Serum bile acid profiles are associated with heart failure with preserved ejection fraction in patients with metabolic dysfunction-associated fatty liver disease: An exploratory study.

AIM: To analyse the association between serum bile acid (BA) profile and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: We enrolled 163 individuals with biopsy-proven MAFLD undergoing transthoracic echocardiography for any indication. HFpEF was defined as left ventricular ejection fraction >50% with at least one echocardiographic feature of HF (left ventricular diastolic dysfunction, abnormal left atrial size) and at least one HF sign or symptom. Serum levels of 38 BAs were analysed using ultra-performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: Among the 163 patients enrolled (mean age 47.0 ± 12.8 years, 39.3% female), 52 (31.9%) and 43 (26.4%) met the HFpEF and pre-HFpEF criteria, and 38 serum BAs were detected. Serum ursodeoxycholic acid (UDCA) and hyocholic acid (HCA) species were lower in patients with HFpEF and achieved statistical significance after correction for multiple comparisons. Furthermore, decreases in glycoursodeoxycholic acid and tauroursodeoxycholic acid were associated with HF status. CONCLUSIONS: In this exploratory study, specific UDCA and HCA species were associated with HFpEF status in adults with biopsy-confirmed MAFLD.

Single-cell RNA sequencing reveals the process of CA19-9 production and dynamics of the immune microenvironment between CA19-9 (+) and CA19-9 (-) PDAC.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the main types of malignant tumor of the digestive system, and patient prognosis is affected by difficulties in early diagnosis, poor treatment response, and a high postoperative recurrence rate. Carbohydrate antigen 19-9 (CA19-9) has been widely used as a biomarker for the diagnosis and postoperative follow-up of PDAC patients. Nevertheless, the production mechanism and potential role of CA19-9 in PDAC progression have not yet been elucidated. METHODS: We performed single-cell RNA sequencing on six samples pathologically diagnosed as PDAC (three CA19-9-positive and three CA19-9-negative PDAC samples) and two paracarcinoma samples. We also downloaded and integrated PDAC samples (three each from CA19-9-positive and CA19-9-negative patients) from an online database. The dynamics of the proportion and potential function of each cell type were verified through immunofluorescence. Moreover, we built an in vitro coculture cellular model to confirm the potential function of CA19-9. RESULTS: Three subtypes of cancer cells with a high ability to produce CA19-9 were identified by the markers TOP2A, AQP5, and MUC5AC. CA19-9 production bypass was discovered on antigen-presenting cancer-associated fibroblasts (apCAFs). Importantly, the proportion of immature ficolin-1 positive (FCN1+) macrophages was high in the CA19-9-negative group, and the proportion of mature M2-like macrophages was high in the CA19-9-positive group. High proportions of these two macrophage subtypes were associated with an unfavourable clinical prognosis. Further experiments indicated that CA19-9 could facilitate the transformation of M0 macrophages into M2 macrophages in the tumor microenvironment. CONCLUSIONS: Our study described CA19-9 production at single-cell resolution and the dynamics of the immune atlas in CA19-9-positive and CA19-9-negative PDAC. CA19-9 could promote M2 polarization of macrophage in the pancreatic tumor microenvironment.

Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson's disease.

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson's disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1ß, which is subsequently secreted into the extracellular space. This secreted IL-1ß then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

[Resveratrol Inhibits T-acute Lymphoblastic Leukemia in Mice by Regulating Notch1 Signaling Pathway].

OBJECTIVE: To observe the effect of resveratrol (Res) on T-acute lymphoblastic leukemia (T-ALL) mice, and further explore its mechanism on Notch1 signaling pathway. METHODS: Twenty-five 6-8 weeks old female C57BL/6 mice were randomly divided into control group, T-ALL group and Res group. Res group was further divided into low-Res, middle-Res and high-Res group. The percentage of leukemia cells in peripheral blood and spleen cell suspension were detected by flow cytometry and Wright-Giemsa staining, pathological morphology of spleen and bone marrow tissues were observed by HE staining, the expression levels of Notch1, Hes-1, c-Myc, miR-19b and PTEN mRNA in spleen tissue were detected by RT-qPCR, and the protein levels of Notch1, Hes-1, c-Myc, p-PTEN and PTEN were detected by Western blot. RESULTS: Compared with control group, the leukemia cells in peripheral blood of mice in T-ALL group were markedly increased, accompanied by diffuse infiltration of leukemia cells in spleen and bone marrow tissues, the mRNA levels of Notch1, Hes-1, c-Myc, miR-19b and the protein levels of Notch1, Hes-1, c-Myc were increased (P <0.01), while the expression of PTEN mRNA and protein were significantly decreased in the spleen tissue of T-ALL mice (P <0.01). The above indicators in the H-Res group were reversed compared with T-ALL group after administration of resveratrol. CONCLUSION: Resveratrol may play a role in anti T-ALL by inhibiting Notch1 signaling pathway in mice.

