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Purpose: We investigate in this study how individual variability in native language speech perception (termed Perceptual Sensitivity ) influences nonnative speech perception in Singaporean Tamil–English bilinguals. Further, we assess if and how contextual and demographic factors influence Perceptual Sensitivity in the acquired languages and if the influence of Perceptual Sensitivity on nonnative speech perception is different across younger and older bilinguals. Method: Perceptual Sensitivity in the native languages was examined by implementing Tamil and English gating tasks in 87 Singaporean Tamil–English bilinguals from two age groups (younger: 19–33 years; older: 55–70 years). Mandarin lexical tone discrimination was implemented as a measure of nonnative speech perception. Results: There was a wide range of variability in Perceptual Sensitivity scores in both languages across both age groups. Perceptual Sensitivity in the first native language (L1 Tamil) was a robust predictor of nonnative speech perception across both age groups, especially for the older bilinguals. However, general intelligence emerged as a stronger predictor than Tamil Perceptual Sensitivity in younger bilinguals. The influence of Tamil Perceptual Sensitivity on lexical tone perception was not tone-specific, supporting a general enhancement of lexical tone perception with better Tamil Perceptual Sensitivity. There was an influence of demographic factors on English Perceptual Sensitivity in older bilinguals, but not for Tamil and not in younger bilinguals. Conclusions: Our findings corroborate with previous studies in showing that native language Perceptual Sensitivity is positively associated with and predicts nonnative speech perception in younger and older adulthood regardless of language similarity but to varying degrees. Specifically, the influence of Perceptual Sensitivity on nonnative speech perception is stronger in older adulthood, suggesting a possible shift in reliance on crystallized language knowledge with age. Proficiency and use, among other demographic and language variables, do not appear to influence L1 Perceptual Sensitivity in a lesser used language (Tamil) as significantly as previously assumed.

Despite the growing number of bicultural bilinguals in the world, the way in which multisensory emotions are evaluated by bilinguals who identify with two or more cultures remains unknown. In the present study, Chinese-English bicultural bilinguals from Singapore viewed Asian or Caucasian faces and heard Mandarin or English speech, and evaluated the emotion from one of the two simultaneously-presented modalities. Reliance on the visual modality was greater when bicultural bilinguals processed Western audio-visual emotion information. Although no differences between modalities emerged when processing East-Asian audio-visual emotion information, correlations revealed that bicultural bilinguals increased their reliance on the auditory modality with more daily exposure to East-Asian cultures. Greater interference from the irrelevant modality was observed for Asian faces paired with English speech than for Caucasian faces paired with Mandarin speech. We conclude that processing of emotion in bicultural bilinguals is guided by culture-specific norms, and that familiarity influences how the emotions of those who speak a foreign language are perceived and evaluated.

Background Improvements in therapies have led to an increasing number of long-term survivors of brain metastases. The present series compares a population of 5-year survivors of brain metastases to a generalized brain metastases population to assess for factors attributable to long-term survival. Methods A single institution retrospective review was performed to identify 5-year survivors of brain metastases who received stereotactic radiosurgery (SRS). A historical control population of 737 patients with brain metastases was used to assess similarities and differences between the long-term survivor population and the general population treated with SRS. Results A total of 98 patients with brain metastases were found to have survived over 60 months. No differences between long-term survivors and controls were identified with regards to the age at first SRS (P = .19), primary cancer distribution (P = .80), and the number of metastases at first SRS (P = .90). Cumulative incidence of neurologic death at 6, 8 and 10 years for the long-term survivor cohort was 4.8%, 16%, and 16% respectively. In the historical controls, cumulative incidence of neurologic death reached a plateau at 40% after 4.9 years. A significant difference in the distribution of burden of disease at the time of the first SRS was found between the 5-year survivors and the control (P = .0049). 58% of 5-year survivors showed no evidence of clinical disease at the last follow-up. Conclusion Five-year survivors of brain metastases represent a diverse histologic population, suggesting a small population of oligometastatic and indolent cancers exist for each cancer type.

While anecdotal evidence suggests that music may facilitate verbal memory, empirical evidence for this is less clear. Here, we examined whether learners’ characteristics such as age, working memory (WM), and musical training may influence the effect of music on word learning. Young and older adults learned novel word-referent mappings presented in three music conditions (spoken in the presence of background music, sung in-key, and sung out-of-key) and a control condition (spoken in quiet) and their performance was assessed immediately after learning. We found that whereas age and, to an extent, musical training had a general effect on word learning, WM modulated the effect of music: performance was worse in the music conditions relative to the control condition for learners with lower WM whereas the opposite pattern was observed for those with higher WM. Our results thus highlight the importance of considering individual characteristics in determining the effect of music on verbal memory.

