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Chemotherapy-induced nausea and vomiting (CINV) is an unbearable side effect. Identifying high emetic risk patients and providing more active antiemetics strategies are mandatory to improve the tolerability of chemotherapy. In this prospective cohort study, leptin, ghrelin, and substance P were measured at baseline, day 3, and day 14 during the first cycle of chemotherapy. Nausea and vomiting were measured each day for the first 4 days of the first cycle of chemotherapy. Eighty-two patients were enrolled. Colorectal cancer (61%) and gastric cancer (35.4%) were common cancer types. All patients received moderate emetic risk chemotherapy. Forty-five (54.9%) patients had nausea, and 15 (18.3%) patients experienced vomiting. In univariate analysis, a higher level of baseline substance P, which is a target of NK1-RA (Neurokinin 1 receptor antagonist), was a significant predictive marker for chemotherapy-induced nausea [odds ratio (OR): 2.6, 95% confidence interval (CI): 1.02-6.62, p = 0.046]. Regarding chemotherapy-induced vomiting, patients with higher levels of substance P had a greater chance of vomiting [OR: 1.72, 95% CI: 0.49-5.99, p = 0.395] than those with lower levels of substance P. In patients receiving moderate emetic risk chemotherapy, active antiemetics, including NK1-RA, could be considered for those with high levels of substance P., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: BCOR acts as a corepressor of BCL6, a potent oncogenic protein in cancers of the lymphoid lineage. We have found the recurrent somatic mutation of BCOR occurred in mature T-cell lymphoma (TCL). The role of BCOR mutation in lymphoid malignancies is unknown., Methods: Lymphoma patient samples were analyzed to identify missense mutations in BCOR using Sanger sequencing. Transfection, RNA interference, immunoprecipitation, western blotting, cell proliferation, cytokine assays and quantitative real-time PCR were employed to determine the functional relevance of the novel K607E mutation in BCOR. The significant transcriptional changes were analyzed by performing DNA microarray profiling in cells expressing BCOR K607E mutant., Results: One hundred thirty-seven lymphoma patient samples were analyzed to identify K607E mutation of the BCOR gene. The BCOR K607E mutation was identified in 15 of 47 NK/T cell lymphoma cases (31.9%), 2 of 18 angioimmunoblastic T-cell lymphoma cases (11.1%), 10 of 30 peripheral T-cell lymphoma, not otherwise specified cases (33.3%), and 13 of 42 diffuse large B-cell lymphoma cases (30.9%). Molecular analysis of BCOR K607E mutation revealed that compared to the wild-type BCOR, the mutant BCOR bound to the BCL6, PCGF1, and RING1B proteins with lesser affinity. Ectopic expression of BCOR K607E mutant significantly enhanced cell proliferation, AKT phosphorylation and the expression of interleukin-2 (IL-2) with up-regulated expression of HOX and S100 protein genes in T cells. BCOR silencing also significantly enhanced cell proliferation, AKT phosphorylation, and IL-2 production., Conclusions: Functional analyses indicated that K607E mutation of BCOR is oncogenic in nature and can serve as a genetic marker of T-cell lymphoma.

Objective: The objective is to investigate the test-retest reliability of subjective visual vertical (SVV) in the upright position and with lateral head tilts through a computerized SVV measuring system using virtual reality (VR) goggles., Materials and Methods: Thirty healthy controls underwent SVV test in upright position, with the head tilted to the right 30°, and with the head tilted to the left 30°. Subjects wore SVV VR goggles, which contained a gyroscope for monitoring the angle of head tilt. Each subject completed 10 adjustments in each head position. The mean value of SVV deviations and SVV imprecision (the intra-individual variability of SVV deviations from the 10 adjustments) were recorded and compared across different head positions. The participants then repeated the same SVV protocol at least 1 week later. The test-retest reliability of SVV deviation and SVV imprecision were analyzed., Results: The SVV deviation (mean ± standard deviation) was 0.22° ± 1.56° in upright position, -9.64° ± 5.91° in right head tilt, and 7.20° ± 6.36° in left head tilt. The test-retest reliability of SVV deviation was excellent in upright position (intra-class correlation coefficient [ICC] = 0.77, P < 0.001), right head tilt (ICC = 0.83, P < 0.001) and left head tilt (ICC = 0.84, P < 0.001). The SVV values from the 10 adjustments made during right and left head tilts were less precise than when measured at upright ( P < 0.001). The test-retest reliability of SVV imprecision was poor at upright (ICC = 0.21, P = 0.26) but fair-to-good in right head tilt (ICC = 0.72, P < 0.001) and left head tilt (ICC = 0.44, P = 0.04)., Conclusion: The test-retest reliability of SVV deviation during lateral head tilts via VR goggles is excellent, which supports further research into the diagnostic value of head-tilt SVV in various vestibular disorders. In addition, the degree of SVV imprecision during head tilt has fair-to-good test-retest reliability, which suggests SVV imprecision may have clinical applicability., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Tzu Chi Medical Journal.)

Old age alone does not reflect an intolerability to chemotherapy. However, upfront dose reduction (UDR) of the first cycle of first-line palliative chemotherapy has sometimes been chosen by physicians for older adults with metastatic cancer due to concerns regarding adverse events. The development of predictive factors for UDR of palliative chemotherapy would be helpful for treatment planning among older adults. This was a secondary analysis of a study on predicting adverse events of first-line palliative chemotherapy in 296 patients (≥70 years) with solid cancer. We assessed the prevalence of UDR of the first cycle of first-line chemotherapy and the association of UDR with the variables of geriatric assessment (GA) and chemotherapy compliance. Among the 296 patients, 177 (59.8%) patients were treated with UDR. The mean percentage of UDR for the total patient group was 19.2% (range: 4-47%) of the standard dose. In a multivariate analysis, poor performance status (PS) and living without a spouse were independent predictive factors of UDR of first-line palliative chemotherapy in older adults. Patients with UDR showed fewer grade 3-5 adverse events versus the standard dose group. Study completion as planned was significantly higher in the UDR group versus the standard dose group. Older adults with UDR better tolerated chemotherapy than patients with a standard dose.

The effects of Ag nanoparticle (Ag NP) addition on interfacial reaction and mechanical properties of Sn-58Bi solder joints using ultra-fast laser soldering were investigated. Laser-assisted low-temperature bonding was used to solder Sn-58Bi based pastes, with different Ag NP contents, onto organic surface preservative-finished Cu pads of printed circuit boards. The solder joints after laser bonding were examined to determine the effects of Ag NPs on interfacial reactions and intermetallic compounds (IMCs) and high-temperature storage tests performed to investigate its effects on the long-term reliabilities of solder joints. Their mechanical properties were also assessed using shear tests. Although the bonding time of the laser process was shorter than that of a conventional reflow process, Cu-Sn IMCs, such as Cu 6 Sn 5 and Cu 3 Sn, were well formed at the interface of the solder joint. The addition of Ag NPs also improved the mechanical properties of the solder joints by reducing brittle fracture and suppressing IMC growth. However, excessive addition of Ag NPs degraded the mechanical properties due to coarsened Ag 3 Sn IMCs. Thus, this research predicts that the laser bonding process can be applied to low-temperature bonding to reduce thermal damage and improve the mechanical properties of Sn-58Bi solders, whose microstructure and related mechanical properties can be improved by adding optimal amounts of Ag NPs.

