NADase CD38 is a key determinant of ovarian aging.

The ovary ages earlier than most other tissues, yet the underlying mechanisms remain elusive. Here a comprehensive analysis of transcriptomic landscapes in different organs in young and middle-aged mice revealed that the ovaries showed earlier expression of age-associated genes, identifying increased NADase CD38 expression and decreased NAD+ levels in the ovary of middle-aged mice. Bulk and single-cell RNA sequencing revealed that CD38 deletion mitigated ovarian aging, preserving fertility and follicle reserve in aged mice by countering age-related gene expression changes and intercellular communication alterations. Mechanistically, the earlier onset of inflammation induced higher expression levels of CD38 and decreased NAD+ levels in the ovary, thereby accelerating ovarian aging. Consistently, pharmacological inhibition of CD38 enhanced fertility in middle-aged mice. Our findings revealed the mechanisms underlying the earlier aging of the ovary relative to other organs, providing a potential therapeutic target for ameliorating age-related female infertility.

Light, pH, and Temperature Triple-Responsive Magnetic Composites for Highly Efficient Phosphopeptide Enrichment.

Smart materials can dynamically and reversibly change their structures and functions in response to external stimuli. In this study, we designed a smart magnetic composite (MNP-pSPA-b-pNIPAm) with a triple response to ultraviolet (UV) light, pH, and temperature. Relying on the response of spiropyranyl acrylate (SPA) and N-isopropylacrylamide (NIPAm) to external stimuli (light, pH, and temperature), MNP-pSPA-b-pNIPAm was used for the controlled capture and release of phosphopeptides. The established phosphopeptide enrichment platform exhibits high sensitivity (detection limit of 0.04 fmol), high selectivity (BSA/ß-casein, 1000:1), and good reusability (6 cycles). In addition, the method was also applied to the enrichment of phosphopeptides in real samples (skim milk, human saliva, and serum), demonstrating the feasibility of this method for phosphoproteomic analysis. After enriching from human nonsmall cell lung cancer cell (A549) lysates with MNP-pSPA-b-pNIPAm, 2595 phosphopeptides corresponding to 2281 phosphoproteins were identified. The novel responsive enrichment probe is highly specific for phosphoproteomic analysis and provides an effective method for studying the significance of protein phosphorylation in complex biological samples.

A Novel TLR4-Binding Domain of Peroxiredoxin From Entamoeba histolytica Triggers NLRP3 Inflammasome Activation in Macrophages.

Macrophages promote early host responses to infection by releasing pro-inflammatory cytokines, and they are crucial to combat amoebiasis, a disease affecting millions of people worldwide. Macrophages elicit pro-inflammatory responses following direct cell/cell interaction of Entamoeba histolytica, inducing NLRP3 inflammasome activation with high-output IL-1ß/IL-18 secretion. Here, we found that trophozoites could upregulate peroxiredoxins (Prx) expression and abundantly secrete Prxs when encountering host cells. The C-terminal of Prx was identified as the key functional domain in promoting NLRP3 inflammasome activation, and a recombinant C-terminal domain could act directly on macrophage. The Prxs derived from E. histolytica triggered toll-like receptor 4-dependent activation of NLRP3 inflammasome in a cell/cell contact-independent manner. Through genetic, immunoblotting or pharmacological inhibition methods, NLRP3 inflammasome activation was induced through caspase-1-dependent canonical pathway. Our data suggest that E. histolytica Prxs had stable and durable cell/cell contact-independent effects on macrophages following abundantly secretion during invasion, and the C-terminal of Prx was responsible for activating NLRP3 inflammasome in macrophages. This new alternative pathway may represent a potential novel therapeutic approach for amoebiasis, a global threat to millions.

Visible-Ultraviolet Upconversion Carbon Quantum Dots for Enhancement of the Photocatalytic Activity of Titanium Dioxide.

