TRIM28 in cancer and cancer therapy.

TRIM28 (tripartite motif protein 28) was initially believed to be a transcription inhibitor that plays an important role in DNA damage repair (DDR) and in maintaining cancer cellular stemness. As research has continued to deepen, several studies have found that TRIM28 not only has ubiquitin E3 ligase activity to promote degradation of substrates, but also can promote SUMOylation of substrates. Although TRIM28 is highly expressed in various cancer tissues and has oncogenic effects, there are still a few studies indicating that TRIM28 has certain anticancer effects. Additionally, TRIM28 is subject to complex upstream regulation. In this review, we have elaborated on the structure and regulation of TRIM28. At the same time, highlighting the functional role of TRIM28 in tumor development and emphasizing its impact on cancer treatment provides a new direction for future clinical antitumor treatment.

Low protein expression of LZTR1 in hepatocellular carcinoma triggers tumorigenesis via activating the RAS/RAF/MEK/ERK signaling.

LZTR1 is a substrate specific adaptor for E3 ligase involved in the ubiquitination and degradation of RAS GTPases, which inhibits the RAS/RAF/MEK/ERK signaling to suppress the pathogenesis of Noonan syndrome and glioblastoma. However, it's still unknown whether LZTR1 destabilizes RAS GTPases to suppress HCC progression by inhibiting these signaling pathway. Lenvatinib is the first-line drug for the treatment of advanced HCC, however, it has high drug resistance. To explore the roles of LZTR1 in HCC progression and the underlying mechanisms of lenvatinib resistance, techniques such as bioinformatics analysis, immunohistochemical staining, RT-qPCR, Western blot, cell functional experiments, small interfering RNA transfection and cycloheximide chase assay were applied in our study. Among these, bioinformatics analysis and immunohistochemical staining results indicated that LZTR1 protein was aberrantly expressed at low levels in HCC tissues, and low protein expression of LZTR1 was associated with poor prognosis of HCC patients. In vitro functional experiments confirmed that low expression of LZTR1 promoted HCC cell proliferation and migration via the aberrant activation of the RAS/RAF/MEK/ERK signaling due to the dysregulation of LZTR1-induced KRAS ubiquitination and degradation. Transwell assays revealed that blocking of LZTR1-mediated KRAS degradation could induce lenvatinib resistance in HCC cells. In conclusion, our study revealed that LZTR1 knockdown promoted HCC cell proliferation and migration, and induced lenvatinib resistance via activating the RAS/RAF/MEK/ERK signaling, which may provide new ideas for HCC treatment.

Advances in the understanding of nuclear pore complexes in human diseases.

BACKGROUND: Nuclear pore complexes (NPCs) are sophisticated and dynamic protein structures that straddle the nuclear envelope and act as gatekeepers for transporting molecules between the nucleus and the cytoplasm. NPCs comprise up to 30 different proteins known as nucleoporins (NUPs). However, a growing body of research has suggested that NPCs play important roles in gene regulation, viral infections, cancer, mitosis, genetic diseases, kidney diseases, immune system diseases, and degenerative neurological and muscular pathologies. PURPOSE: In this review, we introduce the structure and function of NPCs. Then We described the physiological and pathological effects of each component of NPCs which provide a direction for future clinical applications. METHODS: The literatures from PubMed have been reviewed for this article. CONCLUSION: This review summarizes current studies on the implications of NPCs in human physiology and pathology, highlighting the mechanistic underpinnings of NPC-associated diseases.

Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson's Disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder among the elderly population. The pathogenesis of PD encompasses genetic alterations, environmental factors, and age-related neurodegenerative processes. Numerous studies have demonstrated that aberrant functioning of the ubiquitin-proteasome system (UPS) plays a crucial role in the initiation and progression of PD. Notably, E3 ubiquitin ligases serve as pivotal components determining substrate specificity within UPS and are intimately associated with the regulation of various proteins implicated in PD pathology. This review comprehensively summarizes the mechanisms by which E3 ubiquitin ligases and deubiquitinating enzymes modulate PD-associated proteins and signaling pathways, while exploring the intricate relationship between UPS dysfunctions and PD etiology. Furthermore, this article discusses recent research advancements regarding inhibitors targeting PD-related E3 ubiquitin ligases.

NOLC1 was identified as a tumor suppressor gene in thyroid cancer and correlated with prognosis by bioinformatics.

