Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

Experimental Full Network Nonlocality with Independent Sources and Strict Locality Constraints.

Nonlocality arising in networks composed of several independent sources gives rise to phenomena radically different from that in standard Bell scenarios. Over the years, the phenomenon of network nonlocality in the entanglement-swapping scenario has been well investigated and demonstrated. However, it is known that violations of the so-called bilocality inequality used in previous experimental demonstrations cannot be used to certify the nonclassicality of their sources. This has put forward a stronger concept for nonlocality in networks, called full network nonlocality. Here, we experimentally observe full network nonlocal correlations in a network where the source-independence, locality, and measurement-independence loopholes are closed. This is ensured by employing two independent sources, rapid setting generation, and spacelike separations of relevant events. Our experiment violates known inequalities characterizing nonfull network nonlocal correlations by over 5 standard deviations, certifying the absence of classical sources in the realization.

Experimental Demonstration of Genuine Tripartite Nonlocality under Strict Locality Conditions.

Nonlocality captures one of the counterintuitive features of nature that defies classical intuition. Recent investigations reveal that our physical world's nonlocality is at least tripartite; i.e., genuinely tripartite nonlocal correlations in nature cannot be reproduced by any causal theory involving bipartite nonclassical resources and unlimited shared randomness. Here, by allowing the fair sampling assumption and postselection, we experimentally demonstrate such genuine tripartite nonlocality in a network under strict locality constraints that are ensured by spacelike separating all relevant events and employing fast quantum random number generators and high-speed polarization measurements. In particular, for a photonic quantum triangular network we observe a locality-loophole-free violation of the Bell-type inequality by 7.57 standard deviations for a postselected tripartite Greenberger-Horne-Zeilinger state of fidelity (93.13±0.24)%, which convincingly disproves the possibility of simulating genuine tripartite nonlocality by bipartite nonlocal resources with globally shared randomness.

Closing the Locality and Detection Loopholes in Multiparticle Entanglement Self-Testing.

First proposed by Mayers and Yao, self-testing provides a certification method to infer the underlying physics of quantum experiments in a black-box scenario. Numerous demonstrations have been reported to self-test various types of entangled states. However, all the multiparticle self-testing experiments reported so far suffer from both detection and locality loopholes. Here, we report the first experimental realization of multiparticle entanglement self-testing closing the locality loophole in a photonic system, and the detection loophole in a superconducting system, respectively. We certify three-party and four-party GHZ states with at least 0.84(1) and 0.86(3) fidelities in a device-independent way. These results can be viewed as a meaningful advance in multiparticle loophole-free self-testing, and also significant progress on the foundations of quantum entanglement certification.

Experimental Refutation of Real-Valued Quantum Mechanics under Strict Locality Conditions.

Quantum mechanics is commonly formulated in a complex, rather than real, Hilbert space. However, whether quantum theory really needs the participation of complex numbers has been debated ever since its birth. Recently, a Bell-like test in an entanglement-swapping scenario has been proposed to distinguish standard quantum mechanics from its real-valued analog. Previous experiments have conceptually demonstrated, yet not satisfied, the central requirement of independent state preparation and measurements and leave several loopholes. Here, we implement such a Bell-like test with two separated independent sources delivering entangled photons to three separated parties under strict locality conditions that are enforced by spacelike separation of the relevant events, rapid random setting generation, and fast measurement. With the fair-sampling assumption and closed loopholes of independent source, locality, and measurement independence simultaneously, we violate the constraints of real-valued quantum mechanics by 5.30 standard deviations. Our results disprove the real-valued quantum theory to describe nature and ensure the indispensable role of complex numbers in quantum mechanics.

Robust Self-Testing of Multiparticle Entanglement.

Quantum self-testing is a device-independent way to certify quantum states and measurements using only the input-output statistics, with minimal assumptions about the quantum devices. Because of the high demand on tolerable noise, however, experimental self-testing was limited to two-photon systems. Here, we demonstrate the first robust self-testing for multiphoton genuinely entangled quantum states. We prepare two examples of four-photon graph states, the Greenberger-Horne-Zeilinger states with a fidelity of 0.957(2) and the linear cluster states with a fidelity of 0.945(2). Based on the observed input-output statistics, we certify the genuine four-photon entanglement and further estimate their qualities with respect to realistic noise in a device-independent manner.

MetS Risk Score: A Clear Scoring Model to Predict a 3-Year Risk for Metabolic Syndrome.

