Search

Background This study aims to investigate whether indocyanine green (ICG) tumor imaging helps determine the safe surgical margin in laparoscopic hepatectomy. Patients and Methods Eighty-six patients with hepatic malignancies [including hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM)] were included in this study. ICG-R15 testing was performed 5–7 days before surgery. Fluorescence staining of the tumor was detected by a fluorescent laparoscope, and the width of fluorescence band surrounding tumor was measured by an electronic vernier caliper. Results The positive rate of hepatic malignant lesions successfully stained by ICG fluorescence was 96.0% (95/99). HCC with better differentiation demonstrated non-rim fluorescence patterns, while cases with poor differentiation demonstrated rim patterns. CRLM uniformly demonstrated rim pattern. The width of fluorescence surrounding tumors was 0 in HCC with non-rim patterns. The minimum width of fluorescence surrounding tumors in poor differentiated HCC and CRLM were 2.4 ± 1.9 mm and 2.8 ± 2.5 mm, respectively, with no significant difference (P > 0.05). ICG fluorescence imaging revealed eight small lesions, which were not detected preoperatively in seven patients, of which five lesions were confirmed as malignancies by pathology. Conclusions Resection along the ICG fluorescence edge can supply a safe surgical margin only for CRLM, but not for HCC. Otherwise, ICG fluorescence tumor imaging can preliminarily determine the pathological type of hepatic malignancies and histological differentiation of HCC and help detect small lesions that cannot be detected preoperatively.

The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the α and β isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how LXRα plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of LXRα in the VP-LXRα knock-in (LXRαKI) mice or hepatocyte-specific activation of LXRα in the VP-LXRα transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'-tetrachloro-1,4-bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the LXRα-responsive up-regulation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down-regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of LXRα activated mice. We also observed an induction of monocytic myeloid-derived suppressor cells accompanied by down-regulation of dendritic cells and cytotoxic T cells in DEN/TCPOBOP-induced liver tumors, indicating that chronic activation of LXRα may have led to the activation of innate immune suppression. The HCC sensitizing effect of LXRα activation was also observed in the c-MYC driven HCC model. Conclusion: Our results indicated that chronic activation of LXRα promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up-regulation of the IL-6/Janus kinase/STAT3 signaling and complement pathways.

Diabetes and related metabolic syndrome are common metabolic disorders. Gestational diabetes mellitus (GDM) is rather prevalent in the clinic. Although most GDM resolves after therapeutic intervention and/or after delivery, the long-term health effect of GDM remains to be better understood. The constitutive androstane receptor (CAR), initially characterized as a xenobiotic receptor, was more recently proposed to be a therapeutic target for obesity and type 2 diabetes mellitus (T2DM). In this study, high-fat diet (HFD) feeding was used to induce GDM. Upon delivery, GDM mice were returned to chow diet until the metabolic parameters were normalized. Parous non-GDM control females or metabolically normalized GDM females were then subjected to HFD feeding to induce nongestational obesity and T2DM. Our results showed that GDM sensitized mice to metabolic abnormalities induced by a second hit of HFD. Treatment with the CAR agonist 1,4-bis [2-(3,5 dichloropyridyloxy)] benzene efficiently attenuated GDM-sensitized and HFD-induced obesity and T2DM, including decreased body weight, improved insulin sensitivity, inhibition of hyperglycemia and hepatic steatosis, increased oxygen consumption, and decreased adipocyte hypertrophy. In conclusion, our results have established GDM as a key risk factor for the future development of metabolic disease. We also propose that CAR is a therapeutic target for the management of metabolic disease sensitized by GDM.

Activation of the hepatic stellate cells (HSCs) is a key pathogenic event in liver fibrosis. Protein S-glutathionylation (PSSG) of cysteine residues is a distinct form of oxidative response that mo...

BACKGROUND & AIMS: Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3’-phosphoadenosine 5’-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. The goal of this study is to determine whether and how PAPSS2 plays a role in colitis and colonic carcinogenesis. METHODS: Tissue arrays of human colon cancer specimens, gene expression data, and clinical features of cancer patients were analyzed. Intestinal-specific Papss2 knockout mice (Papss2(ΔIE)) were created and subjected to dextran sodium sulfate (DSS)-induced colitis, and colonic carcinogenesis induced by combined treatment of azoxymethane (AOM) and DSS, or AOM alone. RESULTS: The expression of PAPSS2 is decreased in the colon cancers of mice and humans. The lower expression of PAPSS2 in colon cancer patients is correlated with worse survival. Papss2(ΔIE) mice showed heightened sensitivity to colitis and colon cancer by damaging the intestinal mucosal barrier, increasing intestinal permeability and bacteria infiltration, and worsening the intestinal tumor microenvironment. Mechanistically, the Papss2(ΔIE) mice exhibited reduced intestinal sulfomucin content. Metabolomic analyses revealed the accumulation of bile acids including the farnesoid X receptor (FXR) antagonist bile acid tauro-β-muricholic acid (T-β-MCA), and deficiency in the formation of bile acid-sulfates in the colon of Papss2(ΔIE) mice. CONCLUSIONS: We have uncovered an important role of PAPSS2-mediated sulfation in colitis and colonic carcinogenesis. Intestinal sulfation may represent a potential diagnostic marker, and PAPSS2 may serve as a potential therapeutic target for inflammatory bowel disease and colon cancer.

Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by regulating the expression of drug-metabolizing enzymes and transporters. In addition to metabolizing drugs and other xenobiotics, the same enzymes and transporters are also responsible for the production and elimination of numerous endogenous chemicals, or endobiotics. Moreover, both PXR and CAR are highly expressed in the liver. As such, it is conceivable that PXR and CAR have major potentials to affect the pathophysiology of the liver by regulating the homeostasis of endobiotics. In recent years, the physiological functions of PXR and CAR in the liver have been extensively studied. Emerging evidence has suggested the roles of PXR and CAR in energy metabolism, bile acid homeostasis, cell proliferation, to name a few. This review summarizes the recent progress in our understanding of the roles of PXR and CAR in liver physiology.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin, is a potent liver cancer promoter through its sustained activation of the aryl hydrocarbon receptor (Ahr) in rodents. However, the carcinogenic effect of TCDD and AHR in humans has been controversial. It has been suggested that the inter-species difference in the carcinogenic activity of AhR is largely due to different ligand affinity in that TCDD has a 10-fold lower affinity for the human AHR compared with the mouse Ahr. It remains unclear whether the activation of human AHR is sufficient to promote hepatocellular carcinogenesis. The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis. Here we reported the oncogenic activity of human AHR in promoting hepatocellular carcinogenesis. Constitutive activation of the human AHR in transgenic mice was as efficient as its mouse counterpart in promoting diethylnitrosamine (DEN)-initiated hepatocellular carcinogenesis. The growth arrest and DNA damage-inducible gene 45 β (Gadd45b), a signaling molecule inducible by external stress and UV irradiation, is highly induced upon AHR activation. Further analysis revealed that Gadd45b is a novel AHR target gene and a transcriptional coactivator of AHR. Interestingly, ablation of Gadd45b in mice did not abolish the tumor promoting effects of the human AHR. Collectively, our findings suggested that constitutive activation of human AHR was sufficient to promote hepatocarcinogenesis.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin, is a potent liver cancer promoter through its sustained activation of the aryl hydrocarbon receptor (Ahr) in rodents. However, the carcinogenic effect of TCDD and AHR in humans has been controversial. It has been suggested that the inter-species difference in the carcinogenic activity of AhR is largely due to different ligand affinity in that TCDD has a 10-fold lower affinity for the human AHR compared to the mouse Ahr. It remains unclear whether the activation of human AHR is sufficient to promote hepatocellular carcinogenesis. The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis. Here we reported the oncogenic activity of human AHR in promoting hepatocellular carcinogenesis. Constitutive activation of the human AHR in transgenic mice was as efficient as its mouse counterpart in promoting diethylnitrosamine (DEN)-initiated hepatocellular carcinogenesis. The growth arrest and DNA damage-inducible gene 45 β (Gadd45b), a signaling molecule inducible by external stress and UV irradiation, is highly induced upon AHR activation. Further analysis revealed that Gadd45b is a novel AHR target gene and a transcriptional coactivator of AHR. Interestingly, ablation of Gadd45b in mice did not abolish the tumor promoting effects of the human AHR. Collectively, our findings suggested that constitutive activation of human AHR was sufficient to promote hepatocarcinogenesis. Note: This abstract was not presented at the meeting. Citation Format: Peipei Lu, Xinran Cai, Zihui Fang, Wen Xie. Constitutive activation of the human aryl hydrocarbon receptor in mice promotes hepatocarcinogenesis independent of its coactivator Gadd45b [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2604.

Elastic optical networking (EON) has emerged in recent years as a promising solution for implementing flexible bandwidth channels (flexpaths) that efficiently match the allocated bandwidth with the traffic demand using agile granularities of spectrum allocation. However, the additional flexibility in such networks raises challenges in terms of efficient control and management of spectrum resources. Among them, three important issues are (1) mitigation of spectral fragmentation, (2) implementation of impairment awareness and enhancement of robustness against impairments for potentially large-bandwidth flexpaths, and (3) design of an efficient restoration scheme to combat network failures. This paper presents an adaptive spectrum control and management scheme, which includes: dynamic on-demand spectral defragmentation, adaptive combinational quality of transmission (QoT) restoration (ACQR) and supervisory channel-assisted active restoration, to account for the three issues above. We present scalable networking algorithms and experimental demonstrations that address these issues in an EON testbed. Simulation results show that the defragmentation technique is capable of reducing the provisioning blocking probability by half with only one defragmentation module on each link. Then, we also show that the ACQR can efficiently restore many degraded flexpaths on the same impaired link while reducing the restoration blocking probability by a factor of 10 compared with the conventional rerouting method. At last, we show via simulation the advantages of using supervisory channels to determine restoration path quality and selection in EON restorations. This paper also presents experimental demonstrations to corroborate the effectiveness and feasibility of implementing these capabilities in next generation optical networks.

