Exposure to heavy metal elements may significantly increase serum prostate-specific antigen levels with overdosed dietary zinc.

BACKGROUND: Serum prostate-specific antigen (PSA) is a primary metric for diagnosis and prognosis of prostate cancer (PCa). Exposure to heavy metals, such as lead, cadmium, mercury, and zinc can impact PSA levels in PCa patients. However, it is unclear whether this effect also occurs in men without PCa, which may lead to the overdiagnosis of PCa. METHOD: Data on a total of 5089 American men who had never been diagnosed with PCa were obtained from the National Health and Nutrition Examination Survey performed from 2003-2010. The relationship between serum PSA levels (dependent variable) and concentrations of lead (µmol/L), cadmium (nmol/L), and mercury (µmol/L) were investigated with dietary zinc intake being used as a potential modifier or covariate in a weighted linear regression model and a generalized additive model. A series of bootstrapping analyses were performed to evaluate sensitivity and specificity using these models. RESULTS: Regression analyses suggested that, in general, lead, cadmium, or mercury did not show an association with PSA levels, which was consistent with the results of the bootstrapping analyses. However, in a subgroup of participants with a high level of dietary zinc intake (≥14.12 mg/day), a significant positive association between cadmium and serum PSA was identified (1.06, 95% CI, P = 0.0268, P for interaction=0.0249). CONCLUSIONS: With high-level zinc intake, serum PSA levels may rise in PCa-free men as the exposure to cadmium increases, leading to a potential risk of an overdiagnosis of PCa and unnecessary treatment. Therefore, environmental variables should be factored in the current diagnostic model for PCa that is solely based on PSA measurements. Different criteria for PSA screening are necessary based on geographical variables. Further investigations are needed to uncover the biological and biochemical relationship between zinc, cadmium, and serum PSA levels to more precisely diagnose PCa.

Dynamic immuno-nanomedicines in oncology.

Anti-cancer therapeutics have achieved significant advances due to the emergence of immunotherapies that rely on the identification of tumors by the patients' immune system and subsequent tumor eradication. However, tumor cells often escape immunity, leading to poor responsiveness and easy tolerance to immunotherapy. Thus, the potentiated anti-tumor immunity in patients resistant to immunotherapies remains a challenge. Reactive oxygen species-based dynamic nanotherapeutics are not new in the anti-tumor field, but their potential as immunomodulators has only been demonstrated in recent years. Dynamic nanotherapeutics can distinctly enhance anti-tumor immune response, which derives the concept of the dynamic immuno-nanomedicines (DINMs). This review describes the pivotal role of DINMs in cancer immunotherapy and provides an overview of the clinical realities of DINMs. The preclinical development of emerging DINMs is also outlined. Moreover, strategies to synergize the antitumor immunity by DINMs in combination with other immunologic agents are summarized. Last but not least, the challenges and opportunities related to DINMs-mediated immune responses are also discussed.

Dabie bandavirus infection induces macrophagic pyroptosis and this process is attenuated by platelets.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infection with a high mortality rate in humans, which is caused by Dabie bandavirus (DBV), formerly known as SFTS virus. Clinical manifestations of SFTS are characterized by high fever, thrombocytopenia, leukopenia, hemorrhage, gastrointestinal symptoms, myalgia and local lymph node enlargement with up to 30% case fatality rates in human. Macrophage depletion in secondary lymphoid organs have important roles in the pathogenic process of fatal SFTS, but its exact cell death mechanism remains largely unknown. Here, we showed for the first time that DBV infection induced macrophagic pyroptosis, as evidenced by swollen cells, pore-forming structures, accumulation of gasdermin D N-terminal (GSDMD-NT) as well as the release of lactate dehydrogenase (LDH) and IL-1ß in human macrophages. In addition to the upregulation of pyronecrosis genes, the expressions of pyroptosis-related proteins (GSDMD, caspase-1 and IL-1ß) were also elevated. To be noted, platelets were found to play a protective role in DBV-derived pyroptosis. Transcriptome analysis and in vitro studies demonstrated that platelets significantly reduced the gene expressions and protein production of pro-pyroptotic markers and inflammatory cytokines in macrophages, whereas platelets conferred a propagation advantage for DBV. Collectively, this study demonstrates a novel mechanism by which DBV invasion triggers pyroptosis as a host defense to remove replication niches in human macrophages and platelets provide an additional layer to reduce cellular death. These findings may have important implications to the pathogenesis of lethal DBV, and provide new ideas for developing novel therapeutics to combat its infection.

Clusterin and Its Isoforms in Oral Squamous Cell Carcinoma and Their Potential as Biomarkers: A Comprehensive Review.

