PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPis) can effectively treat ovarian cancer patients with defective homologous recombination (HR). Loss or dysfunction of PTEN, a typical tumour suppressor, impairs double-strand break (DSB) repair. Hence, we explored the possibility of inhibiting PTEN to induce HR deficiency (HRD) for PARPi application. METHODS: Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo. RESULTS: In this study, the combination of VO-OHpic with olaparib exhibited synergistic inhibitory effects on ovarian cancer cells was demonstrated. Furthermore, VO-OHpic was shown to enhance DSBs by reducing nuclear expression of PTEN and inhibiting HR repair through the modulation of MRE11-RAD50-NBN (MRN) complex, critical for DSB repair. TCGA and GTEx analysis revealed a strong correlation between PTEN and MRN in ovarian cancer. Mechanistic studies indicated that VO-OHpic reduced expression of MRN, likely by decreasing PTEN/E2F1-mediated transcription. Moreover, PTEN-knockdown inhibited expression of MRN, increased sensitivities to olaparib, and induced DSBs. In vivo experiments showed that the combination of VO-OHpic with olaparib exhibited enhanced inhibitory effects on tumour growth. CONCLUSIONS: Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.

RAD54B mutations enhance the sensitivity of ovarian cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors.

Synthetic lethal targeting of homologous recombination (HR)-deficient ovarian cancers (OvCas) with poly(ADP-ribose) polymerase inhibitors (PARPis) has attracted considerable attention. Olaparib was the first PARPi approved by the Food and Drug Administration, offering significant clinical benefits in BRCA1/2-deficient OvCas. However, only approximately 20% of OvCa patients harbor BRCA1/2 mutations. Given the shared roles that BRCA1/2 have with other HR regulators, alterations in HR genes may also contribute to "BRCAness profiles" in OvCas. RAD54B has been considered a key player in HR repair, although its roles and therapeutic potential in cancers need further investigation. Here, we identified 22 frequently mutated HR genes by whole-exome sequencing of OvCa tissues from 82 patients. To our surprise, 7.3% of patients were found to harbor mutations of RAD54B, the third-highest mutated gene among patients. We determined that RAD54B-mutated tumor tissues harbored more DNA double-strand breaks than normal tissues. Additionally, we found that RAD54B knockdown inhibited HR repair, enhanced sensitivities of OvCa cells with increased DNA double-strand breaks to olaparib, and induced apoptosis. Enhanced inhibitory effects of olaparib on the growth of ES2 xenograft tumors were further demonstrated by RAD54B knockdown. Finally, we show that restoration with wildtype RAD54B rather than RAD54BN593S and RAD54BH219Y, identified in patients, abolished the effects of RAD54B knockdown, indicating these RAD54B mutants probably malfunctioned in HR repair. Our investigations may offer insight into the contributions of RAD54B mutations to synthetic lethality with olaparib treatment in OvCas, enrich the gene list for "HR deficiency scoring," and expand the applications of PARPis.

Molecular dissection on inhibition of Ras-induced cellular senescence by small t antigen of SV40.

Simian virus 40 (SV40) is a potentially oncogenic virus of monkey origin. Transmission, prevalence, and pathogenicity rates of SV40 are unclear, but infection can occur in humans, for example individuals with high contact with rhesus macaques and individuals that received contaminated early batches of polio vaccines in 1950-1963. In addition, several human polyomaviruses, proven carcinogenic, are also highly common in global populations. Cellular senescence is a major mechanism of cancer prevention in vivo. Hyperactivation of Ras usually induces cellular senescence rather than cell transformation. Previous studies suggest small t antigen (ST) of SV40 may interfere with cellular senescence induced by Ras. In the current study, ST was demonstrated to inhibit Ras-induced cellular senescence (RIS) and accumulation of DNA damage in Ras-activated cells. In addition, ST suppressed the signal transmission from BRaf to MEK and thus blocked the downstream transmission of the activated Ras signal. B56γ knockdown mimicked the inhibitory effects of ST overexpression on RIS. Furthermore, KSR1 knockdown inhibited Ras activation and the subsequent cellular senescence. Further mechanism studies indicated that the phosphorylation level of KSR1 rather than the levels of the total protein regulates the activation of Ras signaling pathway. In sum, ST inhibits the continuous hyperactivation of Ras signals by interfering with the normal functions of PP2A-B56γ of dephosphorylating KSR1, thus inhibiting the occurrence of cellular senescence. Although the roles of SV40 in human carcinogenesis are controversial so far, our study has shown that ST of polyomaviruses has tumorigenic potential by inhibiting oncogene-induced senescence (OIS) as a proof of concept.

