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Background: Leukotriene-receptor antagonists (LTRA) and inhaled corticosteroids (ICS) are common controller medications for asthma, but limited studies examine their comparative risks on neuropsychiatric adverse events (NAEs) in patients with asthma., Objective: To investigate the comparative risks of LTRA versus ICS on 7 distinct categories of NAEs in patients with asthma at a nationwide level., Methods: We conducted a nationwide cohort study during 2010-2021. Incident NAEs and their clinical subgroups (eg, psychotic disorders, anxiety disorders, movement disorders, behavioral and emotional disorders, mood disorders, sleep-related disorders, and personality disorders) were assessed. Cox proportional hazards regressions were used to quantify the comparative risks., Results: There were 1,249,897 patients with asthma aged 6 to 64 years. Incidence rates for NAEs were 25.10 per 1000 person-years among patients treated with LTRA and 23.46 per 1000 person-years among those treated with ICS. The incidence rate difference was 1.64 (95% confidence interval [CI]: 0.30-2.98) per 1000 person-years. Positive associations of NAEs and 3 clinical subgroups were found in patients treated with LTRA compared with ICS (hazard ratios [HR]: 1.06 [95% CI: 1.00-1.12] for NAEs; HR: 1.88 [95% CI: 1.24-2.84] for psychotic disorders; HR: 1.10 [95% CI: 1.01-1.20] for anxiety disorders; and HR: 1.27 [95% CI: 1.02-1.58] for behavioral and emotional disorders), but not for movement disorders, mood disorders, sleep-related disorders, and personality disorders., Conclusions: This nationwide cohort study identified heightened risks, ranging from 6% to 88%, of NAEs and 3 clinical subgroups in patients with asthma treated with LTRA compared with ICS. These findings underscore the necessity for clinicians to communicate with patients regarding potential neuropsychiatric harms when prescribing LTRA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers., Methods: A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety., Results: Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively., Conclusion: The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation., Clinicaltrials.gov Identifier: NCT03162510., (© The Author(s) 2024. Published by Oxford University Press.)

Immunotherapy has revolutionized cancer treatment, but the lack of a reliable predictive biomarker for treatment response remains a challenge. Alpha-1,6-Mannosylglycoprotein 6-β-N-Acetylglucosaminyltransferase 5 (MGAT5) is a key regulator of complex N-glycan synthesis, and its dysregulation is associated with cancer progression. The lectin Phaseolus vulgaris leukoagglutinin (PHA-L) specifically binds to mature MGAT5 products. Previous studies have indicated elevated PHA-L staining in head and neck squamous cell carcinoma (HNSCC), which implies increased activity of MGAT5. However, the specific role of MGAT5 in HNSCC remains unclear. In this study, we found significantly higher PHA-L staining and MGAT5 expression in HNSCC tumors compared to adjacent non-tumor tissues. Using a mass spectrometry (MS)-based glycoproteomic approach, we identified 163 potential protein substrates of MGAT5. Functional analysis revealed that protein substrates of MGAT5 regulated pathways related to T cell proliferation and activation. We further discovered that PD-L1 was among the protein substrates of MGAT5, and the expression of MGAT5 protected tumor cells from cytotoxic T lymphocyte (CTL) killing. Treatment of nivolumab alleviated the protective effects of MGAT5 on CTL activity. Consistently, patients with MGAT5-positive tumors showed improved responses to immunotherapy compared to those with MGAT5-negative tumors. Using purified PD-L1 from HNSCC cells and a glycoproteomic approach, we further deciphered that the N35 and N200 sites carry the majority of complex N-glycans on PD-L1. Our findings highlight the critical role of MGAT5-mediated branched N-glycans on PD-L1 in modulating the interaction with the immune checkpoint receptor PD-1. Consequently, we propose that MGAT5 could serve as a biomarker to predict patients' responses to anti-PD-1 therapy. Furthermore, targeting the branched N-glycans at N35 and N200 of PD-L1 may lead to the development of novel diagnostic and therapeutic approaches., (© 2024. The Author(s).)