α1-Antitrypsin (AAT), a serine protease inhibitor, is the third most abundant protein in plasma. Although the best-known function of AAT is irreversible inhibition of elastase, AAT is an acute-phase reactant and is increasingly recognized to have a panoply of other functions, including as an anti-inflammatory mediator and a host-protective molecule against various pathogens. Although a canonical receptor for AAT has not been identified, AAT can be internalized into the cytoplasm and is known to affect gene regulation. Because AAT has anti-inflammatory properties, we examined whether AAT binds the cytoplasmic glucocorticoid receptor (GR) in human macrophages. We report the finding that AAT binds to GR using several approaches, including coimmunoprecipitation, mass spectrometry, and microscale thermophoresis. We also performed in silico molecular modeling and found that binding between AAT and GR has a plausible stereochemical basis. The significance of this interaction in macrophages is evinced by AAT inhibition of LPS-induced NF-κB activation and IL-8 production as well as AAT induction of angiopoietin-like 4 protein, which are, in part, dependent on GR. Furthermore, this AAT–GR interaction contributes to a host-protective role against mycobacteria in macrophages. In summary, this study identifies a new mechanism for the gene regulation, anti-inflammatory, and host-defense properties of AAT.

Senescent renal tubular cells may be linked to diabetic kidney disease (DKD)-related tubulopathy. We studied mice with or without diabetes in which hedgehog interacting protein (HHIP) was present or specifically knocked out in renal tubules (HhipLow-dose streptozotocin was employed to induce diabetes in both HhipCompared with HhipTubular HHIP deficiency prevented DKD-related tubulopathy, possibly via the inhibition of SGLT2 expression and cellular senescence.

A qualitative study using basic interpretive design identified the experiences of stress and barriers to professional help seeking among Filipino Americans (

Background: Sarcomas are rare, aggressive cancers which frequently metastasise to the lungs. Following diagnosis, patients typically undergo staging by means of a CT scan of their chest. This often identifies indeterminate pulmonary nodules (IPNs), but the significance of these in high-grade soft tissue sarcoma (STS) is unclear. Identifying whether these are benign or malignant is important for clinical decision making. This study analyses the clinical relevance of IPNs in high-grade STS. Methods: All patients treated at our centre for high-grade soft tissue sarcoma between 2010 and 2020 were identified from a prospective database. CT scans and their reports were reviewed, and survival data were collected from patient records. Results: 389 suitable patients were identified; 34.4% had IPNs on their CT staging scan and 20.1% progressed into lung metastases. Progression was more likely with IPNs ≥ 5 mm in diameter (p = 0.006), multiple IPNs (p = 0.013) or bilateral IPNs (p = 0.022), as well as in patients with primaries ≥ 5 cm (p = 0.014), grade 3 primaries (p = 0.009) or primaries arising deep to the fascia (p = 0.041). The median time to progression was 143 days. IPNs at diagnosis were associated with an increased risk of developing lung metastases and decreased OS in patients with grade 3 STS (p = 0.0019 and p = 0.0016, respectively); this was not observed in grade 2 patients. Conclusions: IPNs at diagnosis are associated with significantly worse OS in patients with grade 3 STS. It is crucial to consider the primary tumour as well as the IPNs when considering the risk of progression. Surveillance CT scans should be carried out within 6 months.

The brain is one of the most common metastatic sites among breast cancer patients, especially in those who have Her2-positive or triple-negative tumors. The brain microenvironment has been considered immune privileged, and the exact mechanisms of how immune cells in the brain microenvironment contribute to brain metastasis remain elusive. In this study, we found that neutrophils are recruited and influenced by c-Met high brain metastatic cells in the metastatic sites, and depletion of neutrophils significantly suppressed brain metastasis in animal models. Overexpression of c-Met in tumor cells enhances the secretion of a group of cytokines, including CXCL1/2, G-CSF, and GM-CSF, which play critical roles in neutrophil attraction, granulopoiesis, and homeostasis. Meanwhile, our transcriptomic analysis demonstrated that conditioned media from c-Met high cells significantly induced the secretion of lipocalin 2 (LCN2) from neutrophils, which in turn promotes the self-renewal of cancer stem cells. Our study unveiled the molecular and pathogenic mechanisms of how crosstalk between innate immune cells and tumor cells facilitates tumor progression in the brain, which provides novel therapeutic targets for treating brain metastasis.