Although several risk factors for metabolic syndrome (MetS) have been reported, there are few clinical scores that predict its incidence. Therefore, we created and validated a risk score for prediction of 3-year risk for MetS. Three-year follow-up data of 4395 initially MetS-free subjects, enrolled for an annual physical examination from Wenzhou Medical Center were analyzed. Subjects at enrollment were randomly divided into the training and the validation cohort. Univariate and multivariate logistic regression models were employed for model development. The selected variables were assigned an integer or half-integer risk score proportional to the estimated coefficient from the logistic model. Risk scores were tested in a validation cohort. The predictive performance of the model was tested by computing the area under the receiver operating characteristic curve (AUROC). Four independent predictors were chosen to construct the MetS risk score, including BMI (HR=1.906, 95% CI: 1.040-1.155), FPG (HR=1.507, 95% CI: 1.305-1.741), DBP (HR=1.061, 95% CI: 1.002-1.031), HDL-C (HR=0.539, 95% CI: 0.303-0.959). The model was created as -1.5 to 4 points, which demonstrated a considerable discrimination both in the training cohort (AUROC=0.674) and validation cohort (AUROC=0.690). Comparison of the observed with the estimated incidence of MetS revealed satisfactory precision. We developed and validated the MetS risk score with 4 risk factors to predict 3-year risk of MetS, useful for assessing the individual risk for MetS in medical practice.

[Relativity of commercial specification of Menthae Herba based on chemical analysis].

In order to compare the differences of 35 Menthae Herba samples collected on the market and at producing areas, the contents of six total terpenoids, the essential oil and chromatographic fingerprints were analyzed, which provided evidences for drawing up the commodity specifications and grading criteria of Menthae Herba. GC-MS method was used to analyze the chemical constituents of 35 different samples. The chromatographic fingerprints obtained by using GC were then evaluated by similarity analysis, hierarchical clustering analysis and principal component analysis. The relativity between the content of six terpenoids and the essential oil were studied. In this study, the chemical profiles of 35 samples from different producing areas had significant disparity. All samples collected in the report could be categorized into four chemical types, L-menthol, pulegone, carvone and L-menthone, but the chemical profiles had no relationship with the areas. The chromatographic fingerprints of the samples from different types were dissimilar, while the different producing areas were difficult to be separated. It was indicated that the content of volatile oil was positively correlated with the content of L-menthol and the sum of six total terpenoids. The content of the essential oil, L-menthol and the sum of six total terpenoids of Menthae Herba were considered as one of the commercial specifications and grading criteria. These results in the research could be helpful to draw up the commercial specification and grading criteria of Menthae Herba from a view of chemical information.

Alteration of intestinal microbiota is associated with diabetic retinopathy and its severity: Samples collected from southeast coast Chinese.

BACKGROUND: Current approaches for the therapy of diabetic retinopathy (DR), which was one of leading causes of visual impairment, have their limitations. Animal experiments revealed that restructuring of intestinal microbiota can prevent retinopathy. AIM: To explore the relationship between intestinal microbiota and DR among patients in the southeast coast of China, and provide clues for novel ways to prevention and treatment methods of DR. METHODS: The fecal samples of non-diabetics (Group C, n = 15) and diabetics (Group DM, n = 30), including 15 samples with DR (Group DR) and 15 samples without DR (Group D), were analyzed by 16S rRNA sequencing. Intestinal microbiota compositions were compared between Group C and Group DM, Group DR and Group D, as well as patients with proliferative diabetic retinopathy (PDR) (Group PDR, n = 8) and patients without PDR (Group NPDR, n = 7). Spearman correlation analyses were performed to explore the associations between intestinal microbiota and clinical indicators. RESULTS: The alpha and beta diversity did not differ significantly between Group DR and Group D as well as Group PDR and Group NPDR. At the family level, Fusobacteriaceae, Desulfovibrionaceae and Pseudomonadaceae were significantly increased in Group DR than in Group D (P < 0.05, respectively). At the genera level, Fusobacterium, Pseudomonas, and Adlercreutzia were increased in Group DR than Group D while Senegalimassilia was decreased (P < 0.05, respectively). Pseudomonas was negatively correlated with NK cell count (r = -0.39, P = 0.03). Further, the abundance of genera Eubacterium (P < 0.01), Peptococcus, Desulfovibrio, Acetanaerobacterium and Negativibacillus (P < 0.05, respectively) were higher in Group PDR compared to Group NPDR, while Pseudomonas, Alloprevotella and Tyzzerella (P < 0.05, respectively) were lower. Acetanaerobacterium and Desulfovibrio were positively correlated with fasting insulin (r = 0.53 and 0.61, respectively, P < 0.05), when Negativibacillus was negatively correlated with B cell count (r = -0.67, P < 0.01). CONCLUSION: Our findings indicated that the alteration of gut microbiota was associated with DR and its severity among patients in the southeast coast of China, probably by multiple mechanisms such as producing short-chain fatty acids, influencing permeability of blood vessels, affecting levels of vascular cell adhesion molecule-1, hypoxia-inducible factor-1, B cell and insulin. Modulating gut microbiota composition might be a novel strategy for prevention of DR, particularly PDR in population above.