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting up to 20% of children in developed countries. Although probiotics have shown promise as adjuvant treatments for AD, their mechanisms are not well understood., Objective: Building upon our previous studies, we investigated whether Lactobacillus gasseri and its moonlighting glyceraldehyde 3-phosphate dehydrogenase (GAPDH), namely LGp40, could be beneficial in AD management., Methods: In AD mouse models (SKH and C57BL/6J mice) with ovalbumin (OVA) and Dermatophagoides pteronyssinus (Der p) allergens, aligning with the "outside-in" and "inside-out" hypotheses, we administered L. gasseri orally and LGp40 intraperitoneally to investigate their protective effects. The evaluation involved measuring physiological, pathological, and immune function parameters. To delve deeper into the detailed mechanism of LGp40 protection in AD, additional assays were conducted using human skin keratinocytes (HaCaT) and monocytes (THP1) cell lines., Results: L. gasseri and LGp40 enhanced skin barrier function and increased skin moisture retention. They also led to reduced infiltration of Langerhans cells in the dermis and mitigated skewed Th2 and Th17 immune responses. Moreover, LGp40 inhibited allergen-induced keratinocyte apoptosis through the blockade of the caspase-3 cascade and reduced the NLR family pyrin domain containing 3 (NLRP3) inflammasome in macrophages. These inhibitions were achieved through the activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway., Conclusion: The results of this study provide a novel insight into the mechanism of action of probiotics in the prevention and treatment for allergic disorders through the moonlighting GAPDH protein.

Doping sorted graphene quantum dots (GQDs) with heteroatoms and functionalizing them with amino acid could improve their radiative recombination and two-photon properties-including their excitation-wavelength-independent photoluminescence from the ultraviolet to the near-infrared-I (NIR-I) region, absorption, quantum yield, absolute cross section, lifetime, and radiative-to-nonradiative decay ratio-under two-photon excitation (TPE) at a low excitation energy and short photoexcitation duration, as determined using a self-made optical microscopy system with a femtosecond Ti-sapphire laser. Four types of sorted GQDs were investigated: undoped GQDs, nitrogen-doped GQDs (N-GQDs), amino-functionalized GQDs (amino-GQDs), and N-doped and amino-functionalized GQDs (amino-N-GQDs). Among them, the sorted amino-N-GQDs are effective as a two-photon photosensitizer and generate the highest quantity of reactive oxygen species for the elimination of multidrug-resistant cancer cells through two-photon photodynamic therapy (PDT). Larger amino-N-GQDs result in a greater number of C-N and N-functionalities, leading to a superior photochemical effect and more favorable intrinsic luminescence properties, making the dots effective contrast agents for tracking and localizing cancer cells during in-depth bioimaging in a three-dimensional biological environment under TPE in the NIR-II region. Overall, this study highlights the potential of large amino-N-GQDs as a material for future application to dual-modality two-photon PDT and biomedical imaging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Context: Recent studies suggest that the clinical characteristics and biological behavior of pituitary tumors (PITs) in patients with multiple endocrine neoplasia type 1 (MEN1) may not be as aggressive as previously reported. Increased imaging of the pituitary as recommended by screening guidelines identifies more tumors, potentially at an earlier stage. However, it is unknown if these tumors have different clinical characteristics in different MEN1 mutations., Objective: To assess characteristics of patients with MEN1 with and without PITs, and compare among different MEN1 mutations., Methods: Data of patients with MEN1 in a tertiary referral center from 2010 to 2023 were retrospectively analyzed., Results: Forty-two patients with MEN1 were included. Twenty-four patients had PITs, 3 of which were invasive and managed with transsphenoidal surgery. One PIT enlarged during follow-up. Patients with PITs had a higher median age at MEN1 diagnosis than those without PITs. MEN1 mutations were identified in 57.1% of patients, including 5 novel mutations. In patients with PITs, those with MEN1 mutations (mutation+/PIT+ group) had more additional MEN1-associated tumors than those without (mutation-/PIT+ group). The mutation+/PIT+ group had a higher incidence of adrenal tumors and a lower median age at initial manifestation of MEN1 than the mutation-/PIT+ group. The most common neuroendocrine neoplasm was nonfunctional in the mutation+/PIT+ group and insulin-secreting in the mutation-/PIT+ group., Conclusion: This is the first study comparing characteristics of patients with MEN1 with and without PITs harboring different mutations. Patients without MEN1 mutations tended to have less organ involvement and it might be reasonable for them to receive less intensive follow-up., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival [PFS], clinical benefit rate, adverse events, duration of response, time to progression, overall survival [OS]) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC., (© 2023. The Author(s).)