Thyroid cancer (THCA) is the most common endocrine malignancy, mainly affecting women's unilateral glandular lobes. However, for relapsed and distant metastasis of THCA patients, the existing early diagnosis and treatment methods were still insufficient, and a new method was urgently needed to diagnose and treat them. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) was one of the most phosphorylated proteins in the cell, which was located mainly in the nucleolus. In addition, more and more studies have confirmed that NOLC1 plays a crucial role in various pathological processes, such as the occurrence and progression of cancer and viral infection. A previous study showed that NOLC1, as a member of RNA-binding protein, was significantly correlated with the prognosis of THCA patients. However, further exploration of NOLC1 in THCA is limited. To further explore the role of NOLC1 in THCA, we conducted expression and survival prognosis analysis of NOLC1 using multiple databases. We also evaluated the correlation between NOLC1 gene expression and clinical characteristics of THCA patients. Furthermore, we analyzed the relationship between NOLC1 and other genes, followed by enrichment analysis to investigate its metabolic pathways and molecular metabolism processes. Additionally, we examined the association between immune cell infiltration in tumor microenvironment and NOLC1. Notably, through vitro experiments, we confirmed the tumor suppressive effect of NOLC1 on the proliferation and migration of human THCA cells, providing evidence for clinical diagnosis of THCA. Furthermore, we confirmed the tumor suppressive effect of NOLC1 in vivo xenograft assay. To sum up, our results suggest that NOLC1 is a tumor suppressor gene for THCA.

Carexduanensis (Carexsect.Rhomboidales), a new species of Cyperaceae from limestone areas of Guangxi, China.

Carexduanensis Z.C.Lu, Y.F.Lu & X.F.Jin, a new species in limestone areas of Guangxi, China, was discovered and described. The morphology showed that C.duanensis is similar to C.calcicola, but differs in having culms central, leaf blades 3-5.5 mm wide, bracts longer than spikes, utricles 4-5 mm long, shorter, and nutlets abruptly contracted into an erect beak at apex. SEM microphotographs of utricles and nutlets are provided for the new and related species, C.calcicola.

Role of angiomotin family members in human diseases (Review).

Angiomotin (Amot) family members, including Amot, Amot-like protein 1 (Amotl1) and Amot-like protein 2 (Amotl2), have been found to interact with angiostatins. In addition, Amot family members are involved in various physiological and pathological functions such as embryonic development, angiogenesis and tumorigenesis. Some studies have also demonstrated its regulation in signaling pathways such as the Hippo signaling pathway, AMPK signaling pathway and mTOR signaling pathways. Amot family members play an important role in neural stem cell differentiation, dendritic formation and synaptic maturation. In addition, an increasing number of studies have focused on their function in promoting and/or suppressing cancer, but the underlying mechanisms remain to be elucidated. The present review integrated relevant studies on upstream regulation and downstream signals of Amot family members, as well as the latest progress in physiological and pathological functions and clinical applications, hoping to offer important ideas for further research.

Carexlinanensis (sect. Mitratae), a new species of Cyperaceae from Zhejiang, East China.

Carexlinanensis X.D.Qiu & X.F.Jin, a new species in sect. Mitratae of the sedge family (Cyperaceae) from north-western Zhejiang is described and illustrated. We performed a statistical comparison of the new species with other closely-related species from the same section. Carexlinanensis is similar to Carexsachalinensis F.Schmidt, but differs in having leaf blades 1-2 mm wide (vs. 2.5-3.5 mm wide), utricles longer than pistillate glumes, with beak margin smooth (vs. barbate) and peduncles of lateral spikes enclosed in bract sheaths (vs. exserted from bract sheaths).

Pan-Cancer Analysis Identifies BCLAF1 as a Potential Biomarker for Renal Cell Carcinoma.