Background: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC)., Methods: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry., Results: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group., Conclusions: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Background: To determine the benefit of pelvic floor muscle exercise with visual biofeedback on promoting patient recovery from incontinence, we investigated variables associated with the early restoration of continence for patients who underwent robot-assisted radical prostatectomy., Methods: Of the 83 patients enrolled, 41 consecutive patients completed pelvic floor muscle exercise (the exercise group), and the other 42 consecutive patients just before the pelvic floor muscle exercise program commenced (the control group). The primary outcome was whether pelvic floor muscle exercise engagement was associated with zero pad continence restoration within 3 months of surgery., Results: Continence restoration percentages (defined as zero pads used per day) at 1, 3, and 6 months after surgery were 49.4%, 77.1%, and 94.0%, respectively. The exercise group achieved significantly higher recovery rates at 1 month (p=0.037), 3 months (p<0.001), and 6 months (p=0.023). Cox regression analysis demonstrated that a lower Gleason score (<8; hazard ratio, 2.167), lower prostate specific antigen (<20 ng/dL; hazard ratio, 2.909), and engagement in pelvic floor muscle exercise (hazard ratio, 3.731) were independent predictors of early recovery from postprostatectomy incontinence. Stratification by age showed that those younger than 65 years did not benefit significantly from exercise (log-rank test, p=0.08), but that their elderly counterparts, aged 65-70 years (p=0.007) and >70 years old (p=0.002) benefited significantly., Conclusion: This study suggests that postoperative engagement in pelvic floor muscle exercise with biofeedback speeds up the recovery of continence in elderly patients (≥65 years old) that undergo robot-assisted radical prostatectomy.

Despite the rapid increase in the use of robotic surgery in urology, the majority of ureteric reconstruction procedures are still performed using laparoscopic or open approaches. This is primarily due to uncertainty regarding the advantages of robotic approaches over conventional ones, and the unique difficulty in identifying the specific area of interest due to the lack of tactile feedback from the current robotic systems. However, with the potential benefits of minimal invasiveness, several pioneering reports have been published on robotic surgery in urology. By reviewing the literature on this topic, we aimed to summarize the techniques, considerations, and consistent findings regarding robotic ureteral reconstruction in adults. Robotic applications for ureteral surgery have been primarily reported for pediatric urology, especially in the context of relieving a congenital obstruction in the ureteral pelvic junction. However, contemporary studies have also consistently demonstrated that robotic surgery could be a reliable option for malignant, iatrogenic, and traumatic conditions, which generally occur in adult patients. Nevertheless, the lack of comparative studies on heterogeneous hosts and disease conditions make it difficult to determine the benefit of the robotic approach over the conventional approach in the general population; thus, qualified prospective trials are needed for wider acceptance. However, contemporary reports have demonstrated that the robotic approach could be an alternative option for ureteral construction, even in the absence of haptic feedback, which can be compensated by various surgical techniques and enhanced three-dimensional visualization., (© 2021 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

This study aimed to assess the efficacy and safety of treatment with avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with relapsed or refractory extranodal natural killer/T-cell lymphoma (ENKTL). In this phase 2 trial, 21 patients with relapsed or refractory ENKTL were treated with 10 mg/kg of avelumab on days 1 and 15 of a 28-day cycle. The primary end point was the complete response (CR) rate based on the best response. Targeted sequencing and immunohistochemistry were performed using pretreatment tumor tissue, and blood samples were drawn before and after treatment for measurement of cytokines and soluble programmed cell death protein 1 (PD1), PD-L1, and PD-L2. The CR rate was 24% (5 of 21), and the overall response rate was 38% (8 of 21). Although nonresponders showed early progression, 5 responders currently continue to receive treatment and have maintained their response. Most treatment-related adverse events were grade 1 or 2; no grade 4 adverse events were observed. Treatment responses did not correlate with mutation profiles, tumor mutation burden, serum levels of cytokines, or soluble PD1/PD-L1 and PD-L2. However, the response to avelumab was significantly associated with the expression of PD-L1 by tumor tissue (P = .001). Therefore, all patients achieving CR showed high PD-L1 expression, and their tumor subtyping based on PD-L1 expression correlated with treatment response. In summary, avelumab showed single-agent activity in a subset of patients with relapsed or refractory ENKTL. The assessment of PD-L1 expression on tumor cells might be helpful for identifying responders to avelumab. This trial was registered at www.clinicaltrials.gov as #NCT03439501., (© 2020 by The American Society of Hematology.)

Exosomes containing microRNAs (miRNAs) might have utility as biomarkers to predict the risk of treatment failure in extranodal NK/T-cell lymphoma (ENKTL) because exosomal cargo miRNAs could reflect tumor aggressiveness. We analyzed the exosomal miRNAs of patients in favorable ( n = 22) and poor outcome ( n = 23) groups in a training cohort. Then, using the Nanostring nCounter ® microRNA array, we compared them with miRNAs identified in human NK/T lymphoma (NKTL) cell line-derived exosomes to develop exosomal miRNA profiles. We validated the prognostic value of serum exosomal miRNA profiles with an independent cohort ( n = 85) and analyzed their association with treatment resistance using etoposide-resistant cell lines. A comparison of the top 20 upregulated miRNAs in the training cohort with poor outcomes with 16 miRNAs that were upregulated in both NKTL cell lines, identified five candidate miRNAs (miR-320e, miR-4454, miR-222-3p, miR-21-5p, and miR-25-3p). Among these, increased levels of exosomal miR-4454, miR-21-5p, and miR-320e were associated with poor overall survival in the validation cohort. Increased levels were also found in relapsed patients post-treatment. These three miRNAs were overexpressed in NKTL cell lines that were resistant to etoposide. Furthermore, transfection of NKTL cell lines with miR-21-5p and miR-320e induced an increase in expression of the proinflammatory cytokines such as macrophage inflammatory protein 1 alpha. These studies show that serum levels of exosomal miR-21-5p, miR-320e, and miR-4454 are increased in ENKTL patients with poor prognosis. Upregulation of these exosomal miRNAs in treatment-resistant cell lines suggests they have a role as biomarkers for the identification of ENKTL patients at high risk of treatment failure.

Because non-anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline-based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies., (© 2020 by The American Society of Hematology.)

microRNAs (miRNAs), endogenous suppressors of target mRNAs, are deeply involved in every step of non-small cell lung cancer (NSCLC) development, from tumor initiation to progression and metastasis. They play roles in cell proliferation, apoptosis, angiogenesis, epithelial-to-mesenchymal transition, migration, invasion, and metastatic colonization, as well as immunosuppression. Due to their versatility, numerous attempts have been made to use miRNAs for clinical applications. miRNAs can be used as cancer subtype classifiers, diagnostic markers, drug-response predictors, prognostic markers, and therapeutic targets in NSCLC. Many challenges remain ahead of their actual clinical application; however, when achieved, the use of miRNAs in the clinic is expected to enable great progress in the diagnosis and treatment of patients with NSCLC.

Programmed death-ligand 1 (PD-L1) expression and CD8-positive tumor-infiltrating lymphocyte (CD8 + TIL) infiltration are essential biomarkers for immune checkpoint inhibitor therapy. The objective of this study was to compare the expression of those biomarkers between initial and recurrent HNSCCs using paired analysis. Prognostic significance of those immunological changes was also investigated. Forty-two consecutive patients with locally recurrent HNSCCs were included. Immunohistochemical staining of CD8 and PD-L1 was done for both initial and recurrent tumor specimens. The IHC findings were verified with mRNA expression profiling. Also, the prognostic impact was analyzed based on overall survival (OS). Recurrent-to-initial (R/I) ratios of CD8 + TILs and PD-L1 were widely variable. CD8 + TIL density and PD-L1 expression decreased in 59.5% and 69% of patients, respectively (R/I ratio < 1). The R/I ratio of CD8A mRNA was significantly higher in patients with a CD8 R/I ratio > 1 (1.7 ± 1.5 vs. 0.6 ± 0.6, p = 0.042). CD8 R/I ratio (> 1) was a good prognosticator for OS (HR 0.293, 95% CI 0.091-0.945, p = 0.040). CD8 + TIL infiltration and PD-L1 expression changed variably following local recurrence of HNSCC. The increase of CD8 + TILs at recurrence was an excellent independent prognosticator.