In Taiwan, breast cancer has the highest incidence among all cancers. Although adjunctive traditional Chinese medicine treatment (TCM) have been used to ameliorate the side effects or discomfort caused by cancer treatments, no study has focused on the assessment of the quality of life of patients undergoing adjunctive TCM treatments. This study compared the quality of life between breast cancer patients treated with and without adjunctive TCM. Questionnaires were collected from 7 hospitals with a Chinese medicine clinic in 2018 to 2019. Breast cancer patients who had cancer stages I, II, or III and also underwent resection surgery were included in the study. They were divided into 2 groups: patients receiving cancer treatments with adjunctive traditional Chinese medicine (TCM group) and those receiving cancer treatments without adjunctive traditional Chinese medicine (non-TCM group). A 1:1 matching was used to obtain the study participants. The EQ-5D questionnaire was used to assess the quality of life. Statistical analysis was performed using the t -test and ANOVA to compare the differences between variables. The conditional multiple regression model was applied to explore the factors associated with quality of life in breast cancer patients. A total of 543 participants were surveyed, and 450 participants were included in the study. The EQ-5D score of the TCM group (81.60 ± 11.67) was significantly higher than that of the non-TCM group (78.80 ± 13.10; P  < .05). The results of a conditional multiple regression model showed that the TCM group had a higher (3.45 points) quality of life than non-TCM group ( P  = .002) after adjusting for other related factors. After stratifying by cancer stage, patients with cancer stages II and III scored 5.58 and 4.35 points higher in the TCM group than did those in the non-TCM group ( P  < .05). Breast cancer patients undergoing cancer treatment with adjunctive traditional Chinese medicine have a higher quality of life than those treated without adjunctive traditional Chinese medicine.

Increased levels of surfactant protein D (SP-D) and lipid-laden foamy macrophages (FMs) are frequently found under oxidative stress conditions and/or in patients with chronic obstructive pulmonary disease (COPD) who are also chronically exposed to cigarette smoke (CS). However, the roles and molecular mechanisms of SP-D and FMs in COPD have not yet been determined. In this study, increased levels of SP-D were found in the bronchoalveolar lavage fluid (BALF) and sera of ozone- and CS-exposed mice. Furthermore, SP-D-knockout mice showed increased lipid-laden FMs and airway inflammation caused by ozone and CS exposure, similar to that exhibited by our study cohort of chronic smokers and COPD patients. We also showed that an exogenous recombinant fragment of human SP-D (rfhSP-D) prevented the formation of oxidized low-density lipoprotein (oxLDL)-induced FMs in vitro and reversed the airway inflammation and emphysematous changes caused by oxidative stress and CS exposure in vivo. SP-D upregulated bone marrow-derived macrophage (BMDM) expression of genes involved in countering the oxidative stress and lipid metabolism perturbations induced by CS and oxLDL. Our study demonstrates the crucial roles of SP-D in the lipid homeostasis of dysfunctional alveolar macrophages caused by ozone and CS exposure in experimental mouse emphysema, which may provide a novel opportunity for the clinical application of SP-D in patients with COPD., (© 2022. The Author(s), under exclusive licence to CSI and USTC.)

