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A 69-year-old woman was admitted after a cardiac arrest. She developed status epilepticus and was later found to have variable morphologies of a "spiked helmet sign" (SHS) on ECGs in the setting of prolonged QT interval, raising the question of whether this sign is a manifestation of QT prolongation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cuproptosis, a new type of copper-induced cell death, is involved in the antitumor activity and resistance of multiple chemotherapeutic drugs. Our previous study revealed that adrenomedullin (ADM) was engaged in sunitinib resistance in clear cell renal cell carcinoma (ccRCC). However, it has yet to be investigated whether and how ADM regulates sunitinib resistance by cuproptosis. This study found that the ADM expression was elevated in sunitinib-resistant ccRCC tissues and cells. Furthermore, the upregulation of ADM significantly enhanced the chemoresistance of sunitinib compared with their respective control. Moreover, cuproptosis was involved in ADM-regulated sunitinib resistance by inhibiting mammalian ferredoxin 1 (FDX1) expression. Mechanically, the upregulated ADM activates the p38/MAPK signaling pathway to promote Forkhead box O3 (FOXO3) phosphorylation and its entry into the nucleus. Consequently, the increased FOXO3 in the nucleus inhibited FDX1 transcription and cell cuproptosis, promoting chemoresistance. Collectively, cuproptosis has a critical effector role in ccRCC progress and chemoresistance and thus is a relevant target to eradicate the cell population of sunitinib resistance., (© 2023 Federation of American Societies for Experimental Biology.)

Background: The 2022 clinical guidelines for management of heart failure with reduced ejection fraction call for quadruple therapy. Quadruple therapy consists of an angiotensin receptor-neprilysin inhibitor (ARNi), sodium-glucose cotransporter-2 inhibitor (SGLT2i), mineralocorticoid receptor antagonist, and beta blocker. The ARNi and sodium-glucose cotransporter-2 inhibitor are newer additions to standard of care with the ARNi replacing ACE (angiotensin-converting enzyme) inhibitors and angiotensin II receptor blockers., Methods: We investigate the cost-effectiveness of sequentially adding the SGLT2i and ARNi to form quadruple therapy as compared with the previous standard of care with ACE inhibitor/mineralocorticoid receptor antagonist/beta blocker. Using a 2-stage Markov model, we projected the expected lifetime discounted costs and quality-adjusted life years (QALYs) of a simulated cohort of US patients who underwent each treatment option and calculated incremental cost-effectiveness ratios. We assessed incremental cost-effectiveness ratios using criteria for health care value (<$50 000/quality-adjusted life year [QALY] indicating high-value, $50 000-150 000/QALY indicating intermediate value, and >$150 000/QALY indicating low-value) and a standard $100 000/QALY cost-effectiveness threshold., Results: Compared with the previous standard of care, the SGLT2i addition had an incremental cost-effectiveness ratio of $73 000/QALY and weakly dominated the ARNi addition. The addition of both the ARNi and SGLT2i for quadruple therapy offered 0.68 additional discounted QALYs over the SGLT2i addition alone at a lifetime discounted cost of $66 700, resulting in an incremental cost-effectiveness ratio of $98 500/QALY. In sensitivity analysis varying drug prices, the incremental cost-effectiveness ratio for quadruple therapy ranged from $73 500/QALY using prices available to the US Department of Veterans Affairs to $110 000/QALY using drug list prices., Conclusions: While quadruple therapy offers intermediate value, it is borderline cost effective compared with adding the SGLT2i alone to previous standard of care. Thus, its cost-effectiveness is sensitive to a payer's ability to negotiate discounts off the increasing list prices for ARNI and SGLT2is. The demonstrated benefits of ARNi and SGLT2is should be weighed against their high prices in payer and policy considerations., Competing Interests: Disclosures None.

