Ligand-channel-enabled ultrafast Li-ion conduction.

Li-ion batteries (LIBs) for electric vehicles and aviation demand high energy density, fast charging and a wide operating temperature range, which are virtually impossible because they require electrolytes to simultaneously have high ionic conductivity, low solvation energy and low melting point and form an anion-derived inorganic interphase1-5. Here we report guidelines for designing such electrolytes by using small-sized solvents with low solvation energy. The tiny solvent in the secondary solvation sheath pulls out the Li+ in the primary solvation sheath to form a fast ion-conduction ligand channel to enhance Li+ transport, while the small-sized solvent with low solvation energy also allows the anion to enter the first Li+ solvation shell to form an inorganic-rich interphase. The electrolyte-design concept is demonstrated by using fluoroacetonitrile (FAN) solvent. The electrolyte of 1.3 M lithium bis(fluorosulfonyl)imide (LiFSI) in FAN exhibits ultrahigh ionic conductivity of 40.3 mS cm-1 at 25 °C and 11.9 mS cm-1 even at -70 °C, thus enabling 4.5-V graphite||LiNi0.8Mn0.1Co0.1O2 pouch cells (1.2 Ah, 2.85 mAh cm-2) to achieve high reversibility (0.62 Ah) when the cells are charged and discharged even at -65 °C. The electrolyte with small-sized solvents enables LIBs to simultaneously achieve high energy density, fast charging and a wide operating temperature range, which is unattainable for the current electrolyte design but is highly desired for extreme LIBs. This mechanism is generalizable and can be expanded to other metal-ion battery electrolytes.

Characterization of T cell receptor repertoire in penile cancer.

Tumor-infiltrating lymphocytes (TILs) play a key role in regulating the host immune response and shaping tumor microenvironment. It has been previously shown that T cell infiltration in penile tumors was associated with clinical outcomes. However, few studies have reported the T cell receptor (TCR) repertoire in patients with penile cancer. In the present study, we evaluated the TCR repertoires in tumor and adjacent normal tissues from 22 patients with penile squamous cell carcinoma (PSCC). Analysis of the T cell receptor beta-variable (TRBV) and joining (TRBJ) genes usage and analysis of complementarity determining region 3 (CDR3) length distribution did not show significant differences between tumor and matched normal tissues. Moreover, analysis of the median Jaccard index indicated a limited overlap of TCR repertoire between these groups. Compared with normal tissues, a significantly lower diversity and higher clonality of TCR repertoire was observed in tumor samples, which was associated with clinical characteristics. Further analysis of transcriptional profiles demonstrated that tumor samples with high clonality showed increased expression of genes associated with CD8 + T cells. In addition, we analyzed the TCR repertoire of CD4 + T cells and CD8 + T cells isolated from tumor tissues. We identified that expanded clonotypes were predominantly in the CD8 + T cell compartment, which presented with an exhausted phenotype. Overall, we comprehensively compared TCR repertoire between penile tumor and normal tissues and demonstrated the presence of distinct T cell immune microenvironments in patients with PSCC.

PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma.

For clear cell renal cell carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, the molecular mechanisms underlying lipid deposition in ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified the epigenetic regulator plant homeodomain finger protein 8 (PHF8) as an important regulator in ccRCC lipid deposition. Moreover, PHF8 is regulated by von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) axis and essential for VHL deficiency-induced lipid deposition. PHF8 transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes the lipid deposition and ccRCC progression. Mechanistically, by forming a complex with c-MYC, PHF8 up-regulates TEA domain transcription factor 1 (TEAD1) in a histone demethylation-dependent manner. Subsequently, TEAD1 up-regulates GLUL transcriptionally. Pharmacological inhibition of GLUL by l-methionine sulfoximine not only repressed ccRCC lipid deposition and tumor growth but also enhanced the anticancer effects of everolimus. Thus, the PHF8-GLUL axis represents a potential therapeutic target for ccRCC treatment.

Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) patient with ARMC5 mutations.

