The Cancer Genome Atlas. The least absolute shrinkage and selection operator model was applied to develop signatures to stratify patients with advanced clear cell renal cell carcinoma. Receiver operating characteristic analysis was used to compare the prognostic accuracy of each factor. Tumor Immune Estimation Resource was used to visualize the relationship between the proportion of antigen-presenting cells and the expression of filtered genes. The "CIBERSORT" and "WGCNA" R Packages were employed to ascertain disparities in immune infiltration levels between advanced clear cell renal cell carcinoma subgroups. The Search Tools for the Retrieval of Interacting Genes database and Cytoscape were used to construct the protein-protein interaction network. CCK-8 and colony formation assays were included in the invitro experiment. RESULTS: In total, 244 potential tumor antigens were identified. Using the least absolute shrinkage and selection operator Cox regression, 21 tumor antigens were selected for developing a risk evaluation signature. The risk score signature can be a useful tool to predict the outcome of advanced clear cell renal cell carcinoma patients. According to the differential clinical, molecular, and immune-related genes, we divided advanced clear cell renal cell carcinoma patients into the immune "cold" subtype and immune "hot" subtype. By developing a logistic score, the immune subtype signature can better distinguish a patient more likely to be immune "cold" subtype or immune "hot" subtype. Interestingly, patients with high risk scores had a higher proportion of immune "hot" subtype than those with a low risk score. Furthermore, the prognostic value was significantly improved when combining risk score and immune subtype. Distinct immune landscapes and signal pathways were observed between different tumor subtypes. Finally, novel tumor antigens related to oxidative stress were identified. CONCLUSION: The tumor-antigens-based risk score and immune subtype signatures identified potentially effective neo-antigens for advanced clear cell renal cell carcinoma messenger RNA vaccine development, and patients with low risk scores and immune "cold" subtype tumors are more prone to benefit from messenger RNA vaccination. Furthermore, our study highlights the significant role of oxidative stress in determining the efficacy of the messenger RNA vaccine.

Identification of a cisplatin resistant-based prognostic immune related gene signature in MIBC.

Cisplatin resistance plays a significant role in the dismal prognosis and progression of muscle-invasive bladder cancer (MIBC). However, the strategies to predict prognosis and cisplatin resistance are inefficient, and it remains unclear whether cisplatin resistance is associated with tumor immunity. In this study, we integrated the transcriptional data from cisplatin-resistant cell lines and a TCGA-MIBC cohort to establish cisplatin-resistance-related cluster classification and a cisplatin-resistance-related gene risk score (CRRGRS). Kaplan-Meier survival curves showed that compared with those in low CRRGRS group, MIBC patients belonging to high CRRGRS group had worse prognosis in TCGA-MIBC cohort and external GEO cohorts. Meanwhile, CRRGRS was able to help forecast chemotherapy and immunotherapy response of MIBC patients in the TGCA cohort and IMvigor210 cohort. Moreover, compared with the low CRRGRS group, the high CRRGS group possessed a relatively immunosuppressive "cold tumor" phenotype with a higher tumor immune dysfunction and exclusion (TIDE) score, ESTIMATE score, stromal score and immune score and a lower immunophenoscore (IPS) score. The upregulated expression levels of immune checkpoint genes, including PD-1, PD-L1 and CTLA4, in the high CRRGRS group also further indicated that a relative immunosuppressive tumor microenvironment may exist in MIBC patients belonging to high CRRGRS group. In addition, we integrated CRRGRS and clinical characteristics with prognostic value to develop a nomogram, which could help forecast overall survival of MIBC patients. Furthermore, DIAPH3 was identified as a regulator of proliferation and cisplatin resistance in MIBC. The expression of DIAPH3 was increased in cisplatin-resistant cell lines and chemotherapy-unsensitive people. Further mechanism exploration revealed that DIAPH3 facilitated tumor proliferation and cisplatin resistance by regulating the NF-kB and epithelial-mesenchymal transition (EMT) pathways. In conclusion, the comprehensive investigations of CRRGRS increased the understanding of cisplatin resistance and provided promising insights to restrain tumor growth and overcome chemoresistance by targeting DIAPH3.