The binding dynamics of the trans -1-methyl-4-(4-hydroxystyryl)pyridinium cation (HSP + ) to cucurbit[6]uril (CB[6]) in the presence of Na + cations were studied to establish the effect of the relative concentrations of the system's components (HSP + , CB[6], and Na + ) on these dynamics. The formation of the HSP + @CB[6] complex was temporally uncoupled from the photoisomerization of trans -HSP + , while a nonlinear effect of the Na + cation concentration on the HSP + @CB[6] dynamics was observed. This nonlinearity is a consequence of Na + having the opposite effect on the association and dissociation rate constants for the HSP + @CB[6] complex, creating a conceptual framework for using such nonlinearities to control multistep reactions in cucurbit[ n ]uril chemistry.

In the era of precision medicine, accurate and reproducible assignment of cell-of-origin (COO) in diffuse large B-cell lymphoma patients has become important. The Lymph2Cx assay is accurately determining COO by analyzing RNA expression of 20 selected genes while the Hans algorithm based on immunohistochemistry is the most popular method for routine daily diagnosis. However, there are discrepancies between the 2 methods, which need to be evaluated for better correlation. We prospectively analyzed 156 cases of diffuse large B-cell lymphoma, not otherwise specified to analyze the characteristics of discrepancy groups of COO determined by Lymph2Cx and Hans algorithm. We investigated the pattern and cause of discrepancy of COO assigned by the 2 methods. Hans algorithm classified 50 cases (32%) as germinal-center B-cell-like (GCB) type and 106 cases (68%) as non-GCB type. Lymph2Cx assay assigned 43 cases (28%) as GCB type, 94 cases (60%) as activated B-cell-like type, and 19 cases (12%) as intermediate/unclassified type. The agreement rate was 86% after exclusion of unclassified type. With regard to the clinicopathologic factors related with discrepancy between Hans algorithm and Lymph2Cx assay, endoscopic biopsy of the gastrointestinal tract (4/11, 36%) showed higher discrepancy rate (P=0.052). Immunophenotypically, CD10/BCL6/MUM1 GCB type and CD10/BCL6//MUM1 (=30%, low level expression) non-GCB type exhibited a significantly higher discrepancy rate (6/13, 46%; 4/13, 31%) (P=0.0001). Activated B-cell-like subgroup via Lymph2Cx assay predicted poor progression-free survival (mean survival duration 28.6 mo, P=0.049) compared with the GCB and unclassified type. Hans algorithm revealed no significant difference in progression-free survival and overall survival (P=0.122 and 0.121). These results suggest that when assigning COO via Hans algorithm, CD10/BCL6/MUM1 GCB type and CD10/BCL6/MUM1 (=30%, low level) non-GCB type require careful interpretation, especially if the MUM1 staining is weak and heterogeneous in the biopsied specimen.

Tunable infrared filters are important for various optical and optoelectronic systems. Ideally, such filters should span wide spectral ranges while retaining constant performance. Here, as a fundamental approach, we theoretically treat tunable resonant filters and realize favorable spectral profiles. Implementing a chirped zero-contrast grating on wedged sublayers, we optimize the resonant tunable filter for operation in the ∼5-14µ m band. To clarify the root causes of the physical processes enabling the observed performance, attendant resonance modal processes and background reflection behavior are analyzed in detail by equivalent models as well as by rigorous electromagnetic models. The key innovative contribution of this research is that it enables efficient filters with simultaneously tuned operational wavelengths and sidebands.

Purpose: This study assessed the effectiveness of the Better Life After Cancer: Energy, Strength, and Support (BLESS) program, a 12-week social capital-based exercise adherence program for breast cancer survivors (BCS), regarding cancer-related fatigue (CRF), quality of life (QOL), physical activity, and psychosocial characteristics., Methods: Forty-eight BCS with moderate or high (≥ 4) CRF participated in this randomized control trial (intervention group n = 23, control group n = 25). The intervention group participated in small group sessions to activate social capital while targeting CRF in supervised physical exercises supplemented by home-based physical exercises. The control group was only given written information on exercise. A questionnaire was used to assess CRF, QOL, physical activity, depression, anxiety, sleep quality, and social capital., Results: The majority of participants had undergone surgery less than 2 years ago. After participating in BLESS, the CRF behavioral/severity domain significantly decreased (t = 2.642, p = 0.011) and physical activity significantly increased (t = - 2.049, p = 0.046) in the intervention group, in comparison with the control group; there were no significant post-intervention differences in the control group. Both groups showed improvements in sleep quality, depression, anxiety, and QOL., Conclusion: The BLESS program decreased behavioral/severity in the CRF and increased physical activity after 12 weeks among BCS. Future research needs to evaluate whether the promising results on physical activity and behavioral fatigue observed in the short term will persist over time. Also, longer-term effects should be examined.

Objectives: To investigate the impact of the remnant ureteral orifice (RUO) on the prognosis of upper tract urothelial carcinoma (UTUC), because the presence of an ipsilateral intact ureteral orifice is not an uncommon finding during follow-up cystoscopy despite the clinical relevance of bladder cuffing during radical nephroureterectomy (RNU) for the management of UTUC., Methods: The records of patients who underwent RNU in all tertiary hospitals in Daegu province (2011-2018) were retrospectively reviewed. Subjects were allocated to RUO or non-RUO groups. Cox proportional hazard models were used to identify variables. The primary endpoint was a 5-year intravesical recurrence-free survival (RFS)., Results: Of the 164 patients enrolled, 45 (27.4%) had an RUO by postoperative cystoscopy. The characteristics of the RUO and non-RUO groups were similar. During mean follow-up of 76.4 months (range: 69.5-83.4), 21 (46.7%) subjects in the RUO group and 25 (21.0%) in the non-RUO group experienced intravesical recurrence (P = .001). Among them, 3 (6.7%) and 14 (8.5%) developed distant metastasis (P = .339), and 3 (6.7%) and 9 (7.6%) succumbed to UTUC (P = .844), respectively. The 5-year RFS was lower in the RUO group than in the non-RUO counterpart (45.6% vs 77.8%, P = .003). Multivariate analysis showed lymphovascular invasion (hazard ratio [HR] = 3.593, P = .002), lymph nodal involvement (HR = 2.336, P = .038), and the presence of RUO (HR = 2.058, P = .026) predicted 5-year RFS., Conclusion: The presence of RUO after RNU was found to be significantly associated with intravesical tumor recurrence, and this finding emphasizes the quality of bladder cuffing during RNU, which could be assessed by complete removal of the natural orifice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Emotional disorders such as anxiety and depression are widespread psychological diseases that affect up to 20% of the world's population. There are many approaches to the discovery of novel agents for the treatment of depressive- and anxiety-like symptoms. However, the efficacy of existing drugs for emotional disorders is only exerted after a few weeks of treatment and have serious side effects. Due to this, new strategies to find suitable and safe options are being sought by many researchers. Among them, a lot of interest has been attracted by plant-derived natural compounds due to their wide range of beneficial effects for new agent development. Flavonoids are natural polyphenol-like compounds found commonly in plants, fruits, vegetables, and medicinal herbs. A diverse range of flavonoids have been studied to investigate their potential therapeutic activities for the treatment of brain-associated disorders, including anxiety and depression. The main aim of this review is to understand the associations between the various flavonoids and the emotional disorders and discuss the therapeutic effects of these natural compounds that were demonstrated during the conduction of recent studies. The current work shows advances in the latest research of some flavonoids as a potential candidate for the treatment of emotional disorders. We summarize their behavioral, molecular, physiological, and neurochemical effects in various in vitro and in vivo models. Therefore, in the present work, the latest studies were collected on the most important flavonoid compounds and their underlying mechanisms of action in emotion-related disorders were discussed.