B-cell lymphoma-2-associated transcription factor 1 (BCLAF1) is a versatile protein involved in the regulation of gene transcription and post-transcriptional processing. Although BCLAF1 exerts a broad tumor suppressor effect or tumor promoter effect in many cancer types, the specific roles concerning its expression levels, and its impact on tumorigenesis in Renal cell carcinoma (RCC) remain unclear. Here, we utilized the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) datasets alongside R software and online tools to unravel the specific roles of BCLAF1 in 33 cancer types, including its expression levels, tumor immune and molecular subtypes, and its correlation with prognosis, diagnosis, DNA methylation, and immune microenvironment. Additionally, we carried out cell biology experiments to independently investigate the expression of BCLAF1 in RCC and its effects on tumor progression. BCLAF1 was differentially expressed in tumor tissues compared to normal tissues across various cancer types and was also differentially expressed in different immune and molecular subtypes. In RCC, patients with high BCLAF1 expression had a better prognosis and BCLAF1 was tightly correlated with the stage, gender, and histological grade of patients. Furthermore, BCLAF1 had higher DNA methylation levels and higher immune infiltration levels in tumor tissues. Additionally, cell functional experiments confirmed the low expression of BCLAF1 in RCC and that BCLAF1 significantly inhibited the proliferation, migration, and invasion, while inducing apoptosis and cell cycle arrest in RCC cells in vitro. Our study under-scored the potential of BCLAF1 as an important actor in tumorigenesis, especially concerning RCC where it may serve as an effective prognostic marker.

The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer.

Ubiquitination, a highly adaptable post-translational modification, plays a pivotal role in maintaining cellular protein homeostasis, encompassing cancer chemoresistance-associated proteins. Recent findings have indicated a potential correlation between perturbations in the ubiquitination process and the emergence of drug resistance in CRC cancer. Consequently, numerous studies have spurred the advancement of compounds specifically designed to target ubiquitinates, offering promising prospects for cancer therapy. In this review, we highlight the role of ubiquitination enzymes associated with chemoresistance to chemotherapy via the Wnt/ß-catenin signaling pathway, epithelial-mesenchymal transition (EMT), and cell cycle perturbation. In addition, we summarize the application and role of small compounds that target ubiquitination enzymes for CRC treatment, along with the significance of targeting ubiquitination enzymes as potential cancer therapies.

Separable Spatial-Temporal Residual Graph for Cloth-Changing Group Re-Identification.

Group re-identification (GReID) aims to correctly associate group images belonging to the same group identity, which is a crucial task for video surveillance. Existing methods only model the member feature representations inside each image (regarded as spatial members), which leads to potential failures in long-term video surveillance due to cloth-changing behaviors. Therefore, we focus on a new task called cloth-changing group re-identification (CCGReID), which needs to consider group relationship modeling in GReID and robust group representation against cloth-changing members. In this paper, we propose the separable spatial-temporal residual graph (SSRG) for CCGReID. Unlike existing GReID methods, SSRG considers both spatial members inside each group image and temporal members among multiple group images with the same identity. Specifically, SSRG constructs full graphs for each group identity within the batched data, which will be completely and non-redundantly separated into the spatial member graph (SMG) and temporal member graph (TMG). SMG aims to extract group features from spatial members, and TMG improves the robustness of the cloth-changing members by feature propagation. The separability enables SSRG to be available in the inference rather than only assisting supervised training. The residual guarantees efficient SSRG learning for SMG and TMG. To expedite research in CCGReID, we develop two datasets, including GroupPRCC and GroupVC, based on the existing CCReID datasets. The experimental results show that SSRG achieves state-of-the-art performance, including the best accuracy and low degradation (only 2.15% on GroupVC). Moreover, SSRG can be well generalized to the GReID task. As a weakly supervised method, SSRG surpasses the performance of some supervised methods and even approaches the best performance on the CSG dataset.

BCLAF1 binds SPOP to stabilize PD-L1 and promotes the development and immune escape of hepatocellular carcinoma.

Interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells allows tumor cells to evade T cell-mediated immune surveillance. Strategies targeting PD-1/PD-L1 have shown clinical benefits in a variety of cancers. However, limited response rates in hepatocellular carcinoma (HCC) have prompted us to investigate the molecular regulation of PD-L1. Here, we identify B cell lymphoma-2-associated transcription factor 1 (BCLAF1) as a key PD-L1 regulator in HCC. Specifically, BCLAF1 interacts with SPOP, an E3 ligase that mediates the ubiquitination and degradation of PD-L1, thereby competitively inhibiting SPOP-PD-L1 interaction and subsequent ubiquitination and degradation of PD-L1. Furthermore, we determined an SPOP-binding consensus (SBC) motif mediating the BCLAF1-SPOP interaction on BCLAF1 protein and mutation of BCLAF1-SBC motif disrupts the regulation of the SPOP-PD-L1 axis. In addition, BCLAF1 expression was positively correlated with PD-L1 expression and negatively correlated with biomarkers of T cell activation, including CD3 and CD8, as well as with the level of immune cell infiltration in HCC tissues. Besides, BCLAF1 depletion leads to a significant reduction of PD-L1 expression in vitro, and this reduction of PD-L1 promoted T cell-mediated cytotoxicity. Notably, overexpression of BCLAF1 sensitized tumor cells to checkpoint therapy in an in vitro HCC cells-Jurkat cells co-culture model, whereas BCLAF1-SBC mutant decreased tumor cell sensitivity to checkpoint therapy, suggesting that BCLAF1 and its SBC motif serve as a novel therapeutic target for enhancing anti-tumor immunity in HCC.