Visible-ultraviolet upconversion carbon quantum dots (CQDs) are synthesized with a hydrothermal method using l-glutamic acid (l-Glu) and m-phenylenediamine (MPD) and then combined with commercial nano-TiO2 to prepare CQDs/TiO2 composites. The fluorescence spectra prove that the prepared CQDs can convert approximately 600 nm visible light into 350 nm ultraviolet light. In photocatalysis experiments, CT-1, a CQDs/TiO2 composite with 1:1 molar ratio of l-Glu to TiO2, has the best degradation efficiency for methyl orange (MO). Transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) experiments confirm that CT-1 is composed of quasi-spherical nano-TiO2 and CQDs with a crystal plane of graphitic carbon. CT-1 can degrade 70.56% of MO (40 ppm) within 6 h under the irradiation of a 600 nm light source, which is close to its degradation rate of 78.75% under 365 nm ultraviolet light. The apparent rate constant of CT-1 degradation equation is 12.7 times that of TiO2. Free radical scavenging experiments and electron spin resonance (ESR) tests show that the degradation ability should be attributed to the existence of h+ and •OH under visible light. Therefore, we provide a simple and low-cost solution with heavy-metal-free products to improve the photocatalytic performance of TiO2.

Knowledge Mapping of Acupuncture for Cancer Pain: A Scientometric Analysis (2000-2019).

OBJECTIVE: This study aimed to demonstrate the state of the present situation and trends concerning the global use of acupuncture for cancer pain in the past 20 years. METHODS: Searched the Web of Science database from 2000 to 2019 related to acupuncture for cancer pain, and then used CiteSpace to conduct scientometric analysis to acquire the knowledge mapping. RESULTS: Yearly output has increased year by year, and the growth rate has become faster after 2012. According to the cluster analysis of institutions, authors, cited references, and keywords, 4, 4, 15, and 14 categories were obtained, respectively. The most productive countries, institutions, and authors are the USA, Mem Sloan Kettering Cancer Center, and Mao JJ, whose frequencies are 196, 24, and 17, respectively. However, the most important of them are Australia, Univ. Maryland, and Bao T, owing to their highest centrality, they are 0.90, 0.21, and 0.09 separately. Moreover, cited references that contributed to the most co-citations are Crew KD (2010), however, the most key cited reference is Roscoe JA (2003). Keywords such as acupuncture, pain, breast cancer, palliative care, and quality of life are the most frequently used. But auricular acupuncture is the crucial keyword. In the cluster analysis of institutions, authors, cited references, and keywords, the more convincing research categories are multiple myeloma, placebo effect, neck malignancies, and early breast cancer, with S values of 0.990, 0.991, 0.990, and 0.923, respectively. Therefore, they can be regarded as research hotspots in this field. CONCLUSION: Based on the scientometric analysis in the past 20 years, the knowledge mapping of the country, institution, author, cited reference, and the keyword is gained, which has an important guiding significance for quickly and accurately positioning the trend in this field.

Systemic Therapy Plus Thermal Ablation Versus Systemic Therapy Alone for Oligometastatic Liver Metastases from Non-small Cell Lung Cancer.

PURPOSE: This study assessed and compared the efficacy and long-term outcomes of systemic therapy plus image-guided thermal ablation versus systemic therapy alone for oligometastatic liver metastases (LMs) from non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. Written informed consent was waived due to the retrospective design. From November 2012 to December 2017, 61 patients (mean age 59.0 years; 35 males) with oligometastatic LMs from NSCLC (≤ 5 metastatic lesions) who received systemic therapy with (n = 21, group A) or without (n = 40, group B) thermal ablation were analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier curves. RESULTS: The demographic and clinical characteristics were not significantly different between the groups (all P ≥ .05). In total, 28 LMs were entirely ablated, rendering a technical success rate of 100%, without major complications. The overall 6-month response rate was significantly higher in group A than in group B [57.1% (12/21) vs. 26.3% (10/38); P = .026]. The median PFS in group A was significantly longer than in group B [11.0 (95% CI 7.9-16.2) months vs. 5.2 (95% CI 3.7-7.9) months; P = .001]. However, the median OS was not significantly different [27.7 (95% CI 20.6-44.4) months vs. 17.7 (95% CI 14.5-27.5) months; P = .152]. CONCLUSION: Systemic therapy plus thermal ablation may prolong PFS but not OS in oligometastatic LMs from NSCLC.

