Associations between taxi drivers' aggressive driving behavior and sleep, cognition, and psychological factors: negative binomial regression analysis.

Objectives: Aggressive driving behavior is a significant predictor of traffic accidents. In particular, the driving behavior of taxi drivers is a critical issue that can impact the safety of both drivers and passengers. This study explored the sleep, cognitive, and psychological factors associated with taxi drivers' aggressive driving behavior. Methods: In this descriptive study, a self-report questionnaire was distributed to taxi drivers in Seoul and Gyeonggi Province from August 22 to December 30, 2022. In all, 992 respondents were analyzed using negative binomial regression. Results: The mean score for aggressive driving behavior among taxi drivers was 13.76 ± 11.47, with sub-scores of 3.46 ± 3.48 for lapse, 3.31 ± 3.16 for error, and 6.99 ± 5.76 for violation. Contributing factors included sleep disorders, cognitive decline, and psychological factors. A higher score for aggressive driving behavior was associated with an increased severity of insomnia and daytime sleepiness, higher rates of cognitive failure, and elevated levels of depression and stress. Conclusion: Our findings highlight the importance of addressing the sleep, cognitive, and psychological factors associated with aggressive driving behaviors among taxi drivers. Further study is needed to evaluate the causal relationship. In addition, it is imperative to develop educational programs and interventions to manage these issues effectively.

Bilateral Ovarian Fibromatosis in a Postmenopausal Female: A Case Report with Emphasis on MRI Findings and Differential Diagnosis.

Ovarian fibromatosis is a rare non-neoplastic condition that causes ovarian enlargement in women, typically around the age of 25. This enlargement is due to the proliferation of the collagen-producing ovarian stroma. On T2-weighted MRI, a key diagnostic feature of ovarian fibromatosis is the 'black garland sign,' characterized by multilobulated very low signal intensity along the ovarian surface. This condition also features the preservation of normal ovarian stroma or follicles internally. We present a case involving a 65-year-old postmenopausal female who was pathologically misdiagnosed with ovarian fibroma. However, the diagnosis was later revised to ovarian fibromatosis based on characteristic MRI findings. The case report discusses the differential diagnosis and pathologic findings associated with ovarian fibromatosis.

Predicting Recurrence after Sublobar Resection in Patients with Lung Adenocarcinoma Using Preoperative Chest CT Scans.

Background Sublobar resection for lung cancer is usually guided by cutoff values for consolidation size (maximal diameter of the solid tumor component) and consolidation-to-tumor ratio (CTR). The effects of these factors as continuous variables and the reason for established cutoffs are, to the knowledge of the authors, unexplored. Purpose To quantitatively assess the predictive value of CTR and consolidation size for cancer recurrence risk after sublobar resection in clinical stage IA lung adenocarcinoma. Materials and Methods This retrospective study reviewed sublobar resection for clinical stage IA lung adenocarcinoma performed between January 2010 and December 2019. A restricted cubic spline function verified linearity by estimating recurrence probabilities using CTR and consolidation size obtained on preoperative CT scans. Statistical analyses included a Cox proportional hazards model to identify risk factors for cancer recurrence and the Cochran-Armitage trend test for the association between CTR and consolidation size. Results Of 1032 enrolled patients (age, 63.9 years ± 9.9 [SD]; 464 male patients), 523 (50.7%) and 509 (49.3%) underwent wedge resection and segmentectomy, respectively. Among patients with a CTR between 1% and 50% (n = 201), 187 (93.0%) had a consolidation size of less than or equal to 10 mm (P < .001). There was a positive association between the risk of recurrence with CTR and consolidation size (r2 = 0.727; P < .001). The recurrence rate showed the greatest increase when CTR was greater than 50% or consolidation size was greater than 10 mm. Specifically, the recurrence rate increased from 2.1% (three of 146) at 26%-50% CTR to 8.3% (nine of 108) at 51%-75% CTR, and from 4.4% (eight of 183) for 6-10-mm consolidation size to 11.9% (23 of 194) for 11-15-mm consolidation size. The probability of recurrence exhibited linearity and increased with CTR and consolidation size. Conclusion Cancer recurrence risk after sublobar resection for stage IA adenocarcinoma consistently rises with CTR and consolidation size. Current guideline cutoffs for sublobar resection remain clinically relevant given observed recurrence rates. © RSNA, 2024 Supplemental material is available for this article.

