SKYSCRAPER-02: Tiragolumab in Combination With Atezolizumab Plus Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer.

PURPOSE: The phase III SKYSCRAPER-02 study determined whether the benefits of atezolizumab plus carboplatin and etoposide (CE) could be enhanced by the addition of tiragolumab in untreated extensive-stage small-cell lung cancer (ES-SCLC). We report final progression-free survival (PFS) and overall survival (OS) analyses. METHODS: Patients received tiragolumab 600 mg/placebo, plus atezolizumab 1,200 mg and CE (four cycles), then maintenance tiragolumab/placebo plus atezolizumab. Primary end points were investigator-assessed PFS and OS in patients without history/presence of brain metastases (primary analysis set [PAS]). Additional end points included PFS and OS in all patients regardless of brain metastases status (full analysis set [FAS]), response, and safety. RESULTS: Four hundred ninety patients were randomly assigned (FAS): 243 to tiragolumab arm and 247 to control arm. At the cutoff date (February 6, 2022; median duration of follow-up, 14.3 months [PAS] and 13.9 months [FAS]), final analysis of PFS in the PAS (n = 397) did not reach statistical significance (stratified hazard ratio [HR], 1.11; P = .3504; median, 5.4 months tiragolumab v 5.6 months control). At the cutoff date (September 6, 2022; median duration of follow-up, 21.2 months [FAS]), median OS in the PAS at final OS analysis was 13.1 months in both arms (stratified HR, 1.14; P = .2859). Median PFS and OS in the FAS were consistent with the PAS. The proportion of patients with immune-mediated adverse events (AEs) in the tiragolumab and control arms was 54.4% and 49.2%, respectively (grade 3/4: 7.9% and 7.7%). AEs leading to treatment withdrawal occurred in 8.4% and 9.3% of tiragolumab- and control-treated patients, respectively. CONCLUSION: Tiragolumab did not provide additional benefit over atezolizumab and CE in untreated ES-SCLC. The combination was well tolerated with no new safety signals.

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.

A Rapid Quantitative Analysis of Bicomponent Fibers Based on Cross-Sectional In-Situ Observation.

To accelerate the industrialization of bicomponent fibers, fiber-based flexible devices, and other technical fibers and to protect the property rights of inventors, it is necessary to develop fast, economical, and easy-to-test methods to provide some guidance for formulating relevant testing standards. A quantitative method based on cross-sectional in-situ observation and image processing was developed in this study. First, the cross-sections of the fibers were rapidly prepared by the non-embedding method. Then, transmission and reflection metallographic microscopes were used for in-situ observation and to capture the cross-section images of fibers. This in-situ observation allows for the rapid identification of the type and spatial distribution structure of the bicomponent fiber. Finally, the mass percentage content of each component was calculated rapidly by AI software according to its density, cross-section area, and total test samples of each component. By comparing the ultra-depth of field microscope, differential scanning calorimetry (DSC), and chemical dissolution method, the quantitative analysis was fast, accurate, economical, simple to operate, energy-saving, and environmentally friendly. This method will be widely used in the intelligent qualitative identification and quantitative analysis of bicomponent fibers, fiber-based flexible devices, and blended textiles.

Estimating mean local posterior predictive benefit for biomarker-guided treatment strategies.

Precision medicine has emerged from the awareness that many human diseases are intrinsically heterogeneous with respect to their pathogenesis and composition among patients as well as dynamic over the course therapy. Its successful application relies on our understanding of distinct molecular profiles and their biomarkers which can be used as targets to devise treatment strategies that exploit current understanding of the biological mechanisms of the disease. Precision medicine present challenges to traditional paradigms of clinical translational, however, for which estimates of population-averaged effects from large randomized trials are used as the basis for demonstrating improvements comparative effectiveness. A general approach for estimating the relative effectiveness of biomarker-guided therapeutic strategies is presented herein. The statistical procedure attempts to define the local benefit of a given biomarker-guided therapeutic strategy in consideration of the treatment response surfaces, selection rule, and inter-cohort balance of prognostic determinants. Theoretical and simulation results are provided. Additionally, the methodology is demonstrated through a proteomic study of lower grade glioma.