Silicon microring resonator has been recognized as a competitive structure for the electro-optic modulator due to its potential for high-density integration. There are two silicon-ring-based modulation methods: push-pull coupling modulation and index modulation. Previous investigations show that the push-pull coupling modulation seems to outperform the index modulation because of its ultralarge optical modulation bandwidth and chirp-free property. However, there is no performance comparison for these two schemes in power consumption, which has emerged as an important parameter for photonics integrated circuit design. This paper thus studies the power efficiency of these two methods. The analysis of the static characteristics of the ring shows that the index modulation requires a much lower driving voltage than that of the push-pull coupling modulation when the modulator is operated at low frequencies. The dynamic analysis based on the coupled-mode theory in time indicates that the required driving voltage of the push-pull coupling modulation is still higher than that of the index modulation when the modulation frequency is not very high. To solve this problem, we propose a chirp-free two-ring modulator consisting of a push-pull coupling modulator embedded into a ring with the same resonance. We demonstrate that the two-ring modulator can reach its transmission null before the push-pull coupling modulator becomes critical coupled. As a result, the power requirement of the two-ring modulator is lower than that of the push-pull coupling modulator.

Autophagy is an evolutionarily conserved catabolic process by which cells degrade intracellular proteins and organelles in the lysosomes. Canonical autophagy requires all autophagy proteins (ATGs), whereas noncanonical autophagy is activated by diverse agents in which some of the essential autophagy proteins are dispensable. How noncanonical autophagy is induced and/or inhibited is still largely unclear. In this study, we demonstrated that AMDE-1, a recently identified chemical that can induce canonical autophagy, was able to elicit noncanonical autophagy that is independent of the ULK1 (unc-51-like kinase 1) complex and the Beclin1 complex. AMDE-1-induced noncanonical autophagy could be specifically suppressed by various V-ATPase (vacuolar-type H+-ATPase) inhibitors, but not by disturbance of the lysosome function or the intracellular ion redistribution. Similar findings were applicable to a diverse group of stimuli that can induce noncanonical autophagy in a FIP200-independent manner. AMDE-1-induced LC3 lipidation was colocalized with the Golgi complex, and was inhibited by the disturbance of Golgi complex. The integrity of the Golgi complex was also required for multiple other agents to stimulate noncanonical LC3 lipidation. These results suggest that the Golgi complex may serve as a membrane platform for noncanonical autophagy where V-ATPase is a key player. V-ATPase inhibitors could be useful tools for studying noncanonical autophagy.

We demonstrate a flexible-bandwidth network testbed with a real-time, adaptive control plane that adjusts modulation format and spectrum-positioning to maintain quality of service (QoS) and high spectral efficiency. Here, low-speed supervisory channels and field-programmable gate arrays (FPGAs) enabled real-time impairment detection of high-speed flexible bandwidth channels (flexpaths). Using premeasured correlation data between the supervisory channel quality of transmission (QoT) and flexpath QoT, the control plane adapted flexpath spectral efficiency and spectral location based on link quality. Experimental demonstrations show a back-to-back link with a 360-Gb/s flexpath in which the control plane adapts to varying link optical signal to noise ratio (OSNR) by adjusting the flexpath’s spectral efficiency (i.e., changing the flexpath modulation format) between binary phase-shift keying (BPSK), quaternary phase-shift keying (QPSK), and eight phase-shift keying (8PSK). This enables maintaining the data rate while using only the minimum necessary bandwidth and extending the OSNR range over which the bit error rate in the flexpath meets the quality of service (QoS) requirement (e.g. the forward error correction (FEC) limit). Further experimental demonstrations with two flexpaths show a control plane adapting to changes in OSNR on one link by changing the modulation format of the affected flexpath (220 Gb/s), and adjusting the spectral location of the other flexpath (120 Gb/s) to maintain a defragmented spectrum.

We propose and demonstrate an adaptive quality of transmission restoration scheme combining methods of lightpath rerouting and modulation format switching to combat real-time impairments in flexible bandwidth networks. Testbed demonstration achieved error-free performance.

We propose and demonstrate silicon photonic integrated circuits (PICs) for free-space spatial-division-multiplexing (SDM) optical transmission with multiplexed orbital angular momentum (OAM) states over a topological charge range of -2 to +2. The silicon PIC fabricated using a CMOS-compatible process exploits tunable-phase arrayed waveguides with vertical grating couplers to achieve space division multiplexing and demultiplexing. The experimental results utilizing two silicon PICs achieve SDM mux/demux bit-error-rate performance for 1‑b/s/Hz, 10-Gb/s binary phase shifted keying (BPSK) data and 2-b/s/Hz, 20-Gb/s quadrature phase shifted keying (QPSK) data for individual and two simultaneous OAM states.

We demonstrate a flexible-bandwidth network testbed with a real-time adaptive control plane that adjusts modulation format and spectrum-positioning to maintain QoS and high spectral efficiency. A low-speed supervisory channel and FPGAs enable real-time impairment detection.