Improving Blueberry Anthocyanins' Stability Using a Ferritin Nanocarrier.

Blueberries are fruits known for their high level of anthocyanins, which have high nutritional value and several biological properties. However, the chemical instability of anthocyanins is one of the major limitations of their application. The stability of blueberry anthocyanin extracts (BAEs) encapsulated in a ferritin nanocarrier was investigated in this study for several influencing parameters, including pH, temperature, UV-visible light, redox agents, and various metal ions. The outcomes supported the positive role of protein nanoparticles in enhancing the stability of blueberry anthocyanins by demonstrating that the stability of encapsulated BAE nanoparticles with ferritin carriers was significantly higher than that of free BAEs and a mixture of BAEs and ferritin carriers. This study provides an alternative approach for enhancing blueberry anthocyanin stability using ferritin nanocarrier encapsulation.

HSP90 inhibition downregulates DNA replication and repair genes via E2F1 repression.

Mantle cell lymphoma (MCL) is an especially aggressive and highly heterogeneous mature B-cell lymphoma. Heat shock protein 90 (HSP90) is considered an attractive therapeutic target in a variety of cancers, including MCL, but no HSP90 inhibitors have succeeded in the clinical trials to date. Exploring fine mechanisms of HSP90 inhibition in cancer cells may shed light on novel therapeutic strategies. Here, we found that HSP90 knockdown and continuous inhibition with ganetespib inhibited growth of MCL cells in vitro and in vivo. To our surprise, transient exposure over 12 h was almost as efficient as continuous exposure, and treatment with ganetespib for 12 h efficiently inhibited growth and induced G1 cell cycle arrest and apoptosis of MCL cells. Transcriptome analysis complemented by functional studies was performed to define critical MCL signaling pathways that are exceptionally sensitive to HSP90 inhibition and vital to cell fate. Six genes (cell division cycle 6, cell division cycle 45, minichromosome maintenance 4, minichromosome maintenance 7, RecQ-mediated genome instability 2, and DNA primase polypeptide 1) involved in DNA replication and repair were identified as consistently downregulated in three MCL cell lines after transient ganetespib treatment. E2F1, an important transcription factor essential for cell cycle progression, was identified as a ganetespib target mediating transcriptional downregulation of these six genes, and its stability was also demonstrated to be maintained by HSP90. This study identifies E2F1 as a novel client protein of HSP90 that is very sensitive and worthy of targeting and also finds that HSP90 inhibitors may be useful in combination therapies for MCL.

Poly (ADP-ribose) polymerase inhibitors combined with other small-molecular compounds for the treatment of ovarian cancer.

Ovarian cancer is a heterogeneous disease with complex molecular and genetic hallmarks. Benefitting from profound understanding of molecular mechanisms in ovarian cancer pathogenesis, novel targeted drugs have been actively explored in preclinical studies and clinical trials. Considered as one of the most potent and effective targeted therapies for the treatment of ovarian cancer, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) take advantages of synthetic lethality mechanisms to prevent DNA damage repair in cancer cells and cause their death, especially in cancers with BRCA mutations. Mounting evidence has indicated that the combination of PARPis with cytotoxic drugs or other targeted drugs has shown favorable synergistic effects. Excitingly, the antitumor activity of combination therapy of PARPis has been actively tested in multiple clinical trials and in-vitro or in-vivo experiments. In this review, we will briefly discuss the molecular mechanisms of PARPis combined with other therapeutic small-molecular compounds for the treatment of ovarian cancer.

