XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial.

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Neoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial.

Neoadjuvant chemoimmunotherapy has emerged as a potential treatment option for resectable head and neck squamous cell carcinoma (HNSCC). In this single-arm phase II trial (NCT04826679), patients with resectable locally advanced HNSCC (T2‒T4, N0‒N3b, M0) received neoadjuvant chemoimmunotherapy with camrelizumab (200 mg), nab-paclitaxel (260 mg/m2), and cisplatin (60 mg/m2) intravenously on day one of each three-week cycle for three cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included pathologic complete response (pCR), major pathologic response (MPR), two-year progression-free survival rate, two-year overall survival rate, and toxicities. Here, we report the perioperative outcomes; survival outcomes were not mature at the time of data analysis. Between April 19, 2021 and March 17, 2022, 48 patients were enrolled and received neoadjuvant therapy, 27 of whom proceeded to surgical resection and remaining 21 received non-surgical therapy. The ORR was 89.6% (95% CI: 80.9, 98.2) among 48 patients who completed neoadjuvant therapy. Of the 27 patients who underwent surgery, 17 (63.0%, 95% CI: 44.7, 81.2) achieved a MPR or pCR, with a pCR rate of 55.6% (95% CI: 36.8, 74.3). Treatment-related adverse events of grade 3 or 4 occurred in two patients. This study meets the primary endpoint showing potential efficacy of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin, with an acceptable safety profile, in patients with resectable locally advanced HNSCC.

Epitaxial Strain Enhanced Ferroelectric Polarization toward a Giant Tunneling Electroresistance.

A substantial ferroelectric polarization is the key for designing high-performance ferroelectric nonvolatile memories. As a promising candidate system, the BaTiO3/La0.67Sr0.33MnO3 (BTO/LSMO) ferroelectric/ferromagnetic heterostructure has attracted a lot of attention thanks to the merits of high Curie temperature, large spin polarization, and low ferroelectric coercivity. Nevertheless, the BTO/LSMO heterostructure suffers from a moderate FE polarization, primarily due to the quick film-thickness-driven strain relaxation. In response to this challenge, we propose an approach for enhancing the FE properties of BTO films by using a Sr3Al2O6 (SAO) buffering layer to mitigate the interfacial strain relaxation. The continuously tunable strain allows us to illustrate the linear dependence of polarization on epitaxial strain with a large strain-sensitive coefficient of ∼27 µC/cm2 per percent strain. This results in a giant polarization of ∼80 µC/cm2 on the BTO/LSMO interface. Leveraging this large polarization, we achieved a giant tunneling electroresistance (TER) of ∼105 in SAO-buffered Pt/BTO/LSMO ferroelectric tunnel junctions (FTJs). Our research uncovers the fundamental interplay between strain, polarization magnitude, and device performance, such as on/off ratio, thereby advancing the potential of FTJs for next-generation information storage applications.

Silencing lncRNA-DARS-AS1 suppresses nonsmall cell lung cancer progression by stimulating miR-302a-3p to inhibit ACAT1 expression.

Long noncoding RNAs (LncRNAs) have been gaining attention as potential therapeutic targets for lung cancer. In this study, we investigated the expression and biological behavior of lncRNA DARS-AS1, its predicted interacting partner miR-302a-3p, and ACAT1 in nonsmall cell lung cancer (NSCLC). The transcript level of DARS-AS1, miR-302a-3p, and ACAT1 was analyzed using qRT-PCR. Endogenous expression of ACAT1 and the expression of-and changes in-AKT/ERK pathway-related proteins were determined using western blotting. MTS, Transwell, and apoptosis experiments were used to investigate the behavior of cells. The subcellular localization of DARS-AS1 was verified using FISH, and its binding site was verified using dual-luciferase reporter experiments. The binding of DARS-AS1 to miR-302a-3p was verified using RNA co-immunoprecipitation. In vivo experiments were performed using a xenograft model to determine the effect of DARS-AS1 knockout on ACAT1 and NSCLC. lncRNA DARS-AS1 was upregulated in NSCLC cell lines and tissues and the expression of lncRNA DARS-AS1 was negatively correlated with survival of patients with NSCLC. Knockdown of DARS-AS1 inhibited the malignant behaviors of NSCLC via upregulating miR-302a-3p. miR-302a-3p induced suppression of malignancy through regulating oncogene ACAT1. This study demonstrates that the DARS-AS1-miR-302a-3p-ACAT1 pathway plays a key role in NSCLC.