A novel DNA methylation signature revealed GDF6 and RCC1 as potential prognostic biomarkers correlated with cell proliferation in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) accounts for the majority (80%-90%) of renal cell carcinoma (RCC) patients at the time of diagnosis, and approximately 15% of ccRCC patients will develop distant metastasis or recurrence during their lifetime. Increasing number of studies have revealed that the aberrant DNA methylations is closely correlated with the tumorigenesis in ccRCC. RESULTS: In this study, we utilized a LASSO (least absolute shrinkage and selection operator) model to identify a combination of 13 probes-based DNA methylation signature that associated with the progression-free survival (PFS) of ccRCC patients. First, differentially methylated regions (CpGs) related to PFS and phenotypes were identified. Next, prognostic DNA methylation probes were selected from the differentially methylated probes (DMPs) and calculated risk scores to stratify patients with ccRCC. The performance of this signature was validated in an independent testing set using various analyses, including Kaplan-Meier analysis for PFS and receiver operating characteristic (ROC) curve analysis. Based on our 13-DNA methylation probes signature, ccRCC patients were successfully stratified into high- and low-risk groups. Combining DNA methylation signature with clinical variables such as T stage, M stage and tumor grade could further improve the accuracy of prediction. Moreover, we highlight two molecular biomarkers (RCC1 and GDF6) corresponding to our probes. Invitro experiments showed that knockdown of RCC1 or GDF6 in ccRCC cell lines reduced cell proliferation, which indicated that both biomarkers are associated with tumorigenesis. CONCLUSIONS: The 13-probes-based DNA methylation signature has the potential to serve as an independent tool for survival outcome improvement and treatment strategy selection for ccRCC patients. In addition, our findings suggest that RCC1 and GDF6 may serve as promising markers for ccRCC.

Anti-proliferative effect of Cannabidiol in Prostate cancer cell PC3 is mediated by apoptotic cell death, NFκB activation, increased oxidative stress, and lower reduced glutathione status.

Prostate cancer is the second most frequent cancer diagnosed in men in the world today. Almost all prostate cancers are adenocarcinomas and develop from gland cells. We used the PC3 prostate cancer cell line, which is well studied and derived from a bone metastasis of a grade IV prostatic adenocarcinoma. Cannabidiol (CBD), a major non-psychoactive constituent of cannabis, is a cannabinoid with anti-tumor properties but its effects on prostate cancer cells are not studied in detail. Here, we found cannabidiol decreased prostate cancer cell (PC3) viability up to 37.25% and induced apoptotic cell death in a time and dose-dependent manner. We found that CBD activated the caspases 3/7 pathways and increased DNA fragmentation. Furthermore, we observed an increase of pro-apoptotic genes Bax, an increased level of reactive oxygen species, lower reduced glutathione level, and altered mitochondrial potential in response to CBD treatment leading to lower cellular ATP. Overall, our results suggest that CBD may be effective against prostate cancer cells.

RCC1 functions as a tumor facilitator in clear cell renal cell carcinoma by dysregulating cell cycle, apoptosis, and EZH2 stability.