Topographical associations between islet endocrine cells and duct epithelial cells in the adult human pancreas.

OBJECTIVES: The pancreatic ducts, endocrine islets and exocrine acini are three functionally related components. From birth to adulthood, the islets and ducts are regarded as independent entities. The objective of this study is to investigate the topographical associations between the islet endocrine cells and duct epithelial cells in the adult human pancreas. MATERIALS AND METHODS: Panels of immunomarkers for the exocrine acinar cells (amylase), duct cells [cytokeratin 19 (CK19)], endocrine cells (chromogranin A, neurone specific enolase, synaptophysin) and islet hormones (glucagon, insulin, somatostatin, pancreatic polypeptide) were applied to sequential pancreatic tissue sections obtained from autopsy specimens of 10-nondiabetic human adults. Double immunofluorescent staining with CK19 and islet hormones was performed to confirm the islet to duct interrelationship. RESULTS: Sequential sectioning and immunostaining showed that 45% of the 172 islets examined appeared as single endocrine cell units or small clusters of < 10 endocrine cells on at least one plane of section. A topographical association was found between the islet endocrine cells and duct epithelial cells. Topographical associations with CK 19-stained duct cells occurred in 10.9% of the islet insulin-containing beta-cells and in 8.9% of the islet glucagon-producing alpha-cells. The frequency of topographical associations increased toward the more distally located duct systems. The CK19-stained duct cells and amylase-labelled acinar cells were less frequently in association with other islet hormone-producing cells. CONCLUSIONS: Topographical associations between islet endocrine cells and pancreatic duct cells are frequent in adult human pancreas. The islet-duct association suggests possible functional interactions between the two interrelated pancreatic compartments.

Synergistic increase in cardiovascular risk in diabetes mellitus with nonalcoholic fatty liver disease: a meta-analysis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been linked to an increased risk of cardiovascular disease (CVD). To explore the impact of diabetes mellitus (DM) as a cardiovascular risk factor, this meta-analysis quantitatively assessed the association of NAFLD and CVD in diabetic patients. METHODS: PubMed, EMBASE, and the Cochrane Library database were analyzed until the end of March 2017. Original studies analyzing the association between NAFLD and cardiovascular risk factors in the diabetic population were included. The available data related to outcome were extracted for the effect estimate using a random-effects model. The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. RESULTS: Of the 770 initially identified studies, 11 studies involving 8346 patients were finally included. The Newcastle-Ottawa Quality Assessment Scale scores suggested that the studies included were of high quality. The pooled effects estimate showed that diabetic patients with NAFLD showed a two times increased risk for CVD compared with patients without NAFLD (odds ratio=2.20, 95% confidence interval: 1.67-2.90). Subgroup analysis also yielded a markedly increased risk, with odds ratio (95% confidence interval) values of 2.28 (1.61-3.23) and 1.90 (1.48-2.45) in cross-sectional and cohort studies, respectively. CONCLUSION: This is the first meta-analysis investigating the relationship between NAFLD and CVD independent of the impact of DM. Our findings suggested that NAFLD increases the risk of CVD in populations with comparable DM profiles. Diabetic patients diagnosed with NAFLD might benefit from a more early cardiovascular risk assessment, thereby reducing CVD morbidity and mortality.

[Bioinformatics analysis to the differentially expressed genes of normal mucosa and carcinoma of colon].

OBJECTIVE: To systemically analyze the differentially expressed genes from normal mucosa and carcinoma of colon obtained by SSH method. METHODS: An automatic platform for the analysis of nucleotides based on Linux was constructed, and one of the three subtracted libraries from SSH (T -N) was systematically analyzed by this platform. Part of the results was verified by semi- quantity RT-PCR. RESULT: The automatic platform for the analysis of nucleotides based on Linux was successfully constructed. There were 15 contigs from the subtracted T-N libraries, among which 2 had no match with known genes in the GenBank. The expressions of genes Homo Sapiens thymosin beta 4 (THY) and Homo Sapiens HbxAg transactivated protein 2 (XTP) had trends of increase with the progress of normal tissue-adenoma-adenocarcinoma when verified by semi- quantity RT-PCR. CONCLUSION: Linux-based automatic platform provides an efficient way to systematically analyze the nucleotide sequences, which may be used in study on the mechanism of colorectal carcinogenesis.

[Severe acute respiratory syndrome].