The discovery of new tumor subtypes has been aided by transcriptomics profiling. However, some new subtypes can be irreproducible due to data artifacts that arise from disparate experimental handling. To deal with these artifacts, methods for data normalization and batch-effect correction have been utilized before performing sample clustering for disease subtyping, despite that these methods were primarily developed for group comparison. It remains to be elucidated whether they are effective for sample clustering. We examined this issue with a re-sampling-based simulation study that leverages a pair of microRNA microarray data sets. Our study showed that (i) normalization generally benefited the discovery of sample clusters and quantile normalization tended to be the best performer, (ii) batch-effect correction was harmful when data artifacts confounded with biological signals, and (iii) their performance can be influenced by the choice of clustering method with the Prediction Around Medoid method based on Pearson correlation being consistently a best performer. Our study provides important insights on the use of data normalization and batch-effect correction in connection with the design of array-to-sample assignment and the choice of clustering method for facilitating accurate and reproducible discovery of tumor subtypes with microRNAs., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Chronic inflammation is one of the definite factors leading to the occurrence and development of tumors, including prostate cancer (PCa). The androgen receptor (AR) pathway is essential for PCa tumorigenesis and inflammatory response. However, little is known about the AR-regulated NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome pathway in human PCa. In this study, we explored the expression of inflammatory cytokine and AR in high-grade PCa and observed that NLRP3 inflammasome-associated genes were upregulated in high-grade PCa compared with that in low-grade PCa and benign prostatic hyperplasia and were associated with AR expression. In addition, we identified circAR-3-a circRNA derived from the AR gene-which is involved in the AR-regulated inflammatory response and cell proliferation by activating the NLRP3 inflammatory pathway. While circAR-3 overexpression promoted cell proliferation and the inflammatory response, its depletion induced opposite effects. Mechanistically, we noted that circAR-3 mediated the acetylation modification of NLRP3 by KAT2B and then promoted NLRP3 inflammasome complex subcellular distribution and assembly. Disturbing NLRP3 acetylation or blocking inflammasome assembly with an inhibitor suppressed the progression of PCa xenograft tumors. Our findings provide the first evidence that targeting NLRP3 acetylation or inflammasome assembly may be effective in inhibiting PCa progression., (© 2022 Federation of American Societies for Experimental Biology.)

The COVID pandemic disrupted health care spending and utilization, and the Medicare Shared Savings Program (MSSP), Medicare's largest value-based payment model with 11.2 million assigned beneficiaries, was no exception. Despite COVID, the 513 accountable care organizations (ACO) in MSSP returned a program record $1.9 billion in net savings to Medicare in 2020. To understand the extent of COVID's impact on MSSP cost and quality, we describe how ACO spending changed in 2020 and further analyze changes in measured quality and utilization. We found that non-COVID per capita spending in MSSP fell by 8.3 percent from $11,496 to $10,537 (95% confidence interval(CI),-1,223.8 to-695.4, p<0.001), driven by 14.6% and 7.5% reductions in per capita acute inpatient and outpatient spending, respectively. Utilization fell across inpatient, emergency, and outpatient settings. On quality metrics, preventive screening rates remained stable or improved, while control of diabetes and blood pressure worsened. Large reductions in non-COVID utilization helped ACOs succeed financially in 2020, but worsening chronic disease measures are concerning. The appropriateness of the benchmark methodology and exclusion of COVID-related spending, especially as the virus approaches endemicity, should be revisited to ensure bonus payments reflect advances in care delivery and health outcomes rather than COVID-related shifts in spending and utilization patterns., Competing Interests: The authors have declared that no competing interests exist.

Medicare Accountable Care Organizations (ACOs) have achieved high-quality performance and recent cost savings, but little is known about how local market conditions influence provider adoption. The authors describe physician practice participation in Medicare ACOs at the county level and use adjusted logistic regression to assess the association between ACO presence and 3 characteristics hypothesized to influence ACO formation: physician market concentration, Medicare Advantage (MA) penetration, and commercial health insurance market concentration. Analyses are repeated on urban and rural county subgroups to examine geographic differences in ACO adoption. Practice participation in ACOs grew 19% nationally from 5.4% to 6.4% of practices between 2015 to 2017, but participation lagged in the West and rural counties, the latter of which had relatively concentrated physician markets and low MA penetration. After controlling for urban location, population density, and other covariates, ACO presence in a county was independently associated with less concentrated physician markets and moderate MA penetration but not commercial insurance concentration. The evidence suggests that Medicare ACO programs have continued appeal to physician practices, but additional engagement strategies may be needed to expand adoption in rural areas. In addition, greater practice competition and MA experience may facilitate ACO adoption. These insights into the relationship between market conditions and ACO participation have important implications for policy efforts to accelerate Medicare payment transformation.

