Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor.

Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study.

BACKGROUND AND AIMS: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. APPROACH AND RESULTS: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. CONCLUSIONS: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.

Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits.

ADNP syndrome, involving the ADNP transcription factor of the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). Although Adnp-haploinsufficient (Adnp-HT) mice display various phenotypic deficits, whether these mice display abnormal synaptic functions remain poorly understood. Here, we report synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIα hyperactivity in Adnp-HT mice. These mice show impaired and inflexible contextual learning and memory, additional to social deficits, long after the juvenile-stage decrease of ADNP protein levels to ~10% of the newborn level. The adult Adnp-HT hippocampus shows hyperphosphorylated CaMKIIα and its substrates, including SynGAP1, and excessive long-term potentiation that is normalized by CaMKIIα inhibition. Therefore, Adnp haploinsufficiency in mice leads to cognitive inflexibility involving CaMKIIα hyperphosphorylation and excessive LTP in adults long after its marked expressional decrease in juveniles.

Characteristics of spinal and bulbar muscular atrophy in South Korea: a cross-sectional study of 157 patients.

Spinal and bulbar muscular atrophy, namely Kennedy disease, is a rare progressive neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene on the X chromosome. We assessed the clinical history, laboratory findings, functional scales and electrophysiological data, as well as the levels of luteinizing hormone, follicle-stimulating hormone and testosterone, in 157 Korean patients with genetically confirmed spinal and bulbar muscular atrophy (mean age at data collection = 56.9 years; range = 33-83 years). Hand tremor was the first symptom noticed by patients at a median age of 35 years, followed by gynaecomastia, orofacial fasciculation, cramps and fatigability in ascending order. Clinical symptoms such as paraesthesia and dysphagia appeared during the later stages of the disease. Cane use during ambulation began at a median age of 62 years. There were statistically significant differences between patients and controls in the results of sensory nerve studies, motor conduction velocity, and distal latencies. Furthermore, among the hormone markers analysed, the level of luteinizing hormone exhibited a negative correlation with the spinal and bulbar muscular atrophy functional rating scale, Korean version. However, among the patients with a disease duration of ≤5 years, the levels of luteinizing hormone showed a significant correlation with assessments using the amyotrophic lateral sclerosis functional rating scale-revised, spinal and bulbar muscular atrophy functional rating scale, Korean version and the 6-minute walk test. In conclusion, our findings provide clinical information from a substantial number of patients with spinal and bulbar muscular atrophy in Korea that accorded with that of patients with this disease worldwide but with updated clinical features.

Efficacy of leuprorelin in spinal and bulbar muscular atrophy: a 3-year observational study.

OBJECTIVE: This study aimed to investigate the long-term effects and functional outcomes of androgen suppression therapy using leuprorelin among Korean patients with spinal and bulbar muscular atrophy (SBMA). METHODS: This observational study enrolled patients with genetically confirmed SBMA who provided informed consent. Leuprorelin was administered via subcutaneous injection every 12 weeks. The primary outcome measure was the change in total Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS) scores. RESULTS: A total of 48 SBMA patients were evaluated in this study. Among them, 39 patients underwent androgen suppression therapy over a 3-year period. The total SBMAFRS score decreased from 41.72 ± 5.55 to 36.74 ± 7.74 (p < 0.001) in patients who completed their treatment. The subgroup with a baseline SBMAFRS score of ≥ 42 had a significantly lower decline in SBMAFRS score than did those with a baseline SBMAFRS score of ≤ 41. We determined that at a baseline, SBMAFRS cutoff value of 41.5 could predict good prognosis, with a corresponding area under the curve of 0.689. CONCLUSION: Despite androgen suppression therapy, all enrolled participants exhibited a decrease in the overall SBMAFRS score. However, those with a baseline SBMAFRS of ≥ 42 showed a mild decrease in scores, indicating a more favorable prognosis. These findings suggest that a higher baseline motor function was a key prognostic indicator in SBMA treatment and that initiating early leuprorelin treatment in patients with high baseline function may lead to good clinical outcomes.

Changes in liver stiffness values assessed using transient elastography in chronic hepatitis B patients treated with tenofovir disoproxil fumarate: a prospective observational study.