Objectives: The optimal duration of anti-PD-1 for cancer therapy has not been tested, especially when using combination therapy. Epidermal growth factor receptor (EGFR) pathway blocker was the top compound that enhanced T-cell killing of tumor cells in a high-throughput immune-oncology screen, possibly by stimulate the antigen presentation machinery and other mechanisms. We explored the effect of combination of EGFR inhibition with a short course of anti-PD-1 therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC)., Method: We analyzed the effect of a short course of anti-PD-1 with continuous afatinib on the survival of a real-world cohort of R/M HNSCC patients. Patient characteristics, treatments, efficacies, and toxicities were reviewed and recorded for analysis., Results: From November 2016 to May 2018, 51 consecutive patients received pembrolizumab and afatinib. The cutoff date was June 30, 2022. The most common toxicities (all grades) were diarrhea (62.7%), skin rash (43.1%), mucositis (31.4%), and paronychia (23.5%). The objective response rate was 54.9% (95% confidence interval [CI] 40.3-68.9%). Median progression-free survival was 5.9 months (95% CI: 4.4-7.6 months), and the median overall survival was 10.5 months (95% CI: 6.8-16.5 months). The 12-month, 24-month, 36-month, and 48-month survival rate was 47.0%, 22.5%, 17.7%, and 12.6% respectively., Conclusions: This retrospective study showed that short course pembrolizumab with afatinib therapy has acceptable efficacy in R/M HNSCC patients. The durable response and long-term survival rates were similar to prospective clinical trials. Short course anti-PD-1 therapy, especially in combination with EGFR blocker, is worth for further prospective study., (© 2022. The Author(s).)

Background: The extra-intestinal effects of probiotics for preventing allergic diseases are well known. However, the probiotic components that interact with host target molecules and have a beneficial effect on allergic asthma remain unknown. Lactobacillus gasseri attenuates allergic airway inflammation through the activation of peroxisome proliferator- activated receptor γ (PPARγ) in dendritic cells. Therefore, we aimed to isolate and investigate the immunomodulatory effect of the PPARγ activation component from L. gasseri., Methods: Culture supernatants of L. gasseri were fractionated and screened for the active component for allergic asthma. The isolated component was subjected to in vitro functional assays and then cloned. The crystal structure of this component protein was determined using X-ray crystallography. Intrarectal inoculation of the active component-overexpressing Clear coli (lipopolysaccharide-free Escherichia coli) and intraperitoneal injection of recombinant component protein were used in a house dust mite (HDM)-induced allergic asthma mouse model to investigate the protective effect. Recombinant mutant component proteins were assayed, and their structures were superimposed to identify the detailed mechanism of alleviating allergic inflammation., Results: A moonlighting protein, glycolytic glyceraldehyde 3-phosphate dehydrogenase (GAPDH), LGp40, that has multifunctional effects was purified from cultured L. gasseri, and the crystal structure was determined. Both intrarectal inoculation of LGp40-overexpressing Clear coli and intraperitoneal administration of recombinant LGp40 protein attenuated allergic inflammation in a mouse model of allergic asthma. However, CDp40, GAPDH isolated from Clostridium difficile did not possess this anti-asthma effect. LGp40 redirected allergic M2 macrophages toward the M1 phenotype and impeded M2-prompted Th2 cell activation through glycolytic activity that induced immunometabolic changes. Recombinant mutant LGp40, without enzyme activity, showed no protective effect against HDM-induced airway inflammation., Conclusions: We found a novel mechanism of moonlighting LGp40 in the reversal of M2-prompted Th2 cell activation through glycolytic activity, which has an important immunoregulatory role in preventing allergic asthma. Our results provide a new strategy for probiotics application in alleviating allergic asthma., (© 2022. The Author(s).)

Purpose: EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen presentation during anti-PD-1 monotherapy in humans remain unknown. We hypothesized that afatinib, an irreversible EGFR tyrosine kinase inhibitor, would improve outcomes in patients treated with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) by promoting antigen presentation and immune activation in the tumor microenvironment., Patients and Methods: The ALPHA study (NCT03695510) was a single-arm, Phase II study with Simon's 2-stage design. Afatinib and pembrolizumab were administered to patients with platinum-refractory, recurrent, or metastatic HNSCC. The primary endpoint was the objective response rate (ORR). The study applied gene expression analysis using a NanoString PanCancer Immune Profiling Panel and next-generation sequencing using FoundationOne CDx., Results: From January 2019 to March 2020, the study enrolled 29 eligible patients. Common treatment-related adverse events were skin rash (75.9%), diarrhea (58.6%), and paronychia (44.8%). Twelve patients (41.4%) had an objective partial response to treatment. The median progression-free survival was 4.1 months, and the median overall survival was 8.9 months. In a paired tissue analysis, afatinib-pembrolizumab were found to upregulate genes involved in antigen presentation, immune activation, and natural killer cell-mediated cytotoxicity. Unaltered methylthioadenosine phosphorylase and EGFR amplification may predict the clinical response to the therapy., Conclusions: Afatinib may augment pembrolizumab therapy and improve the ORR in patients with HNSCC. Bioinformatics analysis suggested the enhancement of antigen presentation machinery in the tumor microenvironment., (©2022 The Authors; Published by the American Association for Cancer Research.)