Although the Affordable Care Act's Medicaid expansion reduced uninsurance, less is known about its impact on mortality, especially in the context of the opioid epidemic. We conducted a difference-in-differences study comparing trends in mortality between expansion and nonexpansion states from 2011 to 2016 using the Centers for Disease Control and Prevention mortality data. We analyzed all-cause deaths, health care amenable deaths, drug overdose deaths, and deaths from causes other than drug overdose among adults aged 20 to 64 years. Medicaid expansion was associated with a 2.7% reduction ( p = .020) in health care amenable mortality, and a 1.9% reduction ( p = .042) in mortality not due to drug overdose. However, the expansion was not associated with any change in all-cause mortality (0.2% reduction, p = .84). In addition, drug overdose deaths rose more sharply in expansion versus nonexpansion states. The absence of all-cause mortality reduction until drug overdose deaths were excluded indicate that the opioid epidemic had a mitigating impact on any potential lives saved by Medicaid expansion.

Background: The 2016 presidential election and the controversial policy agenda of its victor have raised concerns about how the election may have impacted mental health., Objective: Assess how mental health changed from before to after the November 2016 election and how trends differed in states that voted for Donald Trump versus Hillary Clinton., Design: Pre- versus post-election study using monthly cross-sectional survey data., Participants: A total of 499,201 adults surveyed in the Behavioral Risk Factor Surveillance System from May 2016 to May 2017., Exposure: Residence in a state that voted for Trump versus state that voted for Clinton and the candidate's margin of victory in the state., Main Measures: Self-reported days of poor mental health in the last 30 days and depression rate., Key Results: Compared to October 2016, the mean days of poor mental health in the last 30 days per adult rose from 3.35 to 3.85 in December 2016 in Clinton states (0.50 days difference, p = 0.005) but remained statistically unchanged in Trump states, moving from 3.94 to 3.78 days (- 0.17 difference, p = 0.308). The rises in poor mental health days in Clinton states were driven by older adults, women, and white individuals. The depression rate in Clinton states began rising in January 2017. A 10-percentage point higher margin of victory for Clinton in a state predicted 0.41 more days of poor mental health per adult in December 2016 on average (p = 0.001)., Conclusions: In states that voted for Clinton, there were 54.6 million more days of poor mental health among adults in December 2016, the month following the election, compared to October 2016. Clinicians should consider that elections could cause at least transitory increases in poor mental health and tailor patient care accordingly, especially with the 2020 election upon us.

Background: Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancers. We aimed to evaluate the incidence and prognostic impact of hepatic adverse events (AEs) in a territory-wide cohort of patients who received ICIs., Methods: Patients were identified from a territory-wide database who received ICIs in 2014-2018. Hepatic AEs were defined as any elevation of liver biochemistries including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels. Hepatic AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0., Results: Total of 1480 patients were identified (mean age 60 years, male 65.5%) and the commonest malignancies being lung cancer (39.6%), liver cancer (16.5%), and gastrointestinal cancer (10.0%). Grade 1-2 and grade 3-4 hepatic AEs occurred in 41.3% and 14.9% of patients during ICI treatment, respectively. Patients with liver cancer had the highest rate of hepatic AEs (grade 1-2:54.1%; grade 3-4:32.8%). Among 711 patients with hepatic AEs, 383 (53.9%) had raised ALT/AST only, and 328 (46.1%) had concomitant raised ALT/AST and bilirubin levels. In the whole cohort, median overall survival of patients without any hepatic AEs, grade 1-2 and grade 3-4 hepatic AEs during ICI treatment was 9.0 months, 7.2 months, and 3.3 months (P < .001), respectively. Similar results on overall survival were obtained among different types of cancers., Conclusions: Hepatic AEs occur in more than half of patients receiving ICIs for cancer treatment, with approximately 15% being grade 3-4 AEs. Occurrence of hepatic AEs is associated with worse prognosis., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Hepatitis B core-related antigen (HBcrAg) is a novel serum viral marker. Recent studies showed that its level correlates with the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to evaluate the accuracy of serum HBsAg and HBcrAg levels at baseline to predict HCC., Methods: 1400 CHB patients who received nucleos(t)ide analogues (NA) treatment since December 2005 were included. Their stored serum samples at baseline were retrieved to measure HBsAg and HBcrAg levels. The primary endpoint was the cumulative incidence of HCC., Results: 85 (6.1%) patients developed HCC during a mean (± SD) follow-up duration of 45 ± 20 months. Serum HBcrAg level above 2.9 log10 U/mL at baseline was an independent factor for HCC in hepatitis B e antigen (HBeAg)-negative patients by multivariable analysis (adjusted hazard ratio 2.13, 95% CI 1.10-4.14, P = 0.025). HBcrAg above 2.9 log 10 U/mL stratified the risk of HCC in HBeAg-negative patients with high PAGE-B score (P = 0.024 by Kaplan-Meier analysis), and possibly in cirrhotic patients (P = 0.08). Serum HBsAg level did not show any correlation with the risk of HCC in all patients or any subgroups., Conclusion: Serum HBcrAg level predicts the risk of HCC accurately in NA-treated HBeAg-negative CHB patients.