BACKGROUND/AIMS: Regression of liver fibrosis during antiviral therapy in chronic hepatitis B (CHB) patients has been demonstrated, but data on the influence of long-term treatment with tenofovir disoproxil fumarate (TDF) on liver stiffness (LS) measured by transient elastography are scarce. We aimed to investigate the changes in LS values during the 144-week TDF therapy in treatment-naïve CHB patients. METHODS: This prospective observational study was conducted from April 2015 to July 2020 at CHA Bundang Medical Center. Laboratory tests and LS measurements were performed at baseline and repeated at weeks 12, 24, 48, 96, and 144. A significant decline in LS was defined as ≥ 30% decrease in LS value at week 96 from baseline. RESULTS: A total of 48 treatment-naïve CHB patients initiating TDF therapy were screened, and 36 patients were included in the final analysis (median age, 46 [interquartile range, 34.5-55.8] years; 19 men [52.8%]). During TDF therapy, the median LS values decreased from 13.8 kPa at baseline to 8.7 kPa, 6.5 kPa, and 6.4 kPa at weeks 48, 96, and 144, respectively (all P < 0.001). At week 96, virological and biochemical responses were achieved in 34 (94.4%) patients and 20 (76.9%) patients, respectively. Moreover, 21 of 36 (58.3%) patients showed a significant decline in LS value. A higher baseline LS value was a single independent predictor for the reduction in LS value at week 96 from baseline (P < 0.001). CONCLUSIONS: During the 144-week TDF therapy, LS values declined significantly in treatment-naïve CHB patients.

De Novo ANCA-Negative Pauci-Immune Crescentic Glomerulonephritis After COVID-19 mRNA Vaccination: A Case Report.

To prevent the spread of the coronavirus disease 2019 (COVID-19) pandemic, vaccines have been authorized for emergency use and implemented worldwide. We present a case of de novo glomerulonephritis (GN) after use of the COVID-19 mRNA vaccine BNT162b2. A 48-year-old man with no relevant medical history was referred for sudden and persistent worsening of renal insufficiency 1.5 months after the second vaccine dose. He had arthralgia and skin rash a week after vaccination. Abdominal pain and diarrhea started 2 weeks later, and he was admitted to the hospital for enteritis treatment. Colonoscopy showed multiple ulcerations and petechiae suggestive of vasculitis in the terminal ileum. After prednisolone therapy, his gastrointestinal symptoms improved, but his renal function continued to deteriorate. Based on kidney biopsy findings and nephrotic-range proteinuria (5,306 mg/24 hours), he was diagnosed with anti-neutrophil cytoplasmic autoantibody (ANCA)-negative pauci-immune crescentic GN (CrGN). He received high-dose steroid pulse therapy and oral cyclophosphamide, and then, gradually underwent steroid tapering, with improvement in proteinuria and renal function over several weeks. Several cases of GN suspected to be related to COVID-19 vaccines have been reported. To our knowledge, this is the first case report of ANCA-negative pauci-immune crescentic CrGN with extrarenal involvement after COVID-19 mRNA vaccination. Our finding expands the spectrum of COVID-19 vaccine-associated GN.

Comparison of the outcomes between sorafenib and lenvatinib as the first-line systemic treatment for HBV-associated hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND/AIM: In a randomized controlled trial, lenvatinib was non-inferior to sorafenib in overall survival (OS) of patients with unresectable hepatocellular carcinoma (uHCC). This study aimed to compare the effects of sorafenib and lenvatinib as first-line systemic therapy against uHCC with real-world data in chronic hepatitis B patients. METHODS: This retrospective single-center study involved 132 patients with HBV-related uHCC. Propensity score matching (PSM) was used to balance the baseline characteristics, including age, sex, serum alpha-fetoprotein levels, Child-Pugh class, tumor size, and tumor stage. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), time to progression (TTP), and tumor response. RESULTS: After PSM, the final analysis included 44 patients treated with lenvatinib and 88 with sorafenib. The OS (7.0 vs 9.2 months, p = 0.070) and PFS (4.6 vs 2.4 months, p = 0.134) were comparable between the two drugs. Multivariable analysis showed that lenvatinib and sorafenib were not independent prognostic factors of OS (adjusted hazard ratio = 1.41, 95% confidence interval = 0.96-2.08, p = 0.077) after adjustment for baseline alpha-fetoprotein levels, total bilirubin levels, alanine aminotransferase level, performance status, tumor stage, and tumor size. However, the lenvatinib group had a significantly prolonged TTP (5.2 vs 2.5 months, p = 0.018) and a higher objective response rate (18.2% vs 4.5%, p = 0.020) and disease control rate (77.3% vs 47.7%, p = 0.001) than the sorafenib group. CONCLUSIONS: Our study demonstrated that lenvatinib had a comparable OS and PFS but longer TTP and better tumor response compared to sorafenib in patients with HBV-related uHCC.

