Development of novel androgen receptor antagonists based on the structure of darolutamide.

Androgen signaling pathway plays an important role in the occurrence and development of prostate cancer (PCa), and anti-androgen drugs are one of the most effective therapies for PCa. Darolutamide 4 (ODM-201) is a promising second- generation antiandrogen because of its unique chemical structure and good activity against androgen receptor (AR). Herein, the structure-activity relationship of ODM-201 was studied, and 37 analogues were synthesized. Half of them exhibited similar or better anti-AR transcriptional activity compared to ODM-201. In addition, the inhibitory activity of compound 28t against the two resistant mutants (AR-F876L and AR-T877A) was superior to that of ODM-201. This study provides a new clue for the further optimization of ODM-201 and the development of anti-CRPC drugs.

Early prediction and prevention of infected pancreatic necrosis.

Approximately 20%-30% of patients with acute necrotizing pancreatitis develop infected pancreatic necrosis (IPN), a highly morbid and potentially lethal complication. Early identification of patients at high risk of IPN may facilitate appropriate preventive measures to improve clinical outcomes. In the past two decades, several markers and predictive tools have been proposed and evaluated for this purpose. Conventional biomarkers like C-reactive protein, procalcitonin, lymphocyte count, interleukin-6, and interleukin-8, and newly developed biomarkers like angiopoietin-2 all showed significant association with IPN. On the other hand, scoring systems like the Acute Physiology and Chronic Health Evaluation II and Pancreatitis Activity Scoring System have also been tested, and the results showed that they may provide better accuracy. For early prevention of IPN, several new therapies were tested, including early enteral nutrition, antibiotics, probiotics, immune enhancement, etc., but the results varied. Taken together, several evidence-supported predictive markers and scoring systems are readily available for predicting IPN. However, effective treatments to reduce the incidence of IPN are still lacking apart from early enteral nutrition. In this editorial, we summarize evidence concerning early prediction and prevention of IPN, providing insights into future practice and study design. A more homogeneous patient population with reliable risk-stratification tools may help find effective treatments to reduce the risk of IPN, thereby achieving individualized treatment.

Material basis and core chemical structure of Dendrobium officinale polysaccharides against colitis-associated cancer based on anti-inflammatory activity.

It has been claimed that Dendrobium officinale polysaccharides (PSs) can degrade into oligosaccharide and then transform into short-chain fatty acids in the intestine after oral administration, and play an anti-colitis-associated cancer (CAC) effect by inhibiting intestinal inflammation. However, the material basis and core chemical structure underlying the anti-colon cancer properties of PSs have not yet been elucidated. In this study, PSs were degraded into enzymatic oligosaccharides (OSs) using ß-mannanase. The results of in vivo experiments revealed that PSs and OSs administered by gastric lavage had similar antitumor effects in CAC mice. OS-1 (Oligosaccharide compounds 1) and OS-2 (Oligosaccharide compounds 2) were further purified and characterized from OSs, and it was found that OS-1, OS-2, OSs, and PSs had similar and consistent anti-inflammatory activities in vitro. Chemical structure comparison and evaluation revealed that the chemical structure of ß-D-Manp-(1 â†’ 4)-ß-D-Glcp corresponding to OS-1 was the least common PS structure with anti-colitic activity. Therefore, our findings suggest that OSs are the material basis for PSs to exert anti-CAC activity and that the chemical structure of ß-D-Manp-(1 â†’ 4)-ß-D-Glcp corresponding to OS-1 is the core chemical structure of PSs against CAC.

Association of energy delivery with short-term survival in mechanically ventilated critically ill adult patients: a secondary analysis of the NEED trial.