Background & Aims: Antiviral treatment is known to improve survival in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). Yet, the treatment uptake in CHB patients remains low. We aimed to report the secular trend in antiviral treatment uptake from 2007-2017, and to compare the effect of different nucleos(t)ide analogue (NA) initiation times (before vs. after HCC diagnosis) on survival., Methods: A 3-month landmark analysis was used to compare overall survival in patients not receiving NA treatment ( i.e. no NA), patients receiving NAs after their first HCC treatment ( i.e. post-HCC NA), and patients receiving NAs ≤3 months before their first HCC treatment ( i.e. pre-HCC NA). A propensity score-weighted Cox proportional hazards model was used to balance clinical characteristics between the 3 groups and to estimate hazard ratios (HRs)., Results: The uptake of antiviral treatment in HCC patients increased from 47.3% in 2007 to 98.3% in 2017. The pre-HCC NA group contributed mostly to the uptake rate, which increased from 72.7% to 96.0% in the past decade. In addition, 3,843 CHB patients (407 no NA; 2,932 pre-HCC NA; 504 post-HCC NA) with HCC, receiving at least 1 type of HCC treatment, were included in the analysis. Lack of NA treatment at the time of HCC diagnosis increased the risk of death (weighted HR 3.05; 95% CI 2.70-3.44; p <0.001). The impact of the timing of NA treatment was insignificant (weighted HR 0.90; 95% CI 0.78-1.04; p  = 0.161)., Conclusions: The uptake of antiviral treatment in HCC patients increased over the past decade. NA treatment, regardless of whether it was initiated before or after HCC diagnosis, improved survival. It is never too late to initiate NA treatment, even after HCC diagnosis., Lay Summary: More and more patients who have hepatitis B-related liver cancer received antiviral treatment over the past decade. The timing of starting antiviral treatment, regardless of whether it was before or after liver cancer happens, does not really matter in terms of survival benefits., Competing Interests: VWS Wong has served as an advisory committee member for 3vbio, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, and Terns, and a speaker for Bristol Myers Squibb, Echosens, Gilead Sciences, and Merck. He has also received an unrestricted grant from Gilead Sciences. TCFY has served as an advisory committee member and a speaker for Gilead Sciences. HLYC has served as an advisory committee member for AbbVie, APTORUM, Aligos, Arbutus, Hepion, Intellia, Janssen, Gilead, MedImmune, Merck, Roche, Vir Biotechnology, GRAIL, Vaccitech, and VenatoRx, and as a speaker for Mylan, Gilead, and Roche. GLHW has served as an advisory committee member for Gilead Sciences and Janssen, and as a speaker for Abbott, AbbVie, Bristol Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen, and Roche. She received a research grant from Gilead. The other authors declare that they have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Background: Because of high-risk behaviours, sedentary lifestyle and side effects of medications, psychiatric patients are at risk of viral hepatitis, alcohol-related liver disease and non-alcoholic fatty liver disease. We aimed to study the incidence of hepatocellular carcinoma (HCC) and cirrhotic complications in psychiatric patients., Methods: We identified consecutive adult patients in all public hospitals and clinics in Hong Kong with psychiatric diagnoses between year 2003 and 2007 using the Clinical Data Analysis and Reporting System, which represents in-patient and out-patient data of approximately 80% of the 7.4-million local population. The patients were followed for liver-related events (HCC and cirrhotic complications) and deaths until December 2017. Age- and sex-standardized incidence ratio (SIR) of HCC in psychiatric patients to the general population was estimated by Poisson model., Results: We included 105,763 psychiatric patients without prior liver-related events in the final analysis. During a median (interquartile range) follow-up of 12.4 (11.0-13.7) years, 1461 (1.4%) patients developed liver-related events; 472 (0.4%) patients developed HCC. Compared with the general population, psychiatric patients had increased incidence of HCC (SIR 1.42, 95% confidence interval [CI] 1.28-1.57, P < 0.001). The SIR was highest in patients with drug-induced (SIR 3.18, 95% CI 2.41-4.11, P < 0.001) and alcohol-induced mental disorders (SIR 2.98, 95% CI 2.30-3.81, P < 0.001), but was also increased in patients with psychotic disorders (SIR 1.39, 95% CI 1.16-1.65, P < 0.001) and mood disorders (SIR 1.16, 95% CI 1.00-1.34, P = 0.047). Liver disease was the fifth most common cause of death in this population, accounting for 595 of 10,614 (5.6%) deaths. Importantly, 569 (38.9%) patients were not known to have liver diseases at the time of liver-related events. The median age at HCC diagnosis (61 [range 26-83] years) was older and the median overall survival (8.0 [95% CI 5.0-10.9] months) after HCC diagnosis was shorter in this cohort of psychiatric patients than other reports from Hong Kong., Conclusions: HCC, cirrhotic complications, and liver-related deaths are common in psychiatric patients, but liver diseases are often undiagnosed. More efforts are needed to identify liver diseases in the psychiatric population so that treatments and screening for HCC and varices can be provided to patients in need.