Background: Carotid blowout syndrome (CBS) is a rupture of the carotid artery and is mainly caused by radiation and resection of head and neck cancers or direct tumor invasion of the carotid artery wall. It is a life-threatening clinical situation. There is no established and effective mode of management of CBS. Furthermore, there is no established preceding sign or symptom; therefore, preventive efforts are not clinically meaningful., Case Summary: We described two cases of CBS that occurred in patients with head and neck cancer after definitive chemoradiotherapy (CRT) using three-dimensional conformal intensity-modulated radiation therapy. Two men aged 61 and 56 years with locally advanced head and neck cancer were treated with definitive CRT. After completing CRT, both of them achieved complete remission. Subsequently, they had persistent severe pain in the oropharyngeal mucosal region and the irradiated neck despite the use of opioid analgesics and rehabilitation for relief of contracted skin. However, continuous follow-up imaging studies showed no evidence of cancer recurrence. Eleven to twelve months after completing CRT, the patients visited the emergency room complaining about massive oronasal bleeding. Angiograms showed rupture of carotid artery pseudoaneurysms on the irradiated side. Despite attempting to secure hemostasis with carotid arterial stent insertion and coil embolization, both patients died because of repeated bleeding from the pseudoaneurysms., Conclusion: In patients with persistent pain in irradiated sites, clinicians should be suspicious of progressing or impending CBS, even in the three-dimensional conformal intensity-modulated radiation therapy era., Competing Interests: Conflict-of-interest statement: The authors disclose no potential conflicts of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The objective of the current study was to investigate the clinical activity of, safety of, and predictive biomarkers for afatinib, an irreversible pan-ErbB kinase inhibitor, in patients with recurrent and/or metastatic esophageal squamous cell carcinoma (R/M-ESCC)., Methods: Patients with R/M-ESCC that was refractory to platinum-based chemotherapy were enrolled in the current multicenter, single-arm, phase 2 study and received afatinib at a dose of 40 mg/day. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, overall survival, the disease control rate, and the safety profile. To identify predictive biomarkers, single-nucleotide variations, short insertions/deletions, and somatic copy number alterations were assessed using whole-exome sequencing and their associations with clinical outcomes were analyzed., Results: Among 49 enrolled patients, the objective response rate and disease control rate were 14.3% and 73.3%, respectively. With a median follow-up of 6.6 months, the median progression-free survival and overall survival were 3.4 months and 6.3 months, respectively. Treatment-related adverse events were noted to have occurred in 33 patients (67.3%), with the majority being of grade 1 to 2 (adverse events were graded and recorded based on the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). Whole-exome sequencing demonstrated that the ESCC genomes of patients who demonstrated a response to afatinib were enriched with genomic alterations of TP53 and epidermal growth factor receptor (EGFR). As a predictive marker, a score derived from TP53 disruptive mutations and EGFR amplifications and/or missense mutations demonstrated a significant association with the response to afatinib. The score based on the mutational status of EGFR and TP53 achieved a performance of an area under the curve of 0.86 in predicting the sensitivity of afatinib., Conclusions: The results of the current study demonstrated that afatinib can confer modest clinical benefits with manageable toxicity in patients with platinum-resistant R/M-ESCC. Identification of TP53 alterations and EGFR amplifications may serve as predictive markers with which to identify patients with R/M-ESCC who may benefit from afatinib., Lay Summary: Esophageal squamous cell carcinoma (ESCC) is a type of cancer with a dismal prognosis and very limited treatment options. The clinical efficacy of afatinib was evaluated in patients with recurrent and/or metastatic ESCC, with adverse events demonstrating the modest efficacy with manageable toxicity of this irreversible, pan-ErbB kinase inhibitor. Whole-exome sequencing analysis of 41 cases of ESCC further revealed that the patients harboring epidermal growth factor receptor (EGFR) amplifications and disruptive TP53 mutations are more likely to benefit from treatment with afatinib. The results of the current study have highlighted the clinical value of EGFR and TP53 as predictive biomarkers of platinum-resistant recurrent and/or metastatic ESCC for afatinib sensitivity., (© 2020 American Cancer Society.)

Given the more aggressive phenotype and prognosis of the upper tract urothelial carcinoma (UTUC) than those of bladder tumor, radical removal of the entire ureter along with ipsilateral kidney has long been the standard of care. However, recent advances in diagnostic imaging and endoscopic armamentarium have markedly enhanced the role of nephron-sparing approaches for well-selected cases, especially with low-risk features. Historically, this strategy was exclusively considered for managing a patient unfit to undergo radical nephroureterectomy (RNU). After observing effective oncologic control for these imperative cases, an elective risk-based indication was introduced with care. Two representative modalities in this strategy include endoscopic management via retrograde ureterorenoscopy (URS) or antegrade percutaneous approach and segmental ureterectomy (SU). SU, which includes different types of unstandardized procedures, is the most widely reported alternative to RNU. Despite the lack of qualified evidence regardless of the strategy applied, systemic reviews have consistently revealed similar survival after endoscopic management and RNU for low-grade and noninvasive UTUC. However, selected patients with high-grade and invasive UTUC could benefit from SU while maintaining the oncologic outcomes observed after RNU. Based on these findings, the currently available guidelines have extended the use of the nephron-sparing approach gradually, recommending segmental resection especially for the distal ureteral tumors even in patients with high-risk features. Nonetheless, the fact that evidence supporting these conclusions remains poor and potentially biased cannot be overemphasized., Competing Interests: Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2020.03.66). The series “Urothelial Carcinoma” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

This work reports the synthesis and application of highly tuned cadmium-free green and red InPZnSe 1-x S x /ZnS quantum dots (QDs) in QD enhanced liquid crystal displays (LCD). The emissions of the quantum dots were synthetically tuned to sharp emissions at low full-width at half maximum. The QDs were incorporated in LCD devices as quantum dot enhancement film (QDEF) or as a quantum dot incorporated color filter (QDCF). Synthetic tuning of the gradient inter-shell in the QDs leads to reduced full width at half-maximum, resulting in sharp green and red emissions from both types of devices. The application of the same QDs to devices using these different integration techniques shows the superiority of QDCF devices over QDEF ones. The RGB color gamut of a QDCF-LCD was 81.4% of REC.2020 in the CIE 1931 color space compared to 71.2% obtained for a QDEF-LCD display. The improved performance of QDCF was mainly due to the optimal interactions between the green QDs and the green color filter. The superior performance of cadmium-free InPZnSe 1-x S x /ZnS QDCFs in LCDs make them well-suited for ultra-high-definition TV formats.

Salivary duct carcinoma (SDC) is one of the most aggressive subtypes of salivary gland cancers. Conventional chemotherapy and/or radiation have shown only limited clinical efficacy in the treatment of recurrent or metastatic SDC. Currently, clinically approved targeted-therapeutics are not generally applicable except in very limited cases, and there exists a strong need for the development of treatment against this unique tumor type. To further interrogate genomic features of SDC, we have conducted multi-omic profiling of the SDC to describe the genomic alterations prevalent in this disease. Whole-genome sequencing, whole exome-sequencing and transcriptome sequencing were performed on a discovery cohort of 10 SDC samples. Targeted genomic profiling was performed in additional 32 SDC samples to support the findings obtained from the original discovery cohort. The cancer cohort was characterized by an average mutation burden of 85 somatic exonic mutations per tumor sample. The cohort harbored a mutational signature of BRCA and APOBEC/AID. Several genes, including TP53, RB1, SMAD4, HRAS, APC, PIK3CA and GNAQ were recurrently somatically altered in SDC. A novel fusion gene, generated by genomic rearrangement, MYB-NHSL1, was also noted. Our findings represent a significant layer in the systematic understanding of potentially clinically useful genomic and molecular targets for a subset of recurrent/metastatic SDC.