BACKGROUND: RCC1 functions as a pivotal guanine nucleotide exchange factor and was reported to be involved in mitosis, the assembly of the nuclear envelope, nucleocytoplasmic transport in cell physiological processes. Recent studies reported that RCC1 could regulate immunological pathways and promote the growth of some malignant solid tumors. However, the prognostic value and exact function of RCC1 remain unknown in patients with clear cell renal cell carcinoma (cRCC). METHODS: The UALCAN and KM plotter portals were used to analyze the expression profile and related tumor prognosis of RCC1 in ccRCC using data from TCGA. The expression profile of RCC1 was also confirmed in clinical samples using qRT-PCR, western blotting, and immunohistochemistry. The role of RCC1 on ccRCC cells in vitro was confirmed by a series of functional assays. Animal experiments were performed to verify the suppressive effect of RCC1 knockdown on tumor growth in vivo. The correlation of RCC1 expression with that of EZH2 was explored in clinical samples using IHC. The interaction between RCC1 and EZH2 was further verified using a CO-IP assay and a protein stability assay. RESULTS: RCC1 was upregulated in ccRCC tissues compared with normal tissues in TCGA dataset and paired clinical samples. RCC1 promoted ccRCC progression by accelerating the cell cycle and suppressing apoptosis. In addition, RCC1 could bind EZH2 and regulate its expression at the posttranscriptional level. RCC1 and EZH2 expression showed a strong correlation in clinical samples. Further investigation proved that RCC1 regulated EZH2 protein stability through the ubiquitin-proteasome pathway. CONCLUSIONS: RCC1 could be a potential therapeutic target in ccRCC. The RCC1/EZH2 axis takes part in the development of ccRCC.

Developing and validating utility parameters to establish patient-reported outcome-based perioperative symptom management in patients undergoing prostatectomy: a multicentre, prospective, observational cohort study protocol.

INTRODUCTION: Symptom monitoring and alerting based on patient-reported outcomes have proven valuable in a postoperative setting. However, the parameters of the implemented patient-centred symptom management system for patients with prostate cancer (PC) remain unclear. This study aims to develop a perioperative symptom scale (PSS) to monitor symptoms, determine the appropriate timing for symptom assessment and establish intervention criteria for physicians. METHODS AND ANALYSIS: We will prospectively recruit 387 patients undergoing PC surgery in 3 hospitals. The Chinese version of the MD Anderson Symptom Inventory (MDASI) will be used for longitudinal symptom data collection, presurgery and 1, 2, 3, 5, 7, 14, 21, 28, 42 and 90 days post surgery. A PSS will be generated when symptoms change significantly over time. A linear mixed model will be used to determine appropriate follow-up time points. The functional status determined by MDASI interference can then be used to establish alarm thresholds. ETHICS AND DISSEMINATION: This study was approved by the Lishui Municipal Central Hospital Ethics Committee on 13 April 2022 (No. LSMCHEC-2022-54) and the Ethics Committee of Huzhou Central Hospital on 5 July 2023 (No. HZCHEC-202306017-01), the Ethics Committee of the First Affiliated Hospital of Huzhou Normal College on 20 June 2023 (No. HZYYEC-2023KYLL055). The latest protocol used in this study was V.2.0, dated on 25 February 2023. Before publication in a peer-reviewed journal, our findings will be presented and discussed at relevant medical conferences. TRIAL REGISTRATION NUMBER: ChiCTR2200059110.

SAA1 Has Potential as a Prognostic Biomarker Correlated with Cell Proliferation, Migration, and an Indicator for Immune Infiltration of Tumor Microenvironment in Clear Cell Renal Cell Carcinoma.

The tumor microenvironment (TME) plays an important part in the initiation and development of clear cell renal cell carcinoma (ccRCC). However, an understanding of the immune infiltration in TME is still unknown. Our study aims to explore the correlation between the TME and the clinical features, as well as the prognosis of ccRCC. In the present study, ESTIMATE and CIBERSORT computational methods were applied to calculate the proportion of tumor-infiltrating immune cells (TICs) and the amount of immune and stromal fractions in the ccRCC form The Cancer Genome Atlas (TCGA) database. Then, we sought to find out those immune cell types and genes which may play a significant role and validated them in the GEO database. Furthermore, an immunohistochemical analysis of our external validation dataset was used to detect SAA1 and PDL1 expression in the ccRCC cancer tissues and corresponding normal tissues. Statistical analysis was performed to study the relationship between SAA1 and clinical characteristics, as well as PDL1 expression. Furthermore, a ccRCC cell model with SAA1 knockdown was constructed, which was used for cell proliferation and the migration test. The intersection analysis of the univariate COX and PPI analysis were performed to imply Serum Amyloid A1 (SAA1) as a predictive factor. The expression of SAA1 was significantly negatively correlated to OS and positively correlated to the clinical TMN stage system. The genes in the high-expression SAA1 group were basically enriched in immune-related activities. The proportion of mast cells resting was negatively correlated with SAA1 expression, indicating that SAA1 may be involved in the maintenance of the immune status for the TME. Moreover, the PDL1 expression was positively related to the SAA1 expression and negatively correlated with the patients' prognosis. Further experiments revealed that the knockdown of SAA1 inhibited ccRCC development through suppressing cell proliferation and migration. SAA1 may be a novel marker for the prognosis prediction of ccRCC patients and may play a vital role in the TME by mast cell resting and PDL1 expression. SAA1 has the potential to become a therapeutic target and indicator for immune target therapy in ccRCC treatment.