Oral squamous cell carcinoma (OSCC) is a prevalent type of head and neck cancer, ranked as the sixth most common cancer worldwide, accounting for approximately 300,000 new cases and 145,000 deaths annually. Early detection using biomarkers significantly increases the 5-year survival rate of OSCC by up to 80-90%. Clusterin (CLU), also known as apolipoprotein J, is a sulfated chaperonic glycoprotein expressed in all tissues and human fluids and has been reported to be a potential biomarker of OSCC. CLU has been implicated as playing a vital role in many biological processes such as apoptosis, cell cycle, etc. Abnormal CLU expression has been linked with the development and progression of cancers. Despite the fact that there are many studies that have reported the involvement of CLU and its isoforms in OSCC, the exact roles of CLU and its isoforms in OSCC carcinogenesis have not been fully explored. This article aims to provide a comprehensive review of the current understanding of CLU structure and genetics and its correlation with OSCC tumorigenesis to better understand potential diagnostic and prognostic biomarker development. The relationship between CLU and chemotherapy resistance in cancer will also be discussed to explore the therapeutic application of CLU and its isoforms in OSCC.

ZnO@ZIF-8 Core-Shell Structure Gas Sensors with Excellent Selectivity to H2.

As the energy crisis becomes worse, hydrogen as a clean energy source is more and more widely used in industrial production and people's daily life. However, there are hidden dangers in hydrogen storage and transportation, because of its flammable and explosive features. Gas detection is the key to solving this problem. High quality sensors with more practical and commercial value must be able to accurately detect target gases in the environment. Emerging porous metal-organic framework (MOF) materials can effectively improve the selectivity of sensors as a result of high surface area and coordinated pore structure. The application of MOFs for surface modification to improve the selectivity and sensitivity of metal oxides sensors to hydrogen has been widely investigated. However, the influence of MOF modified film thickness on the selectivity of hydrogen sensors is seldom studied. Moreover, the mechanism of the selectivity improvement of the sensors with MOF modified film is still unclear. In this paper, we prepared nano-sized ZnO particles by a homogeneous precipitation method. ZnO nanoparticle (NP) gas sensors were prepared by screen printing technology. Then a dense ZIF-8 film was grown on the surface of the gas sensor by hydrothermal synthesis. The morphology, the composition of the elements and the characters of the product were analyzed by X-ray diffraction analysis (XRD), transmission electron microscope (TEM), scanning electron microscope (SEM), energy dispersive spectrometer (EDS), Brunauer-Emmett-Teller (BET) and differential scanning calorimetry (DSC). It is found that the ZIF-8 film grown for 4 h cannot form a dense core-shell structure. The thickness of ZIF-8 reaches 130 nm at 20 h. Through the detection and analysis of hydrogen (1000 ppm), ethanol (100 ppm) and acetone (50 ppm) from 150 °C to 290 °C, it is found that the response of the ZnO@ZIF-8 sensors to hydrogen has been significantly improved, while the response to ethanol and acetone was decreased. By comparing the change of the response coefficient, when the thickness of ZIF-8 is 130 nm, the gas sensor has a significantly improved selectivity to hydrogen at 230 °C. The continuous increase of the thickness tends to inhibit selectivity. The mechanism of selectivity improvement of the sensors with different thickness of the ZIF-8 films is discussed.

Enhancing Formaldehyde Selectivity of SnO2 Gas Sensors with the ZSM-5 Modified Layers.

High performance formaldehyde gas sensors are widely needed for indoor air quality monitoring. A modified layer of zeolite on the surface of metal oxide semiconductors results in selectivity improvement to formaldehyde as gas sensors. However, there is insufficient knowledge on how the thickness of the zeolite layer affects the gas sensing properties. In this paper, ZSM-5 zeolite films were coated on the surface of the SnO2 gas sensors by the screen printing method. The thickness of ZSM-5 zeolite films was controlled by adjusting the numbers of screen printing layers. The influence of ZSM-5 film thickness on the performance of ZSM-5/SnO2 gas sensors was studied. The results showed that the ZSM-5/SnO2 gas sensors with a thickness of 19.5 µm greatly improved the selectivity to formaldehyde, and reduced the response to ethanol, acetone and benzene at 350 °C. The mechanism of the selectivity improvement to formaldehyde of the sensors was discussed.

ESRRA promotes gastric cancer development by regulating the CDC25C/CDK1/CyclinB1 pathway via DSN1.