Regulation of angiopoietin-like protein 8 expression under different nutritional and metabolic status.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with increasing prevalence worldwide. Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein family, is involved in glucose metabolism, lipid metabolism, and energy homeostasis and believed to be associated with T2DM. Expression levels of ANGPTL8 are often significantly altered in metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus. Studies have shown that ANGPTL8, together with other members of this protein family, such as angiopoietin-like protein 3 (ANGPTL3) and angiopoietin-like protein 4 (ANGPTL4), regulates the activity of lipoprotein lipase (LPL), thereby participating in the regulation of triglyceride related lipoproteins (TRLs). In addition, members of the angiopoietin-like protein family are varyingly expressed among different tissues and respond differently under diverse nutritional and metabolic status. These findings may provide new options for the diagnosis and treatment of diabetes, metabolic syndromes and other diseases. In this review, the interaction between ANGPTL8 and ANGPTL3 or ANGPTL4, and the differential expression of ANGPTL8 responding to different nutritional and metabolic status during the regulation of LPL activity were reviewed.

A Water Quality Prediction Method Based on the Deep LSTM Network Considering Correlation in Smart Mariculture.

An accurate prediction of cage-cultured water quality is a hot topic in smart mariculture. Since the mariculturing environment is always open to its surroundings, the changes in water quality parameters are normally nonlinear, dynamic, changeable, and complex. However, traditional forecasting methods have lots of problems, such as low accuracy, poor generalization, and high time complexity. In order to solve these shortcomings, a novel water quality prediction method based on the deep LSTM (long short-term memory) learning network is proposed to predict pH and water temperature. Firstly, linear interpolation, smoothing, and moving average filtering techniques are used to repair, correct, and de-noise water quality data, respectively. Secondly, Pearson's correlation coefficient is used to obtain the correlation priors between pH, water temperature, and other water quality parameters. Finally, a water quality prediction model based on LSTM is constructed using the preprocessed data and its correlation information. Experimental results show that, in the short-term prediction, the prediction accuracy of pH and water temperature can reach 98.56% and 98.97%, and the time cost of the predictions is 0.273 s and 0.257 s, respectively. In the long-term prediction, the prediction accuracy of pH and water temperature can reach 95.76% and 96.88%, respectively.

MHC class IIα polymorphism and its association with resistance/susceptibility to Vibrio harveyi in golden pompano (Trachinotus ovatus).

The major histocompatibility complex (MHC) plays an important role in the vertebrate immune response to antigenic peptides, and it is essential for recognizing foreign pathogens in organisms. In this study, MHC class IIα (Trov-MHC IIα) from the golden pompano (Trachinotus ovatus) was first cloned and identified. The gene structure of Trov-MHC IIα was contained four exons and three introns. High levels of polymorphism were found in the exon 2 of Trov-MHC IIα. A total of 29 different MHC class IIα alleles with high polymorphism were identified from 80 individuals. The ratio of non-synonymous substitutions (dN) to synonymous substitutions (dS) was 3.157 (>1) in the peptide binding regions (PBRs) of Trov-MHC IIα, suggesting positive balancing selection. Six alleles were selected to analyze the association between alleles and resistance/susceptibility to Vibrio harveyi in golden pompano. The results showed that Trov-DAA*6401 and Trov-DAA*6702 alleles were associated with the resistance to V. harveyi in golden pompano, while alleles Trov-DAA*6304 and Trov-DAA*7301 were associated with the susceptibility to V. harveyi in golden pompano. This study confirmed the association between alleles of MHC class IIα and disease resistance, and also detected some alleles which might be correlated with high V. harveyi-resistance. These disease resistance-related MHC alleles could be used as potential genetic markers for molecular marker-assisted selective breeding in the golden pompano.

Identification of a pyridine derivative inducing senescence in ovarian cancer cell lines via P21 activation.