Bioinformatics Prediction and Experimental Verification Identify CAB39L as a Diagnostic and Prognostic Biomarker of Kidney Renal Clear Cell Carcinoma.

Background and Objectives: Calcium-binding protein 39-like (CAB39L) has been reported to be downregulated and possessed diagnostic and prognostic values in several types of cancer. However, the clinical value and mechanism of CAB39L in kidney renal clear cell carcinoma (KIRC) remain unclear. Materials and Methods: Bioinformatics analysis was conducted using different databases including TCGA, UALCAN, GEPIA, LinkedOmics, STRING, and TIMER. One-way variance analysis and t-test were chosen to investigate the statistical differences of CAB39L expression in KIRC tissues with different clinical characteristics. The receiver operating characteristic (ROC) curve was chosen to assess the discriminatory capacity of CAB39L. Kaplan-Meier curves were employed for assessing the influence of CAB39L on the progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) of KIRC patients. The independent prognostic significance of clinical parameters for OS such as CAB39L expression in KIRC patients was estimated by Cox analysis. A series of in vitro functional experiments and Western blot (WB) and immunohistochemistry (IHC) were used to validate the relative protein expression and function of CAB39L. Results: The mRNA and protein levels of CAB39L were relatively downregulated in KIRC samples. Meanwhile, hypermethylation of the CAB39L promoter region was possibly associated with its low expression in KIRC. The ROC curve showed that the mRNA expression of CAB39L had a strong diagnostic value for both early and late KIRC. Kaplan-Meier survival curves indicated that a higher mRNA level of CAB39L predicted good PFS, DSS, and OS. The mRNA expression of CAB39L was an independent prognostic factor (hazard ratio = 0.6, p = 0.034) identified by multivariate Cox regression analysis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis exhibited that CAB39L was mainly associated with substance and energy metabolism. Finally, overexpression of CAB39L impaired the proliferation and metastasis of KIRC cells in vitro. Conclusions: CAB39L possesses prognostic and diagnostic capacity in KIRC.

POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma.

