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Established prognostic factors for head and neck squamous cell carcinoma (HNSCC) mostly consist of clinical and tumor features assessed before treatment. We report a novel application of DNA methylation in peripheral blood before and after radiation therapy to further improve outcomes stratification.Peripheral blood samples from patients with nonmetastatic HNSCC were obtained for methylation analysis 1 week before and 1 month after radiation therapy. Patients were randomized 1:1 to a Discovery Cohort or a Validation Cohort. In the Discovery Cohort, associations between genome-wide methylation change (posttreatment minus pretreatment) and recurrence-free survival (RFS) as well as overall survival (OS) were evaluated using Cox regression. A methylation risk score (MRS) was then constructed from methylation levels at the top associated sites, filtered for residing within the regulatory regions of genes expressed in cells of hematopoietic lineage. The prognostic value of MRS was separately assessed in the Discovery and Validation Cohorts.Between December 2013 and September 2018, 115 patients participated in this study. Human papilloma virus negative status, oral cavity cancer, gastrostomy tube insertion, and higher neutrophil count before radiation therapy were associated with shorter RFS and OS (P.05). Genes downstream of the methylation sites comprising MRS are HIF1A, SF1, LGALS9, and FUT5, involved in hypoxia response, blood cell maturation, and immune modulation. High MRS (in the top third) was significantly associated with worse RFS (hazard ratio [HR], 7.1; 95% confidence interval [CI], 1.4-35.5; P = .016) and OS (HR, 15.9; 95% CI, 1.6-153.6; P = .017) in the Discovery Cohort, independent of the aforementioned risk factors. These findings were replicated in the Validation Cohort, for which high MRS also independently predicted worse RFS (HR, 10.2; 95%, CI 2.4-43.4; P = .002) and OS (HR, 3.7; 95% CI, 1.3-10.4; P = .015).We successfully trained and validated a signature of DNA methylation in peripheral blood before and after radiation therapy that stratified outcomes among patients with HNSCC, implicating the potential for genomics-tailored surveillance and consolidation treatment.

A Fourier series non-stationary coherency model with respect to the site conditions for the horizontal component was developed. The evolution of the model was achieved using parameters related to the site, inter-station distance, and time. First, based on the simulation of a non-stationary ground-motion field considering the wave-passage effect and site-response effect, the approach used for the estimation of coherency using wavelet transform is presented. Subsequently, the Fourier series non-stationary coherency model is formulated. The parameters are considered piecewise constant variables to represent the non-stationarity of the estimated coherency. The entire non-stationary strong ground motion was divided into ten parts according to the cumulative energy. The effects of the site and inter-station distance on the proposed model are presented. Parameters related to the site and inter-station distance were obtained. Finally, the proposed model is compared with the ground motion records at the SMART-1 array during Event 45, the stationary model, and the data from the Argostoli rock site dense array. This indicates that the Fourier series non-stationary coherency model with respect to site conditions for the horizontal component can well match the correlation of the realistic spatially variable seismic ground motion, which is related to the site, time, and inter-station distance.

Job automation is a critical decision that has brought about profound changes in the workplace. However, the question of what drives job automation remains unclear. This study conducts an interdisciplinary review of five theoretical frameworks on job automation, paying particular attention to the role played by artificial intelligence and machine learning. It highlights the concepts and mechanisms underlying each of the frameworks, compares and contrasts their similarities and differences, and highlights challenges and suggests opportunities of job automation. It also proposes an integrated framework on job automation by addressing the research gaps in extant frameworks and thereby contributes to the research and practice on this important topic.

DNA polymorphic markers and self-defined ethnicity groupings are used to group individuals with shared ancient geographic ancestry. Here we studied whether ancestral relationships between individuals could be identified from metabolic screening data reported by the California newborn screening (NBS) program. NBS data includes 41 blood metabolites measured by tandem mass spectrometry from singleton babies in 17 parent-reported ethnicity groupings. Ethnicity-associated differences identified for 71% of NBS metabolites (29 of 41, Cohen's dgt; 0.5) showed larger differences in blood levels of acylcarnitines than of amino acids (Plt; 1e-4). A metabolic distance measure, developed to compare ethnic groupings based on metabolic differences, showed low positive correlation with genetic and ancient geographic distances between the groups' ancestral world populations. Several outlier group pairs were identified with larger genetic and smaller metabolic distances (Black versus White) or with smaller genetic and larger metabolic distances (Chinese versus Japanese) indicating the influence of genetic and of environmental factors on metabolism. Using machine learning, comparison of metabolic profiles between all pairs of ethnic groupings distinguished individuals with larger genetic distance (Black versus Chinese, AUC = 0.96), while genetically more similar individuals could not be separated metabolically (Hispanic versus Native American, AUC = 0.51). Additionally, we identified metabolites informative for inferring metabolic ancestry in individuals from genetically similar populations, which included biomarkers for inborn metabolic disorders (C10:1, C12:1, C3, C5OH, Leucine-Isoleucine). This work sheds new light on metabolic differences in healthy newborns in diverse populations, which could have implications for improving genetic disease screening.