Case Report: Temporary pacing using active fixation lead and invasive electrophysiology studies for immune checkpoint inhibitor associated reversible advanced atrioventricular block.

A case of immune checkpoint inhibitors (ICIs)-associated myocarditis with reversible advanced atrioventricular block (AVB) was reported. We innovatively used active fixation lead connected to an external device for prolonged temporary pacing until atrioventricular conduction recovered. Invasive electrophysiology studies were performed to evaluate atrioventricular conduction in detail. Long-term follow-up for nearly 120-days and repeated long-term electrocardiography was conducted to ensure the conduction system was truly recovered.

Dysregulation of deubiquitination in breast cancer.

Breast cancer (BC) is a highly frequent malignant tumor that poses a serious threat to women's health and has different molecular subtypes, histological subtypes, and biological features, which act by activating oncogenic factors and suppressing cancer inhibitors. The ubiquitin-proteasome system (UPS) is the main process contributing to protein degradation, and deubiquitinases (DUBs) are reverse enzymes that counteract this process. There is growing evidence that dysregulation of DUBs is involved in the occurrence of BC. Herein, we review recent research findings in BC-associated DUBs, describe their nature, classification, and functions, and discuss the potential mechanisms of DUB-related dysregulation in BC. Furthermore, we present the successful treatment of malignant cancer with DUB inhibitors, as well as analyzing the status of targeting aberrant DUBs in BC.

Effect of ubiquitin protease system on DNA damage response in prostate cancer (Review).

Genomic instability is an essential hallmark of cancer, and cellular DNA damage response (DDR) defects drive tumorigenesis by disrupting genomic stability. Several studies have identified abnormalities in DDR-associated genes, and a dysfunctional ubiquitin-proteasome system (UPS) is the most common molecular event in metastatic castration-resistant prostate cancer (PCa). For example, mutations in Speckle-type BTB/POZ protein-Ser119 result in DDR downstream target activation deficiency. Skp2 excessive upregulation inhibits homologous recombination repair and promotes cell growth and migration. Abnormally high expression of a deubiquitination enzyme, ubiquitin-specific protease 12, stabilizes E3 ligase MDM2, which further leads to p53 degradation, causing DDR interruption and genomic instability. In the present review, the basic pathways of DDR, UPS dysfunction, and its induced DDR alterations mediated by genomic instability, and especially the potential application of UPS and DDR alterations as biomarkers and therapeutic targets in PCa treatment, were described.

Erratum: SPOP targets oncogenic protein ZBTB3 for destruction to suppress endometrial cancer.

[This corrects the article on p. 2797 in vol. 9, PMID: 31911863.].

Temperature fluctuation and acute myocardial infarction in Beijing: an extended analysis of temperature ranges and differences.

Purpose: Few studies examined the relationship between temperature fluctuation metrics and acute myocardial infarction (AMI) hospitalizations within a single cohort. We aimed to expand knowledge on two basic measures: temperature range and difference. Methods: We conducted a time-series analysis on the correlations between temperature range (TR), daily mean temperature differences (DTDmean), and daily mean-maximum/minimum temperature differences (TDmax/min) and AMI hospitalizations, using data between 2013 and 2016 in Beijing, China. The effects of TRn and DTDmeann over n-day intervals were compared, respectively. Subgroup analysis by age and sex was performed. Results: A total of 81,029 AMI hospitalizations were included. TR1, TDmax, and TDmin were associated with AMI in J-shaped patterns. DTDmean1 was related to AMI in a U-shaped pattern. These correlations weakened for TR and DTDmean with longer exposure intervals. Extremely low (1st percentile) and high (5°C) DTDmean1 generated cumulative relative risk (CRR) of 2.73 (95% CI: 1.56-4.79) and 2.15 (95% CI: 1.54-3.01). Extremely high TR1, TDmax, and TDmin (99th percentile) correlated with CRR of 2.00 (95% CI: 1.73-2.85), 1.71 (95% CI: 1.40-2.09), and 2.73 (95% CI: 2.04-3.66), respectively. Those aged 20-64 had higher risks with large TR1, TDmax, and TDmin, while older individuals were more affected by negative DTDmean1. DTDmean1 was associated with a higher AMI risk in females. Conclusion: Temperature fluctuations were linked to increased AMI hospitalizations, with low-temperature extremes having a more pronounced effect. Females and the older adult were more susceptible to daily mean temperature variations, while younger individuals were more affected by larger temperature ranges.