Cellular senescence is a state of irreversible cell growth arrest. Increasing evidence suggests that cellular senescence contribute to tumour suppression in vivo. However, only a few anti-cancer drugs have been discovered to induce cellular senescence. Searching for new compounds which can inhibit cancer cell growth by inducing senescence is becoming one of the most attractive research fields. To test the effects of candidate compounds on cancer cell growth, cell proliferation assays, senescence-associated ß-galactosidase (SA-ß-gal) staining, and flow cytometry assay were performed. Immunofluorescence, western blot, and qRT-PCR experiments were used to further study the molecular mechanisms of the candidate compounds. We demonstrated that a pyridine derivative, 4-(4-fluorophenyl)-2-phenyl-5, 6, 7, 8-tetrahydroquinoline (FPTHQ), from a pool of 46 compounds can induce senescence of ovarian cancer cells in a dose-dependent manner. FPTHQ caused growth inhibition by inducing G0/G1 cell cycle arrest in A2780 cells. Increased activities of SA-ß-gal were observed in FPTHQ-treated A2780, OVCAR-3 and SKOV-3 cell lines. In addition, FPTHQ treatment increased the protein levels of MMP3 and the mRNA levels of IL-6 and IL-8 in A2780 cells, indicating the appearance of senescence-associated secretary phenotype (SASP) in the cells. Furthermore, we found that p21 was up-regulated and DNA damage was accumulated in FPTHQ-treated ovarian cancer cells. So far, our data suggest that FPTHQ can induce senescence in multiple ovarian cancer cell lines through activation of p21 signalling pathway by causing excessive DNA damage.

Roles of partitioning-defective protein 6 (Par6) and its complexes in the proliferation, migration and invasion of cancer cells.

A pivotal regulator of cell polarity and homeostasis, partitioning-defective protein 6 (Par6) forms multicomponent complexes that not only regulate cell polarity and stabilize cell morphology, but have also been demonstrated to participate in the proliferation, migration and invasion of cancer cells. The transforming growth factor (TGF)-ß and extracellular signal-regulated kinase (Erk) 1/2 pathways are the most thoroughly studied pathways involving Par6 in many cancers. Aurothiomalate has been used to disrupt the interaction between Par6 and atypical protein kinase C within the multicomponent complexes, and has been shown to effectively block transformed growth and metastasis in vitro and/or in vivo in a variety of cancers, including pancreatic, prostate and lung cancers, as well as alveolar rhabdomyosarcoma. It is likely that with further revelations regarding the critical roles of Par6 in cancer initiation, progression and metastasis, targeted therapies against Par6 will be discovered and prove effective preclinically, and hopefully clinically, in cancer treatment.

2D-DIGE and MALDI TOF/TOF MS analysis reveal that small GTPase signaling pathways may play an important role in cadmium-induced colon cell malignant transformation.

Cadmium is a toxic heavy metal present in the environment and in industrial materials. Cadmium has demonstrated carcinogenic activity that induces cell transformation, but how this occurs is unclear. We used 2D-DIGE and MALDI TOF/TOF MS combined with bioinformatics and immunoblotting to investigate the molecular mechanism of cadmium transformation. We found that small GTPases were critical for transformation. Additionally, proteins involved in mitochondrial transcription, DNA repair, and translation also had altered expression patterns in cadmium treated cells. Collectively, our results suggest that activation of small GTPases contributes to cadmium-induced transformation of colon cells.

Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B.

Ribosomal protein (RP) mutations in diseases such as 5q- syndrome both disrupt hematopoiesis and increase the risk of developing hematologic malignancy. However, the mechanism by which RP mutations increase cancer risk has remained an important unanswered question. We show here that monoallelic, germline inactivation of the ribosomal protein L22 (Rpl22) predisposes T-lineage progenitors to transformation. Indeed, RPL22 was found to be inactivated in ∼ 10% of human T-acute lymphoblastic leukemias. Moreover, monoallelic loss of Rpl22 accelerates development of thymic lymphoma in both a mouse model of T-cell malignancy and in acute transformation assays in vitro. We show that Rpl22 inactivation enhances transformation potential through induction of the stemness factor, Lin28B. Our finding that Rpl22 inactivation promotes transformation by inducing expression of Lin28B provides the first insight into the mechanistic basis by which mutations in Rpl22, and perhaps some other RP genes, increases cancer risk.