Antihyperlipidemic drug rosuvastatin suppressed tumor progression and potentiated chemosensitivity by downregulating CCNA2 in lung adenocarcinoma.

Rosuvastatin (RSV) is widely used to treat hyperlipidemia and hypercholesterolemia and is recommended for the primary and secondary prevention of cardiovascular diseases (CVD). In this study, we aimed to explore its action and mechanism in lung adenocarcinoma (LUAD) therapy. Lewis and CMT64 cell-based murine subcutaneous LUAD models were employed to explore the effects of RSV monotherapy combined with cisplatin and gemcitabine. Human lung fibroblasts and human LUAD cell lines were used to assess the effects of RSV on normal and LUAD cells. Bioinformatics and RNA interference were used to observe the contribution of cyclin A2 (CCNA2) knockdown to RSV inhibition and to improve chemosensitivity in LUAD. RSV significantly suppressed grafted tumor growth in a murine subcutaneous LUAD model and exhibited synergistic anti-tumor activity with cisplatin and gemcitabine. In vitro and in vivo experiments demonstrated that RSV impaired the proliferation and migration of cancer cells while showing little inhibition of normal lung cells. RNA interference and CCK8 detection preliminarily indicated that RSV inhibited tumor growth and enhanced the chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2. RSV suppressed LUAD progression and enhanced chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2, which should be prior consideration for the treatment of LUAD, especially for patients co-diagnosed with hyperlipidemia and hypercholesterolemia.

Gas chromatography ion mobility spectroscopy: A rapid and effective tool for monitoring oil oxidation.

Oil autoxidation is an early process of food deterioration, monitoring oil oxidation is therefore of great significance to ensure food quality and safety. In this study, a detection method of the primary and secondary oxidative products was developed by gas chromatography ion mobility spectrometry (GC-IMS).The secondary oxidative products was analyzed by GC-IMS. Then, the relationships between peroxide values and the contents of secondary oxidative products were investigated by constructing a prediction model of peroxide value of rapeseed oil with the help of secondary oxidative products and chemometrics. The coefficient of determination Q2 of the model validation set is 0.96, and the RMSECV is 0.1570 g/100 g. These validation results indicated that secondary oxidative products could also reflect the content of the primary oxidative products. Moreover, 10 characteristic markers related to oxidative rancidity were identified for monitoring edible oil rancidity and oxidative stability.

Development and application of a fully automatic multi-function cassette module Mortenon M1 for radiopharmaceutical synthesis.