BACKGROUND: Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a highly heterogeneous disease with divergent manifestations ranging from asymptomatic subclinical Cushing syndrome (CS) to overt Cushing syndrome with severe complications. ARMC5 mutations occur in 20 to 55% PBMAH patients usually with more severe phenotypes. Different ARMC5 mutations might be associated with diverse phenotypes of PBMAH. CASE PRESENTATION: A 39-year-old man was admitted to our hospital with progressive weight gain and severe hypertension. He presented typical CS and its classical metabolic and bone complications like hypertension and osteoporosis. The laboratory results showed high levels of cortisol and low levels of ACTH. Low- and high-dosed dexamethasone suppression tests were negative. Contrast-enhanced computed tomography (CT) revealed multiple bilateral irregular macronodular adrenal masses. Adrenal venous sampling (AVS) confirmed that the right adrenal gland with larger nodules secreted more hormone that the left side did. Right adrenalectomy and subsequent contralateral subtotal resection were conducted. His blood pressure and CS symptoms as well as comorbidities including backache and muscle weakness improved. Whole exome sequencing identified one ARMC5 germline mutation (c.1855C > T, p. R619*), five ARMC5 somatic mutations (four novel mutations) in his right and left adrenal nodules. CONCLUSIONS: This PBMAH patient was identified with one ARMC5 germline mutation and five different somatic ARMC5 mutations (four novel mutations) in the different nodules of the bilateral adrenal masses. AVS combined with CT imagine could be helpful to determine the dominant side for adrenalectomy. Genetic testing is important for the diagnosis and management of the patient with PBMAH.

Genotype-phenotype correlation in patients with 21-hydroxylase deficiency.

Introduction: 21-hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia (CAH). However, patients with 21OHD manifest various phenotypes due to a wide-spectrum residual enzyme activity of different CYP21A2 mutations. Methods: A total of 15 individuals from three unrelated families were included in this study. Target Capture-Based Deep Sequencing and Restriction Fragment Length Polymorphism was conducted on peripheral blood DNA of the three probands to identify potential mutations/deletions in CYP21A2; Sanger sequencing was conducted with the DNA from the family members of the probands. Results: Dramatically different phenotypes were seen in the three probands of CAH with different compound heterozygous mutations in CYP21A2. Proband 1 manifested simple virilizing with mutations of 30-kb deletion/c.[188A>T;518T>A], the latter is a novel double mutants classified as SV associated mutation. Although both probands carry the same compound mutations [293-13C>G]:[518T>A], gonadal dysfunction and giant bilateral adrenal myelolipoma were diagnosed for proband 2 and proband 3, respectively. Conclusion: Both gender and mutations contribute to the phenotypes, and patients with the same compound mutations and gender could present with different phenotypes. Genetic analysis could help the etiologic diagnosis, especially for atypical 21OHD patients.

Upregulation of KHDC1L promotes the proliferation and inhibits apoptosis in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) remains a dreadful malignancy bearing poor clinical efficacy, with emerging evidences indicating RNA-binding proteins' (RBPs') relevance to the evolution of the disease. Categorized as RBPs, the K-homology domain-containing 1 (KHDC1) family is proved to be closely related to cell survival and death. As a novel KHDC1 member, only one study is currently available in osteoarthritis synovial cells to unveil KHDC1L's function of promoting proliferation. Nevertheless, to the best of our knowledge, the role of KHDC1L in human tumour is yet to be fully explored. On the basis of The Cancer Genome Atlas (TCGA) database and cell lines comparison with normal counterparts in this study, we first discovered KHDC1L to be overexpressed in HNSCC. According to bioinformatics analysis, apoptosis and P53 pathways were remarkably enriched in the KHDC1L low-expression group in TCGA database. Moreover, in vitro experiments were applied to verify that upregulation of KHDC1L could promote the proliferation and inhibit apoptosis in HNSCC cells CAL27. Transcriptome sequencing ascertained downstream differentially expressed genes to be significantly enriched in PI3K-AKT pathways. Furthermore, as validated by western blot, we found an elevated expression level of pAKT/AKT and Bcl-2, constant expression level of BAX, together with decreased activity of Caspase-3 and PARP-1 in the KHDC1L-upregulated group. In conclusion, our study pioneeringly elaborated that KHDC1L could promote proliferation and inhibit apoptosis in HNSCC cell CAL27 via AKT and Bcl-2 pathways, representing a crucial step for seeking a new diagnostic and therapeutic target in HNSCC.

Comprehensive Analysis Reveals PTK6 as a Prognostic Biomarker Involved in the Immunosuppressive Microenvironment in Breast Cancer.

