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Objectives: To identify the preoperative risk factors for prediction of non-transplantable recurrence (NTR) after tumor resection for early-stage hepatocellular carcinoma (HCC) to assist in patient selection relative to upfront liver resection (LR) versus liver transplantation (LT). Methods: Patients who underwent curative resection for transplantable HCC and chronic liver disease were identified from an international multi-institutional database. NTR was defined as recurrence beyond the Milan or UCSF criteria, and the preoperative risk factors of NTR were investigated. Results: Among 293 patients with transplantable HCC within Milan criteria and 320 within UCSF criteria, 113 (38.6%) and 131 (40.9%) patients developed tumor recurrence, respectively. Among patients who recurred, NTR was present in 32 (28.3%) patients within Milan and 35 (26.7%) within UCSF criteria. When either Milan or UCSF criteria was adopted, three preoperative risk factors including liver cirrhosis, tumor size > 3 cm, and multiple lesions were consistently identified as risk factors associated with NTR after curative resection. By summing up the three factors, a scoring model was established and the incidence of NTR among patients with 0, 1 or ≥ 2 risk factors incrementally increased from 4.5%, 13.3% to 20.5% when Milan criteria was used, and from 4.5%, 12.4% to 33.9% when UCSF criteria was adopted. The model demonstrated very good discriminatory power on internal validation (n = 5,000) (c-index 0.689 for Milan criteria, and 0.715 for UCSF criteria). Conclusions: Whereas surgical resection may be optimal first-line treatment for patients with no or one risk factor, patients with ≥ 2 risk factors should be considered for upfront liver transplantation. [ABSTRACT FROM AUTHOR]

Background: The surgical approach to treat Bismuth type I and II hilar cholangiocarcinoma (HCCA) has been a topic of debate. We sought to characterize whether bile duct resection (BDR) with or without concomitant hepatic resection (HR) was associated with R0 margin status, as well as define the impact of HR+BDR versus BDR alone on long-term survival. Methods: Patients who underwent curative-intent HR+BDR for HCCA between 2000 and 2014 were identified from a multi-institutional database. Perioperative and long-term outcomes were compared among patients who underwent BDR only, BDR+left hepatic resection (LHR), and BDR+right hepatic resection (RHR) for Bismuth type I and II HCCA. Results: Among 257 patients with HCCA, 61 (23.7%) patients had a Bismuth type I (n=25, 41.0%) or II (n=36, 59.0%) lesion. The incidence of R0 resection after BDR only was the same as among patients after LHR and RHR (BDR 70.0% vs. BDR+LHR 71.4% vs. BDR+RHR 76.5%, p=0.891). In contrast, severe complications were more likely after LHR and RHR than BDR only (BDR 21.4% vs. BDR+LHR 60.0% and BDR+RHR 50.0%, p=0.041). Overall (median: BDR 20.9 vs. BDR+LHR 23.2 and BDR+RHR 25.0 months, p=0.213) and recurrence-free (median: BDR 13.4 vs. BDR+LHR 15.3 and BDR+RHR 25.0, p= 0.109) survival were comparable. On multivariable analysis, while CA19-9>37.0U/ml (Ref. CA19-9≤37.0U/ml, HR 3.2, 95% CI 1.1–9.4, p=0.035) and AJCC T3-T4 disease (Ref. T1-T2, HR 4.6, 95% CI 1.5–13.7, p=0.007) were associated with long-term survival, surgical approach was not (BDR+LHR: HR 1.0, 95% CI 0.5–2.2, p=0.937; BDR+RHR: HR 0.6, 95% CI 0.3–1.3, p=0.197). Conclusion: R0 resection, overall survival, and recurrence-free survival were comparable among well-selected patients who had BDR versus BDR+HR for Bismuth type I and II HCCA. [ABSTRACT FROM AUTHOR]

To improve the prognostic accuracy of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for intrahepatic cholangiocarcinoma (ICC) with establishment and validation of a modified TNM (mTNM) staging system. Data on patients who underwent curative-intent resection for ICC was collected from 15 high-volume centers worldwide (n = 643). An external validation dataset was obtained from the SEER registry (n = 797). The mTNM staging system was proposed by redefining T categories, and incorporating the recently proposed N status as N0 (no lymph node metastasis [LNM]), N1 (1–2 LNM) and N2 (≥3 LNM). The 8th AJCC TNM staging system failed to stratify overall survival (OS) of stage II versus IIIA, stage IIIB versus IV, as well as overall stage III versus IV among all patients from the two databases, as well as stage I versus II, and stage III versus III among patients who had ≥6 LNs examined. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the multi-institutional (Median OS, stage I 69.8 vs. II 37.1 vs. III 18.9 vs. IV 16.4 months, all p < 0.05), and SEER (Median OS, stage I 87.0 vs. II 29.3 vs. III 17.7 vs. IV 14.2 months, all p < 0.05) datasets, which was also verified among patients who had ≥6 lymph node harvested from both databases. The modified TNM staging system for ICC using the new T and N definitions provided an improved means to stratify patients relative to long-term OS versus the 8th AJCC staging. [ABSTRACT FROM AUTHOR]

Background: To define early versus late recurrence based on post-recurrence survival (PRS) among patients undergoing curative resection for hepatocellular carcinoma (HCC). Methods: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The optimal cut-off time point to discriminate early versus late recurrence was determined relative to PRS. Results: Among 1004 patients, 443 (44.1%) patients experienced recurrence with a median recurrence-free survival time of 12 months. A cut-off time point of 8 months was defined as the optimal threshold based on sensitivity analyses relative to PRS for early (n = 165, 37.2%) versus late relapse (n = 278, 62.8%) (p = 0.008). Early recurrence was associated with worse PRS (median PRS, 27.0 vs. 43.0 months, p = 0.019), as well as overall survival (OS) (median OS, 32.0 versus 74.0 months, p < 0.001) versus late recurrence. In addition, patients who recurred early were more likely to recur at extra- ± intrahepatic (35.5% vs. 19.8%, p = 0.003) sites and were less likely to have the recurrence treated with curative intent (33.8% vs. 45.7%, p = 0.08). Patients undergoing curative re-treatment of late recurrence had a comparable OS with patients who had no recurrence (median OS, 139.0 vs. 140.0 months); patients with early recurrence had inferior OS after curative re-treatment versus patients with no recurrence (median OS, 69.0 vs. 140.0 months, p = 0.036), yet still better than patients who received palliative treatment for early recurrence (median OS, 69.0 vs. 21.0 months, p < 0.001). Conclusions: Eight months was identified as the cut-off value to differentiate early versus late recurrence. Curative-intent treatment for recurrent intrahepatic tumors was associated with reasonable long-term outcomes. [ABSTRACT FROM AUTHOR]