DNA polymerase delta 1 catalytic subunit (POLD1) plays a vital role in genomic copy with high fidelity and DNA damage repair processes. However, the prognostic value of POLD1 and its relationship with tumor immunity in clear cell renal cell carcinoma (ccRCC) remains to be further explored. Transcriptional data sets and clinical information were obtained from the TCGA, ICGC, and GEO databases. Differentially expressed genes (DEGs) were derived from the comparison between the low and high POLD1 expression groups in the TCGA-KIRC cohort. KEGG and gene ontology (GO) analyses were performed for those DEGs to explore the potential influence of POLD1 on the biological behaviors of ccRCC. The prognostic clinical value and mutational characteristics of patients were described and analyzed according to the POLD1 expression levels. TIMER and TISIDB databases were utilized to comprehensively investigate the potential relevance between the POLD1 levels and the status of the immune cells, as well as the tumor infiltration of immune cells. In addition, RT-qPCR, Western blot, immunohistochemistry and several functional and animal experiments were performed for clinical, in vitro and in vivo validation. POLD1 was highly expressed in a variety of tumors including ccRCC, and further verified in a validation cohort of 60 ccRCC samples and in vitro cell line experiments. POLD1 expression levels in the ccRCC samples were associated with various clinical characteristics including pathologic tumor stage and histologic grade. ccRCC patients with high POLD1 expression have poor clinical outcomes and exhibit a higher rate of somatic mutations than those with low POLD1 expression. Cox regression analysis also showed that POLD1 could act as a potential independent prognostic biomarker. The DEGs associated with POLD1 were significantly enriched in the immunity-related pathways. Moreover, further immune infiltration analysis indicated that high POLD1 expression was associated with high NK CD56bright cells, Treg cells, and myeloid-derived suppressor cells' (MDSCs) infiltration scores, as well as their marker gene sets of immune cell status. Meanwhile, POLD1 exhibited resistance to various drugs when highly expressed. Finally, the knockdown of POLD1 inhibited the proliferation and migration, and promoted the apoptosis of ccRCC cells in vitro and in vivo, as well as influenced the activation of oncogenic signaling. Our current study demonstrated that POLD1 is a potential prognostic biomarker for ccRCC patients. It might create a tumor immunosuppressive microenvironment and inhibit the susceptibility to ferroptosis leading to a poor prognosis.

LINC00941 Promotes Cell Malignant Behavior and Is One of Five Costimulatory Molecule-Related lncRNAs That Predict Prognosis in Renal Clear Cell Carcinoma.

Background and Objectives: A significant role was played by costimulatory molecules in renal cancer. However, the lncRNAs regulating costimulatory molecules have not been fully investigated. Materials and Methods: Data from the next-sequence file and clinical data were downloaded from the Cancer Genome Atlas (TCGA) database. All analyses were conducted using the R and GraphPad Prism software. Results: A total of 1736 costimulatory molecule-related lncRNAs were determined under the threshold of |Cor| > 0.5 and p-value < 0.001. Furthermore, a prognosis prediction signature consisting of five lncRNAs: LINC00941, AC016773.1, AL162171.1, HOTAIRM1, and AL109741.1 was established with great prediction ability. By combining risk score and clinical parameters, a nomogram plot was constructed for better clinical practice. A biological enrichment analysis indicated that E2F targets, coagulation, IL6/JAK/STAT3 signaling, G2/M checkpoint, and allograft rejection pathways were activated in high-risk patients. Furthermore, a higher infiltration level of resting CD4+ T cell, M2 macrophage, and resting mast cells, while a lower CD8+ T cell infiltration was observed in high-risk patients. It is worthy of note that, low-risk patients might respond better to PD-1 checkpoint therapy. A correlation analysis of LINC00941 revealed that it was positively correlated with Th2 cells, Th1 cells, macrophages, and Treg cells, but negatively correlated with Th17 cells. A pathway enrichment analysis indicated that the pathways of the inflammatory response, G2M checkpoint, and IL6/JAK/STAT3 signaling were significantly activated in patients with high LINC00941 expression. In vitro experiments indicated that LINC00941 can enhance the malignant biological behaviors of renal cancer cells. Conclusions: Our study established a costimulatory molecule-related lncRNAs-based prognosis model with a great prediction prognosis. In addition, LINC00941 could enhance the malignant biological behaviors of renal cancer cells.

Management of Primary Female Urethral Adenocarcinoma: Two Rare Case Reports and Literature Review.