The significant mortality rate that is currently experienced by female breast cancer (BC) patients highlights the importance of locating potent and dependable biomarkers in BC patients. Over the past few years, a number of studies have demonstrated that PTK6 was dysregulated in a variety of cancers. However, its expression and the clinical importance it may have in patients with BC have not been explored. Based on datasets from the TCGA database and GTEx database, we studied the expressions and functions of PTK6 across 33 different kinds of cancer. In this study, we investigated the differential expression of PTK6 in tumor tissue compared to nontumor tissue as well as in various stages of cancer. ROC assays were used to conduct an investigation into the diagnostic potential of PTK6 in BC. After that, the Kaplan-Meier method, univariate analysis, and multivariate analysis were carried out in order to investigate the PTK6 gene's potential prognostic significance in patients with BC. ssGSEA was utilized in order to conduct an investigation of the immune infiltration. In this study, we discovered that the expressions of PTK6 were significantly raised in the majority of different types of malignancies, including BC. The diagnostic value of PTK6 expression was validated by ROC tests, demonstrating an AUC greater than 0.7. A positive PR, ER, and HER2 status was found to be related with high expression levels of PTK6. According to the results of a survival analysis, patients who had a high level of PTK6 expression had a shorter overall survival time than those who had a low level of PTK6 expression. Besides, we observed that PTK6 expressions were positively correlated with the abundance of NK CD56bright cells and Th17 cells and negatively correlated with that of Th1 cells, macrophages, B cells, T cells, aDC, DC, cytotoxic cells, Tem, TFH, NK CD56dim cells, Treg, and Tgd. In conclusion, PTK6 expression was found to be linked with the clinical phenotype of BC, and as a result, this finding may have consequences for the diagnosis, prognosis, and treatment of individuals with BC.

A healthier water use strategy in primitive forests contributes to stronger water conservation capabilities compared with secondary forests.

Water conservation is an important ecological function of forest ecosystems, plant water use strategy is a key factor in regulating forest ecosystem water balance. However, there are still insufficient studies on the water conservation capacity and water use strategies of different forest types, especially in climate-sensitive areas. In this study, we determined the stable isotope values (δD, δ18O and d-excess) of plant water, soil water and precipitation from two typical stand types (primary forest and secondary forest) on Changbai Mountain to reveal plant water use and evaluated the water conservation capacity. The results indicated that rainwater infiltrated into the soil combined with piston flow and preferential flow in the primary forest, and preferential flow was the only form of flow in the secondary forest. The main tree species in the primary forest formed a relatively stable water use niche. Among them, the water use pattern of Quercus mongolica Fisch. ex Ledeb (Qm.) was transformed between shallow and deep soil layers with strong ecological plasticity. The dominant species in secondary forest derived water from similar soil layers with intense interspecific competition. By comparing the water use patterns, the secondary forest conformed to the hypothesis of "two water worlds", while the primary forest conformed to the hypothesis of one reservoir. The primary forest ecosystem had stronger water conservation capacity than secondary forest ecosystem due to the regulable water use strategies of plants and the stable water conservation capacity of the soil. These results will provide theoretical support and a reference for plan future forest management strategies in the climate-sensitive areas.

Manganese methionine hydroxy analog chelated affects growth performance, trace element deposition and expression of related transporters of broilers.