OBJECTIVE: Severe acute respiratory syndrome(SARS), caused by SARS- associated coronavirus(SCV), is the first severe infectious disease in this century. SARS is pathologically characterized by interstitial exudative inflammation of lung with the formation of hyaline membrane in acute phase. Haemorrhagic inflammation exists in extrapulmonary organs. Clinical diagnosis is a dynamic process and includes the suspected case, probable case and definite case. Diagnostic standard of SARS will be revised with further understanding of the disease. Chinese term of SARS has been recommended in the paper.

Mitochondrial dysfunction and cellular metabolic deficiency in Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-ß (Aß) deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aß precursor protein is cleaved to produce both extracellular and intracellular Aß, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aß neurotoxicity. In this review, we summarize the pathways of Aß generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.

Magnetic resonance imaging of Alzheimer's disease: from diagnosis to therapeutic evaluation.

Alzheimer's disease (AD) is a devastating late-life dementia that produces progressive loss of memory and mental faculties in elderly people. It is important to identify the earliest evidence of AD and to monitor the development of this disease for us to make positive response to its management. Magnetic resonance imaging (MRI) is powerful to image the tissue or organ without damnification. MRI can be employed to diagnose the early AD development and monitor the key biomarker development in AD. MRI may be helpful not only in diagnosing early AD, but also in evaluating its development. This article reviews the progress of MRI on the diagnosis and detection of AD, and makes comments on its therapeutic application.

[Ningbo Renze hospital in modern times].

After the Opium War in 1842, the Western forces came into China in great numbers. In order to give missionary sermons, the Anglican Mission set up Renze hospital in Ningbo in the 1870s. As the expansionist product of western imperialist powers in China, Renze hospital had colonial characteristics, but the missionaries' medical activities played a certain advocational role in the development of the medical health advancement of Ningbo in modern times, as well as a role in the changes in social values and bad habits.

Amyloid oligomers in diabetic and nondiabetic human pancreas.

The amyloid hypothesis of type 2 diabetes mellitus postulates that elevated levels of normally expressed monomeric proteins of human islet amyloid polypeptide (hIAPP) trigger oligomerization that independently causes fibril formation and disease progression. The aim of this study was to demonstrate the existence of amyloid oligomers in human pancreatic islets. Human pancreas tissues were obtained at autopsy of 8 nondiabetic control subjects (mean age = 75.8 +/- 11.7 years, 4 males), 8 type 2 diabetic cases without islet amyloid (mean age = 78.8 +/- 8.5 years, 4 males), and 8 type 2 diabetic patients with islet amyloid (mean age = 73.7 +/- 14.2 years, 4 males). Several markers for insulin, IAPP, amyloid fibrils (thioflavin T), and apoptosis (cleaved caspase-3) were used in combination with an oligomer-specific antibody. Two distinct forms of oligomers were found in pancreatic islets. Small spherical puncta were found in approximately 3% to 20% of the islet cells of nondiabetic subjects, and large curvilinear structures as extracellular oligomers were identified frequently in diabetic islets. Large oligomers were spatially localized adjacent to amyloid fibrils and were associated with apoptosis. This report demonstrates the presence of 2 morphologic classes of amyloid oligomers in human pancreatic islets. The observations warrant function studies to investigate the clinical implications of the amyloid oligomerization in the pathogenesis of type 2 diabetes.

Phycocyanin protects INS-1E pancreatic beta cells against human islet amyloid polypeptide-induced apoptosis through attenuating oxidative stress and modulating JNK and p38 mitogen-activated protein kinase pathways.

It is widely accepted that human islet amyloid polypeptide (hIAPP) aggregation plays an important role in the loss of insulin-producing pancreatic beta cells. hIAPP-induced cytotoxicity is mediated by generation of reactive oxygen species (ROS). Phycocyanin (PC) is a natural compound from blue-green algae that is widely used as food supplement. Currently, little is known about the effects of PC on beta cells with the presence of hIAPP. The aim of this study was to investigate the in vitro protective effects of PC on INS-1E rat insulinoma beta cells against hIAPP-induced cell death, as well as the underlying mechanisms. Our results showed that hIAPP-induced cell death with apoptotic characteristics including growth inhibition, chromatin condensation and DNA fragmentation. However, cytotoxicity of hIAPP was significantly attenuated by co-incubation of the cells with PC. The results of Western blotting showed that activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP) in hIAPP-treated cells was blocked by PC. Moreover, PC significantly prevented the hIAPP-induced overproduction of intracellular ROS and malondialdehyde (MDA), as well as changes in activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzymes. Furthermore, hIAPP triggered the activation of mitogen-activated protein kinases (MAPKs), and these effects were effectively suppressed by PC. Taken together, our results suggest that PC protects INS-1E pancreatic beta cells against hIAPP-induced apoptotic cell death through attenuating oxidative stress and modulating c-Jun N-terminal kinase (JNK) and p38 pathways.