Objectives: To assess conditional survival (CS) according to recurrence status, as well as conditional disease-free survival (cDFS) among patients with intrahepatic cholangiocarcinoma (ICC).Methods: CS and cDFS were evaluated among ICC patients who underwent curative-intent resection for ICC by using a multi-institutional database. Five-year CS (CS5) at "x" years was calculated separately for patients who did and did not experience recurrence. The cDFS3 at "x" years was defined as the chance to be disease-free for an additional 3 years after not having experienced a recurrence for "x" years postoperatively.Results: Among 1221 patients, median OS was 36.8 months. While estimated actuarial OS decreased over time, CS5 increased as patients survived over longer periods of time and reached 93.9% at 4 years among 139 patients who did not experience a recurrence. Among the 725 (59.4%) patients who did experience a tumor recurrence, CS5 decreased to 17.7% the first postoperative year; however, CS5 subsequently increased to 79.7% for 81 patients who had survived 4 years after surgery. While actuarial DFS decreased from 54.6% at 1 year to 28.2% at 5 years, estimated cDFS3 following liver resection increased over time. Of note, patients with known risk factors for recurrence had even more marked improvements in cDFS3 over subsequent years versus patients without risk factors for recurrence.Conclusion: CS and cDFS changed over time according to the presence of disease-specific risk factors, as well as the presence of recurrence. [ABSTRACT FROM AUTHOR]

To define the chronological changes of long-term survival among patients with non-hepatitis-related hepatocellular carcinoma (Non-Hep-HCC) versus hepatitis C-related HCC (HCV-HCC) over the last two decades. Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. Overall (OS) and recurrence-free survival (RFS) were analyzed and compared among Non-Hep-HCC versus HCV-HCC patients. Propensity score matching (PSM) was utilized to mitigate residual bias. Among 617 patients, 196 (31.8%) patients had HCV-HCC, whereas 421 (68.2%) patients had Non-Hep-HCC. While patients with HCV-HCC had an improvement in OS over time (5-year OS, 2000–2009 55% vs. 2010–2017 67%, p = 0.034), OS among patients with Non-Hep-HCC remain unchanged (5-year OS, 2000–2009 53% vs. 2010–2017 52%, p = 0.905). In the matched cohort, patients with HCV-HCC had a worse OS versus patients with Non-Hep-HCC during 2000 and 2009 (5-year OS, 12% vs. 63%, p = 0.029), but significantly better OS from 2010 to 2017 than patients with Non-Hep-HCC (5-year OS, 86% vs. 73%, p = 0.035). The recurrence timing, patterns and re-treatments were comparable among Non-Hep-HCC and HCV-HCC patients. While OS of patients with HCV-HCC improved over time, the long-term survival of patients with Non-Hep-HCC patients remained unchanged and was more unfavorable. [ABSTRACT FROM AUTHOR]

To investigate the feasibility of Tumor Burden Score (TBS) to predict tumor recurrence following curative-intent resection of non-functional pancreatic neuroendocrine tumors (NF-pNETs). The TBS cut-off values were determined by a statistical tool, X-tile. The influence of TBS on recurrence-free survival (RFS) was examined. Among 842 NF-pNETs patients, there was an incremental worsening of RFS as the TBS increased (5-year RFS, low, medium, and high TBS: 92.0%, 73.3%, and 59.3%, respectively; P < 0.001). TBS (AUC 0.74) out-performed both maximum tumor size (AUC 0.65) and number of tumors (AUC 0.5) to predict RFS (TBS vs. maximum tumor size, p = 0.05; TBS vs. number of tumors, p < 0.01). The impact of margin (low TBS: R0 80.4% vs. R1 71.9%, p = 0.01 vs. medium TBS: R0 55.8% vs. R1 37.5%, p = 0.67 vs. high TBS: R0 31.9% vs. R1 12.0%, p = 0.11) and nodal (5-year RFS, low TBS: N0 94.9% vs. N1 68.4%, p < 0.01 vs. medium TBS: N0 81.8% vs. N1 55.4%, p < 0.01 vs. high TBS: N0 58.0% vs. N1 54.2%, p = 0.15) status on 5-year RFS outcomes disappeared among patients who had higher TBS. TBS was strongly associated with risk of recurrence and outperformed both tumor size and number alone. [ABSTRACT FROM AUTHOR]

To define recurrence patterns and time course, as well as risk factors associated with recurrence following curative resection of pNETs. Patients who underwent curative-intent resection for pNET between 1997 and 2016 were identified from the US Neuroendocrine Tumor Study Group. Data on baseline and tumor-specific characteristics, overall survival (OS), timing and first-site of recurrence, predictors and recurrence management were analyzed. Among 1020 patients, 154 (15.1%) patients developed recurrence. Among patients who experienced recurrence, 76 (49.4%) had liver-only recurrence, while 35 (22.7%) had pancreas-only recurrence. The proportion of liver-only recurrence increased from 54.3% within one-year after surgery to 61.5% from four-to-six years after surgery; whereas the proportion of pancreas-only recurrence decreased from 26.1% to 7.7% over these time periods. While liver-only recurrence was associated with tumor characteristics, pancreas-only recurrence was only associated with surgical margin status. Patients undergoing curative resection of recurrence had comparable OS with patients who had no recurrence (median OS, pancreas-only recurrence, 133.9 months; liver-only recurrence, not attained; no recurrence, 143.0 months, p = 0.499) Different recurrence patterns and timing course, as well as risk factors suggest biological heterogeneity of pNET recurrence. A personalized approach to postoperative surveillance and treatment of recurrence disease should be considered. [ABSTRACT FROM AUTHOR]