Background Programmed cell death protein 1 (PD-1) antibody has been approved for a variety of tumors, but its effective rate is unsatisfactory. New evidence suggests that mast cells are an important component of the tumor microenvironment and are associated with resistance to immunotherapy, but the underlying mechanism is not clear. Methods Bioinformatics analysis of patients with melanoma in TCGA-SKCM and GSE91061 was used to determine the prognostic value of mast cells and their association with anti-PD-1 immunotherapy. HMC-1 cells (mast cell line) and bone marrow-derived mast cells (BMMCs) were used to verify the effect of PD-1 antibody and cromolyn sodium in vitro. The mouse subcutaneous melanoma model was used to verify the effect of the PD-1 antibody on mast cells in vivo. Results Bioinformatics analysis showed that mast cells were a poor prognostic factor associated with resistance to anti-PD-1 immunotherapy. PD-1 was expressed on the mast cell membrane. The PD-1 antibody promoted the release of histamine and cytokines from mast cells via the PI3K/AKT pathway and calcium signaling pathway. The activation of mast cells induced by PD-1 antibody could be partially inhibited by cromolyn sodium. In vivo, cromolyn sodium increased the efficacy of PD-1 antibody and decreased the infiltration of mast cells and the density of microvessels. Conclusion PD-1+ mast cell activated by PD-1 antibody plays a negative role in the tumor microenvironment via the enhanced function of releasing histamine and cytokines. Inhibition of mast cell may provide a new solution to solve the low response rate of anti-PD-1 immunotherapy.

Purpose: This study aims to investigate the different degeneration processes of categorical perception (CP) of Mandarin lexical tones in the normal aging population and the pathological aging population with mild cognitive impairment (MCI). Method: In Experiment I, we compared the identification and discrimination of Tone 1 and Tone 2 across young adults, seniors aged 60–65 years, and older seniors aged 75–80 years with normal cognitive abilities. In Experiment II, we compared lexical tone identification and discrimination across young adults, healthy seniors, and age-matched seniors with MCI. Results: In Experiment I, tone perception was intact in seniors aged below 65 years. Those aged above 75 years could also maintain normal tone identification, whereas they showed poorer tone discrimination correlated with age-related poorer hearing level. In Experiment II, healthy seniors showed normal CP of Mandarin tones. Tone identification was also normal in those with MCI, whereas their tone discrimination had significantly degenerated. Conclusions: In the normal aging population, age-related hearing loss decreased signal audibility, accounting for poorer discrimination of Mandarin lexical tones in seniors above 75 years. In the pathological aging population with MCI, the poorer discrimination of lexical tones may be attributed to the additive effect of age, hearing loss, and cognitive impairment (e.g., impaired working memory and long-term phonological memory). This study uncovered the roles of low-level sensory processing and high-level cognitive processing in lexical tone perception in the Chinese aging population.

Although children develop categorical speech perception at a very young age, the maturation process remains unclear. A cross-sectional study in Mandarin-speaking 4-, 6-, and 10-year-old children, 14-year-old adolescents, and adults (n = 104, 56 males, all Asians from mainland China) was conducted to investigate the development of categorical perception of four Mandarin phonemic contrasts: lexical tone contrast Tone 1-2, vowel contrast /u/-/i/, consonant aspiration contrast /p/-/p

Background The addition of immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy has shown promising antitumor activity in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC), who have poor survival outcomes. We therefore compared the efficacy and adverse events of taxanes-cisplatin (TP) chemotherapy and camrelizumab plus TP chemotherapy in patients with RM-NPC.Materials and methods In this retrospective study, we collected the medical records of 194 patients with RM-NPC between June 30, 2019, and December 31, 2021. The patients received camrelizumab plus TP chemotherapy or TP chemotherapy alone as first-line treatment at Wuhan Union Hospital Cancer Center. The survival outcomes, efficacy, and treatment-related adverse reactions were compared between the groups.Results The medical records of 194 patients with RM-NPC were reviewed. Compared with the TP group, patients in the camrelizumab plus TP group had a longer median progression-free survival (PFS) (13.4 vs. 9.5 months; hazard ratio (HR) 0.628 [95% confidence interval (CI) 0.432–0.912]; P = 0.015) and overall survival (OS) (73.91% vs. 57.84%; HR 0.544 [95% CI 0.336–0.878]; P = 0.013). The results of multivariate analysis indicated that Epstein-Barr virus DNA (EBV DNA) load in plasma before treatment was an independent prognostic indicator associated with PFS (HR 0.488 [95% CI 0.336–0.709]; P P = 0.040)Conclusion Our study revealed that adding camrelizumab to taxanes-cisplatin chemotherapy showed a higher PFS and OS in patients with recurrent or metastatic nasopharyngeal carcinoma and had a manageable safety profile.