A review of methods to reduce the probability of the airborne spread of COVID-19 in ventilation systems and enclosed spaces.

COVID-19 forced the human population to rethink its way of living. The threat posed by the potential spread of the virus via an airborne transmission mode through ventilation systems in buildings and enclosed spaces has been recognized as a major concern. To mitigate this threat, researchers have explored different technologies and methods that can remove or decrease the concentration of the virus in ventilation systems and enclosed spaces. Although many technologies and methods have already been researched, some are currently available on the market, but their effectiveness and safety concerns have not been fully investigated. To acquire a broader view and collective perspective of the current research and development status, this paper discusses a comprehensive review of various workable technologies and methods to combat airborne viruses, e.g., COVID-19, in ventilation systems and enclosed spaces. These technologies and methods include an increase in ventilation, high-efficiency air filtration, ionization of the air, environmental condition control, ultraviolet germicidal irradiation, non-thermal plasma and reactive oxygen species, filter coatings, chemical disinfectants, and heat inactivation. Research gaps have been identified and discussed, and recommendations for applying such technologies and methods have also been provided in this article.

Pore-Size-Tuned Graphene Oxide Membrane as a Selective Molecular Sieving Layer: Toward Ultraselective Chemiresistors.

Conventional graphene oxide (GO)-based gas membranes, having a narrow pore-size range of less than 0.3 nm, exhibit limited gas molecular permeability because of the kinetic diameters of most volatile organic and sulfur compound (VOCs/VSCs) molecules being larger than 0.3 nm. Here, we employ GO nanosheets (NSs) with a tunable pore-size distribution as a molecular sieving layer on two-dimensional (2D) metal oxide NSs-based gas sensors, i.e., PdO-sensitized WO3 NSs to boost selectivity toward specific gas species. The pore size, surface area, and pore density of GO NSs were simply manipulated by controlling H2O2 concentration. In addition, the pore size-tuned GO NSs were coated on cellulose filtering paper as a free-standing nanoporous membrane. Holey GO membrane showed a highly selective H2S permeability characteristic, exhibiting superior cross-selectivity to CH3COCH3 (0.46 nm), C2H5OH (0.45 nm), and C7H8 (0.59 nm) with larger kinetic diameters compared with H2S (0.36 nm). Such pore-size-tuned GO nanoporous layer is scalable and robust, highlighting a great promise for designing low cost and highly efficient gas-permeable membrane for outstanding selective gas sensing platform.

Innovative Nanosensor for Disease Diagnosis.