Primary urethral adenocarcinoma in females is an extremely rare malignancy with unclear origin and only a few retrospective cases have been reported. The controversy continues to exist over the origin of primary urethral adenocarcinoma from periurethral glands (which include the Skene's glands), urethritis glandularis or intestinal metaplasia. Herein, we report one case of a 49-year-old female with distal urethral adenocarcinoma who presented with obstructive voiding. Abdominal and pelvic CT scans and chest radiology were unremarkable. Biopsy of the mass confirmed urethral adenocarcinoma. The patient underwent partial ureterectomy and was disease-free at the 2-years follow-up period. We also present another extremely rare case of primary urethral adenocarcinoma with mucinous features in a 58-year-old female who initially complained of external urethral orifice itching with painless urethral bleeding and was treated with local excision. The patient has not received any neoadjuvant or adjuvant therapy, and experienced tumor recurrence, inguinal lymph nodes metastasis, and even local iliopsoas metastasis during over 10-years follow-up. In conclusion, our current study emphasizes the importance of imaging studies and biopsy in making an accurate preoperative diagnosis of this rare disease, and further highlights the role of multimodal therapy. A combination of radiotherapy, chemotherapy and surgery is recommended for the optimal local and distant disease control. Moreover, better medical compliance and regular follow-up are required in these patients.

[The trends in early precision diagnosis and treatment strategies of multiple endocrine neoplasia type 2].

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma, hyperparathyroidism and extra-endocrine features, and two forms subtyped as MEN2A and MEN2B. Based on the correlation between RET proto-oncogene mutation and MEN2 phenotype, MEN2 could be prevented through prenatal diagnosis and preimplantation genetic testing. Integrating the detection of RET mutation with measurement of serum calcitonin, plasma or urinary metanephrine/normetanephrine, and serum parathyroid hormone levels could accurately predict the progression of MEN2, and then facilitating implementation of personalized precision treatment. In addition, increased awareness of MEN2 is needed, which requires participation of physicians, patients/family members, and relevant organizations, supplemented by psychological support, which could promote the comprehensive management of MEN2. The "5P" strategies for MEN2 represents a paradigm of precision medicine, which could effectively avoid or reduce the clinical adverse outcomes, improve the prognosis and quality of life of MEN2 patients.

Activation of cGAS-STING Signal to Inhibit the Proliferation of Bladder Cancer: The Immune Effect of Cisplatin.

Cisplatin is commonly used in neoadjuvant, adjuvant, and systemic therapy for advanced bladder cancer, but its immune-related mechanism is still unclear. Exploration of the immune effects of cisplatin in bladder cancer would complement the comprehensive mechanism of cisplatin and provide the basis for combination therapy of cisplatin and immunotherapy in bladder cancer. We confirmed the immune effects of cisplatin on T24 and TCCSUP bladder cancer cell lines in vitro and explored the important function of these immune effects in the bladder cancer microenvironment in a mice tumor model. We found cisplatin induced immune response in bladder cancer by RNA sequencing and validated that cGAS-STING signal was deeply involved in this response. Cisplatin induced cGAS-STING signal inhibited the proliferation of bladder cancer and increased the infiltration percentages of CD8+ T cells and dendritic cells in a transplantation mice tumor model. Accumulation of dsDNA and the release of chromatin bound cGAS are important to activate downstream STING. Our findings indicated a cisplatin-related immune effect in bladder cancer, and cisplatin combined with immunotherapy might have a synergistic effect for bladder cancer therapy.

A Case Report of Adrenal Teratoma: Huge but Easy to Misdiagnose.

Primary adrenal teratoma is a rare lesion with a high misdiagnosis rate. In view of the fact that adrenal teratoma and adrenal gland are often inseparable, the removal of the affected adrenal gland seems inevitable. Thus, it is necessary for clinicians to differentiate adrenal teratoma from common adrenal lipoma diseases, such as adrenal angiomyolipoma, adrenal myelolipoma, lipoma, gangliocytoma, and so on. In this study, we reported the clinical and pathologic features of 7 patients surgically treated for adrenal mature teratomas from 2007 to 2020 in our hospital. We compared the clinical characteristics and surgical management in literature review cases with our cases. All patients were females and underwent open adrenalectomy or laparoscopic adrenalectomy, respectively. In our cases, there was no recurrence during the longest follow-up of 13 years. Adrenal teratoma is rare and easy to ignore. And once misdiagnosed, the surgeon may need to adjust the operation temporarily, extend the operation time and finally increase the operative risks. Our aim is mainly to help clinicians to raise awareness of adrenal teratomas, improve the diagnosis rates and optimize the treatment decision-making of this disease.