Background: Estrogen-related receptor-α (ESRRA) is an orphan nuclear receptor, expressing at high level in exuberant metabolism organs and acting as transcription factor. High expression was found in many malignances but no research was done in gastric cancer (GC), where lipid metabolism disorder is common. Methods: Kaplan-Meier plot was utilized to find the relationship between ESRRA expression and patients' prognoses. The expression level of ESRRA was measured by real-time PCR. The protein expression levels were tested with western-blot and immunohistochemistry. Cell cycle and apoptosis was identified with flow cytometry. RNA-seq, bioinformatics analysis, dual-luciferase assay and ChIP assay were used to predict and validate ESRRA's target gene and binding motif. Animal models were also introduced in our study. Results: ESRRA expression is notably higher in GC cell lines and high ESRRA levels are correlated to poor prognoses. ESRRA silencing decreased GC cell viability, migration, and invasion capacities. Its downstream gene DSN1 was spotted by RNA-seq and confirmed by later bioinformatics analyses, dual-luciferase, and ChIP assays. Western-blot showed G2M arrest caused by ESRRA silencing was via CDC25C-CDK1-Cyclin B1 pathway. Conclusion: ESRRA/DSN1/CDC25C-CDK1-Cyclin B1 is of great importance in GC development. ESRRA could be a potential target as well as prognostic marker in GC.

Clinicopathological and immunological characterization of RNA m6 A methylation regulators in ovarian cancer.

BACKGROUND: N6 -methyladenosine (m6 A) modification is one of the critical gene regulatory mechanisms implicated in cancer biology. However, the roles of m6 A regulators in ovarian cancer are still poorly understood. METHODS: We integrated multiple databases including Gene Expression Omnibus (GEO), ROC Plotter, Kaplan-Meier Plotter, and Tumor Immune Estimation Resource (TIMER) to explore clinicopathological significance of m6 A regulators in ovarian cancer. RESULTS: We showed that alterations in the expression of m6 A regulators were related to the malignancy and poor prognosis of ovarian cancer. We found decreased YTHDC1 and increased RBM15 expressions were associated with ovarian cancer cell metastases and HNRNPC was a predictor of paclitaxel resistance. Moreover, dysregulated m6 A regulators were enriched in the activation of cancer-related pathways. Our results further demonstrated that the level of immune cell infiltration and the expression of various immune gene markers were closely associated with the expressions of specific m6 A regulators (RBM15B, ZC3H13, YTHDF1, and IGF2BP1). CONCLUSIONS: Our study establishes a new prognostic profile of ovarian cancer patients based on m6 A regulators, and highlights the potential roles of m6 A regulators in ovarian cancer development.

Association Between Succinate Receptor SUCNR1 Expression and Immune Infiltrates in Ovarian Cancer.

BACKGROUND: The activation of succinate receptor 1 (SUCNR1) by extracellular succinate has been found to regulate immune cell function. However, the clinical significance of SUCNR1 in ovarian cancer and its correlation with tumor-infiltrating lymphocytes remain unclear. METHODS: The genetic alteration and expression patterns of SUCNR1 were analyzed by using cBioPortal and Gene Expression Omnibus (GEO) datasets. Kaplan-Meier Plotter was used to assess the prognostic value of SUCNR1 in patients with ovarian cancer. The correlations between SUCNR1 expression and immune infiltration, gene markers of immune cells, cytokines, chemokines, or T cell exhaustion were explored by using TIMER and TISIDB platforms. We also performed Gene Set Enrichment Analysis (GSEA) to reveal biological function of SUCNR1 in ovarian cancer. RESULTS: The expression of SUCNR1 was closely related to tumor infiltrating lymphocytes, multiple gene markers of immune cells, and T cell exhaustion in ovarian cancer. The expression of SUCNR1 was also associated with the expression of cytokine- or chemokine-related genes. Moreover, GSEA revealed that various immune-related pathways might be regulated by SUCNR1. In addition, we found that SUCNR1 was amplified in ovarian cancer, and the high expression of SUCNR1 predicted worse progression-free survival (p = 0.0073, HR = 1.49, 95% CI = 1.11-2). CONCLUSION: These results highlight the role of SUCNR1 in regulating tumor immunity in ovarian cancer.

Clinical implication and immunological characterisation of the ARF-GEF family member CYTH4 in ovarian cancer.