Comprehensive Effects of Near-Infrared Multifunctional Liposomes on Cancer Cells.

Multifunctional theranostic systems are a recent important development of medical research. We combined the characteristics of near-infrared luminescent quantum dots and thermosensitive magnetoliposomes to develop a multifunctional nano-diagnostic material. This system is based on near-infrared magnetic thermosensitive liposomes, which encapsulate drugs and can control drug localization and release. After incubating cancer cells with the liposomes, the state of the cells was analyzed in real time by near-infrared imaging. Cell viability was significantly inhibited by heat treatment or alternating magnetic field treatment, which thus improved the anti-cancer properties of the liposomes. In the future, by combining near-infrared imaging technology and an external high-frequency alternating magnetic field, we could not only detect cancer cells noninvasively but also conduct image-guided treatments for cancer.

Computed tomography fluoroscopy-guided cutting needle biopsy of pulmonary nodules ≤8 mm: A retrospective study including 117 nodules.

PURPOSE: To evaluate the diagnostic yield and safety of computed tomography (CT) fluoroscopy-guided cutting needle biopsy (CNB) for pulmonary nodules ≤ 8 mm. METHOD: Data of CT fluoroscopy-guided CNB for pulmonary nodules ≤ 8 mm performed in a single institution were retrospectively analyzed. One hundred and seventeen biopsy procedures for 117 pulmonary nodules (mean size, 7.4 mm) in 114 patients were included in the study. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall diagnostic accuracy were calculated. Univariate analyses were performed to elucidate the risk factors for diagnostic failure (i.e., non-diagnostic, false-positive, or false-negative results). Complications were graded per the Clavien-Dindo Classification. RESULTS: One (0.9 %) non-diagnostic biopsy result was found. The diagnostic accuracy was 95.7 % (112/117). The sensitivity and specificity were 95.8 % (91/95) and 95.5 % (21/22), respectively. PPV and NPV were 98.9 % (91/92) and 87.5 % (21/24), respectively. Univariate analyses showed that nodules in the lower lobes (p = 0.006) and prone biopsy position (p = 0.021) were the significant risk factors for diagnostic failure. The incidence of pneumothorax requiring chest tube placement (Grade IIIa) was 6.8 % (8/117). No Grade IIIb or higher complications were observed. CONCLUSION: CT fluoroscopy-guided CNB for pulmonary nodules ≤ 8 mm showed a high diagnostic yield without severe complications.

Prognostic Nomogram for Sorafenib Benefit in Hepatitis B Virus-Related Hepatocellular Carcinoma After Partial Hepatectomy.

BACKGROUND: Predicting the long-term prognosis of individuals who experienced sorafenib treatment following partial hepatectomy due to hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is difficult. This work aims to create an effective prognostic nomogram for HBV related HCC patients who are receiving sorafenib treatment as adjuvant therapy after surgery. METHODS: A total of 233 HBV-related HCC patients treated with or without sorafenib following partial hepatectomy at the Eastern Hepatobiliary Surgery Hospital from 2008 to 2013 were matched with propensity score matching analysis. The optimal cut-off point of the overall survival (OS) factor level was determined by x-tile. The selection of indicators was based on clinical findings. The Cox regression model with an interaction term was employed for evaluating the predictive value. Using a multivariate Cox proportional hazards model, a nomogram was subsequently formulated to analyze 111 patients treated with sorafenib. The nomogram's discriminative ability and predictive accuracy were determined using the concordance index (C-index), calibration, and ROC curve. RESULTS: The matched sorafenib cohort of 111 patients and control cohort of 118 patients were analyzed. Subgroup analysis revealed that low GPC3, pERK, pAKT, serum AFP levels, without MVI, under 50 years old, male, TNM stage I/II and BCLC stage 0/A were significantly associated with a better OS in patients subjected to sorafenib treatment compared to those without sorafenib treatment after surgery. Multivariate analysis of the sorafenib cohort revealed GPC3, pERK, pAKT, serum AST, and BCLC stage as independent factors for OS, and all were included in the nomogram. The survival probability based on the calibration curve showed that the prediction of the nomogram was in good agreement with the actual observation. The C-index of the nomogram for predicting survival was 0.73(95% CI, 0.67-0.78). The area under the ROC curve (AUC) for the nomogram to predict the survival for 1, 3, and 5-year was 0.726, 0.816, and 0.823, respectively. CONCLUSION: This proposed nomogram shows the potential to make a precise prediction regarding the prognosis of HBV-related HCC patients and may help to stratify patients for personalized therapy following partial hepatectomy.