INTRODUCTION: Functions of existing automatic module systems for synthesis of radiopharmaceuticals mainly focus on the radiolabeling of small molecules. There are few modules which have achieved full-automatic radiolabeling of non-metallic and metallic nuclides on small molecules, peptides, and antibody drugs. This study aimed to develop and test a full-automatic multifunctional module system for the safe, stable, and efficient production of radiopharmaceuticals. METHODS: According to characteristics of labeling process of radioactive drugs, using UG and Solidworks softwares, full-automatic cassette-based synthesis module system Mortenon M1 for synthesis of radiopharmaceuticals with various radionuclides, was designed and tested. Mortenon M1 has at least three significant highlights: the cassettes are disposable, and there is no need of manual cleaning; the synthesis method program is flexible and can be edited freely by users according to special needs; this module system is suitable for radiolabeling of both small-molecule and macromolecular drugs, with potentially various radionuclides including 18F, 64Cu, 68Ga, 89Zr, 177Lu, etc. By program control methods for certain drugs, Mortenon M1 was used for radiolabeling of both small-molecule drugs such as [68Ga]-FAPI-46 and macromolecular drugs such as [89Zr]-TROP2 antibody. Quality control assays for product purity were performed with radio-iTLC and radio-HPLC, and the radiotracers were confirmed for application in microPET imaging in xenograft tumor-bearing mouse models. RESULTS: Functional tests for Mortenon M1 module system were conducted, with [68Ga]-FAPI-46 and [89Zr]-TROP2 antibody as goal synthetic products, and it displayed that with the cassette modules, the preset goals could be achieved successfully. The radiolabeling synthesis yield was good ([68Ga]-FAPI-46, 70.63% ± 2.85%, n = 10; [89Zr]-TROP2, 82.31% ± 3.92%, n = 10), and the radiochemical purity via radio-iTLC assay of the radiolabeled products was above 99% after purification. MicroPET imaging results showed that the radiolabeled tracers had reasonable radioactive distribution in MDA-MB-231 and SNU-620 xenograft tumor-bearing mice, and the tumor targeted radiouptake was satisfactory for diagnosis. CONCLUSION: This study demonstrated that the full-automatic module system Mortenon M1 is efficient for radiolabeling synthesis of both small-molecule and macromolecular substrates. It may be helpful to reduce radiation exposure for safety, provide qualified radiolabeled products and reliable PET diagnosis, and ensure stable production and supply of radiopharmaceuticals.

Ni/NiO@NC as a highly efficient and durable HER electrocatalyst derived from nickel(II) complexes: importance of polydentate amino-acid ligands.

Research on Ni/NiO electrocatalysts has advanced significantly, but the main obstacles to their use and commercialization remain their relatively ordinary activity and stability. In this paper, a chelating structure based on the coordination of multidentate ligands and Ni(II) is proposed to limit the growth of Ni and Ni oxide grains. These features reduce the particle size of Ni/NiO, increase particle dispersion, and maintain the high activity and stability of the catalyst. Aspartic acid, as a polydentate ligand, could coordinate with Ni2+ to form structurally stable chelate rings. The latter can limit grain growth, but also coat the active core with thin carbon layers after calcination to further achieve the confinement and protection of nanoparticles. The hydrogen evolution overpotential of prepared nitrogen-doped graphitized carbon shells (Ni/NiO@NC) nanoparticles was 100 mV (vs. RHE) when the current density was 10 mA cm-2 in 1 M KOH. The hydrogen evolution overpotential increased by only 4 mV after 6000 continuous cyclic-voltammetry scans. Moreover, when coated on different conductive substrates, the overpotential of this catalyst dropped to 34.6 mV (vs. RHE) at a current density of 10 mV cm-2. The lowest overpotential of the composite was only 194.9 mV at a current density of 100 mA cm-2, which is comparable with that of noble metal-based electrocatalysts. This work provides a plausible method for designing high-performance electrocatalysts of small size.

Rapid Discovery of Substances with Anticancer Potential from Marine Fungi Based on a One Strain-Many Compounds Strategy and UPLC-QTOF-MS.

The secondary metabolites of marine fungi with rich chemical diversity and biological activity are an important and exciting target for natural product research. This study aimed to investigate the fungal community in Quanzhou Bay, Fujian, and identified 28 strains of marine fungi. A total of 28 strains of marine fungi were screened for small-scale fermentation by the OSMAC (One Strain-Many Compounds) strategy, and 77 EtOAc crude extracts were obtained and assayed for cancer cell inhibition rate. A total of six strains of marine fungi (P-WZ-2, P-WZ-3-2, P-WZ-4, P-WZ-5, P56, and P341) with significant changes in cancer cell inhibition induced by the OSMAC strategy were analysed by UPLC-QTOF-MS. The ACD/MS Structure ID Suite software was used to predict the possible structures with inhibitory effects on cancer cells. A total of 23 compounds were identified, of which 10 compounds have been reported to have potential anticancer activity or cytotoxicity. In this study, the OSMAC strategy was combined with an untargeted metabolomics approach based on UPLC-QTOF-MS to efficiently analyse the effect of changes in culture conditions on anticancer potentials and to rapidly find active substances that inhibit cancer cell growth.

