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Background: Youth comprise one-third of the US homeless population. However, little is known about how homelessness affects health care utilization., Objective: Examine associations of homelessness with hospitalization, primary care, and ED visits, varying by race/ethnicity, among Medicaid-enrolled youth., Research Design: A cross-sectional analysis was conducted using California Medicaid claims data on youth beneficiaries with complex needs. We examined the number of hospitalizations, preventable and nonpreventable ED, and primary care visits using a multivariate regression. We further explored the differential associations by race/ethnicity., Results: Approximately 17% of our sampled youth experienced homelessness in 2018 (N=90,202). Compared with their housed counterparts, youth experiencing homelessness had a 1.9 percentage point (pp) higher likelihood of frequent ED visits (95% CI: 1.7-2.2) but a 2.9 pp lower probability of any primary care visits (95% CI: -3.9 to -1.9). Homelessness was associated with 221 more ED visits (95% CI: 182-260), 100 more preventable ED visits (95% CI: 84-116), 19.9 more hospitalizations (95% CI: 12-27), but 56 fewer primary care visits (95% CI: -104 to -7), per 1000 youth. The associations of homelessness with total ED visits, preventable ED visits, and needed and nonpreventable ED visits were all higher among Whites and, particularly, Blacks than for Hispanics and Asians., Conclusions: Medicaid-enrolled youth who experienced homelessness had more overall ED, preventable ED, and hospital visits, but fewer primary care visits than their housed peers. Our results suggest promoting primary care use should be considered among strategies to improve health and reduce costs., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Erythrocytosis is attributed to various clinical and molecular factors. Many cases of JAK2-unmutated erythrocytosis remain undiagnosed. We investigated the characteristics and causes of JAK2-unmutated erythrocytosis., Methods: We assessed the clinical and laboratory results of patients with erythrocytosis without JAK2 mutations and performed targeted next-generation sequencing (NGS) panels for somatic and germline mutations., Results: In total, 117 patients with JAK2-unmutated erythrocytosis were included. The median hemoglobin and hematocrit levels were 17.9 g/dL and 53.4%, respectively. Erythropoietin levels were not below the reference range. Thrombotic events were reported in 17 patients (14.5%). Among JAK2-unmutated patients, 44 had undergone targeted panel sequencing consisting of myeloid neoplasm-related genes, and 16 had one or more reportable variants in ASXL1 (5/44), TET2, CALR, FLT3, and SH2B3 (2/44). Additional testing for germline causes revealed eight variants in seven genes in eight patients, including NF1, BPGM, EPAS1, PIEZO1, RHAG, SH2B3, and VHL genes. One NF1 pathogenic, one BPGM likely pathogenic, and six variants of undetermined significance were detected., Conclusion: Somatic and germline mutations were identified in 36.4% and 33.3 % of the JAK2-unmutated group; most variants had unknown clinical significance. Not all genetic causes have been identified; comprehensive diagnostic approaches are crucial for identifying the cause of erythrocytosis., (© 2024. The Author(s).)

Objective: This study aimed to assess the treatment compliance, patterns, healthcare resource utilization (HCRU), and costs of anti-epilepsy drugs (AEDs) as the first add-on therapy in patients with epilepsy., Methods: We conducted a retrospective population-based cohort study using Korean National Health Insurance claims data from 2016 to 2020. Patients with epilepsy who newly received AED add-on therapy were identified and followed for up to 12 months to evaluate persistence, adherence, treatment patterns, HCRU, and costs., Results: Among 6,746 patients who initiated AED add-on therapy, 65.5% were persistent on their index AED add-on from the index date until the end of the follow-up period, and the mean persistent time on the index add-on was 307.3 ± 92.3 days. A total of 76.8% patients were adherent, with a medication possession ratio (MPR) ≥80%, and the mean MPR was 88.9 ± 25.4%. Persistence and adherence to the index AED add-on were relatively higher among patients prescribed lamotrigine, levetiracetam, oxcarbazepine, and perampanel than those prescribed carbamazepine, topiramate, or valproate. A total of 41.0% of the patients changed their index AED add-on during the follow-up period. The carbamazepine, topiramate, and valproate groups had higher rates of change than the other AED groups. HCRU and costs tended to be lower in the lamotrigine, levetiracetam, oxcarbazepine, and perampanel groups. Furthermore, perampanel showed the lowest HCRU and costs for all-cause cases as well as the lowest length of stay and outpatient visits for epilepsy-related cases., Conclusion: In this population-based study, the use of lamotrigine, levetiracetam, oxcarbazepine, or perampanel as the first add-on therapy in patients with epilepsy contributed to better treatment compliance and lower HCRU and costs than that of carbamazepine, topiramate, or valproate., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Sang Kun Lee reports financial support was provided by IQVIA Korea. Jung-Ae Kim reports financial support was provided by Eisai Korea Inc. Young Eun Lee reports financial support was provided by Eisai Korea Inc. Min Young Kim is an employee of Eisai Korea Inc., (© 2024 The Authors. Published by Elsevier Ltd.)