As a futuristic diagnosis platform, breath analysis is gaining much attention because it is a noninvasive, simple, and low cost diagnostic method. Very promising clinical applications have been demonstrated for diagnostic purposes by correlation analysis between exhaled breath components and specific diseases. In addition, diverse breath molecules, which serve as biomarkers for specific diseases, are precisely identified by statistical pattern recognition studies. To further improve the accuracy of breath analysis as a diagnostic tool, breath sampling, biomarker sensing, and data analysis should be optimized. In particular, development of high performance breath sensors, which can detect biomarkers at the ppb-level in exhaled breath, is one of the most critical challenges. Due to the presence of numerous interfering gas species in exhaled breath, selective detection of specific biomarkers is also important. This Account focuses on chemiresistive type breath sensors with exceptionally high sensitivity and selectivity that were developed by combining hollow protein templated nanocatalysts with electrospun metal oxide nanostructures. Nanostructures with high surface areas are advantageous in achieving high sensitivity because the sensing signal is dominated by the surface reaction between the sensing layers and the target biomarkers. Furthermore, macroscale pores between one-dimensional (1D) nanostructures can facilitate fast gas diffusion into the sensing layers. To further enhance the selectivity, catalytic functionalization of the 1D metal oxide nanostructure is essential. However, the majority of conventional techniques for catalytic functionalization have failed to achieve a high degree of dispersion of nanoscale catalysts due to aggregation on the surface of the metal oxide, which severely deteriorates the sensing properties by lowering catalytic activity. This issue has led to extensive studies on monolithically dispersed nanoscale particles on metal oxides to maximize the catalytic performances. As a pioneering technique, a bioinspired templating route using apoferritin, that is, a hollow protein cage, has been proposed to obtain nanoscale (∼2 nm) catalyst particles with high dispersity. Nanocatalysts encapsulated by a protein shell were first used in chemiresistive type breath sensors for catalyst functionalization on 1D metal oxide structures. We discuss the robustness and versatility of the apoferrtin templating route for creating highly dispersive catalytic NPs including single components (Au, Pt, Pd, Rh, Ag, Ru, Cu, and La) and bimetallic catalysts (PtY and PtCo), as well as the core-shell structure of Au-Pd (Au-core@Pd-shell). The use of these catalysts is essential to establish high performance sensors arrays for the pattern recognition of biomarkers. In addition, novel multicomponent catalysts provide unprecedented sensitivity and selectivity. With this in mind, we discuss diverse synthetic routes for nanocatalysts using apoferritin and the formation of various catalyst-1D metal oxide composite nanostructures. Furthermore, we discuss detection capability of a simulated biomarker gas using the breath sensor arrays and principal component analysis. Finally, future prospects with the portable breath analysis platform are presented by demonstrating the potential feasibility of real-time and on-site breath analysis using chemiresistive sensors.

WO3 Nanofiber-Based Biomarker Detectors Enabled by Protein-Encapsulated Catalyst Self-Assembled on Polystyrene Colloid Templates.

A novel catalyst functionalization method, based on protein-encapsulated metallic nanoparticles (NPs) and their self-assembly on polystyrene (PS) colloid templates, is used to form catalyst-loaded porous WO3 nanofibers (NFs). The metallic NPs, composed of Au, Pd, or Pt, are encapsulated within a protein cage, i.e., apoferritin, to form unagglomerated monodispersed particles with diameters of less than 5 nm. The catalytic NPs maintain their nanoscale size, even following high-temperature heat-treatment during synthesis, which is attributed to the discrete self-assembly of NPs on PS colloid templates. In addition, the PS templates generate open pores on the electrospun WO3 NFs, facilitating gas molecule transport into the sensing layers and promoting active surface reactions. As a result, the Au and Pd NP-loaded porous WO3 NFs show superior sensitivity toward hydrogen sulfide, as evidenced by responses (R(air)/R(gas)) of 11.1 and 43.5 at 350 °C, respectively. These responses represent 1.8- and 7.1-fold improvements compared to that of dense WO3 NFs (R(air)/R(gas) = 6.1). Moreover, Pt NP-loaded porous WO3 NFs exhibit high acetone sensitivity with response of 28.9. These results demonstrate a novel catalyst loading method, in which small NPs are well-dispersed within the pores of WO3 NFs, that is applicable to high sensitivity breath sensors.

Management of Post-Viral Postural Orthostatic Tachycardia Syndrome With Craniosacral Therapy.

Postural Orthostatic Tachycardia Syndrome (POTS) is a rare disorder of the autonomic nervous system. The number of people afflicted with this dysautonomia has increased dramatically in recent years due to the long-term effects of coronavirus disease (COVID-19); however, it is largely underdiagnosed. This case report is about a patient with post-viral neuropathic POTS. Neuropathic POTS is believed to be due to the damage of small nerve fibers that regulate the constriction of the blood vessels in the limb and abdomen, which leads to interference with vasoconstriction, and therefore causes tachycardia. Current literature emphasizes a treatment that is based on lifestyle modifications, such as increasing water and salt intake, and symptomatic pharmacological treatment. In this case, the 39-year-old male ptient was treated with osteopathic manipulative treatment (OMT), specifically the compression of the fourth ventricle (CV4), which has been associated with the production of hyperparasympathetic and anti-inflammatory effects and, hence, helps overcome the small-fiber neuropathy caused by the viral illness. We found that the CV4 technique led to the successful remission of the patient's symptoms. Therefore, we propose craniosacral therapy as a successful single management modality in patients with POTS.