A Terphenyllin Derivative CHNQD-00824 from the Marine Compound Library Induced DNA Damage as a Potential Anticancer Agent.

With the emergence of drug resistance and the consequential high morbidity and mortality rates, there is an urgent need to screen and identify new agents for the effective treatment of cancer. Terphenyls-a group of aromatic hydrocarbons consisting of a linear 1,4-diaryl-substituted benzene core-has exhibited a wide range of biological activities. In this study, we discovered a terphenyllin derivative-CHNQD-00824-derived from the marine compound library as a potential anticancer agent. The cytotoxic activities of the CHNQD-00824 compound were evaluated against 13 different cell lines with IC50 values from 0.16 to 7.64 µM. Further study showed that CHNQD-00824 inhibited the proliferation and migration of cancer cells, possibly by inducing DNA damage. Acridine orange staining demonstrated that CHNQD-00824 promoted apoptosis in zebrafish embryos. Notably, the anti-cancer effectiveness was verified in a doxycin hydrochloride (DOX)-induced liver-specific enlargement model in zebrafish. With Solafinib as a positive control, CHNQD-00824 markedly suppressed tumor growth at concentrations of 2.5 and 5 µM, further highlighting its potential as an effective anticancer agent.

Acute toxicological evaluation of AT-533 and AT-533 gel in Sprague-Dawley rats.

BACKGROUND: AT-533 is a novel heat shock protein 90 inhibitor that exerting anti-inflammatory, antiviral, and antitumor efficacy. Furthermore, the gel made of AT-533 as raw material named AT-533 gel has the function of repairing keratitis and dermatitis caused by herpes virus infection. However, the acute safety evaluation of AT-533 and AT-533 gel has not been conducted. METHODS AND RESULTS: Herein, we performed acute toxicological studies of AT-533 and AT-533 gel in Sprague-Dawley rats. Fifteen-day acute toxicity study of AT-533 was conducted in both male and female Sprague-Dawley rats at doses of 5, 50, 250 and 500 mg/kg and AT-533 gel at 5 g/kg in the study. During experiment, food consumption and mortality were observed and body weight, hematology, serum biochemistry and histopathological assessment of rats were carried out. No abnormal changes were observed in rats percutaneously treated with AT-533 at 5 mg/kg and 50 mg/kg and AT-533 gel. However, loss of appetite and body weight, adverse reactions, toxicologically relevant alterations in hematology and biochemistry were found in rats percutaneously treated with AT-533 at 250 mg/kg and 500 mg/kg during 15-day acute dermic toxicity study. CONCLUSIONS: The aforementioned results suggested that the LD50 of AT-533 is 228.382 mg/kg and the LD50 of AT-533 gel is greater than 5 g/kg. These findings indicated that AT-533 is non-toxic in rats when the dose less than 50 mg/kg and AT-533 gel can be considered a gel with no toxicity at doses less than 5 g/kg.

Chronic intermittent hypobaric hypoxia improves iron metabolism disorders via the IL-6/JAK2/STAT3 and Epo/STAT5/ERFE signaling pathways in metabolic syndrome rats.

AIM: Our previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) improved iron metabolism disorder in obese rats through the downregulation of hepcidin. This study aimed to observe the molecular mechanism of CIHH in improving iron metabolism disorders, especially by Janus kinase/signal transducer and activation of the transcription (JAK/STAT) signaling pathway in metabolic syndrome (MS) rats. METHODS: Six-week-old male Sprague-Dawley rats were randomly divided into four groups: CON, CIHH (subjected to hypobaric hypoxia simulating 5000-m altitude for 28 days, 6 h daily), MS (induced by high fat diet and fructose water), and MS+CIHH. The serum levels of glucose, lipid metabolism, iron metabolism, interleukin-6 (IL-6), erythropoietin (Epo) and hepcidin were measured. The protein expressions of JAK2, STAT3, STAT5, bone morphogenetic protein 6 (BMP6), small mothers against decapentaplegic 1 (SMAD1) and hepcidin were examined. The mRNA expressions of erythroferrone (ERFE) and hepcidin were analyzed. RESULTS: The MS rats displayed obesity, hyperglycemia, hyperlipidemia, iron metabolism disorder, increased IL-6 and hepcidin serum levels, upregulation of JAK2/STAT3 signaling pathway, decreased Epo serum levels, downregulation of STAT5/ERFE signaling pathway in spleen, upregulation of BMP/SMAD signaling pathway in liver, and increased hepcidin mRNA and protein expression compared to CON rats. All the aforementioned abnormalities in MS rats were ameliorated in MS + CIHH rats. CONCLUSIONS: CIHH improved iron metabolism disorders, possibly by inhibiting IL-6/JAK2/STAT3 and activating Epo/STAT5/ERFE signaling pathway, thus downregulating hepcidin in MS rats.