SLAMF1 is often overexpressed in Epstein Barr virus (EBV)-infected B cell tumors. However, its role in the pathogenesis of EBV-infected B cell tumors remains largely unknown. Here, we generated SLAMF1-deficient EBV+ tumor cells and examined the effect of its deficiency on cell proliferation and cell survival. There were no significant differences in cell proliferation and cell cycle distribution for short periods between the SLAMF1-deficient and wild-type cells. However, the deficient cells were more resistant to an AKT inhibitor (MK-2206). When the both cells were co-cultured and repeatedly exposed to the limitations in nutrition and growth factors, the SLAMF1-deficient cells were gradually decreased. We observed that levels of phospho-AKT were differentially regulated according to the nutritional status between the SLAMF1-deficient and wild-type cells. A decrease in phospho-AKT was observed in SLAMF1-deficient cells as well as an increase in pro-apoptotic Bim just before cell passage, which may have been due to the loss of SLAMF1 under poor growth condition. Overall, SLAMF1 is not a strong survival factor, but it seems to be necessary for cell survival in unfavorable growth condition., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To investigate the association between preoperative retrograde pyelography (RGP), conducted to evaluate upper tract urothelial carcinoma (UTUC), and intravesical recurrence (IVR) after radical nephroureterectomy (RNU)., Materials and Methods: Of 114 patients that underwent RNU, 72 patients without preoperative ureteroscopy and a history of bladder tumor were selectively enrolled. Variables associated with IVR were identified., Results: RGP was performed at a mean duration of 24.9 days prior to RNU in 41 (56.1%) of study subjects. During the mean follow-up period of 64.5 months, IVRs were identified in 32 (44.4%) patients at 22.3±18.8 (mean±SD) months after RNU. Despite similar tumor characteristics in the RGP and non-RGP groups, the incidence of IVR was considerably higher in the RGP group (63.4%) than in the non-RGP group (19.4%, p <0.001). The following variables differed significantly between the IVR and non-IVR groups: age (64.6±8.51 vs. 59.6±9.65 years), tumor location (lower or upper; 53.1% vs. 20%), tumor invasiveness (> pT2; 53.1% vs. 17.5%), preoperative hemoglobin (12.8±1.36 vs. 13.9±1.65), preoperative creatinine (1.29±0.32 vs. 1.11±0.22), and preoperative RGP (81.3% vs. 37.5%), respectively. Multivariate Cox regression model showed that tumor location (p=0.020, HR=2.742), preoperative creatinine level (p=0.004, HR=6.351), and preoperative RGP (p=0.045, HR=3.134) independently predicted IVR., Conclusion: Given the limitations of retrospective single-center series, performance of RGP before RNU was shown to have a negative effect on IVR after surgery., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Secondary hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal condition with various underlying disorders in adult patients and is diagnosed based on the HLH-2004 criteria, which were established based on experience in pediatric patients. However, few studies have prospectively evaluated the treatment outcomes and diagnostic performance of HLH criteria in adult patients with secondary HLH. Thus, we performed a single-center, prospective cohort study of adult patients with suspected HLH, and we analyzed treatment outcomes of patients enrolled between 2017 and 2019 as an interim analysis ( ClinicalTrials.gov Identifier: NCT03117010). Of the 73 patients with suspected HLH, 70 patients completed the evaluation for ≥ 7 of the HLH-2004 criteria, and 55 patients were diagnosed with HLH (55/73, 75%). Although serum ferritin and fever had a sensitivity of more than 90%, both had exceptionally low specificity, whereas soluble CD25 had a sensitivity of more than 90% and specificity of 80%. Forty patients with malignancy-associated HLH had B cell (n = 19) or T- or NK-cell (n = 21) lymphoid malignancy, whereas 15 patients had non-malignant disorders. Non-malignancy-associated HLH had greater than 90% 1-year overall survival (OS) after diagnosis of HLH, whereas that for malignancy-associated HLH was less than 40%. In conclusion, our study showed promising treatment outcomes for patients enrolled in our prospective cohort study, and prospectively demonstrated the diagnostic performance of the HLH-2004 criteria in adult patients with suspected HLH. Given that lymphoma was the most common cause of HLH in adults, thorough evaluation for lymphoma should be performed in adults with suspected HLH.

Naturally occurring spatiotemporal patterns typically have a predictable pattern design and are reproducible over several cycles. However, the patterns obtained from artificially designed out-of-equilibrium chemical oscillating networks (such as the Belousov-Zhabotinsky reaction for example) are unpredictable and difficult to control spatiotemporally, albeit reproducible over subsequent cycles. Here, we show that it is possible to generate reproducible spatiotemporal patterns in out-of-equilibrium chemical reactions and self-assembling systems in water in the presence of sound waves, which act as a guiding physical stimulus. Audible sound-induced liquid vibrations control the dissolution of atmospheric gases (such as O 2 and CO 2 ) in water to generate spatiotemporal chemical patterns in the bulk of the fluid, segregating the solution into spatiotemporal domains having different redox properties or pH values. It further helps us in the organization of transiently formed supramolecular aggregates in a predictable spatiotemporal manner.

The genome-packaging motor of tailed bacteriophages and herpesviruses is a multisubunit protein complex formed by several copies of a large (TerL) and a small (TerS) terminase subunit. The motor assembles transiently at the portal protein vertex of an empty precursor capsid to power the energy-dependent packaging of viral DNA. Both the ATPase and nuclease activities associated with genome packaging reside in TerL. Structural studies of TerL from bacteriophage P22 have been hindered by the conformational flexibility of this enzyme and its susceptibility to proteolysis. Here, an unbiased, synthetic phage-display Fab library was screened and a panel of high-affinity Fabs against P22 TerL were identified. This led to the discovery of a recombinant antibody fragment, Fab4, that binds a 33-amino-acid α-helical hairpin at the N-terminus of TerL with an equilibrium dissociation constant K d of 71.5 nM. A 1.51 Å resolution crystal structure of Fab4 bound to the TerL epitope (TLE) together with a 1.15 Å resolution crystal structure of the unliganded Fab4, which is the highest resolution ever achieved for a Fab, elucidate the principles governing the recognition of this novel helical epitope. TLE adopts two different conformations in the asymmetric unit and buries as much as 1250 Å 2 of solvent-accessible surface in Fab4. TLE recognition is primarily mediated by conformational changes in the third complementarity-determining region of the Fab4 heavy chain (CDR H3) that take place upon epitope binding. It is demonstrated that TLE can be introduced genetically at the N-terminus of a target protein, where it retains high-affinity binding to Fab4.

The long-wave infrared (LWIR) spectral region spanning ∼8-12µ m is useful for many scientific and industrial applications. As traditional multilayer film components are not straightforwardly realized at these bands, we provide design, fabrication, and testing of polarization independent bandstop filters based on the guided-mode resonance (GMR) effect. Focusing on the zero-contrast grating architecture, we successfully fabricate prototype filters in the Ge-on-ZnSe materials system. Applying mask-based photolithography and dry etching, photoresist patterns form the desired Ge grating structures. The resulting devices exhibit clean transmittance nulls and acceptably high sidebands. Moreover, we verify polarization independent notch filtering by assembling two identical GMR filters with gratings oriented orthogonally. This approach to realize effective GMR elements will be useful for various fields including photonic and optoelectronic devices operating in the LWIR region.

CD8+ tumor-infiltrating lymphocytes (TILs) play a major role in antitumor immunity. High endothelial venules (HEVs) are related to diverse immune cells in solid tumors. We analyzed CD8+ and Foxp3+ TILs in combination with HEVs to determine their prognostic role in advanced gastric cancer (AGC). We enrolled 157 patients with AGC in this study. The densities of CD8+ TILs and Foxp3+ TILs were calculated using immunohistochemical staining. HEVs were evaluated by MECA-79 expression. HEVs were identified in 60 (38.2%) cases and was significantly associated with an increased number of CD8+ TILs ( p = 0.027) but not of Foxp3+ TILs ( p = 0.455) and CD20+ TILs ( p = 0.163). A high CD8+/HEV+ level was significantly associated with nodal metastasis ( p = 0.048). In survival analysis, patients with high CD8+/HEV+ levels demonstrated the longest overall survival (OS) ( p = 0.015). Furthermore, a high CD8+/HEV+ level was an independent prognostic factor in AGC ( p = 0.011; hazard ratio (HR) = 0.435; 95% confidence interval (CI) = 0.245-0.837). HEVs were found to play an important role in antitumor immunity associated with CD8+ TILs in AGC. This analysis of HEVs and CD8+ TILs helps stratify patients with AGC and sheds light on tumor immunity.