Patient-Reported Outcomes Between Whole-Breast Plus Regional Irradiation and Whole-Breast Irradiation Only in pN1 Breast Cancer After Breast-Conserving Surgery and Taxane-Based Chemotherapy: A Randomized Phase 3 Clinical Trial (KROG 17-01).

PURPOSE: The role of regional node irradiation (RNI) with whole-breast irradiation (WBI) in patients with pN1 breast cancer receiving taxane-based adjuvant chemotherapy is not well defined. The KROG 1701 trial, a phase 3, multicenter, noninferiority study, aimed to compare the disease-free survival between WBI+RNI and WBI alone in this patient cohort. Comprehensive patient-reported outcomes (PROs) collected at multiple timepoints are reported. METHODS AND MATERIALS: The trial (NCT03269981) enrolled patients with pN1 breast cancer after breast-conserving surgery and taxane-based adjuvant chemotherapy, allocating them to receive either WBI+RNI or WBI only. PROs were assessed using European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaires Core 30and breast cancer-specific module 23 modules at baseline, during radiation therapy, and at subsequent follow-up intervals of 3 to 6 months, and annually up to 4 years. RESULTS: From April 2017 to December 2021, 840 patients were enrolled; 777 received intervention as assigned, and 750 completed baseline PRO questionnaires (387 in WBI+RNI, 363 in WBI only). All PRO domains showed improvements over time (P < .001). During radiation therapy, the WBI+RNI group reported greater fatigue and nausea. Higher arm symptom scores were observed in the WBI+RNI group 3 months post-treatment (P = .030). No other significant PRO domain differences, including arm/breast symptoms, were observed between the 2 groups. CONCLUSIONS: In patients with pN1 breast cancer treated with taxane-based chemotherapy, adding RNI to WBI resulted in minor, temporary declines in specific PRO domains, but these differences were not clinically significant. This indicates that overall patient experience between WBI+RNI and WBI is comparable, supporting the safety and patient tolerability of both treatments.

Clinical impact and potential utility of non-enhanced computed tomography performed immediately after transarterial chemoembolization for hepatocellular carcinoma.

Background: Intratumoral lipiodol deposition following transarterial chemoembolization (TACE) is associated with the prognosis of hepatocellular carcinoma (HCC) patients. However, there is insufficient evidence regarding the actual clinical significance of the imaging tests conducted to evaluate the lipiodol uptake after TACE. This study evaluates the clinical impact and potential utility of performing immediate post-TACE non-enhanced computed tomography (NECT) on the treatment of HCC. Methods: This retrospective study at a tertiary referral center included patients undergoing their first session of conventional TACE for initial treatment of HCC from November 2021 to December 2022 with available immediate post-TACE NECT. Patients were categorized based on lipiodol uptake into Cohorts A (incomplete uptake with additional treatment before the first follow-up 1 month after TACE), B incomplete uptake without additional treatment before first follow-up), and C (complete uptake). Survival curves for the time to progression (TTP) were estimated using the Kaplan-Meier method and were compared by using the log-rank test. Results: Out of 189 patients, 58 (29.6%) showed incomplete lipiodol uptake; 2 in Cohort A and 56 in Cohort B. Cohort C included 131 patients (69.3%). Cohort B had the highest rate of residual viable tumor (48.2%) 1 month after TACE, compared to the other cohorts (0% in Cohort A and 32.1% in Cohort C). The median TTP of Cohort B was 7.9 months [95% confidence interval (CI): 4.6-15.7 months], significantly shorter than the 15.4 months (95% CI: 10.9-20.9 months) for Cohort C (P=0.03). During follow-up, no progression occurred in Cohort A. Conclusions: Assessment of lipiodol uptake by performing immediate post-TACE NECT can stratify HCC patients and facilitate early prediction of therapeutic response. Identifying suboptimal lipiodol uptake immediately after TACE can aid future treatment adjustments and potentially improving oncologic outcomes.

The effect of virtual reality simulation on nursing students' communication skills: a systematic review and meta-analysis.