Background: The objective of the current study was to investigate both short- and long-term outcomes of patients undergoing curative-intent resection for intrahepatic cholangiocarcinoma (ICC) stratified by extent of hepatic resection relative to overall final pathological margin status.Methods: One thousand twenty-three patients with ICC who underwent curative-intent resection were identified from a multi-institutional database. Demographic, clinicopathological, and operative data, as well as overall (OS) and recurrence-free survival (RFS) were compared among patients undergoing major and minor resection before and after propensity score matching.Results: Overall, 608 (59.4%) patients underwent major hepatectomy, while 415 (40.6%) had a minor resection. Major hepatectomy was more frequently performed among patients who had large, multiple, and bilobar tumors. Roughly half of patients (n = 294, 48.4%) developed a postoperative complication following major hepatectomy versus only one fourth of patients (n = 113, 27.2%) after minor resection (p < 0.001). In the propensity model, patients who underwent major hepatectomy had an equivalent OS and RFS versus patients who had a minor hepatectomy (median OS, 38 vs. 37 months, p = 0.556; and median RFS, 20 vs. 18 months, p = 0.635). Patients undergoing major resection had comparable OS and RFS with wide surgical margin (≥10 and 5-9 mm), but improved RFS when surgical margin was narrow (1-4 mm) versus minor resection in the propensity model. In the Cox regression model, tumor characteristics and surgical margin were independently associated with long-term outcome.Conclusions: Major hepatectomy for ICC was not associated with an overall survival benefit, yet was associated with increased perioperative morbidity. Margin width, rather than the extent of resection, affected long-term outcomes. Radical parenchymal-sparing resection should be advocated if a margin clearance of ≥5 mm can be achieved. [ABSTRACT FROM AUTHOR]

Background: Early tumor recurrence after curative resection typically indicates a poor prognosis. The objective of the current study was to investigate the risk factors, treatment, and prognosis of early recurrence of neuroendocrine tumor (NET) liver metastasis (NELM) after hepatic resection.Methods: A total of 481 patients who underwent curative-intent resection for NELM were identified from a multi-institutional database. Data on clinicopathological characteristics, intraoperative details, and outcomes were documented. The optimal cutoff value to differentiate early and late recurrence was determined to be 3 years based on linear regression.Results: With a median follow-up of 60 months, 223 (46.4%) patients developed a recurrence, including 158 (70.9%) early and 65 (29.1%) late recurrences. On multivariable analysis, pancreatic NET, primary tumor lymph node metastasis, and a microscopic positive surgical margin were independent risk factors for early intrahepatic recurrence. While recurrence patterns and treatments were comparable among patients with early and late recurrences, early recurrence was associated with worse disease-specific survival than late recurrences (10-year NELM-specific survival, 44.5 vs 75.8%, p < 0.001). Among the 34 (21.5%) patients who underwent curative treatment for early recurrence, post-recurrence disease-specific survival was better than non-curatively treated patients (10-year NELM-specific survival, 54.2 vs 26.3%, p = 0.028), yet similar to patients with late recurrences treated with curative intent (10-year NELM-specific survival, 54.2 vs 37.4%, p = 0.519).Conclusions: Early recurrence after surgery for NELM was associated with the pancreatic type, primary lymph node metastasis, and extrahepatic disease. Re-treatment with curative intent prolonged survival after recurrence, and therefore, operative intervention even for early recurrences of NELM should be considered. [ABSTRACT FROM AUTHOR]

Background: Liver fibrosis and cirrhosis are well-known risk factors for morbidity and mortality after hepatectomy. Fibrosis index based on the four factors (FIB-4) is a non-invasive method for detection of hepatic fibrosis and cirrhosis with high accuracy. This study aimed to evaluate the predictive value of future liver remnant volume ratios (FLRVR)/FIB-4 after liver resection for posthepatectomy outcomes in patients with fibrosis and cirrhosis. Methods: All patients with severe fibrosis or cirrhosis who underwent a liver resection (≥2 segments) were included. Liver insufficiency was defined according to grade C posthepatectomy liver failure (PLF) proposed by the International Study Group of Liver Surgery(ISGLS). Receiver operating characteristic curves and logistic regression model were used to determine the optimal cutoff of FLRVR/FIB-4 and independent risk factors of postoperative outcomes. Results: The study population consisted of 338 patients. FLRVR/FIB-4 was gradually correlated with short-term outcomes. The optimal value of FLRVR/FIB-4 to predict PLF was 0.13 when considering grade C PLF and postoperative death. A value of 0.24 best predicted postoperative morbidity. At multivariate analysis, FLRVR/FIB-4 remained an independent predictor of PLF (risk ratio(RR) = 0.046; 95 % confidence interval (CI): 0.010-0.215; P < 0.001), postoperative morbidity(RR = 0.272; 95 % CI: 0.167-0.445; P < 0.001) and mortality(RR =0.058; 95 % CI: 0.012-0.277; P < 0.001). Conclusion: FLRVR/FIB-4 is an independent predictive factor of postoperative outcomes after liver resection in patients with cirrhosis. It is a useful preoperative investigation for risk stratification before hepatectomy. [ABSTRACT FROM AUTHOR]

Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex-determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. Hepatocyte-specific Sry knock-in (KI), Sry knockout (KO), and Sry KI with platelet-derived growth factor receptor α (Pdgfrα) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation for 2 weeks or carbon tetrachloride treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. Compared to females, the severity of toxin- or cholestasis-induced liver fibrosis is similarly increased in castrated and uncastrated male mice. Among all Y chromosome-encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. Sry KI mice developed exacerbated liver fibrosis, whereas Sry KO mice had alleviated liver fibrosis, compared to age- and sex-matched control mice after bile duct ligation or administration of carbon tetrachloride. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate Pdgfrα expression, and promote HMGB1 (high mobility group box 1) release and subsequent HSC activation. Pdgfrα KO or treatment with the SRY inhibitor DAX1 in Sry KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. SRY is a strong pro-fibrotic factor and accounts for the sex disparity observed in liver fibrosis, suggesting its critical role as a potentially sex-specific therapeutic target for prevention and treatment of the disease. We identified that a male-specific gene, sex-determining region Y gene (SRY), is a strong pro-fibrotic gene that accounts for the sex disparity observed in liver fibrosis. As such, SRY might be an appropriate target for surveillance and treatment of liver fibrosis in a sex-specific manner. Additionally, SRY might be a key player in the sexual dimorphism observed in hepatic pathophysiology more generally. [Display omitted] • SRY as a male specific gene was upregulated in hepatocytes in liver fibrosis. • SRY overexpression in hepatocytes exacerbated, whereas SRY knockout alleviated liver fibrosis. • Inhibition of SRY, or its downstream target PDGFRα suppressed liver fibrosis. • SRY is a pro-fibrotic gene, and accounts for the sex disparity of liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Activation of sodium channels is essential to action potential generation and propagation. Recent genetic and pharmacological evidence indicates that activation of Nav1.8 channels contributes to chronic pain. Herein, we describe the identification of a novel series of structurally related pyridine derivatives as potent Nav1.8 channel blockers. A-887826 exemplifies this series and potently (IC50 =11nM) blocked recombinant human Nav1.8 channels. A-887826 was ∼3 fold less potent to block Nav1.2, ∼10 fold less potent to block tetrodotoxin-sensitive sodium (TTX-S Na+) currents and was >30 fold less potent to block NaV1.5 channels. A-887826 potently blocked tetrodotoxin-resistant sodium (TTX-R Na+) currents (IC50 =8nM) from small diameter rat dorsal root ganglion (DRG) neurons in a voltage-dependent fashion. A-887826 effectively suppressed evoked action potential firing when DRG neurons were held at depolarized potentials and reversibly suppressed spontaneous firing in small diameter DRG neurons from complete Freund’s adjuvant inflamed rats. Following oral administration, A-887826 significantly attenuated tactile allodynia in a rat neuropathic pain model. Further characterization of TTX-R current block in rat DRG neurons demonstrated that A-887826 (100nM) shifted the mid-point of voltage-dependent inactivation of TTX-R currents by ∼4mV without affecting voltage-dependent activation and did not exhibit frequency-dependent inhibition. The present data demonstrate that A-887826 is a structurally novel and potent Nav1.8 blocker that inhibits rat DRG TTX-R currents in a voltage-, but not frequency-dependent fashion. The ability of this structurally novel Nav1.8 blocker to effectively reduce tactile allodynia in neuropathic rats further supports the role of Nav1.8 sodium channels in pathological pain states. [Copyright &y& Elsevier]

Abstract: Elevated temperature and decreased extracellular pH are hallmarks of inflammatory pain states. Dorsal root ganglia (DRG) neurons are integral in transferring painful stimuli from the periphery to central sites. This study investigated the effect of elevated temperatures on the response of DRG neurons to acute application of acidic solutions. At room temperature (22°C), in response to pH 5.5, there were a variety of kinetic responses consistent with differential expression of TRPV1 and ASIC channels. Increasing the temperature resulted in a significant increase in the peak and total current mediated by TRPV1 in response to an acidic solution. In contrast, the amplitude of a fast activating, rapidly inactivating ASIC1-like current was not affected by increasing the temperature but did result in an increased rate of desensitization that reduced the total current level. This effect on the rate of desensitization was temperature-dependent and could be reversed by returning to 22°C. Likewise, cells exhibiting slowly inactivating ASIC2-like responses also had temperature-dependent increase in the rate of desensitization. The ASIC2-like responses and the TRPV1 responses tended to decrease in amplitude with repetitive application of pH 5.5 even at 22°C. The rate of desensitization of ASIC-like currents activated by less acidic solutions (pH 6.8) was also increased in a temperature-dependent manner. Finally, acidic pH reduced threshold to trigger action potentials, however, the pattern of action potential firing was shaped by the distribution of ASIC and TRPV1 channels. These results indicate that the ambient temperature at which acidosis occurs has a profound effect on the contribution of ASIC and TRPV1 channels, therefore, altering the neuronal excitability. [Copyright &y& Elsevier]

Abstract: The P2X7 receptor is an ATP-sensitive ligand-gated cation channel, expressed predominantly in cells with immune origin. Recent studies have demonstrated that P2X7 may play an important role in pain signaling. In the present study, the expression of P2X7 receptors in non-neuronal cells and neurons isolated from dorsal root ganglia was characterized using patch clamp, pharmacological and confocal microscopy approaches. In small diameter DRG neurons, 100 μM 2′, 3′-O-(4-benzoylbenzoyl)-ATP (BzATP) evoked an inward current, which was inhibited completely by 1 μM A-317491, a potent and selective P2X3 receptor antagonist. In contrast, BzATP evoked concentration-dependent increases in inward currents in non-neuronal DRG cells with an EC50 value of 26 ± 0.14 μM, which were resistant to the blockade by A-317491. The activity to evoke cationic currents by P2X receptor agonists in non-neuronal cells showed a rank order of BzATP > ATP > α,β-meATP. Pyridoxal-phosphate-6-azophenyl-,2′,4′-disulphonic acid (PPADS) and Mg2+ produced concentration-dependent inhibition of BzATP-evoked currents in non-neuronal cells. Confocal microscopy revealed positive immunoreactivity of anti-P2X7 receptor antibodies on non-neuronal cells. No anti-P2X7 immunoreactivity was observed on DRG neurons. Further electrophysiological studies showed that prolonged agonist activation of P2X7 receptors in non-neuronal cells did not lead to cytolytic pore formation. Taken together, the present study demonstrated functional expression of P2X7 receptors in non-neuronal but not in small diameter neurons from rat DRG. Modulation of P2X7 receptors in non-neuronal cells might have impact on peripheral sensory transduction under normal and pathological states. [Copyright &y& Elsevier]