Nitrogen doping and amino group functionalization through chemical modification lead to strong electron donation. Applying these processes to a large π -conjugated system of graphene quantum dot (GQD)-based materials as electron donors increases the charge transfer efficiency of nitrogen-doped amino acid-functionalized GQDs (amino-N-GQDs), resulting in enhanced two-photon absorption, post-two-photon excitation (TPE) stability, TPE cross-sections, and two-photon luminescence through the radiative pathway when the lifetime decreases and the quantum yield increases. Additionally, it leads to the generation of reactive oxygen species through two-photon photodynamic therapy (PDT). The sorted amino-N-GQDs prepared in this study exhibited excitation-wavelength-independent two-photon luminescence in the near-infrared region through TPE in the near-infrared-II region. The increase in size resulted in size-dependent photochemical and electrochemical efficacy, increased photoluminescence quantum yield, and efficient two-photon PDT. Therefore, the sorted amino-N-GQDs can be applicable as two-photon contrast probes to track and localize analytes in in-depth two-photon imaging executed in a biological environment along with two-photon PDT to eliminate infectious or multidrug-resistant microbes.

Immune checkpoint inhibitors have limited efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). We investigated prognostic markers for nivolumab-based therapy in advanced or recurrent PDAC. Consecutive patients receiving nivolumab-based therapy at our institution between 2015 and 2020 were evaluated. Overall survival (OS) was analyzed through univariate and multivariate analyses. Spleen volume was estimated from the width, thickness, and length of the spleen. A total of 45 patients were identified. Biweekly nivolumab was administered as monotherapy ( n = 5) or in combination with chemotherapy or targeted therapy ( n = 40). Among 31 evaluable patients, the response and disease control rates were 7% and 36%, respectively. The baseline median spleen volume was 267 (110-674) mL. Patients with spleens ≥267 mL had significantly shorter median OS (1.9 months, 95% confidence interval [CI], 1.0-2.7) than did those with smaller spleens (8.2 months, 95% CI, 5.6-10.8; P = .003). In the multivariate analysis, spleen volume of <267 mL, ≤2 lines of prior chemotherapy, ECOG performance status of 0-2, add-on nivolumab with stable disease after prior therapy, concomitant or sequential cell therapy, high lymphocyte count, and total bilirubin <1 mg/dL were independent favorable prognostic factors for OS. In the control groups of patients receiving gemcitabine-based chemotherapy ( n = 142) or FOLFIRINOX regimen ( n = 24), spleen volume exhibited no prognostic significance. In heavily pretreated PDAC, a large spleen may predict poor OS following nivolumab-based immunotherapy. Studies with larger cohorts should confirm the prognostic value of spleen volume., Competing Interests: Ono Pharmaceutical Co., Ltd supported nivolumab for an ongoing investigator-initiated clinical trial in pancreatic cancer at National Taiwan University Hospital., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Human SP-D is a potent innate immune molecule whose presence at pulmonary mucosal surfaces allows its role in immune surveillance against pathogens. Higher levels of serum SP-D have been reported in the patients with severe acute respiratory syndrome coronavirus (SARS-CoV). Studies have suggested the ability of human SP-D to recognise spike glycoprotein of SARS-CoV; its interaction with HCoV-229E strain leads to viral inhibition in human bronchial epithelial (16HBE) cells. Previous studies have reported that a recombinant fragment of human SP-D (rfhSP-D) composed of 8 Gly-X-Y repeats, neck and CRD region, can act against a range of viral pathogens including influenza A Virus and Respiratory Syncytial Virus in vitro , in vivo and ex vivo . In this context, this study was aimed at examining the likely protective role of rfhSP-D against SARS-CoV-2 infection. rfhSP-D showed a dose-responsive binding to S1 spike protein of SARS-CoV-2 and its receptor binding domain. Importantly, rfhSP-D inhibited interaction of S1 protein with the HEK293T cells overexpressing human angiotensin converting enzyme 2 (hACE2). The protective role of rfhSP-D against SARS-CoV-2 infection as an entry inhibitor was further validated by the use of pseudotyped lentiviral particles expressing SARS-CoV-2 S1 protein; ~0.5 RLU fold reduction in viral entry was seen following treatment with rfhSP-D (10 µg/ml). These results highlight the therapeutic potential of rfhSP-D in SARS-CoV-2 infection and merit pre-clinical studies in animal models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hsieh, Beirag, Murugaiah, Chou, Kuo, Kao, Madan, Kishore and Wang.)