Virtual reality simulation (VRS) allows individuals to experience a sense of presence in a virtual environment, and it has been increasingly adopted as a novel teaching method in nursing education. VRS can have positive effects, such as patient safety, privacy assurance in healthcare, and enhanced interest and immersion in education. It is important to synthesize the results to date to determine if VRS has the potential to improve communication skills in practical nursing students. This systematic literature review and meta-analysis investigated the effect of VRS on the enhancement of communication skills among nursing students. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were employed for systematic review and meta-analysis. The following "PICO" details were considered: population-nursing students, intervention-VRS targeting communication skills enhancement, comparator-control groups without intervention or those undergoing general classes, and outcomes-communication skills. The search strategy yielded 301 results from nine databases, and 10 studies were selected for inclusion in our analysis. To calculate the overall effect sizes of the primary and secondary outcomes in the included studies, we used MIX 2.0 Pro (Version 2.0.1.6, BiostatXL, 2017) for the meta-analysis. The overall effect size for communication skills was 0.44, signifying a significant effect. A meta-regression analysis examining communication skills revealed significant results for the following factors: Fund (Ref.: No), outcome measurement time (Ref.: Immediately), outcome follow-up (Ref.: No), and debriefing (Ref.: No). Considering factors such as variations in sample size, research approaches, and the effects of independent studies on communication skills, this systematic literature review and meta-analysis suggests that VRS significantly improves nursing students' communication skills overall. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023439064.

Characterization of MET Alterations in 37 Gastroesophageal Cancer Cell Lines for MET-Targeted Therapy.

Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation >10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Next, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in an MKN-45 GC cell xenograft model. Furthermore, a combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE33 cells. Targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells.

Recombinant immune complexes as vaccines against infectious diseases.

New vaccine technologies are needed to combat many existing infections and prepare better for those that may emerge in the future. The conventional technologies that rely on protein-based vaccines are still severely restricted by the sparsity and poor accessibility of available adjuvants. One possible solution to this problem is to enhance antigen immunogenicity by a more natural means by complexing it with antibodies in the form of immune complexes (ICs). However, natural ICs are impractical as vaccines, and significant research efforts have been made to generate them in recombinant form, with plant bioengineering being at the forefront of these efforts. Here, we describe the challenges and progress made to date to make recombinant IC vaccines applicable to humans.

Optimal approach for diagnosing peripheral lung nodules by combining electromagnetic navigation bronchoscopy and radial probe endobronchial ultrasound.

INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) and radial probe endobronchial ultrasound (RP-EBUS) are essential bronchoscopic procedures for diagnosing peripheral lung lesions. Despite their individual advantages, the optimal circumstances for their combination remain uncertain. METHODS: This single-center retrospective study enrolled 473 patients with 529 pulmonary nodules who underwent ENB and/or RP-EBUS biopsies between December 2021 and December 2022. Diagnostic yield was calculated using strict, intermediate, and liberal definitions. In the strict definition, only malignant and specific benign lesions were deemed diagnostic at the time of the index procedure. The intermediate and liberal definitions included additional results from the follow-up period. RESULTS: The diagnostic yield of the strict definition was not statistically different among the three groups (ENB/Combination/RP-EBUS 63.8%/64.2%/62.6%, p = 0.944). However, the diagnostic yield was superior in the ENB + RP-EBUS group for nodules with a bronchus type II or III and a solid part <20 mm (odds ratio 1.96, 95% confidence interval 1.09-3.53, p = 0.02). In terms of complications, bleeding was significantly higher in the ENB + RP-EBUS group (ENB/Combination/RP-EBUS 3.7% /6.2/0.6%, p = 0.002), but no major adverse event was observed. CONCLUSION: The combination of ENB and RP-EBUS enhanced the diagnostic yield for nodules with bronchus type II or III and solid part <20 mm, despite a slightly elevated risk of bleeding. Careful patient selection based on nodule characteristics is important to benefit from this combined approach.

Effectiveness of a Patient Safety Incident Disclosure Education Program: A Quasi-Experimental Study.

