Hypoxia Affects Mitochondrial Stress and Facilitates Tumor Metastasis of Colorectal Cancer Through Slug SUMOylation.

BACKGROUND: Colorectal cancer (CRC) is a malignant tumor. Slug has been found to display a key role in diversified cancers, but its relevant regulatory mechanisms in CRC development are not fully explored. OBJECTIVE: Hence, exploring the function and regulatory mechanisms of Slug is critical for the treatment of CRC. METHODS: Protein expressions of Slug, N-cadherin, E-cadherin, Snail, HIF-1α, SUMO1, Drp1, Opa1, Mfn1/2, PGC-1α, NRF1, and TFAM were measured through western blot. To evaluate the protein expression of Slug and SUMO-1, an immunofluorescence assay was used. Cell migration ability was tested through transwell assay. The SUMOylation of Slug was examined through CO-IP assay. RESULTS: Slug displayed higher expression and facilitated tumor metastasis in CRC. In addition, hypoxia treatment was discovered to upregulate HIF-1α, Slug, and SUMO-1 levels, as well as induce Slug SUMOylation. Slug SUMOylation markedly affected mitochondrial biosynthesis, fusion, and mitogen-related protein expression levels to trigger mitochondrial stress. Additionally, the induced mitochondrial stress by hypoxia could be rescued by Slug inhibition and TAK-981 treatment. CONCLUSION: Our study expounded that hypoxia affects mitochondrial stress and facilitates tumor metastasis of CRC through Slug SUMOylation.

Maternal Thyroid Function and Birth Weight in Twins.

CONTEXT: Thyroid hormones are associated with birth weight in singleton pregnancy. Twin pregnancies need more thyroid hormones to maintain the normal growth and development of the fetuses compared with single pregnancy. OBJECTIVE: We aimed to investigate the association of thyroid hormones and birth weight in twins. METHODS: This was a retrospective cohort study in a Chinese population. Pregnant women who received regular antenatal health care and delivered live-born twins from 2014 to 2019 were included (n = 1626). Linear mixed model with restricted cubic splines and logistic regression models were used to estimate the association of thyroid hormones with birth weight and birth weight discordance in twins. RESULTS: We observed that both thyrotropin (TSH) and free thyroxine (FT4) were not associated with birth weight in twins overall, while when stratifying on fetal sex or chorionicity, there were nonlinear association between FT4 levels and birth weight in boys (Pnonlinear < .001) and in dichorionic (DC) twins (Pnonlinear = 0.03). Women with levels of FT4 lower than the 10th percentile had a higher risk of birth weight discordance in their offspring than women with normal FT4 levels (range, 2.5 to 97.5 percentiles) (odds ratio = 1.58; 95% CI, 1.05-2.33). CONCLUSION: Our study suggests there was an association of FT4, but not TSH, with birth weight and birth weight discordance varied by sex and chorionicity. These findings could have implications for obstetricians to be aware of the importance of FT4 levels in preventing birth weight discordance in twin pregnancy.

High-Performance Poly(vinylidene fluoride-hexafluoropropylene)-Based Composite Electrolytes with Excellent Interfacial Compatibility for Room-Temperature All-Solid-State Lithium Metal Batteries.

Composite solid-state electrolytes (CSEs) have been developed rapidly in recent years owing to their high electrochemical stability, low cost, and easy processing characteristics. Most CSEs, however, require high temperatures or flammable liquid solvents to exhibit their acceptable electrochemical performance. Room-temperature all-solid-state batteries without liquid electrolytes are still unsatisfactory and under development. Herein, we have prepared a composite solid electrolyte with excellent performance using a polymer electrolyte poly(vinylidene fluoride-hexafluoropropylene) and an inorganic electrolyte Li6.4La3Zr1.4Ta0.6O12. With the assistance of lithium salts and plasticizers, the prepared CSE achieves a high ionic conductivity of 4.05 × 10-4 S·cm-1 at room temperature. The Li/CSE/Li symmetric cell can be stably cycled for more than 1000 h at 0.1 mA/cm2 without short circuits. The all-solid-state lithium metal battery using a LiFePO4 cathode displays a high discharge capacity of 148.1 mAh·g-1 and a capacity retention of 90.21% after 100 cycles. Moreover, the high electrochemical window up to 4.7 V of the CSE makes it suitable for high-voltage service environments. The all-solid-state battery using a lithium nickel-manganate cathode shows a high discharge specific capacity of 197.85 mAh·g-1 with good cycle performance. This work might guide the improvement of future CSEs and the exploration of flexible all-solid-state lithium metal batteries.