A Modular Neural Motion Retargeting System Decoupling Skeleton and Shape Perception.

Motion mapping between characters with different structures but corresponding to homeomorphic graphs, meanwhile preserving motion semantics and perceiving shape geometries, poses significant challenges in skinned motion retargeting. We propose M-R2ET, a modular neural motion retargeting system to comprehensively address these challenges. The key insight driving M-R2ET is its capacity to learn residual motion modifications within a canonical skeleton space. Specifically, a cross-structure alignment module is designed to learn joint correspondences among diverse skeletons, enabling motion copy and forming a reliable initial motion for semantics and geometry perception. Besides, two residual modification modules, i.e., the skeleton-aware module and shape-aware module, preserving source motion semantics and perceiving target character geometries, effectively reduce interpenetration and contact-missing. Driven by our distance-based losses that explicitly model the semantics and geometry, these two modules learn residual motion modifications to the initial motion in a single inference without post-processing. To balance these two motion modifications, we further present a balancing gate to conduct linear interpolation between them. Extensive experiments on the public dataset Mixamo demonstrate that our M-R2ET achieves the state-of-the-art performance, enabling cross-structure motion retargeting, and providing a good balance among the preservation of motion semantics as well as the attenuation of interpenetration and contact-missing.

The analysis of complete genome sequence and comparative genomics of Vibrio parahaemolyticus LF1113 in Hainan.

Vibrio parahaemolyticus is a Gram-negative, halophilic and polymorphic coccobacillus. It is world-widely distributed and has resulted in great economic losses since its first appearance. In this study, a pathogenic strain was isolated from diseased pearl gentian grouper and identified as V. parahaemolyticus based on the sequencing results of 16S rDNA gene. In order to gain a comprehensive understanding of this isolation, the whole genome sequencing was conducted. Phylogenetic analysis of the complete genomes of 16 Vibrio species showed that LF1113, ATCC17802, ATCC33787, 2210633, FORC 004, and 160807 were the most closely related. Animal experiments demonstrated that the isolated LF1113 strain was pathogenic in a fish model. This study is the first study to describe the complete genome sequence of a V. parahaemolyticus isolate, which infected pearl gentian grouper from an outbreak in a fish factory farm in Hainan. The results will expand our understanding of genetic characteristics, pathogenesis, diagnostics and disease prevention of V. parahaemolyticus, and lay the foundation for further study.

Menin signaling and therapeutic targeting in breast cancer.

To date, mounting evidence have shown that patients with multiple endocrine neoplasia type 1 (MEN1) may face an increased risk for breast carcinogenesis. The product of the MEN1 gene, menin, was also indicated to be an important regulator in breast cancer signaling network. Menin directly interacts with MLL, EZH2, JunD, NF-κB, PPARγ, VDR, Smad3, ß-catenin and ERα to modulate gene transcriptions leading to cell proliferation inhibition. Moreover, interaction of menin-FANCD2 contributes to the enhancement of BRCA1-mediated DNA repair mechanism. Ectopic expression of menin causes Bax-, Bak- and Caspase-8-dependent apoptosis. However, despite numbers of menin inhibitors were exploited in other cancers, data on the usage of menin inhibitors in breast cancer treatment remain limited. In this review, we focused on the menin associated signaling pathways and gene transcription regulations, with the aim of elucidating its molecular mechanisms and of guiding the development of novel menin targeted drugs in breast cancer therapy.