Magnetic resonance imaging for the diagnosis of malignant mixed Mullerian tumor of ovary: Two case reports.

RATIONALE: Malignant mixed Mullerian tumor (MMMT) is also known as carcinosarcoma, mostly occurring in the uterus, and occurred in ovary is very rare. The disease is highly aggressive. Two cases of MMMT of ovary and their imaging characteristics were collected in our study. PATIENT CONCERNS: A 77-year-old and an 80-year-old woman were admitted to the obstetrics and gynecology department of our hospital on June 22, 2019, and December 10, 2019, respectively. The first patient presented with abdominal distension with poor appetite without obvious triggers. Another patient had been menopausal for 18 years and presented with vaginal bleeding with dull pain in the left lower abdomen without obvious cause. DIAGNOSES: Both patients underwent pelvic magnetic resonance imaging plain and enhanced scan after admission, which indicated pelvic mass. Postoperative pathology confirmed MMMT in the adnexal region. INTERVENTIONS: Both patients underwent total hysterectomy and bilateral adnexectomy. OUTCOMES: Postoperatively, the first patient developed complications such as renal failure and gastrointestinal bleeding and was sometimes unconscious. Symptomatic treatment was not effective, and the patient died about 1 month after discharge. The other patient recovered well after surgery, and imaging examinations confirmed no evidence of regrowth of the tumor during an average 36-month follow-up. LESSONS: The disease is highly malignant and progresses rapidly. The elevation of CA125 should be taken seriously. The imaging findings of MMMT has certain characteristics. Multi-sequence magnetic resonance imaging may help to distinguish this disease from other pelvic tumors. Once found, surgical treatment is needed as soon as possible, followed by postoperative adjuvant radiotherapy and chemotherapy.

Roles of estrogen receptor α in endometrial carcinoma (Review).

Endometrial carcinoma (EC) is a group of endometrial epithelial malignancies, most of which are adenocarcinomas and occur in perimenopausal and postmenopausal women. It is one of the most common carcinomas of the female reproductive system. It has been shown that the occurrence and development of EC is closely associated with the interaction between estrogen (estradiol, E2) and estrogen receptors (ERs), particularly ERα. As a key nuclear transcription factor, ERα is a carcinogenic factor in EC. Its interactions with upstream and downstream effectors and co-regulators have important implications for the proliferation, metastasis, invasion and inhibition of apoptosis of EC. In the present review, the structure of ERα and the regulation of ERα in multiple dimensions are described. In addition, the classical E2/ERα signaling pathway and the crosstalk between ERα and other EC regulators are elucidated, as well as the therapeutic targeting of ERα, which may provide a new direction for clinical applications of ERα in the future.

Regulation of apoptosis by ubiquitination in liver cancer.

Apoptosis is a programmed cell death process critical to cell development and tissue homeostasis in multicellular organisms. Defective apoptosis is a crucial step in the malignant transformation of cells, including hepatocellular carcinoma (HCC), where the apoptosis rate is higher than in normal liver tissues. Ubiquitination, a post-translational modification process, plays a precise role in regulating the formation and function of different death-signaling complexes, including those involved in apoptosis. Aberrant expression of E3 ubiquitin ligases (E3s) in liver cancer (LC), such as cellular inhibitors of apoptosis proteins (cIAPs), X chromosome-linked IAP (XIAP), and linear ubiquitin chain assembly complex (LUBAC), can contribute to HCC development by promoting cell survival and inhibiting apoptosis. Therefore, the review introduces the main apoptosis pathways and the regulation of proteins in these pathways by E3s and deubiquitinating enzymes (DUBs). It summarizes the abnormal expression of these regulators in HCC and their effects on cancer inhibition or promotion. Understanding the role of ubiquitination in apoptosis and LC can provide insights into potential targets for therapeutic intervention.