Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal‐like subtype of breast cancer that is driven by the NAD+ metabolic enzyme nicotinamide N‐methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre‐clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methylation at the promoters of PR/SET Domain‐5 (PRDM5) and extracellular matrix‐related genes. PRDM5 emerged in this study as a pro‐metastatic gene acting via induction of cancer‐cell intrinsic transcription of collagens. Depletion of PRDM5 in tumor cells decreases COL1A1 deposition and impairs metastatic colonization of the lungs. These findings reveal a critical activity of the NNMT‐PRDM5‐COL1A1 axis for cancer cell plasticity and metastasis in basal‐like breast cancer.

Nicotinamide N‐methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer

In general, cancer is one of the most frequent causes of death [...].

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New Strategies in Diagnosis and Treatments for Brain Tumors

Objective Mitochondrial dysfunction and oxidative stress are known to involved in tumor occurrence and progression. This study aimed to explore the molecular subtypes of lower-grade gliomas (LGGs) based on oxidative stress-related and mitochondrial-related genes (OMRGs) and construct a prognostic model for predicting prognosis and therapeutic response in LGG patients. Methods A total of 223 OMRGs were identified by the overlap of oxidative stress-related genes (ORGs) and mitochondrial-related genes (MRGs). Using consensus clustering analysis, we identified molecular subtypes of LGG samples from TCGA database and confirmed the differentially expressed genes (DEGs) between clusters. We constructed a risk score model using LASSO regression and analyzed the immune-related profiles and drug sensitivity of different risk groups. The prognostic role of the risk score was confirmed using Cox regression and Kaplan-Meier curves, and a nomogram model was constructed to predict OS rates. We validated the prognostic role of OMRG-related risk score in three external datasets. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) staining confirmed the expression of selected genes. Furthermore, wound healing and transwell assays were performed to confirm the gene function in glioma. Results We identified two OMRG-related clusters and cluster 1 was significantly associated with poor outcomes (P<0.001). The mutant frequencies of IDH were significantly lower in cluster 1 (P<0.05). We found that the OMRG-related risk scores were significantly correlated to the levels of immune infiltration and immune checkpoint expression. High-risk samples were more sensitive to most chemotherapeutic agents. We identified the prognostic role of OMRG-related risk score in LGG patients (HR=2.665, 95%CI=1.626-4.369, P<0.001) and observed that patients with high-risk scores were significantly associated with poor prognosis (P<0.001). We validated our findings in three external datasets. The results of qRT-PCR and IHC staining verified the expression levels of the selected genes. The functional experiments showed a significant decrease in the migration of glioma after knockdown of SCNN1B. Conclusion We identified two molecular subtypes and constructed a prognostic model, which provided a novel insight into the potential biological function and prognostic significance of mitochondrial dysfunction and oxidative stress in LGG. Our study might help in the development of more precise treatments for gliomas.

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Identification of heterogeneous subtypes and a prognostic model for gliomas based on mitochondrial dysfunction and oxidative stress-related genes

Super-enhancers (SEs), driving high-level expression of genes with tumor-promoting functions, have been investigated recently. However, the roles of super-enhancer-associated lncRNAs (SE-lncRNAs) in tumors remain undetermined, especially in gliomas. We here established a SE-lncRNAs expression-based prognostic signature to choose the effective treatment of glioma and identify a novel therapeutic target.Combined analysis of RNA sequencing (RNA-seq) data and ChIP sequencing (ChIP-seq) data of glioma patient-derived glioma stem cells (GSCs) screened SE-lncRNAs. Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets served to construct and validate SE-lncRNA prognostic signature. The immune profiles and potential immuno- and chemotherapies response prediction value of the signature were also explored. Moreover, we verified the epigenetic activation mechanism of LINC00945 via the ChIP assay, and its effect on glioma was determined by performing the functional assay and a mouse xenograft model.6 SE-lncRNAs were obtained and identified three subgroups of glioma patients with different prognostic and clinical features. A risk signature was further constructed and demonstrated to be an independent prognostic factor. The high-risk group exhibited an immunosuppressive microenvironment and was higher enrichment of M2 macrophage, regulatory T cells (Tregs), and Cancer-associated fibroblasts (CAFs). Patients in the high-risk group were better candidates for immunotherapy and chemotherapeutics. The SE of LINC00945 was further verified via ChIP assay. Mechanistically, BRD4 may mediate epigenetic activation of LINC00945. Additionally, overexpression of LINC00945 promoted glioma cell proliferation, EMT, migration, and invasion in vitro and xenograft tumor formation in vivo.Our study constructed the first prognostic SE-lncRNA signature with the ability to optimize the choice of patients receiving immuno- and chemotherapies and provided a potential therapeutic target for glioma. 