BACKGROUND: The GTP exchange factors on ADP-ribosylation factor (ARF) mediate the GDP/GTP exchange on ARF, serve as regulators in protein trafficking and membrane dynamics, and play critical roles in various cell processes. However, the relationship between the expression of ARF-GEF family genes and clinical implications in ovarian cancer remains unclear. METHODS: We performed a systematic investigation on the role of ARF-GEF family genes in ovarian cancer by using Gene Expression Omnibus (GEO), Kaplan-Meier plotter, Gene set enrichment analysis (GSEA), TIMER and TISIDB database. RESULTS: We found that the ARF-GEF family gene CYTH4 exhibited significant expressional upregulation in ovarian cancer compared to normal ovary tissues. The expression of CYTH4 was also higher in metastases from the omentum than in matched primary ovarian tumours. Kaplan-Meier plotter showed that high expression of CYTH4 predicted worse overall survival, progression free survival and post-progression survival of ovarian cancer patients. Notably, from our correlation analysis, CYTH4 expression showed closely association with tumour-infiltrating immune cells. Intriguingly, the expression of CYTH4 was also significantly correlated with a variety of immunomodulators, chemokines and major histocompatibility complex molecules. CONCLUSION: Overall, our findings provide a valuable source of data about the clinical significance of CYTH4 in ovarian cancer.

m1A Regulator TRMT10C Predicts Poorer Survival and Contributes to Malignant Behavior in Gynecological Cancers.

N1-methyladenosine (m1A) is an important post-transcriptional modification in RNA, and plays critical roles in cellular functions. However, the relationship between m1A regulators and clinical significance of gynecological cancers remains unknown. In this study, we systematically analyzed RNA-seq and clinical data from several public database. Cell proliferation and migration assays were performed to verify the function of the m1A writer TRMT10C in cancer cells. We observed genetic alterations and dysregulated expressions of m1A regulators in gynecological cancer samples. We demonstrated that several m1A regulators could serve as prognostic biomarkers for gynecological cancer patients. The high correlations among the expression of m1A, N6-methyladenosine (m6A), and 5mC regulators were also revealed. Gene set enrichment analysis indicated that the mechanism of TRMT10C in regulating tumorigenesis was related to a variety of cancer-related pathways. Moreover, silencing TRMT10C suppressed the proliferation, colony formation, and migration of ovarian cancer and cervical cancer cells. In summary, our results highlight the importance of m1A regulators in regulating oncogenesis, and indicate that targeting specific m1A regulators might be a potential therapeutic strategy for gynecological cancers.

Expression of ACAP1 Is Associated with Tumor Immune Infiltration and Clinical Outcome of Ovarian Cancer.

ADP-ribosylation factor (Arf) GTPase-activating protein (GAP) with coiled-coil, ankyrin repeat and PH domains 1 (ACAP1) is an Arf6 GAP that regulates membrane trafficking and is critical for the migratory potential of cells. However, the roles of ACAP1 have not been fully explored and its association with clinicopathological features in ovarian cancer is still unknown. In this study, we systematically analyzed multiple databases, including TISIDB, Tumor Immune Estimation Resource (TIMER2.0), Gene Expression Omnibus (GEO), CORTECON, Kaplan-Meier Plotter and LinkedOmics platforms to reveal the clinical significance and function of ACAP1 in ovarian cancer. We found that the expression of ACAP1 was upregulated in ovarian cancer and high ACAP1 expression predicted poor prognosis. Our data demonstrated that the expression and methylation status of ACAP1 were strongly correlated with immune infiltration levels, immunomodulators, and chemokines. Gene set enrichment analysis (GSEA) analysis also showed that the mechanism of ACAP1 in regulating ovarian cancer was related to a variety of immune-related pathways. In addition, we also revealed that the expression of ACAP1 was altered during cell differentiation and associated with cancer cell stemness markers. Our study highlights the clinical significance of ACAP1 in ovarian cancer and provides insight into the novel function of ACAP1 in regulation of tumor immune microenvironment and cancer cell stemness.

Clinical relevance of ARF/ARL family genes and oncogenic function of ARL4C in endometrial cancer.

Members of ADP-ribosylation factor (ARF)/ARF-like protein (ARL) family regulate malignant phenotype of cancer cells. The present study aims to investigate the clinical relevance of ARF/ARL family members in endometrial cancer. We report that several ARF/ARL family genes serve as prognostic biomarkers for endometrial cancer. Through a combination of TCGA database and immunohistochemistry analysis, we revealed that ARL4C, a member of ARL family, was overexpressed in endometrial cancer and might function as an oncogene in endometrial carcinogenesis. Gene set enrichment analysis (GSEA) and functional studies demonstrated that cell cycle and cell adhesion pathways were the potential mechanism of ARL4C in promoting endometrial cancer cell proliferation, migration and invasion. Moreover, we also observed the involvement of ARL4C in metformin-inhibited cellular proliferation of endometrial cancer. Collectively, knowledge of the expression and function of ARF/ARL family genes could provide a potential therapeutic strategy for endometrial cancer.