Anionic Redox Regulated via Metal-Ligand Combinations in Layered Sulfides.

The increasing demand for energy storage is calling for improvements in cathode performance. In traditional layered cathodes, the higher energy of the metal 3d over the O 2p orbital results in one-band cationic redox; capacity solely from cations cannot meet the needs for higher energy density. Emerging anionic redox chemistry is promising to access higher capacity. In recent studies, the low-lying O nonbonding 2p orbital was designed to activate one-band oxygen redox, but they are still accompanied by reversibility problems like oxygen loss, irreversible cation migration, and voltage decay. Herein, by regulating the metal-ligand energy level, both extra capacities provided by anionic redox and highly reversible anionic redox process are realized in NaCr1- y Vy S2 system. The simultaneous cationic and anionic redox of Cr/V and S is observed by in situ X-ray absorption near edge structure (XANES). Under high d-p hybridization, the strong covalent interaction stabilizes the holes on the anions, prevents irreversible dimerization and cation migration, and restrains voltage hysteresis and voltage decay. The work provides a fundamental understanding of highly reversible anionic redox in layered compounds, and demonstrates the feasibility of anionic redox chemistry based on hybridized bands with d-p covalence.

Response of gut microbiota to serum metabolome changes in intrahepatic cholestasis of pregnant patients.

BACKGROUND: Intrahepatic cholestasis in pregnancy (ICP) is the most common liver disease during pregnancy, and its exact etiology and course of progression are still poorly understood. AIM: To investigate the link between the gut microbiota and serum metabolome in ICP patients. METHODS: In this study, a total of 30 patients were recruited, including 15 patients with ICP (disease group) and 15 healthy pregnant patients (healthy group). The serum nontarget metabolomes from both groups were determined. Amplification of the 16S rRNA V3-V4 region was performed using fecal samples from the disease and healthy groups. By comparing the differences in the microbiota and metabolite compositions between the two groups, the relationship between the gut microbiota and serum metabolites was also investigated. RESULTS: The Kyoto Encyclopedia of Genes and Genomes analysis results showed that the primary bile acid biosynthesis, bile secretion and taurine and hypotaurine metabolism pathways were enriched in the ICP patients compared with the healthy controls. In addition, some pathways related to protein metabolism were also enriched in the ICP patients. The principal coordination analysis results showed that there was a distinct difference in the gut microbiota composition (beta diversity) between the ICP patients and healthy controls. At the phylum level, we observed that the relative abundance of Firmicutes was higher in the healthy group, while Bacteroidetes were enriched in the disease group. At the genus level, most of the bacteria depleted in ICP are able to produce short-chain fatty acids (e.g., Faecalibacterium, Blautia and Eubacterium hallii), while the bacteria enriched in ICP are associated with bile acid metabolism (e.g., Parabacteroides and Bilophila). Our results also showed that specific genera were associated with the serum metabolome. CONCLUSION: Our study showed that the serum metabolome was altered in ICP patients compared to healthy controls, with significant differences in the bile, taurine and hypotaurine metabolite pathways. Alterations in the metabolization of these pathways may lead to disturbances in the gut microbiota, which may further affect the course of progression of ICP.

Investigating the theragnostic potential of 131I-caerin peptide in thyroid cancer.