Dopamine synapses play a crucial role in volitional movement and reward-related behaviors, while dysfunction of dopamine synapses causes various psychiatric and neurological disorders. Despite this significance, the true biological nature of dopamine synapses remains poorly understood. Here, we show that dopamine transmission is strongly correlated with GABA co-transmission across the brain and dopamine synapses are structured and function like GABAergic synapses with marked regional heterogeneity. In addition, GABAergic-like dopamine synapses are clustered on the dendrites, and GABA transmission at dopamine synapses has distinct physiological properties. Interestingly, the knockdown of neuroligin-2, a key postsynaptic protein at GABAergic synapses, unexpectedly does not weaken GABA co-transmission but instead facilitates it at dopamine synapses in the striatal neurons. More importantly, the attenuation of GABA co-transmission precedes deficits in dopaminergic transmission in animal models of Parkinson's disease. Our findings reveal the spatial and functional nature of GABAergic-like dopamine synapses in health and disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aims: The microvascular invasion (MVI) of hepatocellular carcinoma (HCC) involves a wide histological spectrum, and it is unclear whether the degree of MVI correlates with patient prognosis or imaging findings. Here, we evaluate the prognostic value of MVI classification and analyze the radiologic features predictive of MVI., Methods: Using a retrospective cohort of 506 patients with resected solitary HCCs, the histological and imaging features of MVI were reviewed and correlated with clinical data., Results: MVI-positive HCCs invading ≥5 vessels or those with ≥50 invaded tumor cells were significantly associated with decreased overall survival (OS). The 5-year OS, recurrence-free survival (RFS), and beyond Milan criteria RFS rates were significantly poorer in patients with severe MVI compared with those with mild or no MVI. Severe MVI was a significant independent predictive factor for OS (odds ratio [OR], 2.962; p<0.001), RFS (OR, 1.638; p=0.002), and beyond Milan criteria RFS (OR, 2.797; p<0.001) on multivariable analysis. On MRI, non-smooth tumor margins (OR, 2.224; p=0.023) and satellite nodules (OR, 3.264; p<0.001) were independently associated with the severe-MVI group on multivariable analysis. Both non-smooth tumor margins and satellite nodules were associated with worse 5-year OS, RFS, and beyond Milan criteria RFS., Conclusion: Histologic risk classification of MVI according to the number of invaded microvessels and invading carcinoma cells was a valuable predictor of prognosis in HCC patients. Non-smooth tumor margin and satellite nodules were significantly associated with severe MVI and poor prognosis.

Amyloid precursor protein (APP) plays an important role in the pathogenesis of Alzheimer's disease (AD), but the normal function of APP at synapses is poorly understood. We and others have found that APP interacts with Reelin and that each protein is individually important for dendritic spine formation, which is associated with learning and memory, in vitro . However, whether Reelin acts through APP to modulate dendritic spine formation or synaptic function remains unknown. In the present study, we found that Reelin treatment significantly increased dendritic spine density and PSD-95 puncta number in primary hippocampal neurons. An examination of the molecular mechanisms by which Reelin regulates dendritic spinogenesis revealed that Reelin enhanced hippocampal dendritic spine formation in a Ras/ERK/CREB signaling-dependent manner. Interestingly, Reelin did not increase dendritic spine number in primary hippocampal neurons when APP expression was reduced or in vivo in APP knockout (KO) mice. Taken together, our data are the first to demonstrate that Reelin acts cooperatively with APP to modulate dendritic spine formation and suggest that normal APP function is critical for Reelin-mediated dendritic spinogenesis at synapses.

Lactate dehydrogenase (LDH) is a key glycolytic enzyme and biomarker of aggressive cancers. LDHA and LDHB are two main LDH subunits, and both are frequently overexpressed in tumors and essential for tumor growth. A number of LDHA/B small-molecule inhibitors have been developed. Here, we report the discovery of the first LDH proteolysis targeting chimera (PROTAC) degrader, compound 22 (MS6105). 22 potently degraded LDHA in a time- and ubiquitin-proteasome system-dependent manner. Using an unbiased global proteomic study, we confirmed that 22 degraded both LDHA and LDHB significantly. 22 was significantly more potent than the parent LDH inhibitor in suppressing the growth of both quasi-mesenchymal state and epithelial state pancreatic cancer cell lines. Furthermore, 22 was bioavailable in mice through intraperitoneal injection. Overall, 22 could be a valuable chemical tool for the research community to explore pathophysiological functions of LDH in vitro and in vivo.

As genetic factors increase the risk of Alzheimer's disease (AD), the families of dementia patients are at risk of AD. We aimed to evaluate the factors affecting preventive behaviors of AD in family members of AD patients. Using constructed questionnaire based on the Health Belief Model (HBM) theoretical framework, this cross-sectional study investigated factors influencing preventive behaviors of AD such the intention to take AD-preventive medicines, prior experience of taking cognitive function supplements, and AD-preventive lifestyle. 147 family members of AD patients were recruited through the Korea Alzheimer's Caregiver Association. Out of 147 participants, 94.6% had intention to take AD-preventive medicines and 46.3% had experience of taking cognitive function supplements. The intention to take AD-preventive medicines were significantly influenced by self-efficacy (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.03, 1.87) and dementia knowledge (OR 3.42, 95% CI 1.13, 10.39), whereas prior experience of cognitive function supplements was significantly associated with cue to action (OR 1.22, 95% CI 1.07, 1.40). AD-preventive lifestyle was significantly influenced by socio-demographics such as age, sex, and marital status, and the HBM factors such as perceived susceptibility, self-efficacy, and cue to action. Self-efficacy, cue to action, dementia knowledge, and perceived susceptibility were significantly associated with preventive behaviors of AD. Also, family members of dementia patients, who are at risk of dementia due to genetic factors, lifestyles, and environment factors, had high level of AD-preventive lifestyle and strong intention to take AD-preventive medicines. Further research could be suggested to understand AD-preventive behavior and intention to take AD-preventive medicines in general population., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Lupus anticoagulant (LA) is composed of heterogeneous autoantibodies, which have a close association with thrombotic events. Due to its heterogeneity, two methods for increasing sensitivity are recommended for LA. An investigation of the thrombotic risk and anticardiolipin (aCL) and anti-β2-glycoprotein I (aB2GPI) antibody profiles was conducted based on the results of using two parallel methods (dilute Russell viper venom time (dRVVT), silica clotting time (SCT)) in a real world clinical laboratory. Of 5120 patients, 684 patients (13%) were LA positive, and 422 patients (8%) experienced thrombotic events including pregnancy complication. Development of thrombotic events was more likely to occur in patients who were positive for both dRVVT and SCT compared with those who were positive for dRVVT or SCT only. In addition, significantly higher positive rates of aCL and aB2GPI and the persistently positive rate of LA at intervals of 12 weeks or longer were observed in patients who were positive for both dRVVT and SCT compared with those who were positive for dRVVT or SCT only. Considering three laboratory tests (LA, aCL, and aB2GPI), high thrombotic risk was observed for patients with both dRVVT and SCT positive LA results. A report on LA results that divides LA positive into two types (LA-single positive and LA-both positive) may be beneficial to clinicians in detection of high-risk thrombotic patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We aimed to investigate the prevalence and relative contributions of LS and non-LS mutations in patients with endometrial cancer in Korea. We retrospectively reviewed the medical records of 204 patients diagnosed with endometrial cancer who underwent a germline next generation sequencing multigene panel test covering MLH1, MSH2, MSH6, PMS2, and EPCAM at three tertiary centers. Thirty patients (14.7%) with pathogenic mutations (12 MLH1; 6 MSH2; 10 MSH6; 2 PMS2) and 20 patients (9.8%) with 22 unclassified variants (8 MLH1; 8 MSH2; 2 MSH6; 3 PMS2; 1 EPCAM) were identified. After excluding four close relatives of a proband, the prevalence of LS was 13.0% (26/200). Patients with LS were more likely than those with sporadic cancer to be younger at diagnosis (48 vs. 53 years, p = 0.045) and meet the Amsterdam II criteria (66.7 vs. 3.5%, p < 0.001). Non-endometrioid histology was more prevalent in patients with MSH6 or PMS2 mutations (41.7%) than those with MLH1 or MSH2 mutations (5.6%, p = 0.026). In this pre-selected cohort of endometrial cancer patients who underwent next generation sequencing, the prevalence of LS was 13%, thus supporting the use of gene panel testing for endometrial cancer patients.