A targeted strategy to identify untargeted metabolites from in vitro to in vivo: Rapid and sensitive metabolites profiling of licorice in rats using ultra-high performance liquid chromatography coupled with triple quadrupole-linear ion trap mass spectrometry.

It is challenging to conduct in vivo metabolic study for traditional Chinese medicines (TCMs) because of complex components, unpredictable metabolic pathways and low metabolite concentrations. Herein, we proposed a sensitive strategy to characterize TCM metabolites in vivo at an orally clinical dose using ultra-high performance liquid chromatography-triple quadrupole-linear ion trap mass spectrometry (UHPLC-QTRAP-MS). Firstly, the metabolism of individual compounds in rat liver microsomes was studied to obtain the metabolic pathways and fragmentation patterns. The untargeted metabolites in vitro were detected by multiple ion monitoring-enhanced product ion (EPI) and neutral loss-EPI scans. Subsequently, a sensitive multiple reaction monitoring-EPI method was developed according to the in vitro results and predicted metabolites to profile the in vivo metabolites. Licorice as a model herb was used to evaluate and validate our strategy. A clinical dose of licorice water extract was orally administered to rats, then a total of 45 metabolites in urine, 21 metabolites in feces and 35 metabolites in plasma were detected. Among them, 18 minor metabolites have not been reported previously and 6 minor metabolites were first detected in vivo. Several isomeric metabolites were well separated and differentiated in our strategy. These results suggested that this new strategy could be widely used for the detection and characterization of in vivo metabolites of TCMs.

Dosimetric and clinical outcomes after volumetric modulated arc therapy for carcinoma of the thoracic esophagus.

PURPOSE: The efficiency of radiation delivery via volumetric modulated arc therapy (VMAT) is indisputable, but outcomes after VMAT for thoracic esophageal carcinoma are largely unknown. METHODS AND MATERIALS: We retrospectively analyzed 65 patients with thoracic esophageal cancer who received VMAT to 50.4 Gy (range, 45-50.4 Gy) with concurrent chemotherapy from November 2012 to March 2016 at a single tertiary cancer center. We then used propensity score matching to match these 65 patients with 130 other patients treated with step-and-shoot intensity modulated radiation therapy (ssIMRT) and concurrent chemotherapy. Differences in continuous and categorical variables were examined with independent-sample t or Wilcoxon tests and χ2 tests. RESULTS: Dosimetrically, VMAT had a higher conformity index (87.75 ± 10.70 VMAT vs 83.20 ± 9.42 ssIMRT, P = .003), a higher heart V5, and a lower V50 than ssIMRT, but lung V5-20, heart V30, heart V40, cordmax, and homogeneity index were similar. At median follow-up intervals of 14.3 months (range, 3.8-34.5 months) for VMAT and 31.8 months (range, 1.8-117.2 months) for ssIMRT, overall survival rates were similar between the treatments (93.5% VMAT vs 91.5% ssIMRT at 1 year; 60.0% VMAT and 61.4% ssIMRT at 2 years; P = .868). Recurrence-free survival rates were similar (73.3% VMAT vs 79.5% ssIMRT at 1 year, 59.9% VMAT and 61.8% ssIMRT at 2 years; P = .614), as were pathologic complete response rates (31.2% VMAT vs 23.3% ssIMRT; P = .41) and toxicity and postoperative complications (radiation pneumonitis 9% VMAT vs 15.4% ssIMRT; pericardial effusion 2% VMAT vs 7% ssIMRT; esophageal fistula and stricture 9% VMAT vs 13% ssIMRT; all P > .05). CONCLUSION: Compared with ssIMRT, VMAT had better target conformity with similar organ sparing and comparable rates of survival, recurrence, and toxicity. These results suggest that VMAT can be safe and effective for esophageal cancer.

Effects of music listening on anxiety and physiological responses in patients undergoing awake craniotomy.