The profile of tetrodotoxin sensitive (TTX-S) and resistant (TTX-R) Na+ channels and their contribution to action potentials and firing patterns were studied in isolated small dorsal root ganglion (DRG) neurons after L5/L6 spinal nerve ligation (SNL). Total TTX-R Na+ currents and Nav 1.8 mRNA were reduced in injured L5 DRG neurons 14 days after SNL. In contrast, TTX-R Na+currents and Nav 1.8 mRNA were upregulated in uninjured L4 DRG neurons after SNL. Voltage-dependent inactivation of TTX-R Na+ channels in these neurons was shifted to hyperpolarized potentials by 4 mV. Two types of neurons were identified in injured L5 DRG neurons after SNL. Type I neurons (57%) had significantly lower threshold but exhibited normal resting membrane potential (RMP) and action potential amplitude. Type II neurons (43%) had significantly smaller action potential amplitude but retained similar RMP and threshold to those from sham rats. None of the injured neurons could generate repetitive firing. In the presence of TTX, only 26% of injured neurons could generate action potentials that had smaller amplitude, higher threshold, and higher rheobase compared with sham rats. In contrast, action potentials and firing patterns in uninjured L4 DRG neurons after SNL, in the presence or absence of TTX, were not affected. These results suggest that TTX-R Na+ channels play important roles in regulating action potentials and firing patterns in small DRG neurons and that downregulation in injured neurons and upregulation in uninjured neurons confer differential roles in shaping electrogenesis, and perhaps pain transmission, in these neurons. [Copyright &y& Elsevier]

• Dual dynamic network structures of epoxy resins was prepared. • Scrificial hydrogen-bonding clusters (SHBC). • A new strategy to surpass the strength-toughness trade-off. • Rapid degradation and reprocessing capabilities. Thermosetting epoxy resins with high strength, high toughness, and recyclability are strongly sought after, but due to crosslinked structure, balancing strength and toughness and achieving degradation and reprocessing of resins is a challenge. Enhancing strength without compromising toughness during designing recyclable epoxy resin is a challenging task. Herein, a solution is demonstrated where isofluorodioxanone diisocyanate (IPDI), Poly (propylene glycol) bis(2-aminopropyl ether) (D230), and naturally occurring vanillin synthesized a novel imine-functionalized epoxy monomer (IDV-EP), and cured with diamino-diphenylmethane (DDM), 2-(4-aminophenyl)-1H-benzimidazol-5-amine (APBIA) and 4, 4-diamino benzoyl triphenylamine (DABA), respectively, for the purpose of building different contents of the sacrificial hydrogen-bonding clusters (SHBC) in topological network structures. As the hydrogen-bonding (H-bonding) binding energy of the crosslinked network increases, the strength and toughness of the resin were increased concurrently, SHBC was demonstrated to be a feasible method to achieve the strength-toughness trade-off of thermosets, in which IDV-EP-DABA illustrated a tensile strength of 90 MPa, an elongation at break of 16.5%, as well as toughness of 9.73 MJ/m3, which was higher than that of the ordinary bisphenol A-type epoxy thermosetting resin (DGEBA/DDM) by 1.8, 3.7 as well as 6.7 times, respectively. Furthermore, the covalent adaptive networks (CANs) formed by imine bonds provide the resins with effective capabilities for swift degradation (rapid degradation in acid/solvent, room temperature and static conditions) and reprocessing (only a slight decrease in the mechanical properties after hot pressed at 180°C/10 MPa for 15 minutes) , showcasing promising prospects for sustainable utilization. [ABSTRACT FROM AUTHOR]

B Introduction: b Females seem be more tolerant to liver ischemia/reperfusion (I/R) injury than males, the mechanisms of which remains unknown. B Conclusion: b SRY is a novel mediator inducing sex specific hepatic I/R via inactivation of Wnt/ -catenin signaling. [Extracted from the article]

B Introduction: b The short- and long-term outcome of minimally invasive versus open surgery for treatment of pancreatic neuroendocrine tumor (pNET) remains undetermined. The objective of the current study was to compare short- and long-term oncologic outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for treatment of pNET. B Conclusion: b Patients undergoing MIDP over ODP in treatment of pNET had comparable oncologic surgical metrics, as well as similar long-term OS. [Extracted from the article]

Objectives: To characterize the prognostic implication of jaundice and preoperative biliary drainage on postoperative outcomes among patients with gallbladder cancer (GBC) undergoing surgical resection.Methods: Patients who underwent surgical resection of GBC identified from a multicenter database between January 2000 and December 2019 were retrospectively analyzed. Data on clinical and pathological details, as well as short- and long-term overall survival (OS), were obtained and compared among patients with and without preoperative jaundice and biliary drainage.Results: Among 449 patients with GBC, median and 1-, 3-, and 5-year OS were 17.4 months, 63.7%, 28.4%, and 22.1%, respectively. Patients who presented with preoperative jaundice (n = 100, 22.3%) were more likely to have advanced disease, a lower incidence of R0 resection (29.0% vs. 69.1%, p < 0.001), as well as a higher incidence of postoperative liver failure (4% vs. 0, p = 0.002), and worse long-term survival versus patients without jaundice (median OS, 10.4 vs. 27.1 months, p < 0.001). Preoperative biliary drainage was performed for the majority of jaundiced patients (77.0%) and was associated with decreased risk of postoperative liver failure (1.3% vs. 13.0%, p = 0.041); preoperative biliary drainage failed to improve long-term survival (median OS, 10.2 months vs. 12.0 months, p = 0.679). On multivariable analysis, R0 resection (17.5 vs. 7.6 months, p < 0.001) and adjuvant therapy (15.6 vs. 6.6 months, p = 0.027) were associated with improved long-term survival among jaundiced patients.Conclusions: While preoperative biliary drainage of jaundiced GBC patients decreased the risk of postoperative liver failure, it did not impact long-term outcomes. Rather, preoperative jaundice was associated with a lower chance at R0 resection and worse long-term survival. [ABSTRACT FROM AUTHOR]