OBJECTIVE: Caerin is a new peptide with tumour toxicity and its uptake by tumour cells is independent of the sodium iodide symporter (NIS). Thyroid cancer is the most common cancers of endocrine malignancy. Radioiodine (131I)-refractory thyroid cancer is the most lethal subtype of the thyroid cancers and remains a clinical challenge. In the current study, we investigated the 131I radiolabeling efficiency of Caerin and the effects of Caerin, 131I-Caerin and free 131I on differentiated and undifferentiated human thyroid cancer cell lines (B-CPAP and CAL-62) in vitro. MATERIALS AND METHODS: Cell Counting Kit-8 was used to assess the cytotoxic effect of Caerin, 131I-Caerin and free 131I on B-CPAP and CAL-62 cells. Laser scanning confocal microscope was exploited to evaluate the uptake and internalization of Caerin by thyroid cancer cells. The Chloramine-T method was used to label the peptide with 131I. And the stability and water partition coefficient (Log P) of 131I-Caerin were studied. RESULTS: Our results demonstrated that Caerin and 131I-Caerin could be accumulated by B-CPAP and CAL-62 cells, resulting in killing of the thyroid cancer cells in vitro. The efficacy of 131I-Caerin is much higher than 131I, especially to undifferentiated CAL-62 cells. The results prove the feasibility of radioiodination of the 131I-Caerin via the Chloramine-T method. Moreover, the result indicate the hydrophobic 131I-Caerin was stable in 72 hours. CONCLUSION: Iodine-131-Caerin can inhibit the cell viability of thyroid cancer and hold certain promise as a theragnostic tool for human thyroid cancers.

Anionic redox reaction in layered NaCr2/3Ti1/3S2 through electron holes formation and dimerization of S-S.

The use of anion redox reactions is gaining interest for increasing rechargeable capacities in alkaline ion batteries. Although anion redox coupling of S2- and (S2)2- through dimerization of S-S in sulfides have been studied and reported, an anion redox process through electron hole formation has not been investigated to the best of our knowledge. Here, we report an O3-NaCr2/3Ti1/3S2 cathode that delivers a high reversible capacity of ~186 mAh g-1 (0.95 Na) based on the cation and anion redox process. Various charge compensation mechanisms of the sulfur anionic redox process in layered NaCr2/3Ti1/3S2, which occur through the formation of disulfide-like species, the precipitation of elemental sulfur, S-S dimerization, and especially through the formation of electron holes, are investigated. Direct structural evidence for formation of electron holes and (S2)n- species with shortened S-S distances is obtained. These results provide valuable information for the development of materials based on the anionic redox reaction.

Correlation between polymorphisms of the NR3C1 gene and glucocorticoid effectiveness in patients with pemphigus vulgaris.

Glucocorticoid (GC) resistance is the major obscule in the treatment of pemphigus vulgaris (PV) for both patients and clinicans with unclear mechanism. A hypotheis for this resistance is the mutations or polymorphisms present in the nuclear receptor subfamily 3, group C, member 1 (NR3C1) gene that encodes receptors for steroid hormones. This study aimed to investigate the association between NR3C1 gene polymorphisms and GC effectiveness in PV patients. 94 PV patients (64 GC-sensitive and 30 GC-resistant) and 100 healthy volunteers were enrolled in this case-control study. The genotyping of single nucleotide polymorphisms (SNPs) in BCL1, Arg23Lys, Asn363Ser 1548 t-insert, and le747Met, together with tag-SNP sites of the NR3C1 gene were evaluated. No significant differences were observed in genotypic and allelic frequencies of the 16 SNPs between PV patients and healthy volunteers. However, SNPs rs 11745958 C/T (OR: 8.95) and rs17209237 A/G (OR: 4.07) may be associated with an increased risk of GC resistance, while rs 33388 A/T (OR: 0.45) and rs7701443 A/G (OR: 0.51) may indicate a decreased risk of GC resistance in PV patients. NR3C1 gene variation may be associated with GC resistance in PV patients. More extensive genetic analyses and mechanistic analysis are required for further exploration.

Antisite occupation induced single anionic redox chemistry and structural stabilization of layered sodium chromium sulfide.

The intercalation compounds with various electrochemically active or inactive elements in the layered structure have been the subject of increasing interest due to their high capacities, good reversibility, simple structures, and ease of synthesis. However, their reversible intercalation/deintercalation redox chemistries in previous compounds involve a single cationic redox reaction or a cumulative cationic and anionic redox reaction. Here we report an anionic redox chemistry and structural stabilization of layered sodium chromium sulfide. It was discovered that the sulfur in sodium chromium sulfide is electrochemically active, undergoing oxidation/reduction rather than chromium. Significantly, sodium ions can successfully move out and into without changing its lattice parameter c, which is explained in terms of the occurrence of chromium/sodium vacancy antisite during desodiation and sodiation processes. Our present work not only enriches the electrochemistry of layered intercalation compounds, but also extends the scope of investigation on high-capacity electrodes.The rational design of intercalation electrodes is largely confined to the optimization of redox chemistry of transition metals and oxygen. Here, the authors report the single anionic redox process in NaCrS2 where it is sulfur rather than chromium that works as the electrochemical active species.