Objective: To investigate the clinical feasibility of attenuation imaging of the hepatic parenchyma in healthy dogs, identify technical factors that influence measured attenuation coefficients, and determine intraobserver repeatability of measurements., Animals: 10 healthy Beagles., Procedures: Attenuation coefficients were calculated for various measurement sites (left vs central division of the liver), scanning planes (transverse vs sagittal plane), scanning depths (10 to 20 mm vs 20 to 30 mm), scanning approaches (intercostal vs subcostal approach), and breathing conditions (free breathing vs breath holding at end expiration). Intraoperator intraday and interday reliability was assessed by computing intraclass correlation coefficients., Results: Attenuation coefficients were not influenced significantly by scanning plane (P = .120 to 1.000), measurement site (P = .292 to .848), or breathing condition (P = .166). However, coefficients were significantly (P < .01) less with deeper scanning depths and significantly (P < .05) more for the subcostal approach than the intercostal approach. The intraday and interday intraclass correlation coefficients showed good repeatability (0.799 and 0.771, respectively), regardless of the scanning plane and measurement site. Scanning the central division of the liver with the right intercostal approach at a depth of 10 to 20 mm from the liver capsule yielded good reliability., Clinical Relevance: Attenuation imaging was a feasible technique for evaluating the hepatic parenchyma in healthy dogs with good repeatability. Measured attenuation coefficients were not affected by the scanning plane, measurement site, or breathing condition.

Lymph node fibroblastic reticular cells (LN-FRCs) provide functional structure to LNs and play important roles in interactions between T cells and antigen-presenting cells. However, the direct impact of LN-FRCs on naive CD4+ T cell differentiation has not been explored. Here, we show that T cell zone FRCs of LNs (LN-TRCs) express CD25, the α chain of the IL-2 receptor heterotrimer. Moreover, LN-TRCs trans-present IL-2 to naive CD4+ T cells through CD25, thereby facilitating early IL-2-mediated signaling. CD25-deficient LN-TRCs exhibit attenuated STAT5 phosphorylation in naive CD4+ T cells during T cell differentiation, promoting T helper 17 (Th17) cell differentiation and Th17 response-related gene expression. In experimental autoimmune disease models, disease severity was elevated in mice lacking CD25 in LN-TRCs. Therefore, our results suggest that CD25 expression on LN-TRCs regulates CD4+ T cell differentiation by modulating early IL-2 signaling of neighboring, naive CD4+ T cells, influencing the overall properties of immune responses., (© 2022 Kim et al.)

Introduction: Small-duct (SD) and large-duct (LD) subtypes of cholangiocarcinoma have been investigated for their prognostic factors. This study aimed to evaluate the diagnostic value of liver magnetic resonance imaging (MRI) in differentiating SD and LD types of intrahepatic cholangiocarcinoma (iCCA) and its prognostic value in predicting survival outcomes., Methods: One hundred forty patients with surgically confirmed iCCAs (93 SD type and 47 LD type) who had available preoperative gadoxetic acid-enhanced liver MR images were retrospectively included. MRI features suggestive of the LD type over the SD type were analyzed using multivariate logistic analyses. Postoperative recurrence-free survival (RFS) and overall survival (OS) for 107 patients with available survival data were compared according to MRI features., Results: MRI features suggestive of the LD type included infiltrative contour (odds ratio [OR] 14.2, 95% confidence interval [CI]: 2.5-81.7, p = 0.003), diffuse biliary dilatation (OR 9.7, 95% CI: 1.2-76.9, p = 0.032), no arterial phase hyperenhancement (OR 17.8, 95% CI: 2.7-118.6, p = 0.003), and vascular invasion (OR 4.5, 95% CI: 1.3-15.4, p = 0.018). When two or more features were combined, sensitivity was 59.6% (28/47), and specificity was 95.7% (89/93) in discriminating the LD type. RFS/OS was significantly shorter in patients with two or more MRI features, compared to those with none or one (310 days vs. 529 days, p = 0.011/964 days vs. 2,023 days, p = 0.010)., Conclusions: Preoperative liver MRI may help predict the pathological subtype of iCCAs as either the SD type or LD type, allowing preoperative identification of patients with poorer survival outcomes., Competing Interests: Corresponding author, Jeong Min Lee, is an editorial board member of Liver Cancer. The other authors have no conflicts of interest to declare., (Copyright © 2022 by S. Karger AG, Basel.)