Purpose: This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Patients and Methods: In this single-center, single-arm, phase 2 trial, patients with resectable stage III–IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety. Results: Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%–57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%–88.9%). The median follow-up duration was 16.1 months (range, 8.3–28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%–99.4%). Grade 3 neoadjuvant therapy–related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%). Conclusions: Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.

Achieving facile control of the wavelength of light emitters is of great significance for many key applications in optoelectronics and photonics, including on-chip interconnection, super-resolution imaging, and optical communication. The Joule heating effect caused by electric current is widely applied in modulating the refractive index of silicon-based waveguides for reconfigurable nanophotonic circuits. Here, by utilizing localized Joule heating in the biased graphene device, we demonstrate electrically controlled wavelength-tunable photoluminescence (PL) from vertical van der Waals heterostructures combined by graphene and two-dimensional transition metal dichalcogenides (2D-TMDCs). By applying a moderate electric field of 6.5 kV·cm

In the current, increasingly dynamic environment, more attention is being devoted to ambidexterity (both explorative and exploitative learning), as it is beneficial to organizational functioning. Despite an abundance of research on organizational ambidexterity, there is a paucity of research examining team-level ambidexterity. In a cross-level empirical study, we examine a leader's dialectical thinking as an antecedent of team-level ambidexterity. We also incorporate collective team identification as a moderator in the study. Our findings support that a leader's dialectical thinking can help facilitate team ambidexterity that, in turn, improves employee performance. Those teams whose members have strong team identification and whose leader is high in dialectical thinking will reap the most benefit from team ambidexterity.

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Background: Li–Fraumeni syndrome (LFS) is associated with germline TP53 mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are often used in clinical counseling. The existing LFS criteria have limitations, suggesting the need for an advanced prediction tool to support clinical decision making for TP53 mutation testing and LFS management.Methods: Based on a Mendelian model, LFSPRO estimates TP53 mutation probability through the Elston–Stewart algorithm and consequently estimates future risk of cancer. With independent datasets of 1,353 tested individuals from 867 families, we evaluated the prediction performance of LFSPRO.Results: LFSPRO accurately predicted TP53 mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center in the United States, the observed to expected ratio (OE) = 1.35 (95% confidence interval, 0.99–1.80); area under the receiver operating characteristic curve (AUC) = 0.85 (0.75–0.93); a population-based sarcoma cohort from the International Sarcoma Kindred Study in Australia, OE = 1.62 (1.03–2.55); AUC = 0.67 (0.54–0.79); and the NCI LFS study cohort, OE = 1.28 (1.17–1.39); AUC = 0.82 (0.78–0.86). LFSPRO also showed higher sensitivity and specificity than the classic LFS and Chompret criteria. LFSPRO is freely available through the R packages LFSPRO and BayesMendel.Conclusions: LFSPRO shows good performance in predicting TP53 mutations in individuals and families in varied situations.Impact: LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for individuals and families with LFS. Cancer Epidemiol Biomarkers Prev; 26(6); 837–44. ©2017 AACR.

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Supplementary Table from Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial

Purpose:This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).Patients and Methods:In this single-center, single-arm, phase 2 trial, patients with resectable stage III–IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety.Results:Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%–57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%–88.9%). The median follow-up duration was 16.1 months (range, 8.3–28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%–99.4%). Grade 3 neoadjuvant therapy–related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%).Conclusions:Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.

PDF file, 333K, Funnel plots of the hazard ratio (HR) for survival.

Supplementary Data from Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial

Purpose: The prognostic value of circulating tumor cells (CTC) detected in breast cancer patients is currently under debate. Different time points of blood collections and various CTC assays have been used in the past decades. Here, we conducted the first comprehensive meta-analysis of published literature on the prognostic relevance of CTC, including patients with early and advanced disease.Experimental Design: A comprehensive search for articles published between January 1990 and January 2012 was conducted; reviews of each study were conducted and data were extracted. The main outcomes analyzed were overall survival (OS) and disease-free survival (DFS) in early-stage breast cancer patients, as well as progression-free survival (PFS) and OS in metastatic breast cancer patients. Pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also conducted.Results: Forty-nine eligible studies enrolling 6,825 patients were identified. The presence of CTC was significantly associated with shorter survival in the total population. The prognostic value of CTC was significant in both early (DFS: HR, 2.86; 95% CI, 2.19–3.75; OS: HR, 2.78; 95% CI, 2.22–3.48) and metastatic breast cancer (PFS: HR, 1.78; 95% CI, 1.52–2.09; OS: HR, 2.33; 95% CI, 2.09–2.60). Further subgroup analyses showed that our results were stable irrespective of the CTC detection method and time point of blood withdrawal.Conclusion: Our present meta-analysis indicates that the detection of CTC is a stable prognosticator in patients with early-stage and metastatic breast cancer. Further studies are required to explore the clinical utility of CTC in breast cancer. Clin Cancer Res; 18(20); 5701–10. ©2012 AACR.

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