Patients with chronic hepatitis B (CHB) are aging because of improved survival under better health care. This has an important implication on the choice of antiviral treatment (AVT), given that long-term safety would be a concern in the presence of multiple comorbidities. We aimed to determine the prevalence of key comorbidities and concomitant medications in a territory-wide CHB cohort in Hong Kong in 2000-2017. CHB patients who have been under the care at primary, secondary, and tertiary medical centers in the public sector were identified through the Clinical Data Analysis and Reporting System of the Hospital Authority, Hong Kong. The demographics and prevalence of key comorbidities, including diabetes mellitus, hypertension, chronic kidney disease, osteopenia/osteoporosis based on diagnosis codes, relevant medications, and/or laboratory parameters, were determined according to CHB patients' first appearance in four time periods: 2000-2004, 2005-2009, 2010-2013, and 2014-2017. In the final analysis, 135,395 CHB patients were included; the mean age increased with time: 41 ± 15 years in 2000-2004; 46 ± 17 years in 2005-2009; 51 ± 16 years in 2010-2013; and 55 ± 15 years in 2014-2017. There was a trend of increasing prevalence of several common comorbidities over the four periods: hypertension 25.5%, 23.8%, 27.2%, and 28.6%; diabetes mellitus 10.6%, 12.5%, 16.1%, and 20.1%; cardiovascular disease 12.5%, 16.9%, 20.9%, and 22.2%; and malignancy 7.0%, 13.2%, 17.3%, and 23.6%, respectively (all P < 0.001). Conclusion: CHB patients are getting older with increasing prevalence of common comorbidities. These comorbidities should be taken into account when choosing AVT., (© 2019 by the American Association for the Study of Liver Diseases.)