Mortality risk of people living with HIV under hypothetical intervention scenarios of PM2.5 and HIV severity: a prospective cohort study.

This study estimated and compared mortality risks among people living with HIV (PLWH) under the real-world and hypothetical scenarios of PM2.5 concentrations and HIV severity. An open cohort from all PLWH receiving antiretroviral therapy in Sichuan during 2010-2019 was constructed, resulting in 541,515 person-years. Annual mean concentrations of PM2.5 were estimated and linked to PLWH by their residential address. The parametric g-formula were used to assess 3- and 5-year mortality risks under the real-world and hypothetical scenarios of PM2.5 (10-35, 35-50, 50-75 µg/m3) and CD4 concentrations (0-200, 200-500, 500-800, 800-1100 counts/µl). The estimated 3- and 5-year mortality risks among the PLWH were 14.43 % and 19.38 %, respectively, which would decrease substantially when annual PM2.5 concentration were reduced to between 10 and 35 µg/m3 (risk difference [RD] = -3.23 % and - 4.06 %) and would increase when PM2.5 concentration were elevated to between 50 and 75 µg/m3 (RD = 3.59 % and 5.04 %). The mortality risk would increase when CD4 concentration were reduced to <200 counts/µl (RD = 15.90 % and 20.27 %) and would decrease when CD4 concentration were ≥ 200 counts/µl, especially to between 800 and 1100 counts/µl (RD = -9.01 % and - 11.75 %). The elevated concentration of PM2.5 may disproportionately affect individuals with immune deficiency, especially those with more severity. The findings would serve as justifications for future intervention design and policy making to alleviate air pollution and improve environmental justice and health equity.

Strong Oxidizing Molten Salts for Strengthening Structural Restoration Enabling Direct Regeneration of Spent Layered Cathode.

As a mainstream technology for recycling spent lithium-ion batteries, direct regeneration is rapidly developed due to its high efficiency and green characteristics. However, efficient reuse of spent LiNix Coy Mn1- x - y O2 cathode is still a significant challenge, as the rock salt/spinel phase on the surface hinders the Li replenishment and phase transformation to the layered structure. In this work, the fundamental understanding of the repair mechanism is confirmed that the oxidizing atmosphere is the crucial factor that can greatly improve the rate and degree of phase restoration. Particularly, a ternary-component molten salt system (LiOH-Li2 CO3 -LiNO3 ) is proposed for direct regeneration of LiNi0.5 Co0.2 Mn0.3 O2 (NCM523), which can in situ generate the strong oxidizing intermediate of superoxide radicals. Additionally, it shows a liquid-like reaction environment at a lower temperature to acceclerate the transport rate of superoxide-ions. Therefore, the synergistic effect of LiOH-Li2 CO3 -LiNO3 system can strengthen the full restoration of rock salt/spinel phases and achieve the complete Li-supplement. As anticipated, the regenerated NCM523 delivers a high cycling stability with a retention of 91.7% after 100 cycles, which is even competitive with the commercial NCM523. This strategy provides a facile approach for the complete recovery of layer structure cathode, demonstrating a unique perspective for the direct regeneration of spent lithium-ion batteries.

A new dataset of oral panoramic x-ray images and parallel network using transformers for medical image segmentation.

INTRODUCTION: Accurate segmentation of the key mandibular region in the oral panoramic X-ray image is crucial for the diagnosis of the mandibular region and the planning of implant surgery. Because the oral panoramic X-ray image contains many important anatomical information for implant treatment evaluation. However, the fuzzy boundary between each region in the image makes the segmentation task very challenging. In data-driven segmentation methods, corresponding datasets are often required. Due to the limited oral data set at present, there is a bottleneck in clinical application. MATERIALS AND METHODS: In this paper, we build a panoramic X-ray image dataset for the mandibular region. The dataset has a total of 711 images. The dataset is divided into 8 categories based on the number of teeth and treatment conditions. The annotations include mandible, normal teeth, treated teeth and implants. In terms of network segmentation. According to the local and global characteristics of the dataset, we designed a CBTrans partition network by paralleling the convolution block and the Swin-transform block of the bottleneck structure. RESULTS: The experimental results show that our proposed network achieves excellent performance on the mandibular region segmentation dataset and the common retina dataset DRIVE. CONCLUSION: CBTrans can better extract features locally and globally by combining CNN of the bottleneck structure and Swin Transformer in parallel. CBTrans demonstrates performance advantages over other similar hybrid architecture models.