Quantity of Candida Colonies in Saliva: A Diagnostic Evaluation for Oral Candidiasis.

OBJECTIVE: To investigate the relationship between the quantity of Candida colonies in saliva and oral candidiasis (OC), as well as to identify the threshold for distinguishing oral candidiasis from healthy carriage. METHODS: A diagnostic test was conducted in 197 patients with different oral problems. The diagnosis of OC was established based on clinical features. Whole saliva samples from the subjects were cultured for Candida species. Receiver operating characteristic (ROC) curve analysis was used in this study. RESULTS: OC patients had significantly more Candida colony-forming units per millilitre saliva (795 cfu/ml) than asymptomatic carriers (40 cfu/ml; P < 0.05). Among different types of candidiasis, the quantity of Candida colonies differed. The number of Candida colonies in pseudomembranous type was significantly higher than that in the erythematous type (P < 0.05). Candida albicans was the predominant species of Candida. The cut-off point with the best fit for OC diagnosis was calculated to be 266 cfu/ml. The sensitivity and specificity were 0.720 and 0.825, respectively. Analysis of the ROC curve indicated that Candida colonies had a high diagnostic value for OC, as demonstrated by the area under the curve (AUC = 0.873). CONCLUSION: Based on this study, the value of 270 cfu/ml was considered a threshold for distinguishing OC from carriage.

[Analysis of Clinical Medication Laws for 451 Patients with HIV Infection in a Real World].

Objective To analyze clinical features and medication laws of patients with human immunodeficiency virus (HIV) infection. Methods Real world data based on Hospital Information System (HIS) were collected from 17 grade 3 hospitals across China from Jan.2006 to Dec.2011. Data of case his- tory in HIV infectors included their general information, features of AIDS, medications of Western drugs and Chinese herbs during hospitalization. Results Data of 451 patients with HIV infection were collected. A total of 261 patients had clear age record. Their age ranged between 18 and 65 [ accounting for 90. 4% (236/ 261 ) ], with an average age of 36. The ratio of male to female was 2. 8:1. They were hospitalized first at De- partment of Lemology (66. 96%), followed by Department of Respiration (8. 2%). They were admitted to hospital first at clinics (79. 6%), and accepted from Emergency Department (20. 18%). Most of them were admitted to hospital due to infectious diseases. Of them, tuberculosis occupied the top (8.29%), followed by bacterial pneumonia (6. 44%). Totally 349 patients had complete medication record. A total of 399 kinds of Western drugs and 80 kinds of Chinese patent medicines were used. The frequency of using antimicrobial drugs was the top (11. 86%), and Compound Sulfamethoxazole was mostly used in 120 cases (2. 81%). Of 80 kinds of Chinese patent medicines, heat clearing and detoxifying herbs were most often used (19. 27%), followed by antipyretics (10. 30%), tonics (8. 97%), and expectorant (7. 31%). Antimicrobial drugs combined heat clearing and detoxifying herbs were the most often seen in clinics. The 451 HIV infec- tors had steady condition after treated by Western drugs and Chinese herbs. The improvement rate reached 51. 33%. Conclusion Antimicrobial drugs were most often used in HIV patients. Heat clearing and detoxif- ying herbs were most often used in HIV patients. Antimicrobial drugs combined heat clearing and detoxif- ying herbs were most often seen in clinics for HIV patients.

A near ambient pressure XPS study of subnanometer silver clusters on Al2O3 and TiO2 ultrathin film supports.

We have investigated model systems of silver clusters with different sizes (3 and 15 atoms) deposited on alumina and titania supports using ambient pressure X-ray photoelectron spectroscopy. The electronic structures of silver clusters and support materials are studied upon exposure to various atmospheres (ultrahigh vacuum, O2 and CO) at different temperatures. Compared to bulk silver, the binding energies of silver clusters are about 0.55 eV higher on TiO2 and 0.95 eV higher on Al2O3 due to the final state effect and the interaction with supports. No clear size effect of the silver XPS peak is observed on different silver clusters among these samples. Silver clusters on titania show better stability against sintering. Al 2p and Ti 2p core level peak positions of the alumina and titania support surfaces change upon exposure to oxygen while the Ag 3d core level position remains unchanged. We discuss the origin of these core level shifts and their implications for catalytic properties of Ag clusters.