Corrigendum: Alterations of the Mice Gut Microbiome via Schistosoma japonicum Ova-Induced Granuloma.

[This corrects the article DOI: 10.3389/fmicb.2019.00352.].

Alterations of the Mice Gut Microbiome via Schistosoma japonicum Ova-Induced Granuloma.

Schistosomiasis, also called bilharziasis, is a neglected tropical disease induced by Schistosoma spp. that causes hundreds of millions of infections. Although Schistosoma ova-induced granulomas commonly cause inflammation, hyperplasia, ulceration, micro abscess formation, and polyposis, the role of the egg granuloma on the gut microbiome remains unclear. To explore the role, gut microbial communities in mice infected with Schistosoma japonicum were surveyed. Female C57BL/6 and BALB/c mice were exposed to cercariae of S. japonicum for 45 and 65 days and then sacrificed. Intestinal contents and feces were collected, DNA was extracted, and high-throughput 16S rRNA gene-based pyrosequencing was used to provide a comparative analysis of gut microbial diversity. The intestinal mucosal tissues were also examined. Histopathologic analysis demonstrated that the basic structure of the colonic mucosa was damaged by ova-induced granuloma. Regarding the gut microbiome, 2,578,303 good-quality sequences were studied and assigned to 25,278 Operational Taxonomic Units (OTUs) at a threshold of 97% similarity. The average number of OTUs for C57BL/6 and BALB/c were 545 and 530, respectively. At the phylum level, intestinal microbial communities were dominated by Firmicutes, Bacteroidetes, Proteobacteria, and Verrucomicrobia. Infection with S. japonicum modified bacterial richness in the fecal associated microbiota. Exposure significantly modified bacterial community composition among different groups. At the phylogenetic levels, LEfSe analysis revealed that several bacterial taxa were significantly associated with the S. japonicum-infected mice. The present results suggest that egg granulomas in the intestine influence differentiation of the gut microbial community under pathophysiological conditions. This result suggests that intestinal microbiome-based strategies should be considered for early diagnosis, clinical treatment, and prognosis evaluation of schistosomiasis.

Different thermal processing effects on peanut allergenicity.

BACKGROUND: Peanut allergy is one of the most common food allergies worldwide. Studies have shown that the incidence of peanut allergies in Western-born Asians is higher than that in Asia-born Asians. Notably, Europeans and Americans mostly eat roasted peanuts, whereas Asians mostly eat boiled or fried peanuts. RESULTS: BALB/c mice were sensitized using purified protein from raw, roasted or boiled peanuts, then fed the same by oral gavage. The relevant allergic reactions were studied using BALB/c mice model, including a rat basophilic leukemia (RBL) cell model, simulated gastric fluid experiments, and ultraviolet (UV) and circular dichroism (CD) spectral analysis. Serological studies showed increased levels of immunoglobulin E, interleukin-4 and interleukin-5, and pathological studies showed mast cell degranulation and inflammatory changes in jejunal tissues, with an increase in thymic stromal lymphopoietin (TSLP) gene expression in all treatment groups compared with the control group (phosphate-buffered saline). Compared with the raw peanut group, sera from the roasted peanut group produced a significant increase in RBL ß-hexosaminidase A release in vitro, and roasted peanuts showed increased resistance to digestion in simulated gastric fluid experiments. Ultraviolet and CD spectral analyses showed that the roasting and boiling processes altered the structure of the major peanut allergens, which may have contributed to the differences observed in peanut allergenicity. CONCLUSION: Our findings indicate that peanut allergies are related to peanut thermal processing methods. In our mouse model, the raw, roasted and boiled peanuts elicited different degrees of allergic response. Compared with raw peanut, roasted peanuts show a higher allergenicity, whereas the boiled peanuts show a lower allergenicity. © 2018 Society of Chemical Industry.