The present study aimed to evaluate the effects of manganese methionine hydroxyl analog chelated (Mn-MHAC) as a manganese (Mn) source on growth performance and trace element deposition in broilers. A total of 432 Arbor Acres commercial female broilers were fed a basal corn-soybean diet containing Mn at 25.64 mg/kg diet for 10 d. They were then randomly assigned to 6 groups, including a control group (the basal diet), a Mn sulfate group (the basal diet supplemented with Mn at 100 mg/kg diet), and 4 Mn-MHAC groups (the basal diet supplemented with Mn-MHAC at 25, 50, 75 and 100 mg Mn/kg diet, respectively). The results showed that compared with the control group, groups supplemented with Mn-MHAC had a positive effect on BW (quadratic, P = 0.017) and ADG (quadratic, P = 0.017). Moreover, the Mn-MHAC (50 mg Mn/kg diet) group had significantly greater BW and ADG (P < 0.05) compared with the other Mn-MHAC groups. Trace element deposition results also showed that tibial Mn increased (linear or quadratic, P = 0.002 and 0.009, respectively) in groups fed diets with increased levels of Mn-MHAC. In contrast, Fe deposition decreased both in the heart (linear, P = 0.020) and tibia (P < 0.05). In addition, the Mn-MHAC supplement noticeably lowered serum Mn-SOD activity (linear or quadratic, P = 0.048 and 0.019, respectively). The relative mRNA levels of divalent metal transporter 1 (DMT1) (P = 0.024), ferroportin 1 (FPN1) (P = 0.049), and Cu transporter-1(CTR1) (P < 0.001) in the duodenum, as well as CTR1 in the jejunum and ileum (P = 0.040 and 0.011, respectively) were higher in the Mn-supplemented group than in the control group. Furthermore, the relative mRNA level of DMT1 in the jejunum and ileum of broilers in the Mn-MHAC group (50 mg Mn/kg diet) did not differ from those in the control group, but was lower than those in the Mn sulfate group (P < 0.05). In conclusion, Mn-MHAC dietary supplementation improved the growth performance and trace element deposition in broilers. From this study, we recommend the optimum Mn-MHAC level to meet the Mn requirement of broilers is 50 to 75 mg Mn/kg diet.

Low-cost batteries based on industrial waste Al-Si microparticles and LiFePO4 for stationary energy storage.

Owing to their high capacity and low working potential, Si-based anodes are regarded as potential alternatives to graphite anodes to meet the higher requirements of Li-ion batteries (LIBs). However, high volume change causes the fracturing and pulverization of the bulk anode and continuous side reactions, which are more severe in large-particle Si anodes, limiting its practical application. Herein, to build a low-cost battery system, we chose a common industrial waste product, Al-Si microparticles (Al-SiMPs, ∼30 µm), as the anode for LIBs and coupled it with a 2.0 M LiFP6 2-MeTHF electrolyte to support its operation. The Al-SiMP anode showed a high specific capacity and a significantly improved electronic conductivity, ensuring high energy and power densities. An ultra-high initial coulombic efficiency (iCE) of 91.6% and a cycling CE of ∼99.9% were obtained in the half-cells, which delivered a capacity of 1300 mA h g-1 and maintained 95.3% after 100 cycles. Paired with low-cost and high-safety LiFePO4 as the cathode, the LFP||Al-SiMP full cells showed decent cycling stability and exhibited a considerable cost advantage, demonstrating a competitive solution for stationary energy storage.

Nanoselenium and Selenium Yeast Have Minimal Differences on Egg Production and Se Deposition in Laying Hens.

The objective of this study was to compare the effects of nanoselenium (NS) and selenium yeast (SY) on the performance, egg selenium (Se) concentration, and anti-oxidative capacity of hens. A total of 216 Brown Hy-line hens (29-week old) were randomly allocated into three treatments (6 replicate/treatment, 12 hens/replicate). The pre-trial period lasted 7 days, and the experimental period lasted 35 days. Dietary treatments included corn-soybean meal basal diet (containing 0.16 µg Se/g, as control group), and basal diet supplemented with 0.3 mg Se/kg diet (Se was from NS or SY), called as SY group or NS group, respectively. At the end of the experiment, one hen per replicate from each treatment was slaughtered. Liver, spleen, and kidney tissues were sampled for the determination of Se concentrations. The results showed that NS or SY supplement significantly improved feed conversion ratio (P < 0.05), soft broken egg rate (P < 0.05), and the serum T-AOC value (P < 0.05) when compared with control group. Remarkably, the deposition of Se increased significantly (P < 0.05) and equivalently in egg, liver, and kidney of hens supplemented with both NS and SY. Interestingly, SY supplement also enhanced the serum CAT and SOD activities (P < 0.05), NS but not SY significantly reduced serum MDA (P < 0.05), whereas RT-PCR results did not show significant differences in the mRNA levels of antioxidant genes among three groups (P > 0.05). Taken together, dietary supplemented with SY or NS improved the Se deposition in eggs, liver and kidney of laying hens, increased antioxidant activity, and NS supplement had greater Se deposition in the kidney tissue than SY supplement. SY or NS supplement could be considered to be applied for Se-enriched egg production.

Histone demethylase PHF8 drives neuroendocrine prostate cancer progression by epigenetically upregulating FOXA2.