Plasma cell leukemia (PCL) is clinically and genetically distinct from multiple myeloma (MM), despite controversies regarding the disease definition. To determine the distinct features of PCL, the genetic property of primary PCL (pPCL) was compared with that of secondary PCL (sPCL) and MM. In patients with pPCL, Eighty-nine non-synonymous mutations were observed in 68 genes. The most frequently mutated genes were TP53 , TSC2 , and TYK2. In comparison with genetic abnormalities of sPCL and MM, 45 genes were present only in pPCL while 28 genes were only in sPCL and 22 genes only in MM. Among the common genes between pPCL and MM, a higher prevalence of TP53 was observed in pPCL, compared to MM ( p  < 0.05), while similar, compared to sPCL ( p =  0.64). In summary, pPCL patients showed a higher level of genetic heterogeneity and distinctive genetic signature in their mutational profile compared to patients with MM and sPCL.

Novel CAR T cells targeting mesothelin (MSLN) expressed on pancreatic cancer cells were developed to overcome the limit of the clinical efficacy of CAR T cell therapy for pancreatic cancer patients. Optimal single-chain variable fragments (scFv) binding to MSLN were selected based on the binding activity and the functional effectiveness of various scFv containing CAR-expressing T cells. Engineered MSLN CAR T cells showed successful anti-tumor activity specific to MSLN expression level. Furthermore, MSLN CAR T cells were evaluated for the anti-cancer efficacy in orthotopic mouse models bearing pancreatic cancer cells, MIA Paca-2, MSLN-overexpressed MIA Paca-2 or endogenously MSLN-expressing AsPC-1. Mice were randomized into control, mock treated, MS501 BBz treated, MS501 28z treated or MS501 28BBz treated group. Mice were monitored by weekly IVIS imaging and tumors were harvested and analyzed by immunohistochemical analyses. MSLN CAR T cells produced the therapeutic effect in orthotopic animal models with complete remission in significant number of mice. Histopathological analysis indicated that CD4+ and CD8+ MSLN CAR T cells infiltrated pancreatic tumor tissue and led to cancer cell eradication. Our results demonstrated the anti-tumor efficacy of MSLN CAR T cell therapy against pancreatic cancer, suggesting its therapeutic potential., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Ethnopharmacological Relevance: Vernicia fordii (Hemsl.) Airy Shaw (V. fordii) is also known as the tung tree and its leaves and fruit are used as an oriental treatment for dyspepsia, edema, and skin diseases, which are known as diabetic complications., Aim of the Study: In this study, we aimed to investigate the methanolic extract (VF5) of the leaves of V. fordii as an insulin secretagogue and its probable mechanism and verify the effect in HFD-fed mice., Materials and Methods: The insulin secretagogue activity of different doses of VF5 (0.1, 0.3 and 1.0 μg/ml) was assessed using in vitro insulin secretion assay and confirmed the anti-diabetic effect in mice fed HFD for 4 weeks with different doses of VF5 (10, 20 and 50 mg/kg oral) for another 6 weeks. Glbenclamide (30 mg/kg, oral) was used as positive control drug. The possible mechanisms were evaluated by using Gö6983 (10 μM), U73122 (10 μM) and nifedipine (10 μM). The major constituents of VF5 were analyzed by UPLC-QToF-MS and 1 H and 13 C NMR spectroscopy., Results: UPLC-QToF-MS and NMR spectroscopy analysis indicated that one of the main active components of VF5 was tigliane-diterpene esters. VF5 functioned as an insulin secretagogue and enhanced mitochondria respiration and insulin homeostasis. We confirmed that VF5 preserved the β-cell and reduced the β-cell expansion which caused by metabolic stress under HFD. The antidiabetic role of VF5 in HFD fed mice was assessed by glucose tolerance test (GTT) and insulin tolerance test (ITT), fasting plasma insulin level, fasting blood glucose level, AKT signal in peripheral tissue in the absence of toxic effects. Mechanistically, insulinotropic effect of VF5 was mediated by activation of PKCα via intracellular Ca 2+ influx and enhanced mitochondria function., Conclusion: VF5 exhibits potent insulin secretagogue function and improves insulin sensitivity and protection of pancreatic β-cells from metabolic stress without toxicity. Taken together, our study suggests that VF5 could be potentially used for treating diabetes and metabolic diseases through improving β-cell function., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Preoperative locoregional treatment (LRT) for hepatocellular carcinoma (HCC) often induces intratumoral necrosis without affecting the overall tumor size, and residual viable tumor size (VTS) on imaging is an important clinical parameter for assessing post-treatment response. However, for surgical specimens, it is unclear whether the VTS would be more relevant to prognosis compared to total tumor size (TTS)., Methods: A total of 142 surgically resected solitary HCC cases were retrospectively reviewed. The TTS and VTS were assessed by applying the modified Response Evaluation Criteria in Solid Tumors method to the resected specimens, and correlated with the clinicopathological features and survival., Results: As applying VTS, 13/142 cases (9.2%) were down-staged to ypT1a. Although the survival analysis results for overall survival according to TTS or VTS were similar, VTS was superior to predict disease-free survival (DFS; p = .023) compared to TTS (p = .08). In addition, multivariate analysis demonstrated VTS > 2 cm to be an independent predictive factor for decreased DFS (p = .001). In the subpopulation of patients with LRT (n = 54), DFS in HCCs with TTS or VTS > 2 cm were significantly shorter than those with TTS or VTS ≤ 2 cm (p = .047 and p = .001, respectively). Interestingly, HCCs with TTS > 2 cm but down-staged to VTS ≤ 2 cm after preoperative LRT had similar survival to those with TTS ≤ 2 cm., Conclusions: Although the prognostic impact of tumor size was similar regardless of whether TTS or VTS was applied, reporting VTS may help to increase the number of candidates for surgery in HCC patients with preoperative LRT.