Virus-induced asthma is prevalent among children, but its underlying mechanisms are unclear. Accumulated evidence indicates that early-life respiratory virus infection increases susceptibility to allergic asthma. Nonetheless, the relationship between systemic virus infections, such as enterovirus infection, and the ensuing effects on allergic asthma development is unknown. Early-life enterovirus infection was correlated with higher risks of allergic diseases in children. Adult mice exhibited exacerbated mite allergen-induced airway inflammation following recovery from EV-A71 infection in the neonatal period. Bone marrow-derived macrophages (BMDMs) from recovered EV-A71-infected mice showed sustained innate immune memory (trained immunity) that could drive naïve T helper cells toward Th2 and Th17 cell differentiation when in contact with mites. Adoptive transfer of EV-A71-trained BMDMs induced augmented allergic inflammation in naïve recipient mice, which was inhibited by 2-deoxy-D-glucose (2-DG) pretreatment, suggesting that trained macrophages following enterovirus infection are crucial in the progression of allergic asthma later in life.

In this study, sorted nitrogen-doped graphene quantum dots were prepared and subsequently conjugated with polymers. The synthesized materials exhibited excitation-wavelength-independent photoluminescence emissions ranging from ultraviolet to near-infrared and were 0.9-8.4 nm in size. The materials also exhibited high-photoluminescence quantum yields and excellent two-photon properties. Therefore, in two-photon bioimaging the materials with different emission spectra can be effective two-photon contrast agents. Specific antibodies were used to label organelles in cancer cells and identify nuclear antigens, thereby enabling the simultaneous detection of four targets in cells at a single two-photon excitation wavelength. The sorted nitrogen-doped graphene quantum dot materials were determined to be considerably more advantageous than organic dyes in identifying multiplexed targets, and they can be effective probes in cellular imaging.

Background: Laparoscopic sacral hysteropexy (SH) is a minimally invasive and effective treatment for uterovaginal prolapse in women who wish to retain the uterus. However, this procedure is limited by a steep learning curve and a long operating time. In this study, we aim to evaluate the surgical outcomes of a modified laparoscopic SH procedure using innovative methods of vaginal mesh attachment, which we hypothesized to be equally effective and time-saving., Methods: This was a prospective, parallel, comparative study conducted at a tertiary referral hospital. A total of 34 women with advanced (POPQ [Pelvic Organ Prolapse Quantification] stages ≧ 2) uterine prolapse, who underwent a laparoscopic SH procedure using lightweight polypropylene Y-mesh grafts (ALYTE), were studied. In half (n = 17) of the cases, fibrin sealant spray (TISSEEL) was applied to the meshes fixed at the anterior and posterior vaginal wall with fewer (six vs at least ten) sutures. A detailed comparison of one-year outcomes between groups was performed., Results: Patient characteristics and perioperative results were comparable between groups with the exception of a significantly shorter total operating time (247.0 vs 292.9 minutes, p = 0.04) noted in the fibrin group. At 1 year, anatomic success (POPQ stage ≦1) rates (76.5% vs 76.5%) were not different between groups. There were eight patients, with four in each group, who had surgical failure. Notably, most (7/8; 87.5%) surgical failures were at the anterior compartment (i.e, recurrent cystocele). No vaginal mesh extrusions were noted. After statistical analysis, we found "cystocele as the dominant prolapse before operation" was a significant predisposing factor for prolapse recurrence (p = 0.019; odds ratio = 8.04)., Conclusion: The modified laparoscopic SH procedure using Y-mesh grafts and fibrin sealant spray with fewer vaginal sutures was equally effective as conventional methods but saved time. Laparoscopic SH using Y-mesh grafts might not be as effective in repairing a concomitant dominant cystocele.