BACKGROUND: The accurate disclosure of patient safety incidents is necessary to minimize patient safety incidents and medical disputes. As prospective healthcare providers, nursing students need to possess the ability to disclose patient safety incidents. PURPOSE: This study was designed to investigate the effect of a patient safety incident disclosure education program for undergraduate nursing students on participants' knowledge and perception of disclosure of these incidents, attitudes toward patient safety, and self-efficacy regarding disclosure of these incidents. METHODS: A quasi-experimental study with a nonequivalent pretest-posttest design was conducted on fourth-year undergraduate nursing students recruited between September 6 and October 22, 2021, through convenience sampling from two universities in South Korea. The experimental group (n = 25) received the education program. The control group (n = 25) received educational materials on the disclosure of patient safety incidents only. Knowledge and perceptions of patient safety incident disclosure, attitudes toward patient safety, and self-efficacy regarding incident disclosure were measured. Data were analyzed using descriptive analysis, t test, χ2 test, Fisher's exact test, Mann-Whitney U test, Wilcoxon signed-rank test, and ranked analysis of covariance. RESULTS: Posttest results revealed knowledge (p < .001), perceptions (p = .031), and self-efficacy (p < .001) with regard to the disclosure of patient safety incidents were all significantly higher in the experimental group than in the control group. Posttest attitudes toward patient safety were not significantly different between the two groups (p = .908). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The patient safety incident disclosure education program effectively enhances the knowledge, perception, and self-efficacy of nursing students with regard to safety incidents. The findings may be used to improve training and educational programs in nursing colleges and hospitals to improve the knowledge, perception, and self-efficacy of nursing students with regard to disclosing patient safety incidents in clinical settings.

Effectiveness of simulation-based interventions on empathy enhancement among nursing students: a systematic literature review and meta-analysis.

BACKGROUND: This study aimed to secure and analyze evidence regarding the enhancement of nursing students' empathy through simulation-based interventions. It comprehensively analyzed self-reported emotions and reactions as primary outcomes, along with the results reported by nursing students who experienced simulation-based interventions, including empathy. METHODS: This systematic literature review and meta-analysis investigated the effects of simulation-based interventions on enhancing empathy among nursing students. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for the systematic review and meta-analysis. The following details were considered: population, nursing students; intervention, simulation-based interventions targeting empathy enhancement; comparators, control groups without intervention or those undergoing general non-simulation-based classes; and outcomes, self-reported empathy. RESULTS: In the systematic review of 28 studies, it was found that the use of simulation-based interventions among nursing students led to an increase in empathy, albeit with a small effect size. This was demonstrated through a pooled, random-effects meta-analysis, yielding an effect size (Hedge's g) of 0.35 (95% CI: 0.14, 0.57, p = 0.001). The results of meta-regression and subgroup analysis significantly increased in empathy for studies published after 2019 (Hedge's g = 0.52, 95% CI: 0.31 to 0.73, p < 0.001), quasi-experimental research design (Hedge's g = 0.51, 95% CI: 0.27 to 0.74, p < 0.001), more than 60 participants (Hedge's g = 0.31, 95% CI: 0.02 to 0.59, p = 0.034), and simulation-based interventions in nursing education (Hedge's g = 0.43, 95% CI: 0.22 to 0.65, p < 0.001). CONCLUSIONS: Considering factors such as variations in sample size, research approaches, and the effects of independent studies on empathy, this systematic literature review and meta-analysis suggests that simulation-based education can significantly improve nursing students' overall empathy skills.

Enhancing nursing competency through virtual reality simulation among nursing students: a systematic review and meta-analysis.