Integrated proteogenomic characterization reveals an imbalanced hepatocellular carcinoma microenvironment after incomplete radiofrequency ablation.

BACKGROUND: Efforts to precisely assess tumor-specific T-cell immune responses still face major challenges, and the potential molecular mechanisms mediating hepatocellular carcinoma (HCC) microenvironment imbalance after incomplete radiofrequency ablation (iRFA) are unclear. This study aimed to provide further insight into the integrated transcriptomic and proteogenomic landscape and identify a new target involved in HCC progression following iRFA. METHODS: Peripheral blood and matched tissue samples were collected from 10 RFA-treated HCC patients. Multiplex immunostaining and flow cytometry were used to assess local and systemic immune responses. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were explored via transcriptomic and proteogenomic analyses. Proteinase-3 (PRTN3) was identified in these analyses. And then, the ability of PRTN3 to predict overall survival (OS) was assessed in 70 HCC patients with early recurrence after RFA. In vitro CCK-8, wound healing and transwell assays were conducted to observe interactions between Kupffer cells (KCs) and HCC cells induced by PRTN3. The protein levels of multiple oncogenic factors and signaling pathway components were detected by western blotting. A xenograft mouse model was built to observe the tumorigenic effect of PRTN3 overexpression on HCC. RESULTS: Multiplex immunostaining revealed no immediate significant change in local immune cell counts in periablational tumor tissues after 30 min of iRFA. Flow cytometry showed significantly increased levels of CD4+ T cells, CD4+CD8+ T cells, and CD4+CD25+CD127- Tregs and significantly decreased the levels of CD16+CD56+ natural killer cells on day 5 after cRFA (p < 0.05). Transcriptomics and proteomics revealed 389 DEGs and 20 DEPs. Pathway analysis showed that the DEP-DEGs were mainly enriched in the immunoinflammatory response, cancer progression and metabolic processes. Among the DEP-DEGs, PRTN3 was persistently upregulated and closely associated with the OS of patients with early recurrent HCC following RFA. PRTN3 expressed in KCs may affect the migration and invasion of heat stress-treated HCC cells. PRTN3 promotes tumor growth via multiple oncogenic factors and the PI3K/AKT and P38/ERK signaling pathways. CONCLUSIONS: This study provides a comprehensive overview of the immune response and transcriptomic and proteogenomic landscapes of the HCC milieu induced by iRFA, revealing that PRTN3 promotes HCC progression after iRFA. TRIAL REGISTRATION: ChiCTR2200055606, http://www.chictr.org.cn/showproj.aspx?proj=32588 .

Secondary bile acids improve risk prediction for non-invasive identification of mild liver fibrosis in nonalcoholic fatty liver disease.

BACKGROUND: Dysregulated bile acid (BA) metabolism has been linked to steatosis, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD). AIM: To determine whether circulating BA levels accurately stage liver fibrosis in NAFLD. METHODS: We recruited 550 Chinese adults with biopsy-proven NAFLD and varying levels of fibrosis. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was performed to quantify 38 serum BAs. RESULTS: Compared to those without fibrosis, patients with mild fibrosis (stage F1) had significantly higher levels of secondary BAs, and increased diastolic blood pressure (DBP), alanine aminotransferase (ALT), body mass index, and waist circumstance (WC). The combination of serum BAs with WC, DBP, ALT, or Homeostatic Model Assessment for Insulin Resistance performed well in identifying mild fibrosis, in men and women, and in those with/without obesity, with AUROCs 0.80, 0.88, 0.75 and 0.78 in the training set (n = 385), and 0.69, 0.80, 0.61 and 0.69 in the testing set (n = 165), respectively. In comparison, the combination of BAs and clinical/biochemical biomarkers performed less well in identifying significant fibrosis (F2-4). In women and in non-obese subjects, AUROCs were 0.75 and 0.71 in the training set, 0.65 and 0.66 in the validation set, respectively. However, these AUROCs were higher than those observed for the fibrosis-4 index, NAFLD fibrosis score, and Hepamet fibrosis score. CONCLUSIONS: Secondary BA levels were significantly increased in NAFLD, especially in those with mild fibrosis. The combination of serum BAs and clinical/biochemical biomarkers for identifying mild fibrosis merits further assessment.