Objectives: Patients with type 2 diabetes mellitus (T2DM) exhibit strong insulin resistance or abnormal insulin production. Probiotics, which are beneficial live micro-organisms residing naturally in the intestinal tract, play indispensable roles in the regulation of host metabolism. However, the detailed mechanisms remain unclear. Here, we evaluate the mechanisms by which probiotic strains mediate glycemic regulation in the host. The findings should enable the development of a safe and natural treatment for patients with T2DM., Research Designs and Methods: Sugar consumption by more than 20 strains of Lactobacillus species was first evaluated. The probiotic strains that exhibited high efficiency of sugar consumption were further coincubated with Caco-2 cells to evaluate the regulation of sugar absorption in gut epithelial cells. Finally, potential probiotic strains were selected and introduced into a T2DM animal model to study their therapeutic efficacy., Results: Among the tested strains, Lactobacillus salivarius AP-32 and L. reuteri GL-104 had higher monosaccharide consumption rates and regulated the expression of monosaccharide transporters. Glucose transporter type-5 and Na + -coupled glucose transporter mRNAs were downregulated in Caco-2 cells after AP-32 and GL-104 treatment, resulting in the modulation of intestinal hexose uptake. Animal studies revealed that diabetic mice treated with AP-32, GL-104, or both showed significantly decreased fasting blood glucose levels, improved glucose tolerance and blood lipid profiles, and attenuated diabetes-mediated liver and kidney injury., Conclusion: Our data elucidate a novel role for probiotics in glycemic regulation in the host. L. salivarius AP-32 and L. reuteri GL-104 directly reduce monosaccharide transporter expression in gut cells and have potential as therapeutic probiotics for patients with T2DM., Competing Interests: Competing interests: P-SH, H-HH, S-HH and Y-WK are employers of Glac Biotech Co, Ltd, Tainan City, Taiwan., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Goat milk (GM), as compared to cow milk (CM), is easier for humans to digest. It also has antioxidant and anti-inflammatory effects and can improve minor digestive disorders and prevent allergic diseases in infants. It is unclear whether GM consumed in pregnant mothers has any protective effects on allergic diseases in infants. In this experimental study with mice, we found GM feeding enhanced immunoglobulin production, antigen-specific (ovalbumin, OVA) immune responses, and phagocytosis activity. The GM-fed mice had an increasing proportion of CD3 + T lymphocytes in the spleen. Splenocytes isolated from these animals also showed significantly increased production of cytokines IFN-γ and IL-10. More importantly, GM feeding during pregnancy and lactation periods can confer protective activity onto offspring by alleviating the airway inflammation of allergic asthma induced by mite allergens. There was a remarkably different composition of gut microbiota between offspring of pregnant mice fed with water or with milk (GM or CM). There was a greater proportion of beneficial bacterial species, such as Akkermansia muciniphila, Bacteroides eggerthii , and Parabacteroides goldsteinii in the gut microbiota of offspring from GM- or CM-fed pregnant mice compared to the offspring of water-fed pregnant mice. These results suggested that improving the nutrition of pregnant mice can promote immunological maturation and colonization of gut microbiota in offspring. This mother-to-child biological action may provide a protective effect on atopy development and alleviate allergen-induced airway inflammation in offspring., (Copyright © 2020 Kao, Wang, Tseng, Wu, Tsai, Hsieh, Chen, Kuo, Liu, Liu and Wang.)