Aim: Studies on the effectiveness of virtual reality (VR) in nursing education have explored its impact on learning outcomes, emotional immersion and engagement, learner self-confidence, and satisfaction, generally showing positive aspects. However, there is a need for a systematic review to examine the specific influence of VR-based education on nursing students' practical competency. Method: According to the PRISMA 2020 guidelines, 22 studies were selected based on inclusion criteria from 579 articles, published from January 1, 2018, to March 31, 2024, across nine major databases including PubMed and EMbase. The target population comprised nursing students, and the intervention focused on VR-based simulations aimed at enhancing competency, compared to control groups receiving either no intervention or conventional non-virtual simulation. The primary outcome, nursing competency, was analyzed using MIX 2.0 Pro (Ver. 2.0.1.6, BiostatXL, 2017) to calculate pooled effect sizes. Result: The pooled effect size for nursing competency was determined to be large, with Hedge's g = 0.88 (95% CI, 0.47 to 1.29). Meta-regression analysis identified several factors associated with an increase in nursing competency. These included studies published after 2022, approval of an IRB, absence of funding, randomized controlled trials (RCTs), interventions reported as shorter than 4 weeks or not reported, sessions fewer than 4 or not reported, session duration under 1 h or not reported, and observational measurement methods. Additional factors enhancing nursing competency were the inclusion of a pre-briefing before simulations, the absence of a debriefing afterward, and the exclusion of other activities during the simulation. Conclusion: By combining the results of the included studies, the systematic review and meta-analysis accounted for variations in sample size, study methodology, and independent intervention effects, providing an overall evaluation of the effectiveness of simulation-based education in improving nursing students' competency. Limitation: The selection criteria for the studies analyzed, which included only those published in English or Korean and reported precise means, standard deviations, and sample sizes, could lead to selection bias and limit the generalization of our study results. Systematic review registration: PROSPERO International Prospective Register of Systematic Reviews: http://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023446348.

Legal Information Retrieval and Entailment Using Transformer-based Approaches.

The challenge of information overload in the legal domain increases every day. The COLIEE competition has created four challenge tasks that are intended to encourage the development of systems and methods to alleviate some of that pressure: a case law retrieval (Task 1) and entailment (Task 2), and a statute law retrieval (Task 3) and entailment (Task 4). Here we describe our methods for Task 1 and Task 4. In Task 1, we used a sentence-transformer model to create a numeric representation for each case paragraph. We then created a histogram of the similarities between a query case and a candidate case. The histogram is used to build a binary classifier that decides whether a candidate case should be noticed or not. In Task 4, our approach relies on fine-tuning a pre-trained DeBERTa large language model (LLM) trained on SNLI and MultiNLI datasets. Our method for Task 4 was ranked third among eight participating teams in the COLIEE 2023 competition. For Task 4, We also compared the performance of the DeBERTa model with those of a knowledge distillation model and ensemble methods including Random Forest and Voting.

Overview and Discussion of the Competition on Legal Information, Extraction/Entailment (COLIEE) 2023.

We summarize the 10th Competition on Legal Information Extraction and Entailment. In this tenth edition, the competition included four tasks on case law and statute law. The case law component includes an information retrieval task (Task 1), and the confirmation of an entailment relation between an existing case and a selected unseen case (Task 2). The statute law component includes an information retrieval task (Task 3), and an entailment/question-answering task based on retrieved civil code statutes (Task 4). Participation was open to any group based on any approach. Ten different teams participated in the case law competition tasks, most of them in more than one task. We received results from 8 teams for Task 1 (22 runs) and seven teams for Task 2 (18 runs). On the statute law task, there were 9 different teams participating, most in more than one task. 6 teams submitted a total of 16 runs for Task 3, and 9 teams submitted a total of 26 runs for Task 4. We describe the variety of approaches, our official evaluation, and analysis of our data and submission results.

Progression-directed therapy in patients with oligoprogressive castration-resistant prostate cancer.

PURPOSE: Oligoprogressive lesions are observed in a subset of patients who progress to castration-resistant prostate cancer (CRPC), while other lesions remain controlled by systemic therapy. This study evaluates the impact of progression-directed therapy (PDT) on these oligoprogressive lesions. MATERIALS AND METHODS: This retrospective study included 40 patients diagnosed with oligoprogressive CRPC. PDT was performed for treating all progressive sites using radiotherapy. Fifteen patients received PDT using radiotherapy for all progressive sites (PDT group) while 25 had additional first-line systemic treatments (non-PDT group). In PDT group, 7 patients underwent PDT and unchanged systemic therapy (PDT-A group) and 8 patients underwent PDT with additional new line of systemic therapy on CRPC (PDT-B group). The Kaplan-Meier method was used to assess treatment outcomes. RESULTS: The prostate specific antigen (PSA) nadir was significantly lower in PDT group compare to non-PDT group (p=0.007). A 50% PSA decline and complete PSA decline were observed in 13 patients (86.7%) and 10 patients (66.7%) of PDT group and in 18 patients (72.0%) and 11 patients (44.0%) of non-PDT group, respectively. The PSA-progression free survival of PDT-B group was significantly longer than non-PDT group. The median time to failure of first-line systemic therapy on CRPC was 30.2 months in patients in PDT group and 14.9 months in non-PDT group (p=0.014). PDT-B group showed a significantly longer time to progression than non-PDT group (p=0.025). Minimal PDT-related adverse events were observed. CONCLUSIONS: PDT can delay progression of disease and enhance treatment efficacy with acceptable tolerability in oligoprogressive CRPC.