Background: To investigate the prognostic value of gene variants and copy number variations (CNVs) in patients with newly diagnosed multiple myeloma (NDMM), an integrative genomic analysis was performed., Methods: Sixty-seven patients with NDMM exhibiting more than 60% plasma cells in the bone marrow aspirate were enrolled in the study. Whole-exome sequencing was conducted on bone marrow nucleated cells. Mutation and CNV analyses were performed using the CNVkit and Nexus Copy Number software. In addition, karyotype and fluorescent in situ hybridization were utilized for the integrated analysis., Results: Eighty-three driver gene mutations were detected in 63 patients with NDMM. The median number of mutations per patient was 2.0 (95% confidence interval [CI] = 2.0-3.0, range = 0-8). MAML2 and BHLHE41 mutations were associated with decreased survival. CNVs were detected in 56 patients (72.7%; 56/67). The median number of CNVs per patient was 6.0 (95% CI = 5.7-7.0; range = 0-16). Among the CNVs, 1q gain, 6p gain, 6q loss, 8p loss, and 13q loss were associated with decreased survival. Additionally, 1q gain and 6p gain were independent adverse prognostic factors. Increased numbers of CNVs and driver gene mutations were associated with poor clinical outcomes. Cluster analysis revealed that patients with the highest number of driver mutations along with 1q gain, 6p gain, and 13q loss exhibited the poorest prognosis., Conclusions: In addition to the known prognostic factors, the integrated analysis of genetic variations and CNVs could contribute to prognostic stratification of patients with NDMM., Competing Interests: The authors have declared that no competing interests exist.

Purpose: This study investigated the efficacy and safety of avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with advanced hepatocellular carcinoma previously treated with sorafenib (NCT03389126)., Patients and Methods: This is a single-arm, single center, phase II trial. Patients with Child-Pugh A score who had at least one measurable lesion were enrolled. Intravenous avelumab 10 mg/kg every 2 weeks was given until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to RECIST v1.1. Secondary endpoints included time to progression (TTP), overall survival (OS), disease control rate (DCR), and safety., Results: A total of 30 patients were enrolled. After a median follow-up of 13.9 months, 27 progression events and 20 death events occurred. There was no complete response, three (10.0%) partial responses, and 19 patients (63.3%) with stable disease. ORR was 10.0% and DCR was 73.3%. The median TTP and OS was 4.4 and 14.2 months, respectively. PD-L1 expression did not affect avelumab response. Prior duration of sorafenib treatment, when dichotomized by the median 2.7 months, was associated with treatment outcome. TTP (6.5 vs. 1.8 months, P = 0.007) and OS (19.0 vs. 7.8 months, P = 0.006) were superior in patients with longer sorafenib duration. There was tendency of higher ORR (20.0% vs. 0.0%, P = 0.22) in those with longer sorafenib duration. Avelumab was well tolerated with seven grade 3 adverse events and no grade 4 adverse events., Conclusions: Avelumab showed moderate efficacy and was well tolerated in advanced hepatocellular carcinoma previously treated with sorafenib., (©2020 American Association for Cancer Research.)

Nuclear factor E2-related factor2 (Nrf2) activation is associated with both cytoprotective effects and malignant behavior of cancer cells. This study aimed to evaluate the clinicopathological implications of the expression of Nrf2, pNrf2, and its regulator Keap1 in human hepatocellular carcinomas (HCCs). Tissue microarrays consisting of 285 surgically resected HCCs were immunohistochemically stained with pNrf2, Nrf2, Keap1, stemness-related markers (keratin 19 (K19), epithelial cell adhesion molecule (EpCAM)), carbonic anhydrase IX (CAIX), epithelial-mesenchymal transition (EMT)-related markers (ezrin, uPAR, E-cadherin), and p53, and the results were correlated with the clinicopathological features. pNrf2 expression was significantly associated with increased proliferative activity, as well as EpCAM, ezrin, p53, and CAIX expression and E-cadherin loss ( p < 0.05, all). Strong cytoplasmic Nrf2 expression was associated with CAIX and ezrin expression ( p < 0.05, both). Keap1 was associated with increased proliferative activity, portal vein invasion, EMT-related markers, and p53 expression in CAIX-negative HCCs ( p < 0.05, all). Both pNrf2 and cytoplasmic Nrf2 expression were associated with decreased overall survival ( p < 0.05, both), and cytoplasmic Nrf2 expression was an independent predictor of decreased overall survival on multivariate analysis (hazard ratio 4.15, p < 0.001). Both pNrf2 and cytoplasmic Nrf2 expression were associated with poor survival and aggressive behavior of HCC. In addition, Keap1 expression was also associated with aggressive HCC behavior in CAIX-negative HCCs, suggesting that Keap1 expression should be interpreted in the context of hypoxia status.