Background: Simple ileocecectomy and right hemicolectomy are two potential operative approaches to treat patients with neuroendocrine neoplasm in the terminal ileum and/or cecum (IC-NENs). We sought to define the long-term outcome of patients undergoing ileocecectomy versus right hemicolectomy for IC-NENs, as well as characterize number of nodes evaluated and lymph node metastasis (LNM) associated with each procedure. Methods: Patients who underwent curative-intent resections for IC-NENs between 2000 and 2016 were identified from a multi-institutional database. The clinicopathologic characteristics, surgical procedures, and the overall (OS) and recurrence-free survival (RFS) were compared among patients who underwent formal right hemicolectomy versus ileocecectomy only. Results: Among 127 patients with IC-NENs, median size of the largest tumor size was 2.0 (IQR 1.2–2.9) cm; 35 (27.6%) patients had multiple lesions. At the time of surgery, 93 (73.2%) patients underwent a right hemicolectomy, whereas 34 (26.8%) had ileocecectomy only. Every patient had a lymph node dissection (LND) with a median number of 16 (IQR 12–22) nodes evaluated. A majority (n = 110, 86.6%) of patients had LNM with a median number of 3 (IQR 2–5) LNM. Patients who underwent hemicolectomy had more lymph nodes evaluated versus patients who had an ileocecectomy only (median, 18 vs. 14, p = 0.004). Patients who underwent formal right hemicolectomy versus ileocecectomy had a similar OS (median OS, 101.9 vs. 144.5 months, p = 0.44) and RFS (median RFS, 70.3 vs. not attained, p = 0.80), respectively. Conclusions: Ileocecectomy had similar long-term outcomes versus right hemicolectomy in treatment of IC-NENs despite a difference in the lymph node harvest. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade is considered a breakthrough in cancer treatment. However, with the low response rates and therapeutic resistance of patients with hepatocellular carcinoma (HCC), the challenges facing the application of this treatment are tremendous. Liver fibrosis is a key driver of tumor immune escape, the underlying mechanism has never been clarified. This study sought to explore the role of liver fibrosis in regulating tumor-infiltrating lymphocytes (TILs) and inducing tumor immunosuppression. Ninety-nine fixed HCC tissue samples were used to analyze the association between liver fibrosis and immune escape using immunohistochemistry. In HCC patients, low FIB-4 values and high CD8+ T cell infiltration were correlated with prolonged survival. Elevated expression of immune checkpoints and attenuated antitumor immunity were observed in CCl4-induced mice liver fibrosis models and human fibrotic livers compared to control group. GOLM1 levels were increased in livers of patients with fibrosis and mice in response to CCl4-induced liver fibrosis. CD8+ T cell infiltrations were significantly decreased and PD-L1 expression was significantly increased in tumor tissues from hepatocyte-specific GOLM1 transgenic mice (Alb/GOLM1 mice) inducing chemical carcinogenesis compared to their corresponding control WT mice. GOLM1 induced PD-L1 expression via EGFR pathway activation. EGFR inhibitors, especially together with anti-PD-L1 therapy, improved the efficacy of immunotherapy in HCC. These findings illustrate the importance of liver fibrosis-induced immunosuppression as a tumor-promoting mechanism. GOLM1, which is highly upregulated in the fibrotic liver, regulates tumor microenvironmental immune escape via the EGFR/PD-L1 signaling pathway. EGFR blockade may bolster the efficacy of immune checkpoint inhibitors for HCC treatment. [ABSTRACT FROM AUTHOR]

Abstract: KCNQ2/3 voltage-gated potassium channels conduct low-threshold, slowly activating and non-inactivating currents to repolarize the neuronal resting membrane potential. The channels negatively regulate neuronal excitability and KCNQ2/3 openers are efficacious in hyperexcited states such as epilepsy and pain. We developed and utilized thallium influx assays to profile novel KCNQ2/3 channel openers with respect to selectivity across KCNQ subtypes and on requirement for tryptophan 236 of KCNQ2, a critical residue for activity of the KCNQ opener retigabine. Using distinct chemical series of openers, a quinazolinone series showed relatively poor selectivity across multiple KCNQ channels and lacked activity at the KCNQ2(W236L) mutant channel. In contrast, several novel benzimidazole openers showed selectivity for KCNQ2/3 and KCNQ2 and retain activity at KCNQ2(W236L). Profiling of several hundred KCNQ2/3 openers across multiple diverse chemical series revealed that openers show differential degrees of selectivity across subtypes, with selectivity most difficult to achieve against KCNQ2. In addition, we report the significant finding that KCNQ openers can pharmacologically differentiate between homomeric and heteromeric channels containing subtypes in common. Moreover, most openers assayed were dependent on the W236 for activity, whereas only a small number appear to use a distinct mechanism. Collectively, we provide novel insights into the molecular pharmacology of KCNQ channels by demonstrating differential selectivity and site of action for KCNQ2/3 openers. The high-throughput thallium influx assays should prove useful for rapid characterization of KCNQ openers and in guiding efforts to identify selective compounds for advancement towards the clinic. [Copyright &y& Elsevier]