Whole Process of Standardization of Diffusion-Weighted Imaging: Phantom Validation and Clinical Application According to the QIBA Profile.

Background: To use the apparent diffusion coefficient (ADC) as reliable biomarkers, validation of MRI equipment performance and clinical acquisition protocols should be performed prior to application in patients. This study aims to validate various MRI equipment and clinical brain protocols for diffusion weighted imaging (DWI) using commercial phantom, and confirm the validated protocols in patients' images. Methods: The performance of four different scanners and clinical brain protocols were validated using a Quantitative Imaging Biomarker Alliance (QIBA) diffusion phantom and cloud-based analysis tool. We evaluated the performance metrics regarding accuracy and repeatability of ADC measurement using QIBA profile. The validated clinical brain protocols were applied to 17 patients, and image quality and repeatability of ADC were assessed. Results: The MRI equipment performance of all four MRI scanners demonstrated high accuracy in ADC measurement (ADC bias, -2.3% to -0.4%), excellent linear correlation to the reference ADC value (slope, 0.9 to 1.0; R2, 0.999-1.000), and high short-term repeatability [within-subject-coefficient-of-variation (wCV), 0% to 0.3%]. The clinical protocols were also validated by fulfilling QIBA claims with high accuracy (ADC bias, -3.1% to -0.7%) and robust repeatability (wCV, 0% to 0.1%). Brain DWI acquired using the validated clinical protocols showed ideal image quality (mean score ≥ 2.9) and good repeatability (wCV, 1.8-2.2). Conclusions: The whole process of standardization of DWI demonstrated the robustness of ADC with high accuracy and repeatability across diverse MRI equipment and clinical protocols in accordance with the QIBA claims.

Systematic identification of a synthetic lethal interaction in brain-metastatic lung adenocarcinoma.

Metastatic lung adenocarcinoma (LuAC) presents a significant clinical challenge due to the short latency and the lack of efficient treatment options. Therefore, identification of molecular vulnerabilities in metastatic LuAC holds great importance in the development of therapeutic drugs against this disease. In this study, we performed a genome-wide siRNA screening using poorly and highly brain-metastatic LuAC cell lines. Using this approach, we discovered that compared to poorly metastatic LuAC (LuAC-Par) cells, brain-metastatic LuAC (LuAC-BrM) cells exhibited a significantly higher vulnerability to c-FLIP (an inhibitor of caspase-8)-depletion-induced apoptosis. Furthermore, in vivo studies demonstrated that c-FLIP knockdown specifically inhibited growth of LuAC-BrM, but not the LuAC-Par, tumors, suggesting the addiction of LuAC-BrM to the function of c-FLIP for their survival. Our in vitro and in vivo analyses also demonstrated that LuAC-BrM is more sensitive to c-FLIP-depletion due to ER stress-induced activation of the c-JUN and subsequent induction of stress genes including ATF4 and DDIT3. Finally, we found that c-JUN not only sensitized LuAC-BrM to c-FLIP-depletion-induced cell death but also promoted brain metastasis in vivo, providing strong evidence for c-JUN's function as a double-edged sword in LuAC-BrM. Collectively, our findings not only reveal a novel link between c-JUN, brain metastasis, and c-FLIP addiction in LuAC-BrM but also present an opportunity for potential therapeutic intervention.

Live attenuated smallpox vaccine candidate (KVAC103) efficiently induces protective immune responses in mice.