Objective: This study investigated the treatment response and cognitive enhancement effects of buspirone augmentation of escitalopram in patients with major depressive disorder (MDD), according to atypical feature subtypes of MDD., Methods: An 8 week, randomized, parallel-controlled, open-label study was conducted. The Columbia Atypical Depression Diagnostic Scale was administered to evaluate atypical features. Patients were assigned randomly to the buspirone augmentation or non-buspirone groups. Symptom severity and cognitive function were evaluated using the 17-item Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Beck Depression Inventory, Beck Anxiety Inventory, digit span test, word fluency test, and Trail Making Tests A and B., Results: A total of 89 patients were recruited. There were no significant differences in the measures between the groups; however, among the MDD patients without atypical features, the digit span and word fluency tests were improved by treatment. In the MDD patients without atypical features, the buspirone augmentation group showed a significant improvement on the digit span test compared to the non-buspirone group., Conclusion: Buspirone augmentation did not demonstrate significant benefits in MDD patients; however, buspirone augmentation showed greater efficacy for the improvement of cognitive function in MDD patients without atypical features. Our study suggests that atypical features are an important factor for cognitive enhancement in buspirone augmentation treatment in patients with MDD.

Comprehensive transcriptome analysis was conducted to elucidate the molecular basis of the interaction between chestnut blight fungus, Cryphonectria parasitica , and single-stranded RNA (ssRNA) mycovirus Cryphonectria hypovirus 1 (CHV1), using RNA-sequencing (RNA-seq). A total of 1,023 differentially expressed genes (DEGs) were affected by CHV1 infection, of which 753 DEGs were upregulated and 270 DEGs were downregulated. Significant correlations in qRT-PCR analysis of 20 randomly selected DEGs and agreement with previously characterized marker genes validated our RNA-seq analysis as representing global transcriptional profiling of virus-free and -infected isogenic strains of C. parasitica . Gene Ontology (GO) analysis of DEGs indicated that "cellular aromatic compound metabolic process" and "transport" were the two most enriched components in the "biological process." In addition, "cytoplasm" was the most enriched term in the "cellular component" and "nucleotide binding" and "cation binding" were the two most enriched terms in the "molecular function" category. These results suggested that altered expression of genes encoding numerous intracellular proteins due to hypoviral infection resulted in changes in specific metabolic processes as well as transport processes. Kyoto Encyclopedia of Genes and Genomes function analysis demonstrated that pathways for "biosynthesis of other secondary metabolites," "amino acid metabolism," "carbohydrate metabolism," and "translation" were enriched among the DEGs in C. parasitica . These results demonstrate that hypoviral infection resulted in massive but specific changes in primary and secondary metabolism, of which antiviral fungal metabolites were highly induced. The results of this study provide further insights into the mechanism of fungal gene regulation by CHV1 at the transcriptome level., (Copyright © 2020 Chun, Ko and Kim.)

The evolution of next-generation sequencing technology has resulted in a generation of large amounts of cancer genomic data. Therefore, increasingly complex techniques are required to appropriately analyze this data in order to determine its clinical relevance. In this study, we applied a neural network-based technique to analyze data from The Cancer Genome Atlas and extract useful microRNA (miRNA) features for predicting the prognosis of patients with lung adenocarcinomas (LUAD). Using the Cascaded Wx platform, we identified and ranked miRNAs that affected LUAD patient survival and selected the two top-ranked miRNAs (miR-374a and miR-374b) for measurement of their expression levels in patient tumor tissues and in lung cancer cells exhibiting an altered epithelial-to-mesenchymal transition (EMT) status. Analysis of miRNA expression from tumor samples revealed that high miR-374a/b expression was associated with poor patient survival rates. In lung cancer cells, the EMT signal induced miR-374a/b expression, which, in turn, promoted EMT and invasiveness. These findings demonstrated that this approach enabled effective identification and validation of prognostic miRNA markers in LUAD, suggesting its potential efficacy for clinical use.

Immune system dysfunction is associated with head and neck squamous cell carcinoma (HNSCC) development and progression and immune checkpoint inhibitors have demonstrated substantial survival benefits in platinum-refractory HNSCC; therefore, we examined the prognostic value of immune-related gene (IRG) expression in HNSCC. We analyzed the expression of 82 IRGs in 71 patients with HNSCC enrolled in a feasibility study for a prospective HNSCC biomarker-driven umbrella trial (Korean Cancer Study Group TRIUMPH study, NCT03292250). CD200R1 was identified as an independent prognostic factor and validated in GEO and TCGA database. CD2000R1 mRNA expression was found to be an independent favorable prognostic factor in patients with HNSCC. Moreover, CD200R1 was found to affect genes and pathways associated with the immune response, while seven differentially expressed genes ( CD8A, DOK2, CX3CR1, TYROBP, CXCL9, CD300LF, IFNG ) were associated with CD200R1 expression. Samples with higher CD200R1 expression displayed higher tumor-infiltrating immune cell counts both in silico and in histological analysis. These findings will help in the development of more accurate prognostic tools and suggest CD200R1 modulation as a HNSCC immunotherapy.

The use of new psychoactive substances (NPSs) as a substitute for illegal drugs is increasing rapidly and is a serious threat to public health. 25C-NBF is a newly synthesized phenethylamine-type NPS that acts as a 5-hydroxyindoleacetic acid (5-HT) receptor agonist, but little is known about its pharmacological effects. Considering that NPSs have caused unexpected harmful effects leading to emergency and even death, scientific confirmation of the potential adverse effects of 25C-NBF is essential. In the present study, we investigated whether 25C-NBF has addictive and neurotoxic potential and causes neurochemical changes. In addictive potential assessments, high conditioned place preference (CPP) scores and stable self-administration (SA) were observed in the 25C-NBF groups (CPP [3 mg kg -1 ]; SA [0.01, 0.03, 0.1 mg kg -1 ]), suggesting the addictive liability of 25C-NBF. In neurotoxic potential assessments, 25C-NBF treatment (single super-high dose [1 × 15, 30, 40 mg kg -1 ]; repeated high dose [4 × 8, 15, 30 mg kg -1 ]) resulted in reduced motor activity (open field test), abnormal motor coordination (rota-rod test) and impaired recognition memory (novel object recognition test), suggesting that 25C-NBF is neurotoxic leading to motor impairment and memory deficits. Subsequently, immunohistochemistry showed that 25C-NBF treatment decreased tyrosine hydroxylase (TH) expression and increased ionized calcium-binding adapter molecule 1 (Iba-1) expression in the striatum. Taken together, our results clearly demonstrate the dangers of recreational use of 25C-NBF, and we suggest that people stop using 25C-NBF and other NPSs whose pharmacological effects are not precisely known.

Objective: Emotional labor is known to be a risk factor for emotional distress. This study aimed to evaluate specific stressors according to the type of occupation and identify protective and adverse factors., Methods: We recruited 349 workers engaged in emotional labor in a suburban city. They were assessed using scales regarding emotional status, job stress, resilience, and job satisfaction. Correlation and regression analyses were performed to evaluate their emotional state according to their stress level. A mediation model using structural equation modeling was utilized to identify the mediating effects of resilience and workplace satisfaction., Results: The correlation analysis indicated that the level of workplace stress was statistically correlated with depressed mood and anxiety and showed a significant inverse correlation with individuals' resilience and job satisfaction. According to the regression analysis, in private institution workers, "emotional disharmony and hurt" had a statistically significant negative effect on their emotional state, and in public institution workers, "emotional demands and regulation" were prominent. Resilience partially mediated the relationship between emotional stress and anxiety/depressive symptoms., Conclusion: Our findings indicate that the causes of stress differed according to the working environment. Preventive strategies such as resilience training and relieving stress on individual factors are needed to promote mental health.