RUNX1 promotes proliferation and migration in non-small cell lung cancer cell lines via the mTOR pathway.

RUNX1, a member of the RUNX family of metazoan transcription factors, participates in the regulation of differentiation, proliferation, and other processes involved in growth and development. It also functions in the occurrence and development of tumors. However, the role and mechanism of action of RUNX1 in non-small cell lung cancer (NSCLC) are not yet clear. We used a bioinformatics approach as well as in vitro and in vivo assays to evaluate the role of RUNX1 in NSCLC as the molecular mechanisms underlying its effects. Using the TCGA, GEO, GEPIA (Gene Expression Profiling Interactive Analysis), and Kaplan-Meier databases, we screened the differentially expressed genes (DEGs) and found that RUNX1 was highly expressed in lung cancer and was associated with a poor prognosis. Immunohistochemical staining based on tissue chips from 110 samples showed that the expression of RUNX1 in lung cancer tissues was higher than that in adjacent normal tissues and was positively correlated with lymph node metastasis and TNM staging. In vitro experiments, we found that RUNX1 overexpression promoted cell proliferation and migration functions and affected downstream functional proteins by regulating the activity of the mTOR pathway, as confirmed by an analysis using the mTOR pathway inhibitor rapamycin. In addition, RUNX1 affected PD-L1 expression via the mTOR pathway. These results indicate that RUNX1 is a potential therapeutic target for NSCLC.

HAKE: A Knowledge Engine Foundation for Human Activity Understanding.

Human activity understanding is of widespread interest in artificial intelligence and spans diverse applications like health care and behavior analysis. Although there have been advances with deep learning, it remains challenging. The object recognition-like solutions usually try to map pixels to semantics directly, but activity patterns are much different from object patterns, thus hindering another success. In this article, we propose a novel paradigm to reformulate this task in two-stage: first mapping pixels to an intermediate space spanned by atomic activity primitives, then programming detected primitives with interpretable logic rules to infer semantics. To afford a representative primitive space, we build a knowledge base including 26+ M primitive labels and logic rules from human priors or automatic discovering. Our framework, Human Activity Knowledge Engine (HAKE), exhibits superior generalization ability and performance upon canonical methods on challenging benchmarks. Code and data are available at http://hake-mvig.cn/.

Neural habituation during acute stress signals a blunted endocrine response and poor resilience.

BACKGROUND: A blunted hypothalamic-pituitary-adrenal (HPA) axis response to acute stress is associated with psychiatric symptoms. Although the prefrontal cortex and limbic areas are important regulators of the HPA axis, whether the neural habituation of these regions during stress signals both blunted HPA axis responses and psychiatric symptoms remains unclear. In this study, neural habituation during acute stress and its associations with the stress cortisol response, resilience, and depression were evaluated. METHODS: Seventy-seven participants (17-22 years old, 37 women) were recruited for a ScanSTRESS brain imaging study, and the activation changes between the first and last stress blocks were used as the neural habituation index. Meanwhile, participants' salivary cortisol during test was collected. Individual-level resilience and depression were measured using questionnaires. Correlation and moderation analyses were conducted to investigate the association between neural habituation and endocrine data and mental symptoms. Validated analyses were conducted using a Montreal Image Stress Test dataset in another independent sample (48 participants; 17-22 years old, 24 women). RESULTS: Neural habituation of the prefrontal cortex and limbic area was negatively correlated with cortisol responses in both datasets. In the ScanSTRESS paradigm, neural habituation was both positively correlated with depression and negatively correlated with resilience. Moreover, resilience moderated the relationship between neural habituation in the ventromedial prefrontal cortex and cortisol response. CONCLUSIONS: This study suggested that neural habituation of the prefrontal cortex and limbic area could reflect motivation dysregulation during repeated failures and negative feedback, which might further lead to maladaptive mental states.

Schottky Barrier Control of Self-Polarization for a Colossal Ferroelectric Resistive Switching.