[Levels of interlukin-6 and tumor necrosis factor-α in saliva of patients with type 2 diabetes mellitus and oral lichen planus].

OBJECTIVE: To study the relationship between type 2 diabetes mellitus (T2DM) and oral lichen planus (OLP) by detecting the level of salivary tumor necrosis factor (TNF-α) and interlukin-6 (IL-6). METHODS: Subjects were divided into 4 groups: T2DM/OLP group 29 patients, T2DM group 39 patients, OLP group 21 patients, and control group 43 individuals. The salivary interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) were detected by enzyme-linked immuno sorbent assay (ELISA). RESULTS: (1) The level of salivary IL-6 in patients with T2DM/OLP [(12.30 ± 16.03) ng/L] was significantly higher than those in T2DM [(6.29 ± 5.91) ng/L] and OLP groups [(3.64 ± 4.47) ng/L], P<0.05. The level of salivary IL-6 was significantly lower in OLP group [(3.64 ± 4.47) ng/L] than in control group [(7.91 ± 4.05) ng/L], P<0.001. The level of salivary TNF-α in T2DM group [(8.80 ± 8.41) ng/L] was significantly lower than those in OLP [(14.02 ± 9.65) ng/L] and control groups [(15.02 ± 6.13) ng/L], P<0.05. (2) The level of salivary TNF-α is significantly negative correlated with pH value of saliva in T2DM/OLP group(r=-0.593, P<0.01);The level of salivary TNF-α and IL-6 are significantly positive correlated with waistline in control group(r=0.312,P=0.05).(3) The levels of salivary IL-6 and TNF-α were positively related to OLP clinical type, P<0.05. (4)When OLP played an overlying role on T2DM, the level of TNF-α was weakened and that of IL-6 was strengthened. CONCLUSION: When T2DM and OLP are in concurrence,there is a synergistic effect,and the secretion of IL-6 increases markedly; The level of salivary TNF-α is associated with local oral environment.

[Correlation between the quantity of oral mucosal micronucleus cells and cancerization].

OBJECTIVE: To explore the relationship between micronuclei and malignant development of oral epithelial dysplasia (OED). METHODS: Oral exfoliated cells were smeared from 30 control subjects, 46 patients with oral lichen planus (OLP), 78 patients with oral leukoplakia (OLK) and hyperplasia, 30 patients with OLK and mild OED, 29 patients with OLK and moderate OED, 15 patients with OLK and severe OED and 22 patients with oral squamous cell carcinoma (OSCC). RESULTS: Micronucleus rates declined according to the order of OSCC, OLK and severe OED, OLK and moderate OED, OLK and mild OED, OLK and hyperplasia, OLP and control groups (P<0.001). CONCLUSION: Micronuclei may reflect the progression of oral epithelial malignant changes. It could be used in monitoring cancerization in following up cases regularly.

Papillomavirus virus like particle-based therapeutic vaccine against human papillomavirus infection related diseases: immunological problems and future directions.

Chronic infection with certain types of human papillomaviruses (HPV), especially HPV-16 and HPV-18, leads to the development of cervical cancer. Prophylactic HPV vaccines based on HPV virus like particles (VLPs) have now been developed. The commercial vaccines, Gardasil and Cervarix are clinically effective in preventing HPV infection but do not have a therapeutic effect against existing chronic HPV infections. However, papillomavirus (PV) VLPs elicit strong cytotoxic T cell (CTL) responses and PV VLPs without any adjuvant have therapeutic effects in animal PV infection model. Alum in Gardasil, Alum and 3-O-deacylated-4'-monophosphoryl lipid A (ASO4) in Cervarix may stimulate IL10 production and inhibit the Th1, CTL immune response of immunized individuals. PV VLPs also stimulate the production of IL10 by CD4(+) T cells, which prevent their CTL generation effect as a therapeutic vaccine. Neutralizing IL10 at the time of PV VLPs immunization increases cytotoxic T cell responses. PV VLPs incorporating PV early protein E2, 6 and 7, together with immune stimulator that promote strong type 1 responses, and at the same time blocking the effect of IL10 may have therapeutic effect against HPV infection related diseases and are worth further basic and clinical investigation.