Neuroendocrine prostate cancer (NEPC) is a more aggressive subtype of castration-resistant prostate cancer (CRPC). Although it is well established that PHF8 can enhance prostate cancer cell proliferation, whether PHF8 is involved in prostate cancer initiation and progression is relatively unclear. By comparing the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with or without Phf8 knockout, we systemically examined the role of PHF8 in prostate cancer development. We found that PHF8 plays a minimum role in initiation and progression of adenocarcinoma. However, PHF8 is essential for NEPC because not only is PHF8 highly expressed in NEPC but also animals without Phf8 failed to develop NEPC. Mechanistically, PHF8 transcriptionally upregulates FOXA2 by demethylating and removing the repressive histone markers on the promoter region of the FOXA2 gene, and the upregulated FOXA2 subsequently regulates the expression of genes involved in NEPC development. Since both PHF8 and FOXA2 are highly expressed in NEPC tissues from patients or patient-derived xenografts, the levels of PHF8 and FOXA2 can either individually or in combination serve as NEPC biomarkers and targeting either PHF8 or FOXA2 could be potential therapeutic strategies for NEPC treatment. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including PHD, VHL, HIF-2A (EPAS1), and SDHx are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.

LSD1 Promotes Bladder Cancer Progression by Upregulating LEF1 and Enhancing EMT.

Epithelial-to-mesenchymal transition (EMT) is one of the important underlying molecular mechanisms for most types of cancers including bladder cancer. The precise underlying molecular mechanism in EMT-mediated bladder cancer progression is far from completed. LSD1, a histone lysine-specific demethylase, is known to promote cancer cell proliferation, metastasis, and chemoresistance. We found in this study that LSD1 is highly upregulated in bladder cancer specimens, especially those underwent chemotherapy, and the elevated levels of LSD1 are highly associated with bladder cancer grades, metastasis status, and prognosis. Inhibiting or knockdown LSD1 repressed not only EMT process but also cancer progression. Mechanistically, LSD1 complexes with ß-catenin to transcriptionally upregulate LEF1 and subsequently enhances EMT-mediated cancer progression. More importantly, LSD1 specific inhibitor GSK2879552 is capable of repressing tumor progression in patient-derived tumor xenograft. These findings altogether suggest that LSD1 can serve as not only a prognostic biomarker but also a promising therapeutic target in bladder cancer treatment.

Correction to: Downregulation of the long noncoding RNA TUG1 inhibits the proliferation, migration, invasion and promotes apoptosis of renal cell carcinoma.

In the original article, we realized that an error occurred when we grouped the separate photos to generate the combined Figure 4 The same image was accidentally pasted twice in one figure, while we were not fully aware of the error at that time. We immediately reviewed the original data again and made sure that no changes need to be made in other parts of the paper. We are sure that the published manuscript was published without prior knowledge of the error and that it does not alter the conclusions of the study.

Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer.

Immune-checkpoint blockades (ICBs) have been routinely implemented to treat metastatic urothelial cancer (mUC), whereas robust biomarkers are urgently warranted. Herein, we explored latent promising biomarkers based on 348 pretreatment mUC samples from IMvigor210. Methods: The genome, transcriptome, immunome, and metabolome were systemically analyzed using the external TCGA dataset for validation. Kaplan-Meier and ROC curve analyses were performed to estimate the predictive capacity of M1-macrophage infiltration. Chi-square/Spearman/Mann Whitney U test are used to determine its correlation to genetic, biochemical, and clinicopathological parameters. Results: M1 frequency is a robust biomarker for predicting the prognosis and response to ICBs, which is non-inferior to tumor mutation burden (TMB) or tumor neoantigen burden (TNB), and exceeds CD8 T cells, T cell inflamed gene expression profile (GEP), and PD-L1 expression. Moreover, M1 infiltration is associated with immune phenotypes (AUC = 0.785) and is negatively correlated with immune exclusion. Additionally, transcriptomic analysis showed immune activation in the high-M1 subgroup, whereas it showed steroid and drug metabolism reprograming in the M1-deficient subset, which characterized the limited sensitivity to ICB therapy. Notably, investigation of the corresponding intrinsic genomic profiles highlighted the significance of TP53 and FGFR alterations. Conclusions: M1 infiltration is a robust biomarker for immunotherapeutic response and immunophenotype determination in an mUC setting. Innate immunity activation involving macrophage polarization remodeling and anti-FGFR mutations may be promising strategies for synergy with anti-PD-L1 treatments and may help prolong the clinical survival of patients with mUC.