Controlling the domain evolution is critical both for optimizing ferroelectric properties and for designing functional electronic devices. Here we report an approach of using the Schottky barrier formed at the metal/ferroelectric interface to tailor the self-polarization states of a model ferroelectric thin film heterostructure system SrRuO3/(Bi,Sm)FeO3. Upon complementary investigations of the piezoresponse force microscopy, electric transport measurements, X-ray photoelectron/absorption spectra, and theoretical studies, we demonstrate that Sm doping changes the concentration and spatial distribution of oxygen vacancies with the tunable host Fermi level which modulates the SrRuO3/(Bi,Sm)FeO3 Schottky barrier and the depolarization field, leading to the evolution of the system from a single domain of downward polarization to polydomain states. Accompanied by such modulation on self-polarization, we further tailor the symmetry of the resistive switching behaviors and achieve a colossal on/off ratio of ∼1.1 × 106 in the corresponding SrRuO3/BiFeO3/Pt ferroelectric diodes (FDs). In addition, the present FD also exhibits a fast operation speed of ∼30 ns with a potential for sub-nanosecond and an ultralow writing current density of ∼132 A/cm2. Our studies provide a way for engineering self-polarization and reveal its strong link to the device performance, facilitating FDs as a competitive memristor candidate used for neuromorphic computing.

Autophagy inhibition and reactive oxygen species elimination by acetyl-CoA acetyltransferase 1 through fused in sarcoma protein to promote prostate cancer.

BACKGROUND: Prostate cancer is a major health issue affecting the male population worldwide, and its etiology remains relatively unknown. As presented on the Gene Expression Profiling Interactive Analysis database, acetyl-CoA acetyltransferase 1 (ACAT1) acts as a prostate cancer-promoting factor. ACAT1 expression in prostate cancer tissues is considerably higher than that in normal tissues, leading to a poor prognosis in patients with prostate cancer. Here, we aimed to study the role of the ACAT1-fused in sarcoma (FUS) complex in prostate cancer and identify new targets for the diagnosis and treatment of the disease. METHODS: We conducted immunohistochemical analysis of 57 clinical samples and in vitro and in vivo experiments using a mouse model and plasmid constructs to determine the expression of ACAT1 in prostate cancer. RESULTS: The relationship between the expression of ACAT1 and the Gleason score was significant. The expression of ACAT1 was higher in tissues with a Gleason score of > 7 than in tissues with a Gleason score of ≤7 (P = 0.0011). In addition, we revealed that ACAT1 can interact with the FUS protein. CONCLUSIONS: In prostate cancer, ACAT1 promotes the expression of P62 and Nrf2 through FUS and affects reactive oxygen species scavenging. These effects are due to the inhibition of autophagy by ACAT1. That is, ACAT1 promotes prostate cancer by inhibiting autophagy and eliminating active oxygen species. The expression of ACAT1 is related to prostate cancer. Studying the underlying mechanism may provide a new perspective on the treatment of prostate cancer.

A Theoretical Study of the Interactions between Persistent Organic Pollutants and Graphene Oxide.

Persistent organic pollutants (POPs) have adverse effects on the human health and ecosystem functioning. Graphene oxide (GO) has been developed to remove trace levels of POPs from wastewater samples. However, many questions involved in these processes are still unresolved (e.g., the role of π-π interaction, the effect of GO on the degradation of POPs, and so on). Revealing the microscopic interactions between GO and POPs is of benefit to resolve these questions. In the present study, a quantum chemical calculation was used to calculate the molecular doping and adsorption energy between eight representative POPs and GO. The influences of GO on the thermodynamic parameters, such as the Gibbs free energy and the highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gap, were also reported. We found the molecular doping is dependent on the species of POPs. The adsorption energy of the majority of POPs on GO is between 7 and 8 kJ/mol. Consequently, the GO may make degradation of POPs in wastewater more productive and lead to a change of kinetics of the degradation of POPs.

TNF Patterns and Tumor Microenvironment Characterization in Head and Neck Squamous Cell Carcinoma.

Background: HNSCC is a heterogeneous disease, which arises from distinct anatomic subsites, associates with various risk factors and possesses diverse molecular pathological features. Generally, HNSCC is considered as an immunosuppressive disease, characterized by abnormal tumor immune microenvironment. The TNF family plays a crucial role in the survival, proliferation, differentiation, and effector functions in both immune and non-immune cells. However, the expression patterns of TNF in HNSCC remains to be systematically analyzed. Methods: We downloaded transcriptional profile data of HNSCC from TCGA and GEO datasets. Unsupervised clustering methods were used to identify different TNF patterns and classify patients for further analysis. PCA was conducted to construct a TNF relevant score, which we called risk score. Results: In this study, we systematically evaluated the patterns of TNF family and tumor immune microenvironment characteristics of HNSCC patients by clustering the expression of 46 members of TNF family. We identified two subtypes with distinct clinical and immune characteristics in HNSCC and constructed a risk scoring system based on the expression profile of TNF family genes. Conclusion: Risk score serves as a reliable predictor of overall survival, clinical characteristics, and immune cell infiltration, which has the potential to be applied as a valuable biomarker for HNSCC immunotherapy.