Activated phosphoinositide 3-kinase δ syndrome (APDS)1 is caused by gain-of-function mutations in PIK3CD , which encodes the catalytic p110δ subunit of phosphoinositide 3 kinase. We describe three patients with APDS1, the first thereof in Korea. Therein, we investigated clinical manifestations of APDS1 and collected data on the efficacy and safety profile of sirolimus, a mammalian target of rapamycin inhibitor and pathway-specific targeted medicine. The same heterozygous PIK3CD mutation was detected in all three patients (E1021K). After genetic diagnosis, all patients received sirolimus and experienced an excellent response, including amelioration of lymphoproliferation and improvement of nodular mucosal lymphoid hyperplasia in the gastrointestinal tract. The median trough level of sirolimus was 5.5 ng/mL (range, 2.8-7.5) at a dose of 2.6-3.6 mg/m². Two patients who needed high-dose, short-interval, immunoglobulin-replacement treatment (IGRT) had a reduced requirement for IGRT after initiating sirolimus, and the dosing interval was extended from 2 and 3 weeks to 4 weeks. The IgG trough level after sirolimus treatment (median, 594 mg/dL; range, 332-799 mg/dL) was significantly higher than that before sirolimus treatment (median, 290 mg/dL; range, 163-346 mg/dL) ( p <0.001). One episode of elevated serum creatinine with a surge of sirolimus (Patient 2) and episodes of neutropenia and oral stomatitis (Patient 1) were observed. We diagnosed the first three patients with APDS1 in Korea. Low-dose sirolimus may alleviate clinical manifestations thereof, including hypogammaglobulinemia., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Epstein-Barr virus (EBV) positivity in diffuse large B cell lymphoma (DLBCL) provokes a critical oncogenic mechanism to activate intracellular signaling by LMP1. LMP1 specifically mimics the role of BTK-dependent B cell receptor. Therefore, a trial considering RCHOP therapy along with ibrutinib (I-RCHOP) in combination was conducted among patients with EBV-positive DLBCL. This study was an open-label, single-arm, prospective multicenter phase II clinical trial. Patients received 560 mg of ibrutinib with RCHOP every 3 weeks until 6 cycles were completed or progression or unacceptable toxicity was observed. The primary endpoint was objective response, while secondary endpoints included toxicity, progression-free survival, and overall survival. A matched case-control analysis was completed to compare the efficacy and toxicity of I-RCHOP and RCHOP, respectively, in EBV-positive DLBCL patients. From September 2016 to August 2019, 24 patients proven to have EBV-positive DLBCL in the tissue were enrolled and received I-RCHOP. Their median age was 58 years (range, 28-84 years). The objective overall response was 66.7%, including 16 patients who achieved complete response after 6 cycles. Patients aged younger than 65 years presented a superior OR (87.5%) as compared with those older than 65 years (25.0%; p = 0.01). In a matched case-control study, I-RCHOP therapy provoked a more favorable complete response rate (87.3%) than did RCHOP (68.8%) in those younger than 65 years. Treatment-related mortality was linked most frequently with I-RCHOP therapy (four patients presented with unusual infection without Gr3/4 neutropenia) in the older age group (age ≥ 65 years). In conclusion, in this phase II trial for EBV-positive DLBCL, I-RCHOP was effective but did not show a significant improvement in response and survival in comparison with RCHOP. Also, I-RCHOP promoted serious toxicity and treatment-related death in older patients.

Background: Pelvic multiparametric magnetic resonance imaging (mpMRI)-determined membranous urethral length (MUL) and its surgical maximization have been reported to impact early- and long-term pad-free urinary continence after robot-assisted radical prostatectomy (RARP)., Objective: The objective of this study was to present evidence (data and video) of important effects on post-RARP continence recovery from both innate mpMRI-assessed and surgical preservation of MUL., Design Setting and Participants: Of 605 men undergoing RARP, 580 with complete follow-up were included: Group 1, prior (N = 355), and Group 2, subsequent (N = 225) to technique change of MUL maximization. Effect of innate, mpMRI-assessed MUL on postoperative continence was assessed., Surgical Procedure: Before technique change, the dorsal venous complex was stapled before transection of the membranous urethra. After the change, the final step of extirpation was transection of the dorsal venous complex and periurethral attachments, thus facilitating surgical maximization of MUL., Measurements: Primary and secondary outcomes for technique change and mpMRI-assessed MUL were both patient-reported 30-day and 1-year pad-free continence after RARP, respectively., Results: Preoperative prostate-specific antigen, age, and disease aggressiveness were significantly higher in Group 2. After technique change and surgical maximization of MUL, 30-day and 1-year pad-free continence were both significantly improved ( p  < 0.05). In multivariate analysis, maximization of MUL significantly increased the likelihood of both early- and long-term continence recovery. For men undergoing MUL preservation, mpMRI-assessed MUL>1.4 cm also independently predicted higher 30-day (odds ratio: 4.85, 95% confidence interval: 1.24-18.9) and 1-year continence recovery (odds ratio: 11.26, 95% confidence interval: 1.07-118)., Conclusions: Prostatic rotation and circumferential release of apical attachments and maximization of MUL improves continence after RARP. Separately, innate MUL>1.4 cm independently increased 30-day and 1-year continence recovery., Patient Summary: Surgeon efforts to maximize MUL during radical prostatectomy are highly encouraged, as maximally preserved MUL likely improves post-RARP continence recovery. In addition, individual patients' mpMRI-assessed MUL (approximately >1.4 cm) independently limits continence recovery., Competing Interests: The authors have no conflicts of interest., (© 2020 Asian Pacific Prostate Society. Published by Elsevier B.V.)

A Ran binding protein (RanBP) homolog, CpRbp1, from Cryphonectria parasitica, has been identified as a protein that is affected by hypovirus infection or tannic acid supplementation. In this study, functional analyses of CpRbp1 were performed by constructing a knockout mutant and analyzing the resulting heterokaryon. Transformation-mediated gene replacement resulted in two putative CpRbp1-null mutants and genotype analyses identified these two mutants as heterokaryotic transformants consisting of two types of nuclei, one with the wild-type CpRbp1 allele and another with the CpRbp1-null mutant allele. Although stable mycelial growth of the heterokaryotic transformant was observed on selective medium containing hygromycin B, neither germination nor growth of the resulting conidia, which were single-cell monokaryotic progeny, was observed on the medium. In trans complementation of heterokaryons using a full-length wild-type allele of the CpRbp1 gene resulted in complemented transformants. These transformants sporulated single-cell monokaryotic conidia that were able to grow on media selective for replacing and/or complementing markers. These results clearly indicate that CpRbp1 is an essential gene, and heterokaryons allowed the fungus to maintain lethal CpRbp1-null mutant nuclei. Moreover, in trans complementation of heterokaryons using chimeric structures of the CpRbp1 gene allowed for analysis of its functional domains, which was previously hampered due to the lethality of the gene. In addition, in trans complementation using heterologous RanBP genes from Aspergillus nidulans was successful, suggesting that the function of RanBP is conserved during evolution. Furthermore, in trans complementation allowed for functional analyses of lethal orthologs. This study demonstrates that our fungal heterokaryon system can be applied effectively to determine whether a gene of interest is essential, perform functional analyses of a lethal gene, and analyze corresponding heterologous genes.

The cost of next-generation sequencing technologies is rapidly declining, making RNA-seq-based gene expression profiling (GEP) an affordable technique for predicting receptor expression status and intrinsic subtypes in breast cancer patients. Based on the expression levels of co-expressed genes, GEP-based receptor-status prediction can classify clinical subtypes more accurately than can immunohistochemistry (IHC). Using data from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets, we identified common predictor genes found in both datasets and performed receptor-status prediction based on these genes. By assessing the survival outcomes of patients classified using GEP- or IHC-based receptor status, we compared the prognostic value of the two methods. We found that GEP-based HR prediction provided higher concordance with the intrinsic subtypes and a stronger association with treatment outcomes than did IHC-based hormone receptor (HR) status. GEP-based prediction improved the identification of patients who could benefit from hormone therapy, even in patients with non-luminal breast cancer. We also confirmed that non-matching subgroup classification affected the survival of breast cancer patients and that this could be largely overcome by GEP-based receptor-status prediction. In conclusion, GEP-based prediction provides more reliable classification of HR status, improving therapeutic decision making for breast cancer patients.