BACKGROUND AND AIMS: The optimal energy delivery for mechanically ventilated patients is controversial, particularly during the first week of ICU admission. This study aimed to investigate the association between different caloric adequacy and 28-day mortality in a cohort of critically ill adults on mechanical ventilation. METHODS: This is a secondary analysis of a multicenter, cluster-randomized controlled trial. Eligible patients were divided into four quartiles (Q1-Q4) according to caloric adequacy calculated by the actual average daily energy delivery during the first seven days of ICU stay divided by energy requirement as a percentage. Cox proportional hazards models were used to examine the impact of different quartiles of caloric adequacy on 28-day mortality in the whole cohort and subgroups with different nutritional risk status at enrollment. RESULTS: A total of 1587 patients were included in this study, with an overall 28-day mortality of 15.8%. The average caloric adequacy was 26.3 ± 11.9% (Q1), 52.5 ± 5.5% (Q2), 71.7 ± 6.4% (Q3), 107.0 ± 22.2% (Q4), respectively (p < 0.001 among quartiles). Compared with Q1, Q3 was associated with lower mortality in the unadjusted model (hazard ratio [HR] = 0.536; 95% confidence interval [CI], 0.375-0.767; P = 0.001) and adjusted model (adjusted HR = 0.508; 95% CI, 0.339-0.761; P = 0.001). This association remained valid in the subgroup of high nutritional risk patients (unadjusted HR = 0.387; 95% CI, 0.238-0.627; P < 0.001 and adjusted HR = 0.369; 95% CI, 0.216-0.630; P < 0.001, respectively), but not in those with low risk. CONCLUSIONS: Energy delivery near the 70% energy requirements in the first week of ICU stay was associated with reduced 28-day mortality among mechanically ventilated critically ill patients, especially in patients with high nutrition risk at admission.

GuiErBai: a potent inhibitor, exhibiting broadly antitumor effect against cervical cancer in vitro and in vivo.

Introduction: Cervical cancer (CC) ranks as the fourth most prevalent malignant tumor among women worldwide, and is the fourth leading cause of cancer-related mortality. GuiErBai (GEB), a compound preparation developed by our research team, is derived from the ancient Chinese medicine of the Miao nationality and is comprised of podophyllotoxin (PTOX), imperatorin, isoimperatorin, and A. dahurica alkaloids. These individual components have demonstrated notable efficacy in tumor treatment. However, the specific anti-tumor effect of the compound Chinese medicine GEB in the context of CC has yet to be validated. Methods: HeLa and SiHa cell lines were utilized for in vitro experiments and treated with 5 mg/mL and 10 mg/mL GEB concentrations, respectively. The cell cycle changes after GEB treatment were assessed using flow cytometry. Transmission electron microscopy was employed to observe autophagic bodies and apoptotic bodies, while MDC staining evaluated the occurrence of autophagy. CCK-8 was used to observe the effect of GEB on cell proliferation, and Transwell assays assessed cell migration and invasion. Western blotting detected cell cycle and apoptosis-related protein expression, along with the expression level of autophagy-related protein LC3I/II. Changes in ROS and mitochondrial membrane potential in cervical cancer cells following GEB treatment were determined using ROS detection and mitochondrial membrane potential detection kits. For the in vivo experiment, a nude mouse model of cervical cancer transplantation based on HeLa cells was established. Experimental animals were divided into negative control, positive control, high-dose GEB (10 mg/mL), and low-dose GEB (5 mg/mL) groups. Results: In HeLa and SiHa cell lines, the G0/G1 phase of tumor cells significantly decreased (p < 0.001), while the G2/M phase increased notably (p < 0.001) following various GEB treatments. Electron microscopy showed GEB promoted apoptotic body and autophagosome formation in both cell lines. Compared to untreated HeLa and SiHa cells, GEB-treated cells exhibited significantly reduced caspase3 protein expression, and substantially increased autophagy-related protein LC3I/II expression. GEB treatment significantly reduced migration and invasion capabilities in both cell lines (p < 0.001), while ROS content and mitochondrial membrane potential were significantly elevated (p < 0.001). GEB effectively inhibited cervical cancer cell proliferation, with the optimal concentration being 10 mg/mL. A successful nude mouse model of cervical cancer transplantation was established using HeLa cells. Post-GEB treatment, the tumor volume and weight in nude mice significantly decreased (p < 0.001), with diminished expression of CD34, VEGF, and caspase3 proteins in tumor tissues. Discussion: GEB exhibits a robust antitumor effect against cervical cancer, both in vitro and in vivo, in a concentration-dependent manner, by regulating autophagy and apoptosis of tumor cells.