Rapamycin and trametinib: a rational combination for treatment of NSCLC.

Mammalian target of rapamycin (mTOR) is one of the most commonly activated pathways in human cancers, including lung cancer. Targeting mTOR with molecule inhibitors is considered as a useful therapeutic strategy. However, the results obtained from the clinical trials with the inhibitors so far have not met the original expectations, largely because of the drug resistance. Thus, combined or multiple drug therapy can bring about more favorable clinical outcomes. Here, we found that activation of ERK pathway was responsible for rapamycin drug resistance in non-small-cell lung cancer (NSCLC) cells. Accordingly, rapamycin-resistant NSCLC cells were more sensitive to ERK inhibitor (ERKi), trametinib, and in turn, trametinib-resistant NSCLC cells were also susceptible to rapamycin. Combining rapamycin with trametinib led to a potent synergistic antitumor efficacy, which induced G1-phase cycle arrest and apoptosis. In addition, rapamycin synergized with another ERKi, MEK162, and in turn, trametinib synergized with other mTORi, Torin1 and OSI-027. Mechanistically, rapamycin in combination with trametinib resulted in a greater decrease of phosphorylation of AKT, ERK, mTOR and 4EBP1. In xenograft mouse model, co-administration of rapamycin and trametinib caused a substantial suppression in tumor growth without obvious drug toxicity. Overall, our study identifies a reasonable combined strategy for treatment of NSCLC.

Yin-xing-tong-mai decoction attenuates atherosclerosis via activating PPARγ-LXRα-ABCA1/ABCG1 pathway.

Atherosclerosis is now the major cause of mortality and morbidity worldwide. Formation of macrophage-derived foam cells is a hallmark of atherosclerosis, which is regulated by cholesterol uptake, intracellular metabolism, and efflux. PPARγ-LXRα-ABCA1/ABCG1 pathway plays an important part in regulating cholesterol efflux and this pathway could be a promising target for treating atherosclerosis. However, due to undesirable systemic effects, PPARγ agonist therapy for atherosclerosis remains challenging. Many traditional Chinese medicine has been well accepted and applied in atherosclerosis treatment. Yin-xing-tong-mai decoction (YXTMD) has been applied for treating atherosclerosis for decades. However, the mechanism remains to be explored. Here, we showed that YXTMD effectively attenuated atherosclerosis in ApoE-/- mice. YXTMD increased cholesterol efflux of foam cell by upregulation of ABCA1 and ABCG1 in vivo and in vitro. Through bioinformatic analysis and experimental validation, we found that PPARγ was an important downstream effector of YXTMD in macrophages. Reduction of PPARγ significantly decreased LXRα, ABCA1, and ABCG1 expression in macrophages, with reduced cholesterol efflux. In conclusion, these findings confirmed that YXTMD attenuated atherosclerosis by activating the PPARγ-LXRα- ABCA1/ABCG1 pathway to enhance cholesterol efflux.

Influencing Indicators and Spatial Variation of Diabetes Mellitus Prevalence in Shandong, China: A Framework for Using Data-Driven and Spatial Methods.

To control and prevent the risk of diabetes, diabetes studies have identified the need to better understand and evaluate the associations between influencing indicators and the prevalence of diabetes. One constraint has been that influencing indicators have been selected mainly based on subjective judgment and tested using traditional statistical modeling methods. We proposed a framework new to diabetes studies using data-driven and spatial methods to identify the most significant influential determinants of diabetes automatically and estimated their relationships. We used data from diabetes mellitus patients' health insurance records in Shandong province, China, and collected influencing indicators of diabetes prevalence at the county level in the sociodemographic, economic, education, and geographical environment domains. We specified a framework to identify automatically the most influential determinants of diabetes, and then established the relationship between these selected influencing indicators and diabetes prevalence. Our autocorrelation results showed that the diabetes prevalence in 12 Shandong cities was significantly clustered (Moran's I = 0.328, p < 0.01). In total, 17 significant influencing indicators were selected by executing binary linear regressions and lasso regressions. The spatial error regressions in different subgroups were subject to different diabetes indicators. Some positive indicators existed significantly like per capita fruit production and other indicators correlated with diabetes prevalence negatively like the proportion of green space. Diabetes prevalence was mainly subjected to the joint effects of influencing indicators. This framework can help public health officials to inform the implementation of improved treatment and policies to attenuate diabetes diseases.