Background/aims: We performed a large-scale, retrospective, nationwide, cohort study to investigate the risk factors for lung cancer among never-smoking Korean females., Methods: The study data were collected from a general health examination and questionnaire survey of eligible populations conducted between January 1, 2003 and December 31, 2004; the data were acquired from the tailored big data distribution service of the National Health Insurance Service. After a 1-year clearance period, 5,860,922 of 6,318,878 never-smoking female participants with no previous history of lung cancer were investigated. After a median follow-up of 11.4 years, 43,473 (0.74%) participants were defined as "newly diagnosed lung cancer"., Results: After adjusting for all variables at baseline, the variables older age, lower body mass index (BMI), less exercise, frequent alcohol drinking, meat-based diet, rural residence, and previous history of cancer were associated with a higher incidence of lung cancer. Low BMI (< 18.5 kg/m2: hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.27 to 1.40) was a significant independent risk factor; as BMI decreased, HR increased. Negative associations between BMI and lung-cancer development were also observed after controlling for age (p for trend < 0.001). Drinking alcohol one to two times a week (HR, 1.25; 95% CI, 1.21 to 1.28) and eating a meat-based diet (HR, 1.08; 95% CI, 1.01 to 1.15) were associated with lung-cancer incidence., Conclusion: Modifiable baseline characteristics, such as BMI, exercise, alcohol consumption, and diet, are risk factors for lung-cancer development among never- smoking females. Thus, lifestyle modifications may help prevent lung cancer.

Background: As diffuse large B-cell lymphoma (DLBCL) is a very heterogeneous group of lymphomas, much effort has gone in trying to identify patients with increased risk for early death or secondary central nervous system (CNS) involvement. To better predict their outcomes, we measured the levels of various cytokines in serum samples of patients with DLBCL and analyzed their clinical outcomes., Methods: We measured the levels of seven serum cytokines at diagnosis in 313 DLBCL patients who were treated with R-CHOP. Their impact on clinical outcomes, including time to secondary CNS involvement and the 3-year overall survival (OS) rate, were analyzed., Results: The median age was 56 years (range, 16-86 years), and 177 patients (57%) were men. Secondary CNS involvement was found in 5.4% (16/294) cases, and time to secondary CNS involvement was significantly short in patients with elevated interleukin (IL)-10 (p = 0.012). With the 3-year OS rate of the whole cohort being 73.6%, serum levels of several cytokines, such as CCL3 > 4.0 pg/mL (54.3% vs. 76.1%, p = 0.001), CCL5 > 450 pg/mL (57.0% vs. 78.1%, p < 0.001), any expression of IL-6 (59.3% vs. 76.6%, p = 0.001), and any expression of IL-10 (68.2% vs. 84.5%, p = 0.001), showed prognostic impact. Higher expressions of these cytokines were associated with worse manifestations of clinical prognostic factors., Conclusions: Our study revealed that some cytokines impact OS and secondary CNS involvement. Future studies are required to elucidate how these findings can be incorporated to the conventional prognostic factors for more tailored approaches., 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 © 2020 Elsevier Ltd. All rights reserved.)

Background: Nuclear protein in testis (NUT) carcinoma is a poorly differentiated carcinoma defined by the presence of NUT gene rearrangement. In the head and neck, the true prevalence of NUT carcinoma is unknown., Methods: We retrospectively investigated NUT expression with clinicopathologic features in 362 patients of poorly differentiated or undifferentiated carcinomas in the head and neck, and reviewed the literature reports., Results: Four (4/362, 1.1%) cases showed strong nuclear expression for NUT-specific monoclonal antibody, and all these tumors were in the sinonasal tract (4/40, 10%). The clinical outcome and histology were diverse unlike previously described. Although previous studies reported different frequency results according to study subjects, frequencies in sinonasal tract are relatively constant (10/80, 12.5%)., Conclusions: This is the largest study on the prevalence of NUT carcinoma in head and neck areas. It is important to include in the differential diagnosis of poorly differentiated carcinoma, particularly in the sinonasal tract., (© 2020 Wiley Periodicals, Inc.)

We explored prognostic roles of circulating microRNAs (miRs) in multiple myeloma (MM) treated with autologous stem cell transplantation (ASCT) following induction chemotherapy. In part I of the study (n = 40), we identified a decreasing dynamics of circulating miR-193a-5p expression from diagnosis to pre-ASCT. In patients who experienced early relapse within one year post ASCT (n = 9) these patterns were distinctive compared to those without early relapse in a 1:2 matched cohort (n = 18). In part II (n = 90), multivariate analyses showed that the International Staging System score and miR-193a-5p expression before ASCT were independent prognostic factors. Conclusively, expression of circulating miR-193a-5p before ASCT could be a prognostic biomarker for transplant-eligible MM., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The Patient Health Questionnaire-9 (PHQ-9) has been standardized in several populations and is widely used in clinical practice and health care. However, it has not been appropriately standardized in the Korean general population, and no normative data have been presented. The aim of this study was to provide the normative data and psychometric properties of the PHQ-9 in the nationally representative population of Korea., Methods: We used the nationwide cross-sectional survey data of Korea from 2014 to 2016. The data of 10,759 individuals aged over 19 years were analyzed in this study. As the distribution of the PHQ-9 scores was not normative, the percentile ranks for raw scores were provided. The survey questionnaires included the PHQ-9, The EuroQol-5 Dimension (EQ-5D), and demographic characteristics. We analyzed the construct validity and internal consistency of the PHQ-9., Results: The normative data of the PHQ-9 were generated according to the sex and different age categories. The correlation coefficient between the sum of the PHQ-9 scores and the EQ-5D index was 0.44, which was moderate. The most appropriate model was the two-factor model with five 'affective-somatic' labeled items and four 'cognitive' labeled items. Cronbach's α for the PHQ-9 was 0.79., Conclusions: Our result supports reliability and validity with two-factor structure of PHQ-9 for measuring depression in the Korean nationally representative population. The Korean normative data on the PHQ-9 according to percentile rank can assist in interpreting and comparing scores with other populations.

Background: Extranodal natural killer (NK) T-cell lymphoma (ENKTL) is a unique clinicopathological entity, typically associated with poor survival outcomes. Most published data have come from east Asian study groups, with little information available from international cohorts. The effects of treatment advances on routine clinical practice across continental territories has not been clear. We aimed to improve understanding of the clinical characteristics and outcomes of patients with ENKTL., Methods: We did a substudy of patients with ENKTL from the T-cell Project, a global prospective cohort study. The T-cell Project registered consecutively diagnosed adults (>18 years) with newly diagnosed, untreated mature T-cell or NK lymphomas (WHO 2001 or 2008 classifications) from 74 centres in 13 countries (in Asia, Europe, North America, and South America). In total, 1695 patients with mature T-cell or NK lymphomas were enrolled between Oct 12, 2006 and Feb 28, 2018 in the T-cell Project. The first patient with ENKTL was enrolled on Feb 15, 2007, and the last on May 26, 2017. Data on baseline characteristics, first-line treatment, treatment response, and survival outcomes were recorded in a central database (locked March 30, 2019). The primary outcome was 5-year overall survival. The T-cell Project is registered on ClinicalTrials.gov, NCT01142674., Findings: 166 patients were diagnosed with ENKTL, comprising 11% of 1553 eligible registered cases and distributed across 40 participating centres in four continents. At a median follow-up of 44 months (IQR 20-61), overall survival at 5 years was 54% (95% CI 44-63) in patients with nasal disease (n=98) and 34% (27-46) in patients with extranasal disease (n=68)., Interpretation: To our knowledge, this study presents the largest international cohort of patients with ENKTL. We describe a clinically significant improvement in the survival of patients with ENKTL treated in routine clinical practice over the past decade, likely to be attributable to the increasing use of treatment protocols specific for ENKTL., Funding: The Fondazione Cassa di Risparmio di Modena, the Associazione Angela Serra per la Ricerca sul Cancro, the Fondazione Italiana Linfomi, Allos Therapeutics, Spectrum Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro, and the National Cancer Institute at the National Institutes of Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)