OBJECTIVE: The purpose of this study was to explore the effects of music listening on the level of anxiety and physiological responses for awake craniotomy. METHODS: An experimental design with randomization was applied in this study. Participants in experimental group (19 patients) selected and listened music at their preferences in the waiting room and throughout the entire surgical procedure in addition to usual care while control group (19 patients) only gave usual care. State-Trait Anxiety Inventory (STAI), heartbeat, breathing, and blood pressure were collected for analysis. RESULTS: The results of this study showed that after music listening, there was significant decrease in the level of anxiety (p<.001). The findings also showed that the music intervention significantly reduced heartbeat rate 84.5 (p<.004), systolic pressure 42 (p<.001), and diastolic pressure 38 (p<.001) over time. We concluded that music listening is associated with a decreased level of anxiety and distress after awake craniotomy patients. CONCLUSION: The results of this study can provide perioperative nursing care in providing music listening when patients were in the waiting room and during surgery to reduce the anxiety so as to reach the goal of human care and improve perioperative nursing care.

Definitive Chemoradiation Therapy for Esophageal Cancer in the Elderly: Clinical Outcomes for Patients Exceeding 80 Years Old.

PURPOSE: The optimal treatment approach for patients ≥80 years ("elderly") with esophageal cancer is not well established. We assessed the clinical outcomes in elderly patients treated with definitive chemoradiation therapy (CCRT) at our institution. METHODS AND MATERIALS: 56 consecutive patients ≥80 years with esophageal cancer treated with conventional CCRT between 2001 and 2016 were propensity score matched 1:2 to generate 2 younger patient cohorts treated with CCRT without surgery: "intermediate" (65-79 years, n=112) and "younger" (<65 years, n=112). Treatment related toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0. The rates of overall survival (OS) and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. RESULTS: The median ages of the 3 cohorts were 81 years (elderly, 80-92 years), 71 years (intermediate, 65-79 years), and 58 years (younger, 20-64 years). The elderly cohort was more likely to have cardiac comorbidities. Although the clinical complete response (cCR) rate deviated significantly among the 3 cohorts, (78%, 72%, and 56%; P=.004), the data failed to identify statistically significant differences among RFS, 2-year, and 5-year OS, or in median survival, which was 15.5 months, 23.6 months, and 20.2 months (P=.468), respectively. The overall severe toxicity rates were 38%, 32%, and 30%, respectively (P=.644), including comparable rate of radiation pneumonitis (P>.05). The elderly cohort, however, did show statistically significant evidence of an increased rate of severe radiation pneumonitis (grade ≥3) which was observed to be 11% versus 4% and 0%, respectively (P=.003). CONCLUSIONS: The studied elderly population showed evidence of similar long-term clinical efficacy after definitive CCRT when compared with cohorts of younger patients with similar prognostic status. An increased rate of pulmonary toxicity was identified, without evidence of differences for nonpulmonary severe adverse events. Understanding the prognostic risk factors of pulmonary toxicity after CCRT may effectuate improved long-term outcomes for elderly population.

Autonomic and electrocardiographic findings in Parkinson's disease.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms and signs. Many reports suggest that diminished heart rate variability occurs early, even prior to the cardinal signs of PD. In a longitudinal study of PD, we evaluated whether heart rate variability (HRV) obtained using a 10-second ECG tracing, and the electrocardiographic QT-interval would be associated with PD severity and progression. Subjects were derived from a longitudinal study of 1741 individuals with early, stable PD. The severity of PD was measured using the global statistical test (GST). In a subset, the heart rate corrected QT-interval (QTcB) was calculated for each electrocardiogram (ECG). The HRV was measured for each ECG and then transformed to fit a normal distribution. The baseline analysis included 653 subjects, with 256 completing the 5-year follow up study. There was an association (P<0.05) between QTcB and PD severity in individuals that were taking QT-interval affecting drugs. A longer QT-interval at baseline was associated with more advanced PD at 5years (P<0.05), and greater disease progression over 5years (P<0.05). There was an association between diminished HRV and an orthostatic decrease in standing blood pressure at baseline in individuals with PD (P<0.05). HRV was not associated with PD severity or progression. In conclusion, we were able to detect measurable associations between the QTcB interval and PD severity, PD severity 5years later, and the change in disease over time. However, routine ECG tracings appear inadequate for the evaluation of autonomic function in PD.