Impact of therapeutic plasmapheresis on the duration of organ failure in patients with hypertriglyceridemia-associated acute pancreatitis.

BACKGROUND: Plasmapheresis is widely used for severe hypertriglyceridemia-associated acute pancreatitis (HTG-AP) to remove excessive triglycerides from plasma. This study aimed to evaluate whether plasmapheresis could improve the duration of organ failure in HTG-AP patients. METHODS: We analyzed a cohort of patients from a multicenter, prospective, long-running registry (the PERFORM) collecting HTG-AP patients admitted to the study sites within 72 h from the onset of symptoms. This study was based on data collected from November 2020 to March 2023. Patients who had organ failure at enrollment were involved in the analyses. The primary outcome was time to organ failure resolution within 14 days. Multivariable Cox regression model was used to evaluate the association between plasmapheresis and time to organ failure resolution. Directed acyclic graph (DAG) was used to identify potential confounders. RESULTS: A total of 122 HTG-AP patients were included (median [IQR] sequential organ failure assessment (SOFA) score at enrollment, 3.00 [2.00-4.00]). Among the study patients, 46 underwent plasmapheresis, and 76 received medical treatment. The DAG revealed that baseline serum triglyceride, APACHE II score, respiratory failure, cardiovascular failure, and renal failure were potential confounders. After adjusting for the selected confounders, there was no significant difference in time to organ failure resolution between patients undergoing plasmapheresis and those receiving exclusive medical treatment (HR = 1.07; 95%CI 0.68-1.68; P = 0.777). Moreover, the use of plasmapheresis was associated with higher ICU requirements (97.8% [45/46] vs. 65.8% [50/76]; OR, 19.33; 95%CI 2.20 to 169.81; P = 0.008). CONCLUSIONS: In HTG-AP patients with early organ failure, plasmapheresis was not associated with accelerated organ failure resolution compared to medical treatment but may be associated with more ICU admissions. TRIAL REGISTRATION: The PERFORM study was registered in the Chinese Clinical Trial Registry (ChiCTR2000039541). Registered 30 October 2020.

Immunohistochemical characteristics of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma: A case report and review.

BACKGROUND: Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is a rare nasopharyngeal malignant tumor that is easy to misdiagnose. Immunohistochemistry plays an indispensable role in distinguishing TL-LGNPPA from other malignancies. However, there is no article to summarize the immunohistochemical characteristics of TL-LGNPPA. Herein, we report a case of TL-LGNPPA and present the immunohistochemical results reported in the Chinese literature. METHODS: An electronic search of the CNKI (China National Knowledge Infrastructure) database was performed. From our literature survey, 53 cases of TL-LGNPPA (including the case described in this report) have been identified in China. We summarize the Chinese literature's clinical characteristics, immunohistochemical results, treatments, and prognosis of 53 cases. RESULTS: Based on our literature survey, 53 cases of TL-LGNPPA (including the case described in this report) have been reported in China. We found TL-LGNPPA and papillary thyroid carcinoma were positive for TTF-1 and CK19. TL-LGNPPA was negative for TG and PAX-8, whereas papillary thyroid carcinoma was positive for TG and PAX-8. However, negative expression of TTF-1 and positive expression of TG were also found in some TL-LGNPPA cases. Our literature survey found that all TL-LGNPPA cases were negative for PAX-8.Therefore, we suggest that simultaneous immunohistochemical determination of TTF-1 and CK19, as well as TG and PAX-8, can increase the diagnostic accuracy of TL-LGNPPA. CONCLUSION: The 4th edition of the World Health Organization Classification of Head and Neck Tumors (WHO-HNT) indicates that NPPA with positive expression of cytokeratin 19 (CK19) and TTF-1 and negative expression of TG is called TL-LGNPPA.