https://humgenomics.biomedcentral.com/counter/pdf/10.1186/s40246-023-00480-w

Integrative analysis of a novel super-enhancer-associated lncRNA prognostic signature and identifying LINC00945 in aggravating glioma progression

Simple Summary The aim of the present review is to discuss novel prognostic and therapeutic markers for clear cell renal cell carcinoma, a subtype of renal cell carcinoma which is the most common variant and is characterized by high aggressiveness, invasiveness and metastatic potential, features that are responsible for the high mortality rate observed for this neoplasm. We firstly provide a background regarding the epidemiology and risk factors, and then, we focus on the established prognostic markers as well as novel ones. Subsequently, we analyze the recent advances in clear cell renal cell carcinoma treatment, and we discuss potential novel biomarkers for targeted therapy. Abstract Renal cell carcinoma (RCC) belongs to a heterogenous cancer group arising from renal tubular epithelial cells. Among RCC subtypes, clear cell renal cell carcinoma (ccRCC) is the most common variant, characterized by high aggressiveness, invasiveness and metastatic potential, features that lead to poor prognosis and high mortality rate. In addition, diagnosis of kidney cancer is incidental in the majority of cases, and this results in a late diagnosis, when the stage of the disease is advanced and the tumor has already metastasized. Furthermore, ccRCC treatment is complicated by its strong resistance to chemo- and radiotherapy. Therefore, there is active ongoing research focused on identifying novel biomarkers which could be useful for assessing a better prognosis, as well as new molecules which could be used for targeted therapy. In this light, several novel targeted therapies have been shown to be effective in prolonging the overall survival of ccRCC patients. Thus, the aim of this review is to analyze the actual state-of-the-art on ccRCC diagnosis, prognosis and therapeutic options, while also reporting the recent advances in novel biomarker discoveries, which could be exploited for a better prognosis or for targeted therapy.

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Recent Advances in the Management of Clear Cell Renal Cell Carcinoma: Novel Biomarkers and Targeted Therapies

Simple Summary Glioma is one of the most common intracranial malignancies and is incurable due to strong aggressiveness and resistance to radiotherapy and chemotherapy. The lack of effective therapeutic targets is a major problem in current treatment. In the present study, we found that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the occurrence and development of glioma. High NNMT expression in glioma is a predictor of short overall survival and poor patient outcome. NNMT knockdown reduced the volume of mice xenograft glioma and the viability of glioma cells. Additionally, overexpression of NNMT epigenetically silenced GAP43 through DNA methylation, histone methylation, and deacetylation modification processes. GAP43 can inhibit the formation of microtubules in tumor and intertumor cell network connections and induce apoptosis through the SIRT1 signaling pathway. Therefore, NNMT could be a potential candidate for the clinical diagnosis and treatment of glioma. Abstract Purpose: Increasing evidence has revealed that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the prognosis of tumors. The present study aimed to investigate the role of NNMT in glioma and to elucidate the associated functional mechanisms. Methods: Clinical samples were analyzed by immunohistochemical staining and Western blotting to evaluate NNMT expression in glioma and normal brain tissues. The correlation between NNMT expression and glioma was analyzed using the Cancer Genome Atlas (TCGA) database. Additionally, NNMT was knocked down in two types of glioma cells, U87 and U251, to evaluate the invasive ability of these cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate NNMT knockdown in the cells. Furthermore, ELISA was used to determine the balance between nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide hydrogen (NAD/NADH ratio), which verified the altered methylation patterns in the cells. The glioma xenograft mouse models were used to verify the regulatory role of NNMT, GAP43, and SIRT1. Results: Analysis based on our clinical glioma samples and TCGA database revealed that overexpression of NNMT was associated with poor prognosis of patients. Knockdown of NNMT reduced the invasive ability of glioma cells, and downregulation of its downstream protein GAP43 occurred due to altered cellular methylation caused by NNMT overexpression. Gene Set Enrichment Analysis confirmed that NNMT modulated the NAD-related signaling pathway and showed a negative association between NNMT and SIRT1. Moreover, the regulatory roles of NNMT, GAP43, and SIRT1 were confirmed in glioma xenograft mouse models. Conclusion: Overexpression of NNMT causes abnormal DNA methylation through regulation of the NAD/NADH ratio, which in turn leads to the downregulation of GAP43 and SIRT1, eventually altering the biological behavior of tumor cells.

