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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.

Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation., Graphical abstract Activation of xenobiotic receptor constitutive androstane receptor (CAR) by its agonist such as TCPOBOP conveys benefits for obesity and diabetes. In this study, it showes that anti-apoptotic factor GADD45B, a coactivator of CAR, is in part required for the anti-obesity effects of CAR activation. Inhibition of hepatic lipogenesis and gluconeogenesis and adipose inflammation by TCPOBOP was largely abolished in mice in the absence of GADD45B.Image 1

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...

Purpose Primary hepatic angiosarcoma is a very rare and highly malignant tumor with poor prognosis. It is difficult to diagnose because of the lack of typical clinical features, and the treatment protocols for PHA are also not clear. Therefore, this study wants to find out the clinical characteristics and surgical treatments of primary hepatic angiosarcoma. Methods Among 8990 patients diagnosed with primary malignant tumor of the liver from January 2000 to December 2019 in our hospital, only four patients were diagnosed with primary hepatic angiosarcoma. The demographics, clinical manifestation, past history, serology test results, MRI features, pathology, treatment modality and prognosis of four patients were collected and analyzed. Results Three of four patients had no clinical symptoms, while one patient's symptom was abdominal pain. The levels of tumor markers of all four patients were within the normal reference range and serological tests were negative for hepatitis B and C virus. The MRI imaging findings of all four patients were mixed mass with highly disordered vascular characteristics. All four patients were misdiagnosed preoperatively. One patient who underwent hepatic lobectomy was still alive for about 18 months after surgery. One patient who underwent hepatic lobectomy has survived for only 6 months due to severe pneumonia. The other two patients who received transarterial chemoembolization survived 16 months and 11 months respectively. Conclusion The clinical symptoms of primary hepatic angiosarcoma are not typical, and primary hepatic angiosarcoma is easily misdiagnosed. The typical imaging manifestations are structural disorder and heterogeneous tumor. Hepatic lobectomy and transarterial chemoembolization may be important surgical treatments to improve the prognosis of patients.

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.

Lymph node metastasis is the primary site of metastasis for patients with gallbladder cancer (GBC). Vascular endothelial growth factor-C (VEGF-C) has been implicated in the control of lymphangiogenesis and lymph node metastasis in various malignant tumors. However, the function of circulating VEGF-C is unclear and it is often difficult to evaluate lymph node metastasis and provide a prognosis for GBC. In the present study, ELISA was used to measure the preoperative serum VEGF-C (sVEGF-C) levels of 51 patients with GBC, 15 patients with chronic cholecystitis and 10 healthy volunteers. The results revealed a significantly increased sVEGF-C level in patients with GBC compared with the healthy donors, however no statistically significant difference was identified between patients with GBC and chronic cholecystitis. sVEGF-C levels were associated with lymph node metastasis in GBC and presented a positive correlation with VEGF-C expression and lymphatic vessel density (LVD) in patients with GBC. The mean survival time with high sVEGF-C was significantly reduced compared with low sVEGF-C. A similar result was also observed for VEGF-C expression and LVD. In summary, sVEGF-C levels may predict lymph node metastasis and the prognosis of patients with GBC.

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.