Passion fruit plants alter the soil microbial community with continuous cropping and improve plant disease resistance by recruiting beneficial microorganisms.

Passion fruit (Passiflora edulis) is widely grown in tropical and subtropical regions, showing high economic and ornamental value. Microorganisms are indicators for the stability and health of the soil ecosystem, which can affect the yield and quality of passion fruit under continuous cropping. High-throughput sequencing and interactive analysis were used to analyse the variation of microbial communities in the noncultivated soil (NCS), cultivated soil (CS), and the rhizosphere soil of purple passion fruit (Passiflora edulis f. edulis ×Passiflora edulis f. flavicarpa, RP) and yellow passion fruit (Passiflora edulis f. flavicarpa, RY). An average of 98,001 high-quality fungal internal transcribed spacer (ITS) sequences, mainly from Ascomycota, Basidiomycota, Mortierellomycota, Mucoromycota and Glomeromycota, as well as an average of 71,299 high-quality bacterial 16S rRNA sequences, mainly from Proteobacteria, Actinobacteria, Acidobacteria, Firmicutes and Chloroflexi, were obtained per sample. It was found that the continuous cropping of passion fruit increased the richness but reduced the diversity of soil fungi, while it dramatically increased the richness and diversity of soil bacteria. In addition, during the continuous cropping, grafting different scions in the same rootstock contributed to the aggregation of differential rhizosphere microbial communities. Among fungal genera, Trichoderma showed higher abundance in RY than in RP and CS, while the opposite was observed in the pathogen Fusarium. Moreover, the co-occurrence network and potential function analyses also showed that the appearance of Trichoderma was related to Fusarium and its contribution to plant metabolism was significantly greater in RY than in RP and CS. In conclusion, the rhizosphere of yellow passion fruit may be beneficial for the enrichment of disease-resistant microbes, such as Trichoderma, which may be an important factor inducing stronger resistance to stem rot. It will help to form a potential strategy for overcoming the pathogen-mediated obstacles in passion fruit and improve its yield and quality.

Utility of adjuvant radioactive iodine therapy after reoperation in papillary thyroid carcinoma with cervical lymph node recurrence.

PURPOSE: The aim of this study was to evaluate the utility of RAI therapy after reoperation for patients with LN relapse. MATERIALS AND METHODS: We retrospectively evaluated PTC patients who had undergone reoperation due to cervical LN recurrence. We used the chi-square test, Fisher's exact test, Student's t test and the Mann-Whitney U test to compare characteristics between patients retreated with RAI and those who did not receive RAI after reoperation. A multivariate logistic regression model was used to determine the association between RAI and biochemical response. By means of the Kaplan-Meier estimator and a multivariate Cox proportional hazard model, we assessed whether administration of RAI after reoperation is associated with improved prognosis. RESULTS: RAI therapy was closely associated with a superior biochemical response in all selected patients according to both univariate (p = 0.012) and multivariate analyses (p = 0.020). Thirteen of 97 patients developed a second recurrence or progression of structural disease during follow-up. A Kaplan-Meier progression-free survival (PFS) curve showed that high post-retreatment thyroglobulin (Tg) levels (≥ 1 ng/mL) were associated with unfavourable prognosis (p = 0.0172). In the subgroup analysis, univariate analysis revealed that only patients without extranodal invasion who received adjuvant RAI therapy achieved better PFS than those who did not receive RAI therapy (p = 0.0203). Multivariate analysis showed that RAI (p = 0.045) also improved PFS in patients without extranodal invasion. CONCLUSIONS: Adjuvant RAI after reoperation for PTC recurrence/persistence was associated with a favourable biochemical response and tended to increase PFS. Specifically, it was significantly associated with improved PFS only in patients without extranodal extension.