Collagen prolyl 4-hydroxylase 2 predicts worse prognosis and promotes glycolysis in cervical cancer.

P4HA2 is one of collagen prolyl 4-hydroxylase (P4H) isoform and increased in several types of human cancer. However, the role of P4HA2 during cervical tumorigenesis remains largely unknown. Here, we report that the protein level of P4HA2 is significantly increased in cervical cancer tissues. Silencing of P4HA2 inhibits cervical cancer cell proliferation, colony formation and migration. We also demonstrate decreased glucose uptake and lactate production in P4HA2 knockdown cells. Mechanistically, P4HA2 promotes cervical cancer cell glycolysis through upregulation of PGK1 and LDHA. We find a positive correlation between P4HA2 and PGK1/LDHA expression in cervical cancer tissues. Importantly, high expression of P4HA2, PGK1 or LDHA has a significantly shorter overall survival period and the survival prediction is enhanced by using combination of P4HA2 and PGK1/LDHA expression. Collectively, we identify P4HA2 as a regulator of glycolysis through PGK1 and LDHA, which may serve as a potential therapeutic target for cervical cancer.

The Enhanced H2 Selectivity of SnO2 Gas Sensors with the Deposited SiO2 Filters on Surface of the Sensors.

This paper reports a study on the enhanced H2 selectivity of SnO2 gas sensors with SiO2 on the surface of the sensors obtained via chemical vapor deposition using dirthoxydimethylsilane as the Si source. The gas sensors were tested for sensing performance towards ethanol, acetone, benzene, and hydrogen at operating temperatures from 150 °C to 400 °C. Our experimental results show that higher selectivity and responses to hydrogen were achieved by the deposition of SiO2 on the surface of the sensors. The sensor with SiO2 deposited on its surface at 500 °C for 8 h exhibited the highest response (Ra/Rg = 144) to 1000 ppm hydrogen at 350 °C, and the sensor with SiO2 deposited on its surface at 600 °C for 4 h attained the maximum response variation coefficient (D = 69.4) to 1000 ppm hydrogen at 200 °C. The mechanism underlying the improvement in sensitivity and the higher responses to hydrogen in the sensors with SiO2 on their surface is also discussed.

Highly Sensitive and Selective Hydrogen Gas Sensor Using the Mesoporous SnO2 Modified Layers.

It is important to improve the sensitivities and selectivities of metal oxide semiconductor (MOS) gas sensors when they are used to monitor the state of hydrogen in aerospace industry and electronic field. In this paper, the ordered mesoporous SnO2 (m-SnO2) powders were prepared by sol-gel method, and the morphology and structure were characterized by X-ray diffraction analysis (XRD), transmission electron microscope (TEM) and Brunauer-Emmett-Teller (BET). The gas sensors were fabricated using m-SnO2 as the modified layers on the surface of commercial SnO2 (c-SnO2) by screen printing technology, and tested for gas sensing towards ethanol, benzene and hydrogen with operating temperatures ranging from 200 °C to 400 °C. Higher sensitivity was achieved by using the modified m-SnO2 layers on the c-SnO2 gas sensor, and it was found that the S(c/m2) sensor exhibited the highest response (Ra/Rg = 22.2) to 1000 ppm hydrogen at 400 °C. In this paper, the mechanism of the sensitivity and selectivity improvement of the gas sensors is also discussed.

Real-time tissue elastography for the detection of vulnerable carotid plaques in patients undergoing endarterectomy: a pilot study.

We examined the utility of ultrasonic real-time tissue elastography (RTE) and conventional B-mode ultrasound (US) in the detection of vulnerable carotid atherosclerotic plaques. This prospective study comprised 19 patients scheduled for carotid endarterectomy. Results obtained from pre-operative RTE and B-mode US and post-operative pathology were compared. RTE encoded low, average and high deformability as blue, green and red, respectively. Tissue hardness was scored on a 5-point scale, and relative strains were calculated. The relative strain was 1.12 ± 0.14 for fibrous plaques (n = 4), 0.28 ± 0.07 for atherosclerotic plaques (n = 5), 0.47 ± 0.31 for intraplaque hemorrhage/thrombosis (n = 5) and 0.98 ± 1.04 for complex plaques (n = 5). The sensitivity, specificity and accuracy of detection of vulnerable plaques were 25%, 100% and 84.2% for B-mode US, 50%, 100% and 89.4% for RTE and 62.5%, 100% and 94.7% for the combination. Ultrasonic RTE is a potential candidate for a non-invasive and effective approach to identify vulnerable atherosclerotic plaques in the carotid artery.