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Overexpression of NNMT in Glioma Aggravates Tumor Cell Progression: An Emerging Therapeutic Target

Objective To investigate the learning curve under different surgical complexity in endoscopic transsphenoidal approach for pituitary adenoma. Methods 273 patients undergoing endoscopic transsphenoidal surgery for pituitary adenoma were collected retrospectively and divided into three groups chronologically (early, middle, and late periods). Surgical complexity was differentiated based on Knosp classification (Knsop grade 0–2 vs. Knosp grade 3–4), tumor maximum diameter (MD) (macroadenomas vs. giant adenomas), and history of previous surgery for pituitary adenoma (first operation vs. reoperation). Then the temporal trends in operative time, surgical outcomes, and postoperative complications were evaluated from early to late. Results The median operative time decrease from 169 to 147 min across the three periods (P = 0.001). A significant decrease in operative time was seen in the simple groups [Knosp grade 0–2 adenoma (169 to 137 min, P < 0.001), macroadenoma (166 to 140 min, P < 0.001), and first operation (170.5 to 134 min, P < 0.001)] but not in their complex counterparts (P > 0.05). The GTR rate increased from 51.6% to 69.2% (P = 0.04). The surgical period was an independent factor for GTR in the simple groups [Knosp grade 0–2 adenoma: OR 2.076 (95%CI 1.118–3.858, P = 0.021); macroadenoma: OR = 2.090 (95%CI 1.287–3.393, P = 0.003); first operation: OR = 1.809 (95%CI 1.104–2.966, P = 0.019)] but not in the complex groups. The biochemical cure rate increased over periods without statistical significance (from 37.5% to 56.3%, P = 0.181). Although intraoperative CSF leakage rose (from 20.9% to 35.2%) and postoperative CSF leakage reduced (from 12.1% to 5.5%), there was no statistically significant trend across the three time periods (P > 0.05). Conclusion This study showed that complex operations might have a prolonged learning curve. Differentiating surgical difficulty and using multivariate combined analysis may be more helpful in clinical practice.

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The learning curve of endoscopic endonasal transsphenoidal surgery for pituitary adenomas with different surgical complexity

Asymmetric septate uterus, commonly known as Robert’s uterus, is an exceedingly rare uterine malformation described for the first time in 1970 by Robert H. Currently, surgery is the therapy of choice for Robert’s uterus, with surgical choices ranging from laparotomy to minimally invasive surgery. In this paper, we reported that a 14-year-old girl with primary dysmenorrhea that gradually worsened three months after menarche had surgery after many imaging evaluations, and that the intraoperative diagnosis was Robert’s uterus. The diagnostic and therapeutic laparo-endoscopic single site(LESS) combined with hysteroscopy surgery for Robert’s uterine abnormality was shown via a step-by-step presentation of the method accompanied by narrated video footage. During the ten-month postoperative follow-up period, the patient had monthly recurrences with normal menstrual volume and no dysmenorrhea, demonstrating that as a minimally invasive treatment, LESS combined with hysteroscopy surgery is a successful methodfor diagnosing and treating this specific malformation.

Laparo-Endoscopic Single Site Combined With Hysteroscopy to Diagnose and Treat Robert’s Uterine Malformation: A Case Report

STUDY DESIGN
Retrospective cohort study.


OBJECTIVE
To evaluate the cross-cultural adaptability and internal consistency of the Chinese version of the Quality-of-Life Profile for Spine Deformities (QLPSD) questionnaire in mainland China.


METHODS
The original QLPSD was translated from Spanish into Chinese with proper cross-cultural adaptation based on the American Academy of Orthopaedic Surgeons guidelines. A total of 129 AIS patients referring to our institution from February 2021 to January 2022 were enrolled in this study. The effects of ceiling and floor were evaluated and the reliability was verified by examining the internal consistency (the Cronbach's α coefficient). Interclass Correlation Coefficient (ICC) was used to test and retest reliability. The C-QLPSD dimensions were compared with the domains in Chinese version of 36-Item Short Form Health Survey (SF-36) and Scoliosis Research Society-22 (SRS-22) questionnaires using Pearson correlation coefficient to assess the concurrent validity.


RESULTS
No significant floor and ceiling effects in C-QLPSD was observed. The total Cronbach's α was estimated at .914, ranging from .768 in back pain dimensions to .862 in psychosocial function dimensions. The C-QLPSD dimensions indicated satisfactory test-retest reliability with ICC range of .784-.870. Construct validity analysis revealed that C-QLPSD was well correlated with SRS-22 and SF-36. The values of total correlation coefficient were calculated at -.924 and -.871, respectively, which were both statistically significant (P < .05).


CONCLUSION
The adapted Chinese version of QLPSD had good internal consistency and excellent test-retest reliability, which can be used to assess the outcome among Chinese-speaking patients with adolescent idiopathic scoliosis.

Xinjie Hong

Papers

Overexpression of NNMT in Glioma Aggravates Tumor Cell Progression: An Emerging Therapeutic Target

The learning curve of endoscopic endonasal transsphenoidal surgery for pituitary adenomas with different surgical complexity

Laparo-Endoscopic Single Site Combined With Hysteroscopy to Diagnose and Treat Robert’s Uterine Malformation: A Case Report

Reliability and Validity of the Adapted Chinese Version of the Quality of Life Profile for Spine Deformities in Adolescents With Idiopathic Scoliosis.