Selenium Biofortification Enhanced miR167a Expression in Broccoli Extracellular Vesicles Inducing Apoptosis in Human Pancreatic Cancer Cells by Targeting IRS1.

Purpose: Pancreatic adenocarcinoma (PAAD) presents an extremely high morbidity and mortality rate. Broccoli has excellent anti-cancer properties. However, the dosage and serious side effects still limit the application of broccoli and its derivatives for cancer therapy. Recently, extracellular vesicles (EVs) derived from plants are emerging as novel therapeutic agents. Thus, we conducted this study to determine the effectiveness of EVs isolated from Se-riched broccoli (Se-BDEVs) and conventional broccoli (cBDEVs) for the treatment of PAAD. Methods: In this study, we first isolated Se-BDEVs and cBDEVs by a differential centrifugation method, and characterized them by using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Then, miRNA-seq was combined with target genes prediction, and functional enrichment analysis to reveal the potential function of Se-BDEVs and cBDEVs. Finally, the functional verification was conducted in PANC-1 cells. Results: Se-BDEVs and cBDEVs exhibited similar characteristics in size and morphology. Subsequent miRNA-seq revealed the expression of miRNAs in Se-BDEVs and cBDEVs. Using a combination of miRNA target prediction and KEGG functional analysis, we found miRNAs in Se-BDEVs and cBDEVs may play an important role in treating pancreatic cancer. Indeed, our in vitro study showed that Se-BDEVs had greater anti-PAAD potency than cBDEVs due to increased bna-miR167a_R-2 (miR167a) expression. Transfection with miR167a mimics significantly induced apoptosis of PANC-1 cells. Mechanistically, further bioinformatics analysis showed that IRS1, which is involved in the PI3K-AKT pathway, is the key target gene of miR167a. Conclusion: This study highlights the role of miR167a transported by Se-BDEVs which could be a new tool for counteracting tumorigenesis.

Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer.

In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.

Dietary selenomethionine attenuates obesity by enhancing beiging process in white adipose tissue.

Imbalanced nutrient intake causes abnormal energy metabolism, which results in obesity. There is feasible evidence that selenium-rich (Se-rich) foods may alleviate obesity and enhance general public health, but the underlying mechanisms remain elusive. Herein we examined the effect of Se supplementation on white adipose tissue beiging process. The mice were fed with a normal diet or a Se-deficient high-fat diet (DHFD) until significant differences in terms of body weight, glucose tolerance and insulin sensitivity. Next, mice in the DHFD group were changed to a high-fat diet (HFD) containing specified amounts of selenomethionine (SeMet) (0, 150, 300, and 600 µg/kg) and continued to feed for 14 weeks. Notably, 150 µg/kg SeMet supplement highly protected mice from DHFD-induced obesity, insulin resistance, and lipid deposits in the liver and kidney, and featured by the enhanced beiging process in white adipose tissue and increased energy expenditure. Moreover, upon cold challenge, 150 µg/kg SeMet supplement enhanced cold tolerance in mice by inducing adipose beiging to promote energy expenditure, as evidenced by the increased expression of uncoupling protein-1 (UCP1) in adipocytes. Similarly, SeMet (10 µM) promoted the differentiation of beige adipocytes from the stromal vascular fraction. Collectively, our data support that optimal supplementation of SeMet could enhance the beiging process to attenuate HFD-induced obesity, which provides new insights into the relationship between dietary SeMet and type 2 diabetes.

Effects of selenium supplementation on concurrent chemoradiotherapy in patients with cervical cancer: A randomized, double-blind, placebo-parallel controlled phase II clinical trial.