Chronic intermittent hypobaric hypoxia ameliorates vascular reactivity through upregulating adiponectin expression of PVAT in metabolic syndrome rats.

Cumulating evidence demonstrated that chronic intermittent hypobaric hypoxia (CIHH) had beneficial effects on the body. This study investigated the role of perivascular adipose tissue (PVAT) in ameliorating effect of CIHH on vascular reactivity by adiponectin in mesenteric artery of metabolic syndrome (MS) rats. Main methods: 6-week-old male Sprague-Dawley rats were randomly divided into four groups: control (CON), MS model, CIHH treatment, and MS + CIHH treatment group. The size of adipocytes in PVAT was measured by scanning electron microscopy. Serum adiponectin was measured. The microvessel recording technique was used to observe the effect of CIHH on contraction and relaxation in mesenteric artery rings. Also, the expressions of interleukin-1ß, tumor necrosis factor-α, adiponectin, AdipoR1, AdipoR2, APPL1, and endothelial nitric oxide synthase (eNOS) were assayed by Western blotting. Key findings: in MS rats, adipocyte size increased, serum adiponectin decreased, contraction reaction increased while relaxation reaction decreased, the expression of pro-inflammatory cytokines was upregulated, while adiponectin was downregulated in PVAT, and the expressions of AdipoR1, AdipoR2, APPL, and phosphorylated-eNOS were downregulated in mesenteric artery. All aforementioned abnormalities of MS were ameliorated in MS + CIHH rats. We concluded that CIHH treatment improves vascular reactivity through upregulating adiponectin expression and downregulating pro-inflammatory cytokine expression of PVAT in MS rats.

The value of artificial intelligence techniques in predicting pancreatic ductal adenocarcinoma with EUS images: A meta-analysis and systematic review.

Conventional EUS plays an important role in identifying pancreatic cancer. However, the accuracy of EUS is strongly influenced by the operator's experience in performing EUS. Artificial intelligence (AI) is increasingly being used in various clinical diagnoses, especially in terms of image classification. This study aimed to evaluate the diagnostic test accuracy of AI for the prediction of pancreatic cancer using EUS images. We searched the Embase, PubMed, and Cochrane Library databases to identify studies that used endoscopic ultrasound images of pancreatic cancer and AI to predict the diagnostic accuracy of pancreatic cancer. Two reviewers extracted the data independently. The risk of bias of eligible studies was assessed using a Deek funnel plot. The quality of the included studies was measured by the QUDAS-2 tool. Seven studies involving 1110 participants were included: 634 participants with pancreatic cancer and 476 participants with nonpancreatic cancer. The accuracy of the AI for the prediction of pancreatic cancer (area under the curve) was 0.95 (95% confidence interval [CI], 0.93-0.97), with a corresponding pooled sensitivity of 93% (95% CI, 0.90-0.95), specificity of 90% (95% CI, 0.8-0.95), positive likelihood ratio 9.1 (95% CI 4.4-18.6), negative likelihood ratio 0.08 (95% CI 0.06-0.11), and diagnostic odds ratio 114 (95% CI 56-236). The methodological quality in each study was found to be the source of heterogeneity in the meta-regression combined model, which was statistically significant (P = 0.01). There was no evidence of publication bias. The accuracy of AI in diagnosing pancreatic cancer appears to be reliable. Further research and investment in AI could lead to substantial improvements in screening and early diagnosis.

Russell Body-Like Inclusions in Granulocytes in Remission of Acute Myeloid Leukemia.