As a sink and source of contaminants, sewage sludge is a good matrix to capture the spatial-temporal trend of chemicals and assess the potential risks these chemicals pose to human health and the environment. In order to understand these chemical risks, a robust statistical sewage sludge sampling strategy for Chinese wastewater treatment plants (WWTPs) must be designed. The purpose of this paper is to develop such a sampling strategy for Chinese WWTPs which may be used optimally. Before creating the sampling design, the distribution of WWTPs was categorically analyzed. These categories include urban agglomeration, wastewater treatment process, and wastewater treatment capacity. Particular attention was given to the studying of population distribution, gross domestic product, WWTP number, wastewater treatment flow, and dry sludge production in each urban agglomeration. In addition, correlation analysis was conducted among these five indexes. Due to the heterogeneity of WWTPs, stratified sampling had to be used to homogenize the sampling units. The eight strategies proposed herein were based on simple random sampling and stratified random sampling methods. Moreover, the aforementioned three categories (urban agglomeration, treatment process, and treatment capacity) were intended to be stratification indicators. Furthermore, Monte Carlo simulations revealed that the treatment capacity based stratified random sampling strategy (Strategy 4) results in the optimal sample representation, with the smallest root mean square error compared to seven other sampling strategies with different strata. This optimal stratified sampling strategy, if employed during the Chinese national sewage sludge survey, has the potential to greatly contribute to data quality and assurance. Unlabelled Image • Population, GDP, and sewage treating indicators in 19 city clusters were analyzed. • The Yangtze River Economic Belt contributes nearly 1/3 of Chinese indicators. • Statistical sampling was developed for Chinese national sewage sludge survey. • Stratified random sampling based on capacity provides the optimal representation. • Excessive stratification may increase in bias. [ABSTRACT FROM AUTHOR]

Background The objective of the current study was to define risk factors associated with the 30-day post-operative risk of VTE after HPB surgery and create a model to identify patients at highest risk of post-discharge VTE. Methods Patients who underwent hepatectomy or pancreatectomy in the ACS-NSQIP Participant Use Files 2011–2015 were identified. Logistic regression modeling was used; a model to predict post-discharge VTE was developed. Model discrimination was tested using area under the curve (AUC). Results Among 48,860 patients, the overall 30-day incidence of VTE after hepatectomy and pancreatectomy was 3.2% (n = 1580) with 1.1% (n = 543) of VTE events occurring after discharge. Patients who developed post-discharge VTE were more likely to be white, had a higher median BMI, have undergone pancreatic surgery, had longer median operative times, and to have had a transfusion. A weighted prediction model demonstrated good calibration and fair discrimination (AUC = 0.63). A score of ≥−4.50 had maximum sensitivity and specificity, resulting in 44% of patients being treating with prophylaxis for an overall VTE risk of 1.1%. Conclusions Utilizing independent factors associated with post-discharge VTE, a prediction model was able to stratify patients according to risk of VTE and may help identify patients who are most likely to benefit from pharmacoprophylaxis. [ABSTRACT FROM AUTHOR]

Background: Surgical management of intrahepatic cholangiocarcinoma routinely includes resection of the hepatic parenchyma, yet the role of lymphadenectomy (LND) is more controversial. The objective of the current study was to define overall utilization, as well as temporal trends, in the utilization of LND among patients undergoing curative-intent hepatectomy for ICC using a nationwide database.Materials and Methods: One thousand four hundred ninety-six patients who underwent curative-intent resection for ICC were identified using the SEER database from 2000 to 2013. The utilization of LND was assessed over time and by geographic region. LND utilization and the incidence of lymph node metastasis (LNM) were evaluated relative to AJCC T categories.Results: At the time of surgery, slightly over one-half of patients (n = 784, 52.4%) had at least one LN evaluated. Specifically, 613 (41.0%) patients had 1-5 LNs evaluated, whereas 171 (11.4%) patients had ≥ 6 LNs evaluated. The proportion of patients who had at least one LN evaluated at the time of surgery did not change with time (2000-2004: 50.5% vs. 2005-2009: 52.0% vs. 2010-2013: 53.7%) (p = 0.636). In contrast, the proportion of patients who had ≥ 6 LNs examined did increase (2000-2004: 6.9% vs. 2005-2009: 10.6% vs. 2009-2013: 14.3%) (p = 0.003). The risk of LNM was higher among patients with advanced T category tumors (Referent T1; T2a: OR 4.2, 95% CI 2.0-8.8, p < 0.001; T2b: OR 2.4, 95% CI 1.1-4.9, p = 0.018; T3: OR 3.6, 95% CI 1.6-7.9, p = 0.001; T4: OR 2.2, 95% CI 1.0-4.9, p = 0.049). In addition, the portion of patients with LNM varied among the different T categories (T1, 23.2%, T2a, 55.3%, T2b, 42.0%, T3, 51.4%, and T4, 39.5%; p = 0.001).Conclusions: Utilization of LND in the surgical management of ICC across the USA remained relatively low and did not change over the last decade. Selective utilization of LND may be problematic as T-stage was not a reliable predictor of nodal status with almost a quarter of patients with early stage disease having LNM. [ABSTRACT FROM AUTHOR]

Background: Patient-provider communication (PPC) is utilized as a value-based metric in pay-for-performance programs. We sought to evaluate the association of PPC with patient-reported health outcomes, as well as healthcare resource utilization among a nationally representative cohort of patients with hepato-pancreato-biliary (HPB) diagnoses.Methods: Patients with HPB diseases were identified from the 2008-2014 Medical Expenditure Panel Survey cohort. A weighted PPC composite score was categorized using the responses from the CAHPS (Consumer Assessment of Healthcare Providers and Systems) survey as optimal, average, or poor. Multivariate analysis was performed using logistic regression.Results: Among 1951 adult-patients, representing 21.7 million HPB patients, reported PPC was optimal (33.4%), average (46.3%), or poor (15.3%). Patients who were older and patients with low income were more likely to report poor PPC (both p < 0.05). Statin use, a quality of care measure, was associated with optimal PPC (OR 1.70, 95% CI 1.10-2.64; p = 0.01). In contrast, patients who reported poor PPC were more likely to have a poor physical (20.8%) or mental (8.8%) health component on their SF12 (both p < 0.05). Furthermore, patients with poor PPC were more likely to report poor mental status (OR 2.97, 95% CI 1.60-5.52), as well as higher emergency department visits (OR 1.95, 95% CI 1.25-3.05) and hospitalizations (OR 1.90, 95% CI 1.02-3.55) (both p < 0.05). Reported PPC was not associated with differences in overall healthcare expenditures or out-of-pocket expenditures.Conclusions: PPC was associated with a wide spectrum of patient-specific demographic and health utilization factors. Self-reported patient satisfaction with provider communication may be impacted by other considerations than simply the patient-provider interaction. [ABSTRACT FROM AUTHOR]