Prognostic role of computed tomography analysis using deep learning algorithm in patients with chronic hepatitis B viral infection.

BACKGROUND/AIMS: The prediction of clinical outcomes in patients with chronic hepatitis B (CHB) is paramount for effective management. This study aimed to evaluate the prognostic value of computed tomography (CT) analysis using deep learning algorithms in patients with CHB. METHODS: This retrospective study included 2,169 patients with CHB without hepatic decompensation who underwent contrast-enhanced abdominal CT for hepatocellular carcinoma (HCC) surveillance between January 2005 and June 2016. Liver and spleen volumes and body composition measurements including subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle indices were acquired from CT images using deep learning-based fully automated organ segmentation algorithms. We assessed the significant predictors of HCC, hepatic decompensation, diabetes mellitus (DM), and overall survival (OS) using Cox proportional hazard analyses. RESULTS: During a median follow-up period of 103.0 months, HCC (n=134, 6.2%), hepatic decompensation (n=103, 4.7%), DM (n=432, 19.9%), and death (n=120, 5.5%) occurred. According to the multivariate analysis, standardized spleen volume significantly predicted HCC development (hazard ratio [HR]=1.01, P=0.025), along with age, sex, albumin and platelet count. Standardized spleen volume (HR=1.01, P<0.001) and VAT index (HR=0.98, P=0.004) were significantly associated with hepatic decompensation along with age and albumin. Furthermore, VAT index (HR=1.01, P=0.001) and standardized spleen volume (HR=1.01, P=0.001) were significant predictors for DM, along with sex, age, and albumin. SAT index (HR=0.99, P=0.004) was significantly associated with OS, along with age, albumin, and MELD. CONCLUSION: Deep learning-based automatically measured spleen volume, VAT, and SAT indices may provide various prognostic information in patients with CHB.

A multicenter, phase II trial of GC1118, a novel anti-EGFR antibody, for recurrent glioblastoma patients with EGFR amplification.

BACKGROUND: We evaluated the therapeutic efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in recurrent glioblastoma (GBM) patients with EGFR amplification. METHODS: This study was a multicenter, open-label, single-arm phase II trial. Recurrent GBM patients with EGFR amplification were eligible: EGFR amplification was determined using fluorescence in situ hybridization analysis when a sample had both the EGFR/CEP7 ratio of ≥2 and a tight cluster EGFR signal in ≥10% of recorded cells. GC1118 was administered intravenously at a dose of 4 mg/kg once weekly. The primary endpoint was the 6-month progression-free survival rate (PFS6). Next-generation sequencing was performed to investigate the molecular biomarkers related to the response to GC1118. RESULTS: Between April 2018 and December 2020, 21 patients were enrolled in the study and received GC1118 treatment. Eighteen patients were eligible for efficacy analysis. The PFS6 was 5.6% (95% confidence interval, 0.3%-25.8%, Wilson method). The median progression-free survival was 1.7 months (range: 28 days-7.2 months) and median overall survival was 5.7 months (range: 2-22.0 months). GC1118 was well tolerated except skin toxicities. Skin rash was the most frequent adverse event and four patients experienced Grade 3 skin-related toxicity. Genomic analysis revealed that the immune-related signatures were upregulated in patients with tumor regression. CONCLUSION: This study did not meet the primary endpoint (PFS6); however, we found that immune signatures were significantly upregulated in the tumors with regression upon GC1118 therapy, which signifies the potential of immune-mediated antitumor efficacy of GC1118.

Three-Dimensional MoS2/MXene Heterostructure Aerogel for Chemical Gas Sensors with Superior Sensitivity and Stability.