Objective: Selenium (Se) is an essential trace element and may affect cervical cancer occurrence and progression. The association between selenium supplementation and acute toxic reactions and clinical outcomes in patients with locally advanced cervical cancer treated with concurrent chemoradiotherapy remains unclear. The aim of this study was to determine the safety profile of add-on Se yeast and assess the potential of Se to ameliorate the hematologic toxicity of concurrent chemoradiotherapy in patients with cervical cancer. Methods: Patients with Federation International of Gynecology and Obstetrics (FIGO) stage IIB cervical cancer who met all inclusion criteria were randomly assigned to either the experimental group or the control group. The experimental group received Se yeast tablets (100 µg Se, twice daily), while the control group received placebos (twice daily) for 5 weeks in total. All patients in both groups received standard treatment, including pelvic external irradiation, concurrent five cycles of chemotherapy, and brachytherapy. Measures included the incidence of myelosuppression, impairment of liver and kidney function, objective response rate (ORR), and blood Se concentrations before, during and after the treatment of the two groups. Results: A total of 104 eligible patients were enrolled in the experimental group (n = 50) or the control group (n = 54). The ORR in the experimental group and control group were 96 and 94%, respectively (p = 0.47). The baseline levels of blood Se before treatment in the experimental and control groups were similar (58.34 ± 17.63 µg/L and 60.21 ± 18.42 µg/L, p = 0.60), but the concentrations became significantly different after course completion between the two groups (76.16 ± 24.47 µg/L and 57.48 ± 14.92 µg/L, respectively, p < 0.01). Se dramatically decreased the incidence of grade 3 myelosuppression (48% vs. 63%, p = 0.034) compared to the control group. In the subgroup of patients with moderately well-differentiated cervical cancer, the incidence of thrombocytopenia induced by concurrent chemoradiotherapy was lower in the experimental group than in the control group (53.8% vs. 78.9%, p < 0.01). However, no difference was observed in liver and kidney injuries between the two groups. Conclusion: Supplementation with Se effectively increased blood Se levels in Se-inadequate cervical cancer patients. As an add-on to standard treatment, Se-yeast significantly decreased the hematologic toxicity of concurrent chemoradiotherapy.

Do high soil geochemical backgrounds of selenium and associated heavy metals affect human hepatic and renal health? Evidence from Enshi County, China.

It is unclear whether the United States Environmental Protection Agency (US EPA) method can accurately assess heavy metal risks in high-Se areas. Herein, a black shale outcropping in Enshi County, China, was taken as the study area, and a carbonate outcropping in Lichuan County was the control area. Selenium and associated heavy metal concentrations in rock, soil, rice, human blood and urine samples and human sensitive hepatic and renal biomarkers were measured. The results showed that the contents of selenium, cadmium, molybdenum and copper in the study area were 3.68 ± 2.72 µg/g, 2.65 ± 1.42 µg/g, 16.3 ± 15.5 µg/g, and 57.3 ± 17.6 µg/g, respectively, in soil (n = 47) and 1.072 ± 0.924 µg/g, 0.252 ± 0.310 µg/g, 2.800 ± 2.167 µg/g, and 10.91 ± 27.42 µg/g, respectively, in rice (n = 47). The daily adult intake levels of selenium, cadmium and molybdenum from rice consumption in the study area (exposure group) exceed the recommended tolerance values in China. According to the US EPA method, these environmental media pose a significant risk to human health. However, in the exposure group (n = 111), the median levels of the sensitive hepatic biomarkers alanine aminotransferase (18 U/L), aspartate aminotransferase (28 U/L) and total bilirubin (10.9 µmol/L) and the sensitive renal biomarkers serum creatinine (70.1 µmol/L), urinary nitrogen (5.73 mmol/L) and uric acid (303.80 µmol/L) were within reference ranges and had values equivalent to those of the control group (P > 0.05). The elements tended to differentiate during migration from one medium to another. Due to the complex interaction between selenium and heavy metals, a survey of human health indicators is indispensable when the US EPA method is used to assess the heavy metal risks in high-Se areas. The recommended molybdenum tolerable intake in the U.S. (2000 µg/d) is reasonable based on a comparison.