Background: Light chain proximal tubulopathy (LCPT) is a rare paraproteinemic renal disease that has been mostly reported in Western patients. LCPT is characterized by the accumulation of immunoglobulin (Ig)-light chain (LC) in the proximal tubule. Immunohistochemical staining for Ig-LC has not been investigated in the context of LCPT. We reported the clinicopathological characteristics and Ig-LC immunoexpression of patients with LCPT for the first time in Korea., Methods: We reviewed the clinicopathological findings of 5 Korean patients diagnosed with LCPT between 2016 and 2018. In addition, immunohistochemical staining for κ-LC and λ-LC was conducted on paraffin-embedded tissues., Results: The median age was 63 years, and the male-to-female ratio was 3:2. The primary renal manifestations were either azotemia or tubular proteinuria. All patients were diagnosed with multiple myeloma with monoclonal κ-LC (#1-2) or λ-LC (#3-5) in the serum and urine. Kidney biopsies revealed diverse and subtle alterations of the proximal tubule, including crystallization, vacuolization, and/or swelling. Electron microscopy revealed crystals in patients #1-2 and non-crystalline particles within numerous/large/dysmorphic lysosomes in patients #3-5. Ig-LC restriction was demonstrated in the proximal tubule as κ-type in patients #1-2 and as λ-type in patients #3-5 by immunohistochemistry and immunofluorescence. Immunohistochemical staining showed diffuse positivity to κ- and λ-LC, although immunofluorescent staining for κ-LC was focal and weak. LCPT has diverse clinicopathological characteristics and subtle morphological alterations, which necessitate ancillary tests for diagnosis., Conclusions: We introduced immunohistochemical staining for Ig-LC as a useful tool for the diagnosis of LCPT, especially in the case of κ-type crystals.

Background: Hyperchromatic crowed groups (HCGs) are defined as three-dimensional aggregates of crowded cells with hyperchromatic nuclei, and are frequently encountered in cervicovaginal liquid-based cytology (LBC). Here, we aimed to examine the prevalence of HCGs in cervicovaginal LBC and the cytomorphological characteristics of various epithelial cell clusters presenting as HCGs., Methods: We first examined the prevalence of HCGs in a "routine cohort" of LBC cytology (n=331), consisting of all cervicovaginal LBCs accessioned over 3 days from outpatient clinics (n=179) and the screening population (n=152). Then we examined a second "high-grade epithelial cell abnormalities (H-ECA) cohort" (n=69) of LBCs diagnosed as high-grade squamous intraepithelial lesion (HSIL), squamous cell carcinoma (SCC), or adenocarcinoma during 1 year., Results: HCGs was observed in 34.4% of the routine cohort and were significantly more frequent in the epithelial cell abnormality category compared to the non-neoplastic category (p=.003). The majority of HCGs represented atrophy (70%). Of the 69 histologically confirmed H-ECA cases, all contained HCGs. The majority of cases were HSIL (62%), followed by SCC (16%). Individually scattered neoplastic cells outside the HCGs were significantly more frequent in SCCs compared to glandular neoplasia (p=.002). Despite the obscuring thick nature of the HCGs, examining the edges and the different focal planes of the HCGs and the background were helpful in defining the nature of the HCGs., Conclusions: HCGs were frequently observed in cervicovaginal LBC and were mostly non-neoplastic; however, neoplastic HCGs were mostly high-grade lesions. Being aware of the cytomorphological features of different HCGs is important in order to avoid potential false-negative cytology interpretation.

Purpose: 2-Deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) accumulation in inflammatory lesions can confound the diagnosis of cancer. In this study, we investigated [ 18 F]FDG accumulation and efflux in relation to the genes and proteins involved in glucose metabolism in murine inflammation and cancer models., Procedures: [ 18 F]FDG accumulation and [ 18 F]FDG efflux were measured in cancer cells (breast cancer, glioma, thyroid cancer, and hepatoma cells) and RAW 264.7 cells (macrophages) activated with lipopolysaccharide (LPS). The levels of mRNA expression were measured by real-time quantitative PCR (qPCR). The expression of glucose metabolism-related proteins was detected by western blotting. Dynamic [ 18 F]FDG positron emission tomography-computed tomography (PET/CT) images were acquired for 2 h in tumor-bearing BALB/c nude mice and inflammatory mice induced by turpentine oil., Results: [ 18 F]FDG accumulation in MDA-MB-231 (breast cancer) increased with time, but that of HepG2 (hepatoma) reached a constant level after 120 min. [ 18 F]FDG efflux in HepG2 was faster than that in MDA-MB-231. HepG2 strongly expressed glucose-6-phosphatase (G6Pase) compared with MDA-MB-231. [ 18 F]FDG accumulation increased with time, and [ 18 F]FDG efflux accelerated after the activation of RAW 264.7 cells. The expression levels of G6Pase, glucose transporter1 and glucose transporter3 (GLUT1 and GLUT3), and hexokinase II (HK II) increased after the activation of RAW 264.7 cells. [ 18 F]FDG efflux in activated macrophages was faster than that in MDA-MB-231 cancer cells. MDA-MB-231 strongly expressed HK II protein compared with the activated RAW 264.7. In murine models, [ 18 F]FDG accumulation in MDA-MB-231 cancer and inflammatory lesions increased with time, but that in HepG2 tumor increased until 20-30 min (SUVmeans ± SD (tumor/muscle), 3.0 ± 1.3) and then decreased (2.1 ± 0.9 at 110-120 min)., Conclusions: There was no difference in the pattern of [ 18 F]FDG accumulation with time in MDA-MB-231 tumors and inflammatory lesions. We found that [ 18 F]FDG efflux accelerated in activated macrophages reflecting increased G6Pase expression after activation and lower expression of HK II protein than that in MDA-MB-231 cancer cells.

Objective: To evaluate the diagnostic performance of the normalized local variance (NLV) ultrasound technique in the assessment of hepatic steatosis, and to identify the factors that influence the NLV value using histopathological examination as the reference standard., Materials and Methods: Forty male Sprague-Dawley rats were fed a methionine-choline-deficient diet for variable periods (0, 2, 4, 6, 8, 10, or 12 days or 2, 3, or 4 weeks; four rats per group). At the end of each diet duration, magnetic resonance spectroscopy (MRS) and NLV examination were performed. Thereafter, the rats were sacrificed and their livers were histopathologically evaluated. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic capability of the NLV value in the detection of varying degrees of hepatic steatosis. Univariate and multivariate linear regressions were used to determine the factors associated with the NLV value., Results: The areas under the ROC curve for the detection of mild, moderate, and severe hepatic steatosis were 0.953, 0.896, and 0.735, respectively. The NLV value showed comparable diagnostic performance to that of MRS in the detection of ≥ mild or ≥ moderate hepatic steatosis. Multivariate linear regression analysis revealed that the degree of hepatic steatosis was the only significant factor affecting the NLV value ( p < 0.001)., Conclusion: The NLV value of ultrasound demonstrated satisfactory diagnostic performance in the assessment of varying degrees of hepatic steatosis. The degree of hepatic steatosis was the only significant factor that affected the NLV value., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2019 The Korean Society of Radiology.)