Background & Aims: Systemic corticosteroids may cause HBV reactivation, but the impact on patients with previous HBV exposure is poorly defined. We aimed to study the risk of HBsAg seroreversion and hepatitis flare in patients with previous HBV exposure., Methods: Patients who were negative for HBsAg and received corticosteroids between 2001-2010 were included. Patients who were positive for antibody to HBsAg (anti-HBs) and/or to HBcAg (anti-HBc) were defined as having previous HBV exposure. The primary endpoint was HBsAg seroreversion; the secondary endpoint was hepatitis flare (alanine aminotransferase >80 U/L) at 1 year., Results: A total of 12,997 patients fulfilled the inclusion criteria: anti-HBs positive only (n = 10,561); anti-HBc positive only (n = 970); anti-HBs & anti-HBc positive (n = 830) and anti-HBs & anti-HBc negative (n = 636). HBsAg seroreversion occurred in 165 patients. Patients who were anti-HBc positive only had a higher risk of HBsAg seroreversion (1-year incidence 1.8%) than those negative for both anti-HBs & anti-HBc (0%; p = 0.014). Patients with previous HBV exposure had a similarly low risk of liver failure as unexposed individuals (1.1% vs. 0.9%). The risk of a hepatitis flare started to increase in those receiving corticosteroids at peak daily doses of 20-40 mg (adjusted hazard ratio [HR] 2.19, p = 0.048) or >40 mg (aHR 2.11, p = 0.015) prednisolone equivalents for <7 days, and was increased at treatment durations of 7-28 days and >28 days (aHR 2.02-3.85; p <0.001-0.012)., Conclusions: In HBsAg-negative patients who were only anti-HBc positive, high peak daily doses of corticosteroids increased the risk of hepatitis flare, but not seroreversion. The rate of liver failure was low and similar in HBV exposed and unexposed individuals; there were no deaths, nor any requirement for liver transplantation., Lay Summary: It is important to know the hepatitis B virus (HBV) status before starting corticosteroid therapy. Patients with resolved HBV infection without detectable immunity are at an increased risk of HBV surface antigen seroreversion after corticosteroid therapy. High peak daily doses of corticosteroids (>40 mg prednisolone equivalents) increase the risk of hepatitis flare, but not seroreversion, in patients with previous exposure to HBV, irrespective of the duration of treatment. Interval monitoring of liver biochemistries is essential for the early detection of hepatitis flares in these patients., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Systemic corticosteroid is used for different medical conditions and may cause hepatitis B virus (HBV) reactivation., Aims: To study the impact of duration and peak dose of corticosteroid on the risk of hepatitis flare in patients with chronic hepatitis B (CHB)., Methods: All patients who received corticosteroid from January 2001 to December 2004 were retrieved from the Hospital Authority, Hong Kong. We stratified patients by daily dose prednisolone equivalents (<20 mg, 20-40 mg, >40 mg) and durations (<7; 7-28; >28 days). The primary endpoint was hepatitis flare (alanine aminotransferase >2×upper limit of normal, ie 80 IU/L) at 1 year., Results: A total of 85 763 patients fulfilled the inclusion criteria (5254 CHB, 80 509 non-CHB). CHB patients had higher risk of hepatitis flare (388/5254 [7.8%]) than those without CHB (2728/80 509 [4.2%]; P < 0.001 by log-rank test). Among CHB patients, peak daily dose >40 mg compared to <20 mg prednisolone equivalents (adjusted hazard ratio [aHR] 1.64, 95% CI 1.26-2.14; P < 0.001) was an independent risk factor of hepatitis flare. Risk of hepatitis flare started to increase in those receiving corticosteroid of peak daily dose >40 mg prednisolone equivalents even for <7 days (aHR 1.55, P = 0.026), which was also increased for 7-28 days and >28 days (aHR 1.90 and 1.64 respectively, both P < 0.001)., Conclusion: Even short courses of high-dose corticosteroid increase the risk of hepatitis flare in CHB patients. Patients receiving high-dose corticosteroid should be considered for antiviral prophylaxis regardless of the duration of treatment., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A regioselective formal [4 + 2] cycloaddition for the assembly of highly functionalized benzene rings was successfully developed. In this reaction, olefinic C-H bond functionalization/cyclization cascade reaction followed by rearomatization led to the desired molecules in one step under mild reaction conditions. This protocol also displays a broad substrate scope and good tolerance to a wide range of functional groups. Additionally, the potential utility for the synthesis of highly conjugated polybenzenes and diversification of natural products was also demonstrated.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC., Competing Interests: The authors declare no conflict of interest.

Background: Although malignant pleural mesothelioma (MPM) is generally a disease associated with more advanced age, the association of age, treatment, and outcomes has not been well-characterized. We evaluated the impact of age on outcomes in patients with MPM to provide data for use in the treatment selection process for elderly patients with potentially resectable disease., Patients and Methods: Overall survival (OS) of patients younger than 70 and 70 years or older with Stage I to III MPM who underwent cancer-directed surgery or nonoperative management in the Surveillance, Epidemiology, and End Results database (2004-2010) was evaluated using multivariable Cox proportional hazard models and propensity score-matched analysis., Results: Cancer-directed surgery was used in 284 of 879 (32%) patients who met inclusion criteria, and was associated with improved OS in multivariable analysis (hazard ratio, 0.71; P = .001). Cancer-directed surgery was used much less commonly in patients 70 years and older compared with patients younger than 70 years (22% [109/497] vs. 46% [175/382]; P < .001), but patients 70 years and older had improved 1-year (59.4% vs. 37.9%) and 3-year (15.4% vs. 8.0%) OS compared with nonoperative management. The benefit of surgery in patients 70 years and older was observed even after propensity score-matched analysis was used to control for selection bias., Conclusion: Surgical treatment is associated with improved survival compared with nonoperative management for both patients younger than 70 years and patients aged 70 years or older., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.