Perception, Knowledge and Behaviors Related to Typhoon: A Cross Sectional Study among Rural Residents in Zhejiang, China.

(1) The objective of this study was to assess the risk perceptions, attitudes, knowledge, and behaviors related to typhoon among rural residents in Zhejiang province of China. A cross-sectional study was conducted among rural residents in Zhejiang province, China. Information was collected from 659 participants using a structured questionnaire. Univariate analysis and multivariable analysis were used to analyze the data. Participants were most concerned about property damage, followed by their health and life. Television, short message service (SMS), relatives and friends were the most common information sources. Most people had not been educated with disaster prevention measures. The complementary log-log (CLL) model showed that understanding typhoon warning signal, preparation time, risk perception of health damage and life threat, and fears of typhoon were independent predictors of adoption of coping behaviors. We found that: 1. Residents' risk perception of health and life threat caused by typhoon is inadequate; 2. There is a gap between residents' cognition or knowledge and behavior in rural areas; 3. The government should further make strategies to develop educational activities, in order to eliminate the gap and improve the ability of preparing for typhoon among rural residents.

Cell-based assays in combination with ultra-high performance liquid chromatography-quadrupole time of flight tandem mass spectrometry for screening bioactive capilliposide C metabolites generated by rat intestinal microflora.

Many plant-derived glycosides are used as medications. It is common that these glycosides show poor intestinal absorption but their metabolites generated by intestinal microflora demonstrate strong bioactivity. Hence, it is crucial to develop a method for the identification and characterization of the metabolites, and consequently reveal the pathway in which the glycosides are processed in gut. In this study, cell-based assays in combination with ultra-high performance liquid chromatography-quadrupole time of flight tandem mass spectrometry (UHPLC-QTOF-MS/MS) were developed for rapid discovery and evaluation of the metabolites of a glycoside compound, capilliposide C (LC-C). 92.7% of LC-C was biotransformed by rat intestinal microflora after 36-h incubation at 37°C. Human cancer cell lines HepG2, PC-3 and A549 was treated with metabolites pool, respectively, which was followed by cell viability assays and characterization of metabolites using UHPLC-QTOF-MS/MS. As a result, significant cytotoxicity was observed for the metabolites pool, from which six metabolites were identified. Based on the metabolites identified, deglycosylation and esterolysis were proposed as the major metabolic pathways of LC-C in rat intestinal microflora. In addition, M4, an esterolysis product of LC-C, was obtained and evaluated for its bioactivity in vitro. As a result, M4 exhibited a reduction in cell viability in HepG2 with an IC50 value of 17.46±1.55µg/mL.

Impact of Depression on Progression of Impairment and Disability in Early Parkinson's Disease.

BACKGROUND: Depression is one of the most common nonmotor symptoms associated with Parkinson's disease (PD), yet the impact of depression on progression of disease is unclear. OBJECTIVE: The aim of this study was to prospectively characterize the relationship between depressive symptoms and measures of disease progression in a large sample of patients with early, medically treated PD. METHODS: Baseline and longitudinal Beck Depression Inventory (BDI) scores from participants in the NINDS Exploratory Trials in PD Long Term Study 1 were correlated with changes in multiple measures of disease severity over 5 years. Multivariate analysis of predictors of change in BDI was performed. RESULTS: Of 1,741 participants, 746 completed 5-year assessments and were included. Mean age was 62.00 years (standard deviation [SD]: 9.22) and mean disease duration was 1.69 years (SD, 1.16). Mean BDI score was 6.24 (SD, 5.02) at baseline and 8.57 (SD, 6.60) at 5 years. Baseline BDI score was strongly associated with rate of change in all examined measures of disease severity. In multivariate analysis, BDI 5-year change was associated with change in UPDRS Part I (excluding depression item; P < 0.01), 33-item Parkinson's Disease Questionnaire (P < 0.01), EuroQOL Five Dimensional Questionnaire (P = 0.02), and Total Functional Capacity (P < 0.01), but was not associated with motor or cognitive measures. This model explained 68.8% of the variance 5-year change of the BDI score. CONCLUSIONS: Worse baseline BDI scores are associated with a decline in multiple measures of disease severity in PD. Worsening of BDI at 5 years was associated with worsening in UPDRS Part I and quality-of-life measures, but not with motor or cognitive measures.