Pro-inflammatory cytokines mediating senescence of vascular endothelial cells in atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory vascular disease, and aging is a major risk factor. The accumulation of senescent vascular endothelial cells (VECs) often leads to chronic inflammation and oxidative stress and induces endothelial dysfunction, contributing to the occurrence and development of AS. Senescent cells can secrete a variety of pro-inflammatory cytokines to induce the senescence of adjacent cells in a paracrine manner, leading to the transmission of signaling of cellular senescence to neighboring cells and the accumulation of senescent cells. Recent studies have demonstrated that several pro-inflammatory cytokines, including IL-17, TNF-α, and IFN-γ, can induce the senescence of VECs. This review summarizes and focuses on the pro-inflammatory cytokines that often induce the senescence of VECs and the molecular mechanisms of these pro-inflammatory cytokines inducing senescence of VECs. Targeting the senescence of VECs induced by pro-inflammatory cytokines may provide a potential and novel strategy for the prevention and treatment of AS.

Inhibitory effects and molecular mechanisms of ginsenoside Rg1 on the senescence of hematopoietic stem cells.

Hematopoietic stem cells (HSCs) produce all blood cell lineages and maintain life-long hematopoiesis. However, the self-renewal ability and differentiation capacity of HSCs reduces with age. The senescence of HSCs can lead to the imbalance of hematopoietic homeostasis and immune disorder and induce a variety of age-related diseases. Recent studies have shown that therapeutic interventions targeting the senescence of HSCs may prevent disease progression. Ginsenoside Rg1 (Rg1), extracted from roots or stems of ginseng, has beneficial antiaging activities. It has been reported that Rg1 can inhibit the senescence of HSCs. Here, we reviewed recent advances of Rg1 in inhibiting the senescence of HSCs and discussed related molecular mechanisms. Bioinformatics and network databases have been widely applied to drug discoveries. Here, we predicted potential antiaging targets of Rg1 explored by bioinformatic methods, which may help discover new targets of Rg1 and provide novel strategies for delaying the aging process of HSCs.

DTCM: Joint Optimization of Dark Enhancement and Action Recognition in Videos.

Recognizing human actions in dark videos is a useful yet challenging visual task in reality. Existing augmentation-based methods separate action recognition and dark enhancement in a two-stage pipeline, which leads to inconsistently learning of temporal representation for action recognition. To address this issue, we propose a novel end-to-end framework termed Dark Temporal Consistency Model (DTCM), which is able to jointly optimize dark enhancement and action recognition, and force the temporal consistency to guide downstream dark feature learning. Specifically, DTCM cascades the action classification head with the dark augmentation network to perform dark video action recognition in a one-stage pipeline. Our explored spatio-temporal consistency loss, which utilizes the RGB-Difference of dark video frames to encourage temporal coherence of the enhanced video frames, is effective for boosting spatio-temporal representation learning. Extensive experiments demonstrated that our DTCM has remarkable performance: 1) Competitive accuracy, which outperforms the state-of-the-arts on the ARID dataset by 2.32% and the UAVHuman-Fisheye dataset by 4.19% in accuracy, respectively; 2) High efficiency, which surpasses the current most advanced method (Chen et al., 2021) with only 6.4% GFLOPs and 71.3% number of parameters; 3) Strong generalization, which can be used in various action recognition methods (e.g., TSM, I3D, 3D-ResNext-101, Video-Swin) to promote their performance significantly.

Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers.

The susceptibility of cells to DNA damage and their DNA repair ability are crucial for cancer therapy. Homologous recombination is one of the major repairing mechanisms for DNA double-strand breaks. Approximately half of ovarian cancer (OvCa) cells harbor homologous recombination deficiency (HRD). Considering that HRD is a major hallmark of OvCas, scholars proposed HRD scoring to evaluate the HRD degree and guide the choice of therapeutic strategies for OvCas. In the last decade, synthetic lethal strategy by targeting poly (ADP-ribose) polymerase (PARP) in HR-deficient OvCas has attracted considerable attention in view of its favorable clinical effort. We therefore suggested that the uses of other DNA damage/repair-targeted drugs in HR-deficient OvCas might also offer better clinical outcome. Here, we reviewed the current small molecule compounds that targeted DNA damage/repair pathways and discussed the HRD scoring system to guide their clinical uses.