The activities of the brain and the heart are dynamic, chaotic, and possibly intrinsically coordinated. This study aims to investigate the effect of Mindfulness-Based Stress Reduction (MBSR) program on the chaoticity of electronic activities of the brain and the heart, and to explore their potential correlation. Electroencephalogram (EEG) and electrocardiogram (ECG) were recorded at the beginning of an 8-week standard MBSR training course and after the course. EEG spectrum analysis was carried out, wavelet entropies (WE) of EEG (together with reconstructed cortical sources) and heart rate were calculated, and their correlation was investigated. We found enhancement of EEG power of alpha and beta waves and lowering of delta waves power during MBSR training state as compared to normal resting state. Wavelet entropy analysis indicated that MBSR mindfulness meditation could reduce the chaotic activities of both EEG and heart rate as a change of state. However, longitudinal change of trait may need more long-term training. For the first time, our data demonstrated that the chaotic activities of the brain and the heart became more coordinated during MBSR training, suggesting that mindfulness training may increase the entrainment between mind and body. The 3D brain regions involved in the change in mental states were identified., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Tumor suppressor genes (TSGs) play a prominent role in cancer and are important in the development of nasopharyngeal carcinoma (NPC), which is endemic in Southern China as well as Southeast Asia. Apart from TSGs, aberrant signalling pathways are also commonly associated with tumor progression. Unsurprisingly, the NF-κB pathway is frequently associated with angiogenesis and promoting tumor growth and development. Functional complementation studies using microcell-mediated chromosome transfer helped to identify IKBB as a putative TSG in NPC. IKBB, an inhibitor of NF-κB, has recently been shown to be inversely associated with tumor growth and metastasis via inactivation of the NF-κB pathway, but its suppressive role is still only poorly understood. This study takes the lead in revealing the suppressive role of IKBB in NPC. IKBB is silenced in the majority of NPC tumor tissues in all stages. Its suppressive role is substantiated by perturbation in tumor formation, cell migration and angiogenesis. Interestingly, IKBB not only affects the 'seed', but also influences the 'soil' by downregulating the transcriptional level of proangiogenic factors Rantes, Upar, IL6, and IL8. For the first time, our data establish the importance of a novel tumor suppressive IKBB gene in abrogating angiogenesis in NPC via the NF-κB signalling pathway, which is likely mediated by crosstalk with the Akt/Gsk3β signalling pathway., (© 2015 UICC.)

Wnt/β-catenin signaling is responsible for the generation of cancer stem cells (CSCs) in many human tumors, including nasopharyngeal carcinoma (NPC). Recent studies demonstrate that Wnt or PORCN inhibitor, Wnt-C59, inhibits tumor growth in MMTV-WNT1 transgenic mice. The effect of Wnt-C59 in human tumors is not clear. In this study, the NPC cell lines investigated manifest heterogeneous responses to Wnt-C59 treatment. Wnt-C59 decreased tumor growth of SUNE1 cells in mice immediately following the administration of Wnt-C59. Mice injected with HNE1 cells did not develop visible tumors after the treatment of Wnt-C59, while control mice developed 100% tumors. Wnt-C59 inhibited stemness properties of NPC cells in a dosage-dependent manner by arresting sphere formation in both HNE1 and SUNE1 cells. Thus, Wnt-C59 has the potential to eradicate CSCs in human tumors. Active β-catenin and Axin2 proteins were strongly expressed in stromal cells surrounding growing tumors, confirming the importance of Wnt signaling activities in the microenvironment being driving forces for cell growth. These novel findings confirm the ability of Wnt-C59 to suppress Wnt-driven undifferentiated cell growth in NPC. Both anti-Wnt signaling and anti-CSC approaches are feasible strategies in cancer therapy.