Development and function of IL-10 IFN-gamma-secreting CD4(+) T cells.

IL-10 IFN-gamma-secreting CD4(+) T cells were first found in the early 1990s. They are suppressive T cells able to inhibit cytotoxic T lymphocytes. These cells (Foxp3-T bet(+)) have a similar function but are distinct from conventional Tregs. The production of IL-10 in these cells requires IL-27 and TGF-beta and was regulated by several signal pathways including Notch, STAT, and NF-kappaB. The crosstalk among these pathways is critical for the generation and function of these cells. IL-10 IFN-gamma-secreting CD4(+) T cells are activated in chronic infection and are responsible for prolonged infection. Thus, their modulation has therapeutic implications for the treatment of infectious diseases. However, it is complicated, and fine-tuning of IFN-gamma and IL-10 secretion by these cells is needed for disease management, as inhibition of these cells will also lead to overimmune responses. On the other hand, increasing their numbers in autoimmune diseases may have beneficial effects.

IFN-gamma promotes generation of IL-10 secreting CD4+ T cells that suppress generation of CD8 responses in an antigen-experienced host.

Ags characterizing tumors or chronic viral infection are generally presented to the host immune system before specific immunotherapy is initiated, and consequent generation of regulatory CD4(+) T cells can inhibit induction of desired effector CD8 T cell responses. IL-10 produced in response to ongoing Ag exposure inhibits generation of CD8 T cells in an Ag-experienced host. We now show that this IL-10 is produced by Ag experienced CD4(+) glucocorticoid-induced tumor necrosis factor receptor(+) T cells that also secrete IFN-gamma upon antigenic stimulation, that IL-10 secretion by these cells is enhanced through IFN-gamma signaling, and, unexpectedly, that IFN-gamma signaling is required for inhibition of generation of Ag-specific CD8 T cell responses in an Ag-experienced host. Systemic inhibition of both IL-10 and IFN-gamma at the time of immunization may therefore facilitate induction of effective immunotherapeutic responses against tumor specific and viral Ags.

Mouse blood vessel imaging by in-line x-ray phase-contrast imaging.

It is virtually impossible to observe blood vessels by conventional x-ray imaging techniques without using contrast agents. In addition, such x-ray systems are typically incapable of detecting vessels with diameters less than 200 microm. Here we show that vessels as small as 30 microm could be detected using in-line phase-contrast x-ray imaging without the use of contrast agents. Image quality was greatly improved by replacing resident blood with physiological saline. Furthermore, an entire branch of the portal vein from the main axial portal vein to the eighth generation of branching could be captured in a single phase-contrast image. Prior to our work, detection of 30 microm diameter blood vessels could only be achieved using x-ray interferometry, which requires sophisticated x-ray optics. Our results thus demonstrate that in-line phase-contrast x-ray imaging, using physiological saline as a contrast agent, provides an alternative to the interferometric method that can be much more easily implemented and also offers the advantage of a larger field of view. A possible application of this methodology is in animal tumor models, where it can be used to observe tumor angiogenesis and the treatment effects of antineoplastic agents.

Overcoming original antigenic sin to generate new CD8 T cell IFN-gamma responses in an antigen-experienced host.

The failure to mount effective immunity to virus variants in a previously virus-infected host is known as original antigenic sin. We have previously shown that prior immunity to a virus capsid protein inhibits induction by immunization of an IFN-gamma CD8+ T cell response to an epitope linked to the capsid protein. We now demonstrate that capsid protein-primed CD4+ T cells secrete IL-10 in response to capsid protein presented by dendritic cells, and deviate CD8+ T cells responding to a linked MHC class I-restricted epitope to reduce IFN-gamma production. Neutralizing IL-10 while delivering further linked epitope, either in vitro or in vivo, restores induction by immunization of an Ag-specific IFN-gamma response to the epitope. This finding demonstrates a strategy for overcoming inhibition of MHC class I epitopes upon immunization of a host already primed to Ag, which may facilitate immunotherapy for chronic viral infection or cancer.