Smallpox, caused by the variola virus belonging to the genus Orthopoxvirus, is an acute contagious disease that killed 300 million people in the 20th century. Since it was declared to be eradicated and the national immunization program against it was stopped, the variola virus has become a prospective bio-weapon. It is necessary to develop a safe vaccine that protects people from terrorism using this biological weapon and that can be administered to immunocompromised people. Our previous study reported on the development of an attenuated smallpox vaccine (KVAC103). This study evaluated cellular and humoral immune responses to various doses, frequencies, and routes of administration of the KVAC103 strain, compared to CJ-50300 vaccine, and its protective ability against the wild-type vaccinia virus Western Reserve (VACV-WR) strain was evaluated. The binding and neutralizing-antibody titers increased in a concentration-dependent manner in the second inoculation, which increased the neutralizing-antibody titer compared to those after the single injection. In contrast, the T-cell immune response (interferon-gamma positive cells) increased after the second inoculation compared to that of CJ-50300 after the first inoculation. Neutralizing-antibody titers and antigen-specific IgG levels were comparable in all groups administered KVAC103 intramuscularly, subcutaneously, and intradermally. In a protective immunity test using the VACV-WR strain, all mice vaccinated with CJ-50300 or KVAC103 showed 100% survival. KVAC103 could be a potent smallpox vaccine that efficiently induces humoral and cellular immune responses to protect mice against the VACV-WR strain.

Marked enhancement of the immunogenicity of plant-expressed IgG-Fc fusion proteins by inclusion of cholera toxin non-toxic B subunit within the single polypeptide.

Immunoglobulin G (IgG)-based fusion proteins have been widely exploited as a potential vaccine delivery platform but in the absence of exogenous adjuvants, the lack of robust immunity remains an obstacle. Here, we report on a key modification that overcomes that obstacle. Thus, we constructed an IgG-Fc vaccine platform for dengue, termed D-PCF, which in addition to a dengue antigen incorporates the cholera toxin non-toxic B subunit (CTB) as a molecular adjuvant, with all three proteins expressed as a single polypeptide. Following expression in Nicotiana benthamiana plants, the D-PCF assembled as polymeric structures of similar size to human IgM, a process driven by the pentamerization of CTB. A marked improvement of functional properties in vitro and immunogenicity in vivo over a previous iteration of the Fc-fusion protein without CTB [1] was demonstrated. These include enhanced antigen presenting cell binding, internalization and activation, complement activation, epithelial cell interactions and ganglioside binding, as well as more efficient polymerization within the expression host. Following immunization of mice with D-PCF by a combination of systemic and mucosal (intranasal) routes, we observed robust systemic and mucosal immune responses, as well as systemic T cell responses, significantly higher than those induced by a related Fc-fusion protein but without CTB. The induced antibodies could bind to the domain III of the dengue virus envelope protein from all four dengue serotypes. Finally, we also demonstrated feasibility of aerosolization of D-PCF as a prerequisite for vaccine delivery by the respiratory route.

Assessment of deep learning-based auto-contouring on interobserver consistency in target volume and organs-at-risk delineation for breast cancer: Implications for RTQA program in a multi-institutional study.

PURPOSE: To quantify interobserver variation (IOV) in target volume and organs-at-risk (OAR) contouring across 31 institutions in breast cancer cases and to explore the clinical utility of deep learning (DL)-based auto-contouring in reducing potential IOV. METHODS AND MATERIALS: In phase 1, two breast cancer cases were randomly selected and distributed to multiple institutions for contouring six clinical target volumes (CTVs) and eight OAR. In Phase 2, auto-contour sets were generated using a previously published DL Breast segmentation model and were made available for all participants. The difference in IOV of submitted contours in phases 1 and 2 was investigated quantitatively using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). The qualitative analysis involved using contour heat maps to visualize the extent and location of these variations and the required modification. RESULTS: Over 800 pairwise comparisons were analysed for each structure in each case. Quantitative phase 2 metrics showed significant improvement in the mean DSC (from 0.69 to 0.77) and HD (from 34.9 to 17.9 mm). Quantitative analysis showed increased interobserver agreement in phase 2, specifically for CTV structures (5-19 %), leading to fewer manual adjustments. Underlying IOV differences causes were reported using a questionnaire and hierarchical clustering analysis based on the volume of CTVs. CONCLUSION: DL-based auto-contours improved the contour agreement for OARs and CTVs significantly, both qualitatively and quantitatively, suggesting its potential role in minimizing radiation therapy protocol deviation.