miRNA-20a upregulates TAK1 and increases proliferation in osteosarcoma cells.

AIM: The aim of this study is to explore the function of miR-20a in osteosarcoma. MATERIALS & METHODS: miR-20a expression was measured by real-time PCR. miR-20a mimics, inhibitor and scramble siRNA were transfected into osteosarcoma cells to observe effects on colony formation and tumor growth. Moreover, relationships of miR-20a with TAK1 were investigated by western blot and luciferase activity. RESULTS: We found that miR-20a was downregulated in osteosarcoma, and overexpression of miR-20a reduced colony formation and tumor growth. Furthermore, the data revealed that the function of miR-20a was probably exerted via targeting the TAK1 expression. Overexpression of miR-20a sensitizes the osteosarcoma cells to chemotherapeutic drugs. CONCLUSION: Our data identify the role of miR-20a in osteosarcoma growth, indicating its potential application in chemotherapy.

Comparison of endoscopic ultrasonography and magnifying endoscopy for assessment of the invasion depth of shallow gastrointestinal neoplasms: a systematic review and meta-analysis.

OBJECTIVES: To conduct a meta-analysis to provide accurate evidence regarding the preferred diagnostic method, magnifying endoscopy (ME) or endoscopic ultrasonography (EUS), for assessment of the depth of invasion of the gastrointestinal neoplasms. METHODS: PubMed, EMBASE, Ovid Medline, and the Cochrane Library databases were searched for studies published between January 1946 and October 2016, regarding the use of EUS and ME to assess the invasion depth of gastrointestinal cancers. The quality of diagnostic studies was evaluated using the QUADAS2 instrument. The Meta-DiSc software (version 1.4) was used for meta-analysis of the pooled data regarding the diagnostic accuracy of EUS and ME of the invasion depth of gastrointestinal neoplasms. RESULTS: Our meta-analysis included the data of 754 patients with gastrointestinal cancers contributed by seven prospective studies. All studies were of high quality (QUADAS2). The receiver operating characteristic (ROC) planes were not observed in shoulder and arm forms for either EUS or ME, with Spearman's correlation coefficients of -0.821 and 0.234 for EUS and ME, respectively. The p values of the diagnostic odds ratio for EUS and ME were 0.0038 and 0.0131, respectively. The sensitivity and specificity of EUS for the diagnosis of the depth of invasion of gastrointestinal cancers were 0.75 (95% CI 0.69-0.81) and 0.84 (95% CI 0.79-0.88), respectively. In comparison, the sensitivity and specificity for ME were 0.74 (95% CI 0.67-0.69) and 0.85 (95% CI 0.80-0.89), respectively. The values of area under the summary ROC (SROC) curves for EUS and ME were 0.8499 and 0.8757, respectively, with a non-significant Z value between EUS and MR (0.296 < 1.96). CONCLUSIONS: Both EUS and ME provide a comparable performance for judging the depth of invasion of gastrointestinal neoplasms. However, there is heterogeneity between studies contributed by non-threshold effects.