There has been great interest in the idea that time, number, and space share a common magnitude system. However, only a handful of studies examined bidirectional interaction between time and number and the results varied depending on the specifics of the methods and stimulus properties of each study. The present study investigated bidirectional interaction between time and number using estimation tasks. We used duration (Experiment 1) and numerosity (Experiment 2) estimation tasks to investigate the effect of numerosity-on-duration and duration-on-numerosity estimation. The results from the two experiments demonstrated that numerosity influences duration processing but not vice versa; that is, there was unidirectional interaction between numerosity and time. The duration of stimulus presentation was overestimated for stimuli larger in (task-irrelevant) numerosity. Possible mechanisms underlying the unidirectional interaction between time and number are discussed., (© 2018 Scandinavian Psychological Associations and John Wiley & Sons Ltd.)

Premature ovarian failure (POF) is a major side effect of chemotherapy in young cancer patients. To develop pharmaceutical agents for preserving fertility, it is necessary to understand the mechanisms responsible for chemotherapy-induced follicle loss. Here, we show that treatment with cisplatin, a widely used anticancer drug, depleted the dormant follicle pool in mouse ovaries by excessive activation of the primordial follicles, without inducing follicular apoptosis. Moreover, we show that co-treatment with the antioxidant melatonin prevented cisplatin-induced disruption of the follicle reserve. We quantified the various stages of growing follicles, including primordial, primary, secondary, and antral, to demonstrate that cisplatin treatment alone significantly decreased, whereas melatonin co-treatment preserved, the number of primordial follicles in the ovary. Importantly, analysis of the PTEN/AKT/FOXO3a pathway demonstrated that melatonin significantly decreased the cisplatin-mediated inhibitory phosphorylation of PTEN, a key negative regulator of dormant follicle activation. Moreover, melatonin prevented the cisplatin-induced activating phosphorylation of AKT, GSK3β, and FOXO3a, all of which trigger follicle activation. Additionally, we show that melatonin inhibited the cisplatin-induced inhibitory phosphorylation and nuclear export of FOXO3a, which is required in the nucleus to maintain dormancy of the primordial follicles. These findings demonstrate that melatonin attenuates cisplatin-induced follicle loss by preventing the phosphorylation of PTEN/AKT/FOXO3a pathway members; thus, melatonin is a potential therapeutic agent for ovarian protection and fertility preservation during chemotherapy in female cancer patients., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Spermatogenesis- and oogenesis-specific helix-loop-helix transcription factor 2 (SOHLH2) is exclusively expressed in germ cells of the gonads. Previous studies show that SOHLH2 is critical for spermatogenesis in mouse. However, the regulatory mechanism of SOHLH2 during early spermatogenesis is poorly understood. In the present study, we analyzed the gene expression profile of the Sohlh2-deficient testis and examined the role of SOHLH2 during spermatogenesis. We found 513 genes increased in abundance, while 492 genes decreased in abundance in 14-day-old Sohlh2-deficient mouse testes compared to wildtype mice. Gene ontology analysis revealed that Sohlh2 disruption effects the relative abundance of various meiotic genes during early spermatogenesis, including Spo11, Dmc1, Msh4, Prdm9, Sycp1, Sycp2, Sycp3, Hormad1, and Hormad2. Western blot analysis and immunostaining showed that SYCP3, a component of synaptonemal complex, was significantly less abundant in Sohlh2-deficient spermatocytes. We observed a lack of synaptonemal complex formation during meiosis in Sohlh2-deficient spermatocytes. Furthermore, we found that SOHLH2 interacted with two E-boxes on the mouse Sycp1 promoter and Sycp1 promoter activity increased with ectopically expressed SOHLH2. Taken together, our data suggest that SOHLH2 is critical for the formation of synaptonemal complexes via its regulation of Sycp1 expression during mouse spermatogonial differentiation.

Background: Ras dexamethasone-induced protein (RASD1) is a member of Ras superfamily of small GTPases. RASD1 regulates various signaling pathways involved in iron homeostasis, growth hormone secretion, and circadian rhythm. However, RASD1 function in oocyte remains unknown., Methods: Using immunohistochemistry, immunofluorescence, and quantitative real-time RT-PCR, RASD1 expression in mouse ovary and RASD1 role in oocyte maturation-related gene expression, spindle formation, and chromosome alignment were analyzed. RNAi microinjection and time-lapse video microscopy were used to examine the effect of Rasd1 knockdown on oocyte maturation., Results: RASD1 was highly detected in oocytes transitioning from primordial to secondary follicles. Rasd1 was highly expressed in germinal vesicle (GV), during GV breakdown, and in metaphase I (MI) stage as oocytes mature, and its expression was significantly downregulated in MII stage. With knockdown of Rasd1, maturation in GV oocytes was arrested at MI stage, showing disrupted meiotic spindling and chromosomal misalignment. In addition, Obox4 and Arp2/3, engaged in MI-MII transition and cytokinesis, respectively, were misregulated in GV oocytes by Rasd1 knockdown., Conclusion: These findings suggest that RASD1 is a novel factor in MI-MII oocyte transition and may be involved in regulating the progression of cytokinesis and spindle formation, controlling related signaling pathways during oocyte maturation., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