Schlafen-5 inhibits LINE-1 retrotransposition.

Long interspersed element 1 (LINE-1) is the only currently known active autonomous transposon in humans, and its retrotransposition may cause deleterious effects on the structure and function of host cell genomes and result in sporadic genetic diseases. Host cells therefore developed defense strategies to restrict LINE-1 mobilization. In this study, we demonstrated that IFN-inducible Schlafen5 (SLFN5) inhibits LINE-1 retrotransposition. Mechanistic studies revealed that SLFN5 interrupts LINE-1 ribonucleoprotein particle (RNP) formation, thus diminishing nuclear entry of the LINE-1 RNA template and subsequent LINE-1 cDNA production. The ability of SLFN5 to bind to LINE-1 RNA and the involvement of the helicase domain of SLFN5 in its inhibitory activity suggest a mechanism that SLFN5 binds to LINE-1 RNA followed by dissociation of ORF1p through its helicase activity, resulting in impaired RNP formation. These data highlight a new mechanism of host cells to restrict LINE-1 mobilization.

PSG7 indicates that age at diagnosis is associated with papillary thyroid carcinoma: A study based on the cancer genome atlas data.

The age of the patients at diagnosis (age at diagnosis) is a self-contained element of danger for the prognosis of patients with papillary thyroid carcinoma (PTC), which has been well recognized and continuously adopted by the international cancer staging system. However, few studies have investigated its intrinsic mechanisms. In this study, we aim to comprehensively reveal the age-related pathogenesis of PTC and identify potential prognostic biomarkers. We divided the samples into two groups, young and elderly, to filter differentially expressed genes in The Cancer Genome Atlas (TCGA), with an age of 55 years serving as a cutoff. Moreover, we combined univariate, LASSO, and multivariate Cox regression analyses to construct age-related signatures for predicting progression-free survival. Additionally, functional enrichment analysis, immune infiltration analysis, differential expression analysis, clinicopathological correlation analysis, and drug sensitivity analysis were performed in different risk subgroups and expression subgroups. We screened 88 upregulated genes and 58 downregulated genes. Both the LASSO regression model that is validated in TCGA and the model of six age-related prognostic genes (IGF2BP1, GPRC6A, IL37, CRCT1, SEMG1, and PSG7) can be used to evaluate the progression-free survival of PTC patients. The GO, KEGG, and GSEA analyses revealed that each key gene was closely associated with PTC development. Furthermore, CD8+ T cells decreased significantly, while regulatory T cells increased dramatically in the high-risk and PSG7 high expression groups. PSG7 was remarkably correlated with clinicopathological parameters (pathologic stage, T stage, and N stage) of PTC patients, and PSG7 expression was elevated in tumor samples from both TCGA and the Gene Expression Omnibus and was strongly associated with progressive stage and poor prognosis. Our results provide an innovative understanding of the age-related molecular mechanisms of PTC development. PSG7 was identified to exert a critical role in PTC progression and may serve as a promising strategy for predicting the prognosis of PTC.

The Zinc-Finger protein ZCCHC3 inhibits LINE-1 retrotransposition.

Long-interspersed element 1 (LINE-1) is an autonomous non-LTR retrotransposon. Its replication can cause mutation and rearrangement of host genomic DNA, which may result in serious genetic diseases. Host cells therefore developed defense strategies to restrict LINE-1 mobilization. In this study, we reported that CCHC-type zinc-finger protein ZCCHC3 can repress LINE-1 retrotransposition, and this activity is closely related to its zinc-finger domain. Further studies show that ZCCHC3 can post-transcriptionally diminish the LINE-1 RNA level. The association of ZCCHC3 with both LINE-1 RNA and ORF1 suggests that ZCCHC3 interacts with LINE-1 RNP and consequently causes its RNA degradation. These data demonstrate collectively that ZCCHC3 contributes to the cellular control of LINE-1 replication.