CRSP8 promotes thyroid cancer progression by antagonizing IKKα-induced cell differentiation.

CRSP8 plays an important role in recruiting mediators to genes through direct interaction with various DNA-bound transactivators. In this study, we uncovered the unique function of CRSP8 in suppressing thyroid cancer differentiation and promoting thyroid cancer progression via targeting IKKα signaling. CRSP8 was highly expressed in human thyroid cancer cells and tissues, especially in anaplastic thyroid cancer (ATC). Knockdown of CRSP8 suppressed cell growth, migration, invasion, stemness, and induced apoptosis and differentiation in ATC cells, while its overexpression displayed opposite effects in differentiated thyroid cancer (DTC) cells. Mechanistically, CRSP8 downregulated IKKα expression by binding to the IKKα promoter region (-257 to -143) to negatively regulate its transcription. Knockdown or overexpression of IKKα significantly reversed the expression changes of the differentiation and EMT-related markers and cell growth changes mediated by CRSP8 knockdown or overexpression in ATC or DTC cells. The in vivo study also validated that CRSP8 knockdown inhibited the growth of thyroid cancer by upregulating IKKα signaling in a mouse model of human ATC. Furthermore, we found that CRSP8 regulated the sensitivity of thyroid cancer cells to chemotherapeutics, including cisplatin and epirubicin. Collectively, our results demonstrated that CRSP8 functioned as a modulator of IKKα signaling and a suppressor of thyroid cancer differentiation, suggesting a potential therapeutic strategy for ATC by targeting CRSP8/IKKα pathway.

Targeting the NCOA3-SP1-TERT axis for tumor growth in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a high mortality rate and lacks an effective therapeutic target. Elevated expression of human telomerase reverse transcriptase (TERT) is an important hallmark in cancers, but the mechanism by which TERT is activated differentially in cancers is poorly understood. Here, we have identified nuclear receptor coactivator-3 (NCOA3) as a new modulator of TERT expression and tumor growth in HCC. NACO3 specifically binds to the TERT promoter at the -234 to -144 region and transcriptionally activates TERT expression. NCOA3 promotes HCC cell growth and tumor progression in vitro and in vivo through upregulating the TERT signaling. Knockdown of NACO3 suppresses HCC cell viability and colony formation, whereas TERT overexpression rescues this suppression. NCOA3 interacts with and recruits SP1 binding on the TERT promoter. Knockdown of NCOA3 also inhibits the expression of the Wnt signaling-related genes but has no effect on the Notch signaling-targeting genes. Moreover, NCOA3 is positively correlated with TERT expression in HCC tumor tissues, and high expression of both NCOA3 and TERT predicts a poor prognosis in HCC patients. Our findings indicate that targeting the NCOA3-SP1-TERT signaling axis may benefit HCC patients.

Sirtuin 5 regulates the proliferation, invasion and migration of prostate cancer cells through acetyl-CoA acetyltransferase 1.

Sirtuin 5 (SIRT5) is a NAD+ -dependent class III protein deacetylase, and its role in prostate cancer has not yet been reported. Therefore, to explore the diagnosis and treatment of prostate cancer, we investigated the effect of SIRT5 on prostate cancer. Sirtuin 5 was assessed by immunohistochemistry in 57 normal and cancerous prostate tissues. We found that the tissue expression levels of SIRT5 in patients with Gleason scores ≥7 were significantly different from those in patients with Gleason scores <7 (P < .05, R > 0). Further, mass spectrometry and pathway screening experiments showed that SIRT5 regulated the activity of the mitogen-activated protein kinase (MAPK) pathway, which in turn modulated the expression of MMP9 and cyclin D1. Being a substrate of SIRT5, acetyl-CoA acetyltransferase 1 (ACAT1) was regulated by SIRT5. SIRT5 also regulated MAPK pathway activity through ACAT1. These results revealed that SIRT5 promoted the activity of the MAPK pathway through ACAT1, increasing the ability of prostate cancer cells to proliferate, migrate and invade. Overall, these results indicate that SIRT5 expression is closely associated with prostate cancer progression. Understanding the underlying mechanism may provide new targets and methods for the diagnosis and treatment of the disease.