Introduction: Primary liver cancer mortality rates have been increasing in the US, but reported decreases among 35-49 year olds may foreshadow future declines. We sought to use age-period-cohort (APC) modeling to evaluate the contribution of cohort effects to hepatocellular carcinoma (HCC) mortality trends in the US.Methods: Data on HCC mortality were obtained from the Centers for Disease Control and Prevention National Center for Health Statistics WONDER Online Multiple Cause of Death database, 1999-2015. Crude mortality rates were plotted by gender and age at death. Gender-specific restricted cubic spline APC models were fit to determine influence of birth cohort on incidence of HCC mortality, in reference to the 1940 birth cohort.Results: Highest mortality rates were found among men ages 70+, with steepest increase in mortality observed among men 55-69 years old. Similar trends were found among females. Accounting for the cohort effect in the APC model markedly improved model fit (likelihood ratio test p < 0.001). Relative to the 1940 birth cohort, risk of mortality due to HCC was significantly higher in later as well as earlier cohorts.Conclusions: HCC-associated mortality continues to increase, secondary to an increase in the risk of HCC-associated mortality in more recent birth cohorts among both men and women. [ABSTRACT FROM AUTHOR]

Sex affects the risk, treatment responses and outcome of many types of cancers. The mechanism of gender disparity in development of hepatocellular carcinoma (HCC) remains obscure. Sex-determining region on Y chromosome (SRY) was overexpressed in approximate 84% male patient HCC. Moreover, we are the first to generate a liver-specific transgenic (TG) murine model with overexpression of the male specific gene SRY. Subject to a single intraperitoneal injection N-nitrosodiethylamine (DEN) at day 14, TG and wildtype (WT) mice of both genders were sacrificed at different time points (6-13.5 months). Overexpression of SRY in male TG and ectopic expression of SRY in female TG livers promoted DEN-induced hepatocarcinogenesis compared to age- and sex-matched WT. This accelerated tumorigenesis in TG of both genders was a consequence of increased injury and inflammation, fibrosis, and compensatory enhancement in hepatocytes proliferation secondary to activation of downstream targets Sox9 and platelet-derived growth factor receptor α (PDGFRα)/phosphoinositide 3-kinase (PI3K)/Akt and c-myc/CyclinD1. In conclusion, activation of SRY and its downstream Sox9 and PDGFRα pathways are commonly involved in male hepatocarcinogenesis, which provides novel insights into gender disparity and sex-specific therapeutic strategies of HCC. [ABSTRACT FROM AUTHOR]

Background Cholecystectomy is a routine procedure for treatment of upper abdominal pain (UAP) and other atypical symptoms associated with gallstones. UAP, however, persists in some cases postoperatively. The present study was to identify the risk factors relevant to persistent UAP after cholecystectomy. Methods 1714 symptomatic patients undergoing cholecystectomy for gallstones were enrolled. All the patients were asked to complete a biliary symptom questionnaire. The risk factors for persistent postcholecystectomy UAP and features related to sustained relief of postcholecystectomy UAP were evaluated. Results 172 (10%) patients complained UAP after cholecystectomy. In multivariate analysis, female gender, preoperative UAP occurring >24h before admission, and each episode of UAP >30min were independently associated with persistent postoperative UAP (all p < 0.05). 132 (76.7%) patients reported sustained relief of postcholecystectomy UAP, the causes of which remained unknown but were attributed to functional postcholecystectomy syndrome. Shorter duration of preoperative UAP (occurring within 24 h before admission), less frequency of postoperative UAP (≤1 episode per day) and administration of choleretic medications were independently associated with postoperative UAP relief (all p < 0.05). Conclusion Females with longer historical and more frequent preoperative UAP are more likely to develop postcholecystectomy UAP. Choleretic medications are effective in relieving postoperative UAP. [ABSTRACT FROM AUTHOR]

[Display omitted] The voltage-gated sodium channel Na v 1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Na v 1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Na v 1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Na v 1.7 blockers. The design of these molecules focused on maintaining potency at Na v 1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Na v 1.8, another sodium channel isoform that is an active target for the development of new pain treatments. [ABSTRACT FROM AUTHOR]

γ-Hydroxynitrile glucosides (prinsepicyanosides A-E) were isolated alongside 11 known compounds from seeds of Prinsepia utilis Royle. Their structures were determined by detailed analysis of NMR and MS spectroscopic data. The relative configuration of prinsepicyanoside C was established by Cu-Kα X-ray crystallography. Prinsepicyanoside A, osmaronin, and 4-(hydroxylmethyl)-5H-furan-2-one exhibited borderline antibacterial activity against Salmonella gallinarum, Vibrio parahaemolyticus, and Vibrio cholera with MIC values of 30.1, 20.7, and 22.8μg/mL, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Eight new (1−8) and two known (9 and 10) sesquiterpenic acids featuring α-methylene-γ-carboxyl units were isolated from the whole plants of Inula wissmanniana, along with two new germacranolides (11 and 12). Their structures were elucidated based on detailed spectroscopic analysis, including HRESIMS, 1D and 2D NMR, and X-ray crystallography. Notably, the skeleton of 1 was firstly discovered from nature, while that of 2 was discovered for the second time. All the compounds were evaluated for their inhibition against LPS-induced nitric oxide (NO) production in RAW264.7 macrophages. Compound 11 exhibited the strongest activity with the IC50 value of 1.04μM. [Copyright &y& Elsevier]

2-Amino-4-azaindoles have been identified as a structurally novel class of BKCa channel openers. Their synthesis from 2-chloro-3-nitropyridine is described together with their in vitro properties assessed by 86Rb+ efflux and whole-cell patch-clamp assays using HEK293 cells stably transfected with the BKCa α subunit. In vitro functional characterization of BKCa channel opening activity was also assessed by measurement of relaxation of smooth muscle tissue strips obtained from Landrace pig bladders. The preliminary SAR data indicate the importance of steric bulk around the 2-amino substituent. [Copyright &y& Elsevier]