DBGSA: a novel method of distance-based gene set analysis.

When compared with single gene functional analysis, gene set analysis (GSA) can extract more information from gene expression profiles. Currently, several gene set methods have been proposed, but most of the methods cannot detect gene sets with a large number of minor-effect genes. Here, we propose a novel distance-based gene set analysis method. The distance between two groups of genes with different phenotypes based on gene expression should be larger if a certain gene set is significantly associated with the given phenotype. We calculated the distance between two groups with different phenotypes, estimated the significant P-values using two permutation methods and performed multiple hypothesis testing adjustments. This method was performed on one simulated data set and three real data sets. After a comparison and literature verification, we determined that the gene resampling-based permutation method is more suitable for GSA, and the centroid statistical and average linkage statistical distance methods are efficient, especially in detecting gene sets containing more minor-effect genes. We believe that this distance-based method will assist us in finding functional gene sets that are significantly related to a complex trait. Additionally, we have prepared a simple and publically available Perl and R package (http://bioinfo.hrbmu.edu.cn/dbgsa or http://cran.r-project.org/web/packages/DBGSA/).

Zn-, Cd-, and Pb-transcription factor IIIA: properties, DNA binding, and comparison with TFIIIA-finger 3 metal complexes.

Properties of the metal ion binding sites of Zn-transcription factor IIIA (TFIIIA) were investigated to understand the potential of this type of zinc finger to undergo reactions that remove Zn(2+) from the protein. Zn-TFIIIA was purified from E. coli containing the cloned sequence for Xenopus laevis oocyte TFIIIA and its stoichiometry of bound Zn(2+) was shown to depend on the details of the isolation process. The average dissociation constant of Zn(2+) in Zn-TFIIIIA was 10(-7). The dissociation constant for Zn-F3, the third finger from the N-terminus of TFIIIA, was 1.0 x 10(-8). The reactivity of Zn-TFIIIA with a series of metal binding ligands, including 2-carboxy-2'-hydroxy-5'-sulfoformazylbenzene (zincon), 4-(2-pyridylazo)-resorcinol (PAR), and 3-ethoxy-2-oxo-butyraldehyde-bis-(N(4)-dimethylthiosemicarbazone) (H(2)KTSM(2)) revealed similar kinetics. The reactivity of PAR with Zn-TFIIIA declined substantially when the protein was bound to the internal control region (ICR) of the 5S ribosomal DNA. Both Cd(2+) and Pb(2+) disrupt TFIIIA binding to its cognate DNA sequence. The Pb(2+) dissociation constant of Pb-F3 was measured as 2.5 x 10(-8). According to NMR spectroscopy, F3 does not fold into a regular conformation in the presence of Pb(2+).

Interprotein metal exchange between transcription factor IIIa and apo-metallothionein.

Zn(2+) and Cd(2+) ion exchange between transcription factor IIIA (TFIIIA) and apo-metallothionein (MT) were studied using a combination of methods including chromatography, ultrafiltration and UV spectroscopy. Under near stoichiometric conditions, apoMT was able to remove most if not all of the zinc ions from TFIIIA, whether or not the TFIIIA was bound to the 5S DNA internal control region (ICR), and concomitantly inhibit its DNA-binding activity as indicated by an electrophoretic mobility shift assay. The kinetics of the two processes were similar. The rate of the metal exchange reaction increased with the concentrations of both reactants. A second-order rate constant of 30+/-10 M(-1)s(-1) was calculated. Similar observations were made for the reaction between apoMT and Cd-substituted TFIIIA, which proceeded without observable intermediates according to a spectrophotometric analysis. A very slow metal ion exchange occurred between Cd-TFIIIA and Zn-MT, but not between Cd-MT and Zn-TFIIIA. Comparative studies on the reaction of TFIIIA with a small competing ligand, ethylenedinitrilo-tetraacetic acid (EDTA), were also conducted. Although EDTA reacts with free Zn-TFIIIA, under similar conditions it failed to compete for Zn(2+) bound as Zn-TFIIIA-ICR.