A narrative review of the role of glucocorticoid receptors in prostate cancer: developments in last 5 years.

Background and Objective: Glucocorticoids, secreted from the adrenal gland, are commonly used in the treatment of castration-resistant prostate cancer (CRPC) because of their anti-inflammatory and anti-toxic effects. However, glucocorticoids have been reported to have the opposite effects within the course of treatment. Many studies have shown that glucocorticoid receptors (GRs) are involved in the establishment of a dominant population of androgen-independent malignant cells, which may result in CRPC. In this review, we summarized the mechanisms of GRs in CRPC and the clinical application of glucocorticoids based on the present evidence. Methods: We summarized the isoforms of GRs and the mechanisms involved in CRPC. An updated literature search was performed from the ClinicalTrials database, the National Center for Biotechnology Information database and European Union Drug Regulating Authorities Clinical Trials database. The focus was on the timeframe from 2017 to 2022. At least one primary or secondary outcome [prostate-specific antigen (PSA) response rate, progression-free survival (PFS) or overall survival (OS) and median time to PSA progression] according to studies should be included. Key Content and Findings: The molecular structures and applications of the isoforms of GR have been intensively researched in the past 60 years. In recent years, researchers have pointed out that GRs may be involved in the development of CRPC via genomic and non-genomic effects. Clinical trials in the past 5 years have focused on the efficacy of drugs regarding CRPC. The use of glucocorticoids during treatments of CRPC follows the guidelines (e.g., NCCN Guidelines®, guidelines of CSCO, etc.). Based on the collected data, prednisone appears to be the most widely used steroid hormone, followed by dexamethasone. Comparisons of the PSA response rate and the median time to PSA progression revealed that the efficacy of the 2 hormones is similar; however, further research on the effect of steroid hormone in CRPC is still required. Conclusions: Various GR isoforms may play an important part in the development of CRPC, whose mechanism remains unclear. Most clinical trials have focused on the use of prednisone in the last 5 years. The efficacy of prednisone and dexamethasone is similar.

Identification of Biomarkers Related to M2 Macrophage Infiltration in Alzheimer's Disease.

Many studies have demonstrated that neuroinflammation contributes to the onset and development of Alzheimer's disease (AD). The infiltration of immune cells in the brain was observed in AD. The purpose of the present study was to verify potential mechanisms and screen out biomarkers related to immune infiltration in AD. We collected the expression profiling datasets of AD patients and healthy donors from the NCBI's Gene Expression Omnibus (GEO) database. We confirmed that immune-related mechanisms were involved in AD using differentially expressed genes analysis and functional enrichment analysis. We then found that M2 macrophage infiltration was most positively correlated with AD according to the CIBERSORT algorithm and a weighted gene co-expression network analysis (WGCNA). TLR2, FCGR2A, ITGB2, NCKAP1L and CYBA were identified as hub genes correlated with M2 macrophage infiltration in AD. Furthermore, the expression levels of these hub genes were positively correlated with Aß42 and ß-secretase activity. A diagnostic model of these hub genes was constructed, which showed a high area under the curve (AUC) value in both the derivation and validation cohorts. Overall, our work further expanded our understanding of the immunological mechanisms of AD and provided new insights into therapeutic strategies in AD.

Penile metastasis from rectal carcinoma: A case report.