SARS-CoV-2 hijacks cellular kinase CDK2 to promote viral RNA synthesis.

The coronavirus disease 2019 (COVID-19) pandemic has devastated global health. Identifying key host factors essential for SARS-CoV-2 RNA replication is expected to unravel cellular targets for the development of broad-spectrum antiviral drugs which have been quested for the preparedness of future viral outbreaks. Here, we have identified host proteins that associate with nonstructural protein 12 (nsp12), the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 using a mass spectrometry (MS)-based proteomic approach. Among the candidate factors, CDK2 (Cyclin-dependent kinase 2), a member of cyclin-dependent kinases, interacts with nsp12 and causes its phosphorylation at T20, thus facilitating the assembly of the RdRp complex consisting of nsp12, nsp7 and nsp8 and promoting efficient synthesis of viral RNA. The crucial role of CDK2 in viral RdRp function is further supported by our observation that CDK2 inhibitors potently impair viral RNA synthesis and SARS-CoV-2 infection. Taken together, we have discovered CDK2 as a key host factor of SARS-CoV-2 RdRp complex, thus serving a promising target for the development of SARS-CoV-2 RdRp inhibitors.

A High Throughput Cell-Based Screen Assay for LINE-1 ORF1p Expression Inhibitors Using the In-Cell Western Technique.

Long interspersed nuclear element 1 (LINE-1) is a dominant autonomous retrotransposon in human genomes which plays a role in affecting the structure and function of somatic genomes, resulting in human disorders including genetic disease and cancer. LINE-1 encoded ORF1p protein which possesses RNA-binding and nucleic acid chaperone activity, and interacts with LINE-1 RNA to form a ribonucleoprotein particle (RNP). ORF1p can be detected in many kinds of tumors and its overexpression has been regarded as a hallmark of histologically aggressive cancers. In this study, we developed an In-Cell Western (ICW) assay in T47D cells to screen the compounds which can decrease the expression of ORF1p. Using this assay, we screened 1,947 compounds from the natural products library of Target Mol and Selleckchem, among which three compounds, Hydroxyprogesterone, 2,2':5',2″-Terthiophene and Ethynyl estradiol displayed potency in diminishing LINE-1 ORF1p expression level. Further mechanistic studies indicated the compounds act by affecting LINE-1 RNA transcription. Notably, we demonstrated that the compounds have an inhibitory effect on the proliferation of several lung and breast cancer cell lines. Taken together, we established a high throughput screening system for ORF1p expression inhibitors and the identified compounds provide some clues to the development of a novel anti-tumor therapeutic strategy by targeting ORF1p.

Effect of dietary selenium intake on gut microbiota in older population in Enshi region.

BACKGROUND: The microbial ecosystem in the human gut varies between individuals with differences in diet. Selenium is one of most common trace elements in everyday diet, and selenium intake affects the human gut microbiota. We studied the effect of selenium intake on the gut microbiota in regions of Enshi with different distributions of selenium. METHODS: One hundred elderly subjects (>65 years) were recruited from high-selenium and low-selenium areas in Enshi and blood, nail, and fecal specimens were obtained. The selenium contents in these samples were determined in triplicate by hydride generation atomic fluorescence spectrometry. DNA was extracted from fecal specimens and the microbial diversity was analyzed by 16 S RNA. RESULTS: The selenium contents in the blood and nails were significantly different between the high- and low-selenium areas, and the composition of the intestinal microbiota, including abundance and extent of intestinal flora, was altered. The function and metabolic pathways of the gut microbiota showed clear differences. CONCLUSIONS: As a trace element in human diet, selenium intake is an important factor that affects the intestinal microbiota and is likely involved in many human diseases. This study provides new clues and ideas for studying the correlation between selenium and human health.