Mir-150 Up-Regulates Glut1 and Increases Glycolysis in Osteosarcoma Cells

Objective: Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. Many studies have shown that microRNAs play a critical role in proliferation and metastasis with this tumour type. However, whether aberrant expression might contribute to a metabolism switch in osteosarcoma cases is not clearly understood. In this study, we explored expression and function of miR-150 in osteosarcoma cells. Materials and methods: Expression of miR-150 was assessed by real-time PCR in cell lines and human patient tissues. Scramble siRNA, miR-150 inhibitor, and miR-150 mimics were transfected into osteosarcoma cells to determine their effects on proliferation rate, glucose uptake and lactate secretion. Finally, the relationship between Glut1 and the miR-150 level was explored by luciferase reporter assay and western blotting. Result: miR-150 was consistently decreased in cell lines and osteosarcoma tissues as compared to osteoblast cells and normal bone. Ectopic overexpression of miR-150 inhibited osteosarcoma cell proliferation and suppressed glucose uptake and lactate secretion. Loss of function of miR-150, on the other hand, enhanced osteosarcoma cell proliferation and increased glucose uptake and lactate secretion. Western blot and luciferase reporter assays showed that miR-150 may function by regulating Glut1 expression. Conclusion: These data suggest that miR-150 is involved in regulation of glycolysis in osteosarcoma cells by influencing Glut1 expression.

TLE1 function and therapeutic potential in cancer.

Groucho (Gro)/Transducin-like enhancer of split (TLE) family proteins act as co-repressors of many transcription factors, and are involved in key signaling pathways. TLE1 negatively regulates inflammation and has potential roles in various diseases, including cancer. Previous studies suggest TLE1 could be used as a diagnostic marker and is a possible therapeutic target in various malignancies. It is therefore important to elucidate the mechanisms underlying TLE1 function during cancer initiation and metastasis. In this review, we highlight the functions of TLE1 in cancer and explore targeted approaches for cancer diagnosis and treatment. In particular, we discuss the TLE1 function in pancreatic cancer.

A novel method for detection of HBVcccDNA in hepatocytes using rolling circle amplification combined with in situ PCR.

BACKGROUND: Intrahepatic hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is the original template for HBV replication. The persistence of cccDNA is responsible for the recurrence of HBV infection. The detection of cccDNA can help the development of new antiviral drugs against HBV replication links, and reduce the resistance and recurrence as well as to discover extrahepatic HBV infection. In situ polymerase chain reaction (IS-PCR) can be used to determine the distribution and localization of cccDNA in liver tissues, but it is hampered by its low sensitivity and specificity. We developed a novel method to detect HBV cccDNA using rolling circle amplification (RCA) combined with IS-PCR. METHODS: Biopsy liver tissues were obtained from 26 patients with HBV infection, including 10 chronic hepatitis B (CHB), 6 liver cirrhosis (LC) and 10 hepatocellular carcinoma (HCC) patients. Four pairs of primers were designed to mediating RCA for the first round amplification of HBV cccDNA specifically. The liver tissue sections from patients were treated by plasmid-safe ATP-dependent DNase (PSAD) prior to RCA. After RCA, HBV cccDNA was further amplified by a pair of selective primers labeled digoxigenin that target the gap region between the two direct repeat regions (DR1 and DR2) of the virus via IS-PCR. RESULTS: HBVcccDNA was expressed and located in hepatocyte nucleus in 19 patients (73.07%). Compared with the IS-PCR, the introduction of RCA increase the limit of detection. RCA combined with IS-PCR yielded strong positive signals in HCC liver tissue in spite of low copy number cccDNA (2 copies of target sequence per cell), meanwhile, no positive signal was detected via negative control. CONCLUSIONS: RCA combined with IS-PCR is an effective and practicable method which could detect the presence of low copy number of cccDNA sensitively and specifically, and reflect the relationship between cccDNA expression level and liver tissue pathological characteristics.

Photoelectrochemical biosensor for detection of adenosine triphosphate in the extracts of cancer cells.

A photoelectrochemical sensing strategy for highly sensitive detection of small molecules was developed based on the recognition interaction between aptamer and target molecule-ATP.

Thiol proteases: inhibitors and potential therapeutic targets.

A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here.