BACKGROUND: Russell bodies are mostly found in pathological plasma cells and have never been reported in other types of cells. Here, we present a rare case of Russell-like bodies in granulocytes from a 65-year-old woman with acute myeloid leukemia (AML) in remission who had been treated with IA chemotherapy. METHODS: The nature and origin of Russell-like bodies were evaluated by Wright-Giemsa staining, tissue biopsy and immunohistochemical staining, serum immunofixation electrophoresis. RESULTS: The bone marrow aspirate smear revealed many different circular, refractive Russell-like inclusions in the cytoplasm of some myelocytes and metamyelocytes. Tissue biopsy of left waist lesion showed fatty necrosis infiltrated with multifocal lymphocytes, phagocytes, and plasma cells and subcutaneous small focal calcifications. The result of serum immunofixation electrophoresis revealed that the level of IgG was 30.3 g/L (↑) and λ light chain was weakly positive. CONCLUSIONS: Russell body-like inclusions in granulocytes should be noted. It is necessary for further clinical observation and monitoring to determine whether the disease progressed to MM on the basis of serum immuno-fixation electrophoresis.

Erratum: Lentinan-functionalized Selenium Nanoparticles target Tumor Cell Mitochondria via TLR4/TRAF3/MFN1 pathway: Erratum.

[This corrects the article DOI: 10.7150/thno.46467.].

Trends of calcium silicate biomaterials in medical research and applications: A bibliometric analysis from 1990 to 2020.

Background: Calcium silicate biomaterials (CSB) have witnessed rapid development in the past 30 years. This study aimed to accomplish a comprehensive bibliometric analysis of the published research literature on CSB for biomedical applications and explore the research hotspot and current status. Methods: Articles related to CSB published in the last three decades (1990-2020) were retrieved from Web of Science Core Collection. The R bibliometrix package and VOSviewer were used to construct publication outputs and collaborative networking among authors, their institutes, countries, journals' matrices and keywords plus. Results: A total of 872 publications fulfilling the search criteria were included. CSB is mainly reported for bone tissues and dental applications. Among researchers, Chang J from Chinese Academy of Sciences and Gandolfi MG from the University of Bologna are the most productive author in these two fields, respectively. China was the leading contributor to the research on CSB in the medical field. A total of 130 keywords appeared more ten or more times were identified. The term "mineral trioxide aggregate" ranked first with 268 occurrences. The co-occurrence analysis identified three major clusters: CSB in dentistry, bone tissue and vitro bioactivity. Conclusion: Calcium silicate biomaterials have a promising scope for various biomedical applications ranging from regeneration of hard tissues (bone and teeth) to skin, tumor, cardiac muscle and other soft tissues. This study may help researchers further understand the frontiers of the field.

Single-cell sequencing reveals heterogeneity between pancreatic adenosquamous carcinoma and pancreatic ductal adenocarcinoma with prognostic value.

Pancreatic adenosquamous carcinoma (ASPC) is a rare subtype of pancreatic cancer with lethal malignancy, and few studies have focused on the heterogeneity of ASPC. Here, we performed a single-cell sequencing procedure on pancreatic tumor tissue from an ASPC patient and a patient with high-grade intraductal papillary mucinous neoplasm (IPMN). Through the combined analysis of single-cell sequencing data from five pancreatic ductal adenocarcinoma (PDAC) patients, one IPMN patient, and one ASPC patient in a public database, we identified 11 main types of cells, including macrophages, B cells, cancer stem cells, ductal cells, fibroblasts, endo/stellate cells, neutrophils, acinar cells, T cells, natural killer (NK) cells, dendritic cells, and mast cells. Then, the different characteristics and differentiation paths of the immune microenvironment among IPMN, ASPC, and PDAC in macrophages, T cells, and cancer-associated fibroblasts (CAFs) were identified through multiple bioinformatics analyses. Two novel special cancer-associated fibroblasts were identified as nCAFs and imCAFs. Then, cancer cells in duct cells were identified using the infercnv software. Two ASPC-specific subgroups of cancer cells with squamous cell features were identified. Finally, the identified specific CAFs and cancer cells were mapped to TCGA-PAAD cohort through the cibersoftx software. All of these identified subgroups were calculated to have a significant prognostic value in pancreatic cancer patients. These findings will promote the clinical application of single-cell sequencing data of pancreatic cancer and deepen our understanding of ASPC.