The concept of integrating diverse functional 2D materials into a heterostructure provides platforms for exploring physics that cannot be accessed in a single 2D material. Here, physically mixing two 2D materials, MXene and MoS2, followed by freeze-drying is utilized to successfully fabricate a 3D MoS2/MXene van der Waals heterostructure aerogel. The low-temperature synthetic approach effectively suppresses significant oxidation of the Ti3C2Tx MXene and results in a hierarchical and freestanding 3D heterostructure composed of high-quality MoS2 and MXene nanosheets. Functionalization of MXene with a MoS2 catalytic layer substantially improves sensitivity and long-term stability toward detection of NO2 gas, and computational studies are coupled with experimental results to elucidate that the mechanism behind enhancements in the gas-sensing properties is effective inhibition of HNO2 formation on the MXene surface, due to the presence of MoS2. Overall, this study has a great potential for expansion of applicability to other classes of two-dimensional materials as a general synthesis method, to be applied in future fields of catalysis and electronics.

Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice.

Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.

Treated chronic hepatitis B is a good prognostic factor of diffuse large B-cell lymphoma.

BACKGROUND/AIMS: Chronic hepatitis B (CHB) is a risk factor for non-Hodgkin lymphoma (NHL). Our recent study suggested that antiviral treatment may reduce the incidence of NHL in CHB patients. This study compared the prognoses of hepatitis B virus (HBV)-associated diffuse large B-cell lymphoma (DLBCL) patients receiving antiviral treatment and HBV-unassociated DLBCL patients. METHODS: This study comprised 928 DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at two referral centers in Korea. All patients with CHB received antiviral treatment. Time-to-progression (TTP) and overall survival (OS) were the primary and secondary endpoints, respectively. RESULTS: Among the 928 patients in this study, 82 were hepatitis B surface antigen (HBsAg)-positive (the CHB group) and 846 were HBsAg-negative (the non-CHB group). The median follow-up time was 50.5 months (interquartile range [IQR]=25.6-69.7 months). Multivariable analyses showed longer TTP in the CHB group than the non-CHB group both before inverse probability of treatment weighting (IPTW; adjusted hazard ratio [aHR]=0.49, 95% confidence interval [CI]=0.29-0.82, p=0.007) and after IPTW (aHR=0.42, 95% CI=0.26-0.70, p<0.001). The CHB group also had a longer OS than the non-CHB group both before IPTW (HR=0.55, 95% CI=0.33-0.92, log-rank p=0.02) and after IPTW (HR=0.53, 95% CI=0.32-0.99, log-rank p=0.02). Although liver-related deaths did not occur in the non-CHB group, two deaths occurred in the CHB group due to hepatocellular carcinoma and acute liver failure, respectively. CONCLUSION: Our findings indicate that HBV-associated DLBCL patients receiving antiviral treatment have significantly longer TTP and OS after R-CHOP treatment than HBV-unassociated DLBCL patients.

Transarterial chemoembolization as an alternative to radioembolization is associated with earlier tumor recurrence than in radioembolization-eligible patients.

Introduction: Although transarterial radioembolization (TARE) using yttrium-90 (90Y) is a treatment option for large hepatocellular carcinoma (HCC), a fraction of patients are ineligible for TARE due to high lung shunt fraction (LSF). Methods: We evaluated if treatment with transarterial chemoembolization (TACE), owing to TARE ineligibility was associated with early HCC progression. Consecutive patients with HCC who were initially TARE candidates were included. Patients with vascular invasion or metastasis were excluded. Primary endpoints were time-to-progression (TTP) and overall survival (OS). The secondary endpoint was objective response rate. Results: In total, 175 patients were included: 144 underwent TARE (TARE-eligible group) and 31 underwent TACE due to high LSF (TARE-ineligible group). This latter group had larger tumors (13.8 cm vs. 7.8 cm, P<0.001) and higher MoRAL scores (1,385.8 vs. 413.3, P=0.002) than the TARE-eligible group. After balancing baseline characteristics with an inverse probability of treatment weighting (IPTW), the TARE-ineligible group showed shorter TTP [adjusted hazard ratio (aHR)=2.16, 95% confidence interval (CI)=1.14-4.07, P=0.02] and OS (aHR=1.80, 95% CI=0.85-3.80, P=0.12), although the latter was not statistically significant. The TARE-ineligible group had a significantly lower objective response rate than the TARE-eligible group (9.7% vs. 56.9%, P<0.001). Conclusion: TARE-ineligible patients had larger tumors and higher MoRAL scores than TARE-eligible patients. Treatment with TACE, owing to high LSF, was associated with a shorter TTP even after balancing tumor size and MoRAL scores.