Open release remains the gold standard in the treatment of carpal tunnel syndrome in cases where conservative treatment fails. However, the efficacy of carpal tunnel release in the elderly has been debated in the literature throughout the years. This review aims to review the current evidence pertaining to the efficacy of carpal tunnel release in the elderly. Based on the current evidence, the outcome of carpal tunnel release is unpredictable in the elderly. Elderly patients are also less satisfied with the operation compared to younger patients. The authors recommend that these messages be conveyed to elderly patients before surgery. Moreover, open carpal tunnel release should be offered in the early stages of treatment whenever operative management is indicated.

Little is known about how foreign DNA is randomly integrated into chromosomes in transgenic animals. In the current study, the insertion sites of 36 transgenic mice were mapped by thermal asymmetric interlaced PCR, and 38 junction sequences were obtained from 30 samples. Analysis of the 38 sequences revealed that 44.7 % of integration events occurred within host gene regions, including 13.2 % (5/38) in exonic regions and 31.6 % (12/38) in intronic regions. The results also revealed that all non-end side integrations of foreign DNA were mediated by short sequence homologies (microhomologies) and that the end side integrations occurred in the presence or absence of microhomologies. In addition, microhomology-mediated mechanisms were also confirmed in four transgenic Arabidopsis thaliana lines. The results indicate that foreign DNA is easily integrated into host gene regions. These results also suggest that the integration of both ends of foreign DNA follows the above-mentioned mechanism in many transgenic/transformed organisms.

SDD17, a delta-15 desaturase from the fungus Saprolegnia can convert arachidonic acid to eicosapentanoic acid in yeast, plant embryos, and mammalian cells. Here, we generated transgenic mice that carried two copies of codon-optimized sdd17 cDNA within a non-coding domain of chromosome 6. RT-PCR analysis revealed that the foreign gene was expressed in the transgenic tissues. Gas chromatography showed that the levels of total unsaturated fatty acids in muscle, liver, and spleen tissues were significantly (p<0.05) increased in transgenic mice compared to non-transgenic mice at 3 or 8 weeks of age. In addition, the serum concentrations of total cholesterol and low-density lipoprotein cholesterol in transgenic females, but not in males, were significantly lower than those in sex-matched non-transgenic mice. These results suggest that endogenous sdd17 expression is beneficial for mammalian health and that its effects on fatty acid profiles may differ between sexes.

CDX2 and liver-intestine (LI)-cadherin are intestine-specific markers and both are physiologically expressed in the small intestine and colon. Recent studies have demonstrated that CDX2 regulates LI-cadherin gene (CDH17) expression in colorectal cancer. The present study investigated the relationship of CDX2 and LI-cadherin expression in gastric cancer. One hundred and nine pairs of tumour and non-cancerous gastric mucosa were collected from gastrectomy specimens. Protein expression levels of CDX2 and LI-cadherin were determined by immunohistochemical staining. Semi-quantitative RT-PCR showed that the mRNAs of both CDX2 and CDH17 were highly expressed in tumour compared with non-cancerous mucosa. Overexpression of CDX2 was significantly associated with CDH17 in gastric adenocarcinoma. Furthermore, the expression of CDX2 and LI-cadherin proteins was strongly coupled in intestinal metaplasia. In conclusion, overexpression of CDH17 is significantly associated with CDX2.

Objective: To observe the clinical effect of Chinese medicine Sansheng Huatan Decoction combined with chemotherapy in treating advanced primary non-small-cell lung cancer and to evaluated the effect of Sansheng Huatan Decoction increasing clinical effect and decreasing toxicity in chemotherapy for non-small-cell lung cancer., Methods: One hundred and sixty patients of advanced primary non-small-cell lung cancer proved by pathological examination were randomized into two groups. The treatment group was treated with Sansheng Huatan Decoction and chemotherapy, and the control group was treated only with chemotherapy. The clinic effect, life quality, natural killer (NK) activities, liver and kidney functions, and blood routine test of the 2 groups were evaluated., Results: The clinical effective rates of the treatment and control groups were 56.7% and 48.2% respectively, and there was no statistic significance (P>0.10). The life quality, NK activities and blood routine test of the treatment group were better than those of the control group., Conclusion: Sansheng Huatan Decoction combined with chemotherapy is a better treatment for non-small-cell lung cancer as compared with chemotherapy.