A Renal Cell Carcinoma with Biallelic Somatic TSC2 Mutation: Clinical Study and Literature Review.

OBJECTIVE: To elucidate the effect of the biallelic somatic TSC2 mutations, identified in one adolescent patient, in renal cell carcinoma (RCC). METHODS: Mutation analyses, immunohistochemistry and real-time polymerase chain reaction (PCR) were conducted. RESULTS: Two novel somatic mutations of TSC2 in unilateral and solitary RCC samples from a 14-year-old female were identified. The pathological features suggest the tumor as a clear-cell renal cell carcinoma. In addition, immunohistochemistry revealed elevated levels of phosphorylated S6K1. Results from in vitro cellular experiments suggest that the mutant TSC2 proteins were quickly degraded and they failed to repress the phosphorylation of S6K1 and STAT3, which leads to constitutive activation of mTORC1 pathway and ultimately cause the development of RCC. CONCLUSION: Detecting TSC2 mutation in patients with early RCC onset would be beneficial and mTOR inhibitor could be a therapeutic option for TSC2 mutation-induced RCC.

Effects of Different Selenium Sources on Laying Performance, Egg Selenium Concentration, and Antioxidant Capacity in Laying Hens.

Supplementation of selenium (Se) is a common practice in the poultry industry via sodium selenite (SS) and selenium yeast (SY), while the effects of nano-selenium (NS) on laying hens are poorly known. This study aimed to compare the effects of NS, SS, and SY on productivity; selenium (Se) deposition in eggs; and antioxidant capacity in laying hens. A total of 288 30-week-old Brown Hy-line laying hens were randomly assigned into four dietary treatments, which included corn-soybean meal basal diet (Con) without Se sources and basal diets supplemented with 0.3 mg Se/kg as SS, SY, or NS, respectively. The results exhibited that Se-supplemented treatments achieved greater egg production, egg weight, and daily egg mass, also better feed conversion ratio than Con group (p < 0.05). Se supplementation significant increased egg Se concentration and decreased the egg Se deposition efficiency (p < 0.05), while SY or NS supplementation had higher Se deposition efficiency than SS group at 35 days (p < 0.05). Moreover, serum glutathione peroxidase (GSH-Px) activity increased in SS or NS group compared to Con group (p < 0.05). The glutathione peroxidase 4 (GPX-4) mRNA levels in liver were significantly higher (p < 0.05) in SS or SY group than in NS group, and mRNA levels of the methionine (Met) metabolism gene glycine N-methyltranserfase (GNMT) were markedly upregulated (p < 0.05) in SY group compared to SS or NS group. Taken together, the results revealed Se from SY is deposited into eggs more efficiently than Se from NS or SS, probably via enhancing the route of Met metabolism. Meanwhile, it might be concluded that SS or SY supplementation directly regulated GSH-Px activity via enhancing GPx4 level, whereas NS via GPx1, thus affecting body oxidation and development.

Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients.

Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.

The roles of the COX2/PGE2/EP axis in therapeutic resistance.

Therapeutic resistance has been and remains to be the major challenge in developing successful treatments for different cancers and therefore, understanding the underlying mechanisms in the development of therapeutic resistance is crucial in combating cancers. Multiple mechanisms underlie the development of therapeutic resistance, and the signaling pathways involved in cancer stem cell repopulation, enhanced epithelial-mesenchymal transition (EMT), inflammatory infiltration, and immunosuppression play pivotal roles in this process. Accumulating evidence indicates that the COX2/PGE2/EP axis plays crucial roles not only in tumor development including initiation and progression but also in the development of therapeutic resistance. In this review, we will first dissect the relationship between the COX2/PGE2/EP axis and therapeutic resistance by focusing on the roles of the COX2/PGE2/EP axis in cancer stem cell repopulation, EMT, and anti-cancer immunity. Then, we will summarize the currently available compounds/drugs targeting each component of this axis as well as some of the underlying mechanisms. We hope that better understanding the underlying mechanisms of the functional compounds will be helpful in seeking additive and/or synergistic effects against therapeutic resistance without or with minimal adverse consequence.