The main causes of early hearing deficit in circling mice have been reported to be early degeneration of the organ of Corti and deterioration of spiral ganglion neurons. As an exact cochlear pathology is essential to explain our previous results regarding the auditory brainstem circuits of developing circling mice, we reinvestigated the cochlear pathology in developing circling mice (14, 22, and 38 days old). It has been reported that the organ of Corti in circling mice completely degenerates as early as postnatal day (P) 21 and that circling mice are deaf by P18. Although we confirmed that circling mice were deaf at P15 and that hair bundles of outer hair cells were defective at P18, complete degeneration of the organ of Corti was not observed by P38 in circling mice. At P22, the type I cell-like spiral ganglion cell density in circling mice was reduced to 78% of that of control mice (ICR mice), but it was not significantly different from that of other control mice (heterozygous (+/cir) mice, littermates of circling mice) that could hear at P22. Our data suggest that other factors, such as absence of neurotransmitter release from inner hair cells, should be considered to explain the early hearing deficit observed at P15 in circling mice., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Although the endovascular aneurysm repair trial 2 (EVAR-2) demonstrated no benefit of EVAR in high-risk (HR) patients, EVAR is still performed widely in this patient cohort. This study compares the midterm outcomes after EVAR in HR patients with those in normal-risk (NR) patients. In turn, these data are compared with the EVAR-2 data., Methods: A retrospective review from January 2006 to December 2013 identified 247 patients (75 HR [30.4%], 172 NR [69.6%]) who underwent elective EVAR for infrarenal aortic aneurysm in an academic tertiary institution and its affiliated Veterans Administration hospital. The same HR criteria used in the EVAR-2 trial were employed. Overall survival, graft-related complications, and reintervention rates were estimated by the Kaplan-Meier method. HR group outcomes were compared with the EVAR-2 data., Results: HR patients had a larger abdominal aortic aneurysm size and had a higher prevalence of cardiac disease (P < .01), chronic obstructive pulmonary disease (P = .02), renal insufficiency (P < .01), and cancer (P < .01). Use of aspirin (63% HR vs 66% NR; P = .6), statin (83% HR vs 72% NR; P = .2), and beta-blockers (71% HR vs 60% NR; P = .2) was similar; in the EVAR-2 trial, the corresponding use of these medications was 58%, 42%, and not available, respectively. Perioperative mortality (0% HR vs 1.2% NR; P = 1.0) and early complication rates (4% HR vs 6% NR; P = .8) were similar. In contrast, perioperative mortality in the EVAR-2 trial was 9%. At a mean follow-up of 3 years, the incidence rates of delayed secondary interventions for aneurysm- or graft-related complications were 7% for HR patients and 10% for NR patients (P = .5). The 1-, 2-, and 4-year survival rates in HR patients (85%, 77%, 65%) were lower than those in NR patients (97%, 97%, 93%; P < .001), but this was more favorable compared with a 36% 4-year survival in the EVAR-2 trial. No difference was seen in long-term reintervention-free survival in HR and NR patients (P = .8). Backward stepwise logistic regression analysis identified five prognostic indicators for post-EVAR death: age, chronic kidney disease stages 4 and 5, congestive heart failure, home oxygen use, and current cancer therapy., Conclusions: EVAR can be performed in patients unfit for open surgical repair with excellent early survival and long-term durability. These outcomes in the HR group compare more favorably to the EVAR-2 trial data. However, not all HR patients for open surgical repair derive the benefit from EVAR. The decision to proceed with EVAR in HR patients should be individualized, depending on the number and severity of risk factors., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Vesicular glutamate transporter 3 (VGLUT3) plays a major role in hearing, and mice lacking the VGLUT3 are congenitally deaf due to absence of glutamate release at the inner hair cell afferent synapses. However, whether VGLUT3 is expressed normally in the cochleae of developing circling mice (homozygous (cir/cir) mice), the animal model for human deafness type DFNB6, has not been established. In this study, we investigated the developmental expression of VGLUT3 in cochlear inner hair cells (IHCs) and spiral ganglion cells (SGCs) of homozygous (cir/cir) mice from postnatal day (P)1 to P14 using immunofluorescence (IF) staining and Western blot. VGLUT3 immunoreactivity (IR) and protein expression increased progressively with age in homozygous (cir/cir) and control mice (heterozygous (+/cir) mice and ICR mice). The rank order of VGLUT3 IR in IHCs and SGCs in P14 mice was homozygous (cir/cir) mice = heterozygous (+/cir) mice > ICR mice. The rank order of total protein expression was homozygous (cir/cir) mice > heterozygous (+/cir) mice = ICR mice at P14. IF staining and Western blot analysis indicated that developmental VGLUT3 expression in cochleae was most prominent in homozygous (cir/cir) mice. The possible contribution of VGLUT3 upregulation in the cochlear degeneration is discussed., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Based on exposure frequency and intrinsic toxicity, lead (Pb) ranks one of the highest priority toxic materials. Continuous regulation of environmental Pb exposure has contributed to dramatically diminished exposure levels of Pb, for example, blood level of Pb. However, the safety level of Pb is not established, as low-level exposure to Pb still shows severe toxicity in high susceptible population and late onset of some diseases from early exposure. In the present study, we focused on food-borne Pb exposure and found broad variations in Pb exposure levels via food among countries. In addition, there are genetic or ethnical variations in Pb-targeted and protective genes. Moreover, various epigenetic alterations were induced by Pb poisoning. Therefore, we suggest a systemic approach including governmental (public) and individual prevention from Pb exposure with continuous biological monitoring and genetic or epigenetic consideration.

New degradable cationic ester lipids with 'T-shape' configurations were synthesized and tested for gene delivery carrier. Their transfection efficiency and toxicity were compared with commercially available cationic lipids, DOTMA, DOSPA, and DC-Chol. They showed efficient transfection activity and almost no toxicity on mammalian cell lines. Their ester bond degradation was monitored by (1)H NMR.