Introduction Historical reservations regarding radiosurgery (SRS) for small-cell-lung-cancer (SCLC) brain metastases (BrM) include concerns for short-interval/diffuse CNS-progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small-cell-lung-cancer (NSCLC) where SRS is well established. Methods Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000-2022 were retrospectively collected (N=892-SCLC/N=4,785-NSCLC). Data from the prospective JLGK0901 SRS trial were analyzed as a comparison cohort (N=98-SCLC/N=794-NSCLC). OS and CNS-progression were analyzed using Cox-Proportional-Hazard and Fine-Gray models, respectively, with multivariable (MV) adjustment (including age/sex/performance-status/year/extracranial disease/BrM-number/BrM-volume). Mutation-stratified analyses were performed in propensity score-matched (PSM) retrospective cohorts of EGFR/ALK-positive-NSCLC, mutation-negative-NSCLC, and SCLC. Results OS was superior with NSCLC over SCLC in the retrospective dataset (median-OS, 10.5 vs 8.6 months, MV-p Conclusion After SRS, SCLC was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC overall but was similar in patients matched on baseline characteristics. Neurological mortality, lesions at CNS-progression, and leptomeningeal-progression were comparable. These findings may better inform clinical decision-making for SCLC patients.

Background Re-irradiation for recurrent gliomas is a controversial treatment option with no clear standard dose or concurrent systemic therapy. Methods This series represents a single-institution retrospective review of patients treated with re-irradiation for recurrent high-grade glioma. After 2012, patients were commonly offered concurrent bevacizumab as a cytoprotective agent against radiation necrosis. Kaplan-Meier method was used to estimate overall survival and progression-free survival. Cox proportional hazards regression was used to identify factors associated with overall survival and progression-free survival. Results Between 2001 and 2021, 52 patients underwent re-irradiation for a diagnosis of recurrent high-grade glioma. 36 patients (69.2%) had a histologic diagnosis of glioblastoma at the time of re-irradiation. The median BED10 (biological equivalent dose 10 Gy) of re-irradiation was 53.1 Gy. Twenty-one patients (40.4%) received concurrent bevacizumab with re-irradiation. Median survival for the entire cohort and for glioblastoma at the time of recurrence patients was 6.7 months and 6.0 months, respectively. For patients with glioblastoma at the time of recurrence, completing re-irradiation (HR 0.03, P < .001), use of concurrent bevacizumab (HR 0.3, P = .009), and the BED10 (HR 0.9, P = .005) were predictive of overall survival. Nine patients developed grade 3-5 toxicity; of these, 2 received concurrent bevacizumab and 7 did not (P = .15). Conclusion High dose re-irradiation with concurrent bevacizumab is feasible in patients with recurrent gliomas. Concurrent bevacizumab and increasing radiation dose may improve survival in patients with recurrent glioblastoma.

Background/Aims The inflammatory arthritides make up a majority of conditions requiring follow-up in rheumatology clinics; a treat-to-target management approach is advocated in patients with inflammatory arthritis (IA), requiring regular monitoring. With rising patient numbers and increasing demand on clinics, integration of digital healthcare has been advocated as a means to improving this, potentially allowing for fewer outpatient visits. The objective of this review is to evaluate the clinical effectiveness of electronic patient-reported outcome measures (ePROMs) as a digital remote monitoring intervention on disease activity and treatment decisions in patients with inflammatory arthritis. Methods Five databases including MEDLINE, Embase, PubMed, Cochrane Library and Web of Science were searched from inception to 29 August 2022. Randomised controlled trials (RCT) and (non-randomised) controlled clinical trials considering remote monitoring with ePROMS in IA samples that assessed disease activity scores, disease flare, treatment escalation and healthcare use were included, with meta-analysis and forest plots conducted for each outcome. Data regarding between-group differences in outcomes were extracted and a risk of bias assessment was completed by two assessors on all included studies using Cochrane Risk of Bias (RoB)-2 tool for RCTs and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) for non-randomised cohorts. Results The literature search identified 4230 abstracts, of which 8 relevant studies were included in the analysis after de-duplication and screening. Seven studies assessed patients with rheumatoid arthritis and one involved patients with axial spondyloarthritis. Most included studies were at high risk of bias. Compared with control, the disease activity in the ePROM group was lower (standardised mean difference (SMD) -0.15; 95% CI -0.27 to -0.03). A second analysis using a stricter definition of ePROM use limiting to studies without other combined interventions (eg. disease education) showed the same direction of effect but was not significant (SMD -0.13; 95% CI -0.31 to 0.04). There were no significant differences between groups in terms of disease flare (OR 2.32; 95% CI 0.21 to 25.28), escalation of immunosuppression (OR 1.12; 95% CI 0.70 to 1.80) or face-to-face clinic visits (OR -0.93; 95% CI -2.14 to 0.28). Conclusion This review suggests there is an advantage in using ePROMs to remotely monitor patients with IA in terms of disease outcomes. Importantly there was no detrimental impact in terms of clinic attendance frequency with ePROMs. There are limitations including heterogeneity in study design and substantial risk of bias in the studies included. ePROMs are likely here to stay, but we need better quality data to fully understand their role in clinical practice. Disclosure N. Arumalla: None. M. Adas: None. C.K.D. Chan: None. M. Gibson: None. Y.L. Man: None. S. Norton: None. J. Galloway: Honoraria; from AbbVie, Celgene, Chugai, Galapagos, Gilead, Janssen, Lilly, Pfizer, Roche and UCB. T. Garrood: None.

Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remain poorly understood. Here, we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL8 and CXCL1. Additionally, stimulation of IL1β secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle that generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood–brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention. Cancer Res; 76(17); 4970–80. ©2016 AACR.

The molecular pathways driving mesenchymal glioblastoma (GBM) are still not well understood. We report here that truncated glioma-associated oncogene homolog 1 (tGLI1) is a tumor-specific transcription factor that facilitates GBM growth, is enriched in the mesenchymal subtype of GBM and glioma stem cells (GSC), and promotes mesenchymal GSC by upregulating transcription of CD44. In an orthotopic GBM xenograft mouse model, tGLI1-overexpressing tumors grew more aggressively with increased proliferation and angiogenesis compared with control and GLI1-overexpressing xenografts. tGLI1 was highly expressed in GBM clinical specimens but undetectable in normal brains, whereas GLI1 was expressed in both tissues. A tGLI1 activation signature (tGAS) correlated with glioma grade, tumor angiogenesis, and poor overall survival, and GBMs with high tGAS were enriched with mesenchymal GBM/GSC gene signatures. Neurospheres contained increased levels of tGLI1, but not GLI1, compared with the monolayer culture; mesenchymal GSC expressed more tGLI1 than proneural GSC. Ectopic tGLI1 expression enhanced the ability of mesenchymal GSC to yield neurospheres in vitro and to form tumors in mouse brains. Selective tGLI1 knockdown reduced neurosphere formation of GBM cells. tGLI1 bound to and transactivated the promoter of the CD44 gene, a marker and mediator for mesenchymal GSC, leading to its expression. Collectively, these findings advance our understanding of GBM biology by establishing tGLI1 as a novel transcriptional activator of CD44 and a novel mediator of mesenchymal GBM and GSC.Significance: These findings highlight the role of a tumor-specific gain-of-function transcription factor tGLI1 in mesenchymal glioma stem cell maintenance and mesenchymal GBM growth. Cancer Res; 78(10); 2589–600. ©2018 AACR.

Supplementary Figure 3. Pano induced pancreatic tumor cell apoptosis.

Supplementary Figure 2. Pancreatic cells are resistant to VV-gp100 oncolysis but sensitive to CAR T cell-mediated cytotoxicity.

Supplementary Table 2. Comparison of ELISPOT responses between the current study and our recent study in pediatric glioma patients

Supplementary Table 1. Associations between baseline IFN-γ ELISPOT values vs. PFS or subsequent IFN-γ ESLIPOT responses

Supplementary Figure 4. Pano did not enhance the cytotoxicity of CARaMEL cells nor oncolysis of VV-gp100.

This file contains Supplemental Figure 1 and Supplemental Tables I and II.

Purpose: WHO grade 2 low-grade gliomas (LGG) with high risk factors for recurrence are mostly lethal despite current treatments. We conducted a phase I study to evaluate the safety and immunogenicity of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes in HLA-A2+ adults with high-risk LGGs in the following three cohorts: (i) patients without prior progression, chemotherapy, or radiotherapy (RT); (ii) patients without prior progression or chemotherapy but with prior RT; and (iii) recurrent patients.Experimental Design: GAAs were IL13Rα2, EphA2, WT1, and Survivin. Synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks for eight courses with intramuscular injections of poly-ICLC, followed by q12 week booster vaccines.Results: Cohorts 1, 2, and 3 enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity was encountered except for one case with grade 3 fever, fatigue, and mood disturbance (cohort 1). ELISPOT assays demonstrated robust IFNγ responses against at least three of the four GAA epitopes in 10 and 4 cases of cohorts 1 and 3, respectively. Cohort 1 patients demonstrated significantly higher IFNγ responses than cohort 3 patients. Median progression-free survival (PFS) periods since the first vaccine are 17 months in cohort 1 (range, 10–47+) and 12 months in cohort 3 (range, 3–41+). The only patient with large astrocytoma in cohort 2 has been progression-free for more than 67 months since diagnosis.Conclusion: The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade 2 glioma patients. These results warrant further evaluations of this approach. Clin Cancer Res; 21(2); 286–94. ©2014 AACR.

Supplementary Figure 1. Panc02-Her2, KPC-Her2 and 24JK-Her2 cells express comparable levels of Her2.