BACKGROUND: Metastasis to the penis is an unusual event, and penile metastasis from rectal carcinoma (PMRC) is extremely rare and associated with a dismal prognosis. Thus far, approximately 80 cases have been reported. CASE SUMMARY: Herein, we report the case of a 49-year-old man with PMRC. The patient presented to the urology clinic with a complaint of penile pain during urination. The patient underwent the Dixon operation for rectal carcinoma 2 mo before the presentation. During hospitalisation, abdominal computed tomography revealed a nodular lesion on the left penis. The postoperative pathological examination revealed a typical intestinal-type adenocarcinoma. Previous cases of PMRC were retrieved from PubMed to characterise the clinicopathological features and identify the prognostic factors of PMRC. CONCLUSION: The analysis suggested that approximately 24 mo is the median time to metastasis occurrence and 150 d is the survival time after diagnosis. Furthermore, poor pathological differentiation, lymph node involvement of the primary RC, metastasis time < 6 mo, penile metastatic nodule diameter > 1 cm, and treatment abandonment are negative predictors of survival outcomes. Close follow-up, surgical resection, chemotherapy, and radiotherapy may potentially improve the prognosis of patients.

Single Cell Mass Spectrometry With a Robotic Micromanipulation System for Cell Metabolite Analysis.

OBJECTIVE: The increasing demand for unraveling cellular heterogeneity has boosted single cell metabolomics studies. However, current analytical methods are usually labor-intensive and hampered by lack of accuracy and efficiency. METHODS: we developed a first-ever automated single cell mass spectrometry system (named SCMS) that facilitated the metabolic profiling of single cells. In particular, extremely small droplets of sub nano-liter were generated to extract the single cells, and the underlying mechanism was verified theoretically and experimentally. This was crucial to minimize the dilution of the trace cellular contents and enhance the analytical sensitivity. Based on the precise 3D positioning of the pipette tip, we established a visual servoing robotic micromanipulation platform on which single cells were sequentially extracted, aspirated, and ionized, followed by the mass spectrometry analyses. RESULTS: With the SCMS system, inter-operator variability was eliminated and working efficiency was improved. The performance of the SCMS system was validated by the experiments on bladder cancer cells. MS and MS2 analyses of single cells enable us to identify several cellular metabolites and the underlying inter-cell heterogeneity. CONCLUSION: In contrast to traditional methods, the SCMS system functions without human intervention and realizes a robust single cell metabolic analysis. SIGNIFICANCE: the SCMS system upgrades the way how single cell metabolites were analyzed, and has the potential to be a powerful tool for single cell metabolomics studies.

Microfluidic Assaying of Circulating Tumor Cells and Its Application in Risk Stratification of Urothelial Bladder Cancer.

Bladder cancer is characterized by its frequent recurrence and progression. Effective treatment strategies need to be based on an accurate risk stratification, in which muscle invasiveness and tumor grade represent the two most important factors. Traditional imaging techniques provide preliminary information about muscle invasiveness but are lacking in terms of accuracy. Although as the gold standard, pathological biopsy is only available after the surgery and cannot be performed longitudinally for long-term surveillance. In this work, we developed a microfluidic approach that interrogates circulating tumor cells (CTCs) in the peripheral blood of bladder cancer patients to reflect the risk stratification of the disease. In a cohort of 48 bladder cancer patients comprising 33 non-muscle invasive bladder cancer (NMIBC) cases and 15 muscle invasive bladder cancer (MIBC) cases, the CTC count was found to be considerably higher in the MIBC group compared with the NMIBC group (4.67 vs. 1.88 CTCs/3 mL, P=0.019), and was significantly higher in high-grade bladder cancer patients verses low-grade bladder cancer patients (3.69 vs. 1.18 CTCs/3mL, P=0.024). This microfluidic assay of CTCs is believed to be a promising complementary tool for the risk stratification of bladder cancer.

A rare case report of femoral neck metastasis secondary from penile carcinoma and literature review.

Metastatic bone diseases are common in the advanced stage of numerous cancers, but rarely reported to be secondary from penile cancer. To date, there are only 9 cases of skeletal metastasis from penile cancer reported in literature worldwide. Herein, we report a rare case of the femoral neck metastasis secondary from penile carcinoma in a 35-year-old Chinese male. Based on the case study and more importantly, the literature review, we attempted to identify the clinical features of the metastatic bone diseases secondary from penile cancer.