Background: Recent reports have suggested that lower vitamin D serum levels are associated with susceptibility to and severity of asthma in different white populations, which may be due to a lack of sunlight exposure, genetic polymorphism of vitamin D pathway genes, and dietary intake. We investigated the associations between vitamin D concentration, genetic polymorphism of the vitamin D receptor (VDR), and asthma traits in Mongolian and Taiwanese populations that inhabited two different geographical areas., Methods: In total, 328 Han Taiwanese subjects and 381 Mongolian subjects were enrolled, and their vitamin D serum levels assayed. Genomic DNA of 178 Han Taiwanese subjects and 90 Mongolian subjects was obtained from blood samples. Single-nucleotide polymorphisms (SNPs) of VDR, ApaI (rs7975232), TaqI (rs731236), BsmI (rs1544410) and FokI (rs2228570), were selected for genotyping. Logistic regression analyses were performed to detect an association between allergic asthma status and the interaction of the VDR SNP and serum vitamin D concentration in the case-control samples., Results: We observed a significantly lower vitamin D level in the Mongolian subjects as compared with the Taiwanese population. In particular, in the population under 14 years of age, the serum vitamin D level was significantly higher in the Taiwanese population, in both non-asthmatic and asthmatic subjects, than in the Mongolian non-asthmatic and asthmatic subjects, respectively ( P  < 0.01). Moreover, the vitamin D level in the asthmatic children was significantly lower than that in the non-asthmatic children in both the Taiwanese and Mongolian populations (P < 0.01, respectively). Furthermore, we found that the rs2228570 genotype (OR, 3.763) of the VDR SNP and the vitamin D concentration (lower than 40 ng/ml, OR: 38.938) both contribute to increased susceptibility to bronchial asthma., Conclusion: Our results demonstrated an association between vitamin D concentration and the risk of asthma in two populations of differing ethnicity living in different geographical areas. This information implies a potential role of vitamin D in the prevention and treatment of asthma worldwide., Competing Interests: The authors declare that they have no competing interests., (© 2019 Published by Elsevier Inc. on behalf of World Allergy Organization.)

Background: Immune checkpoint inhibitors (ICIs) can reinvigorate T cells and activate the immune system to eliminate cancer cells. Head and neck squamous cell carcinoma (HNSCC) is a malignancy with a poor prognosis. The roles of ICIs for HNSCC treatments are emerging., Method: We reviewed the study results of Programmed-Death 1 (PD-1) and PD-ligand-1 (PD-L1) monoclonal antibodies for HNSCC. The ongoing trials of anti-PD-1 and anti-PD-L1 were also reviewed., Results: Nivolumab showed a significant overall survival benefit in platinum-refractory HNSCC patients. For platinum-sensitive or first-line patients, pembrolizumab monotherapy (patients with PD-L1 Combined Positive Score ≥ 20) or pembrolizumab-platinum-fluorouracil improved overall survival vs the EXTREME (cetuximab-platinum-fluorouracil). Many HNSCC studies have combined anti-PD1/PD-L1 therapy with various anticancer agents or radiotherapy to improve treatment efficacy., Conclusion: ICIs demonstrate their efficacies for R/M HNSCC patients. The incorporation of ICIs showed a great impact on the treatment landscape of HNSCC., (© 2019 Wiley Periodicals, Inc.)

We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8 + T cells specifically recognizing the model antigen in an H-2b-restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results. EGFR inhibitors increased both basal and IFNγ-induced MHC class-I presentation, which enhanced recognition and lysis of tumor cell targets by CD8 + cytotoxic T lymphocytes. The ID8 cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen, utilizing the same target tumor cell/T-cell assay, identified single-guide (sg)RNAs targeting EGFR that sensitized tumor cells to T cell-mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in a syngeneic model, further validating EGFR inhibitors as immunomodulatory agents that enhance checkpoint blockade. This assay can be screened in high-throughput with small-molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds and target genes, respectively, that enhance or inhibit T-cell recognition and killing of tumor cells. Retrospective analyses of squamous-cell head and neck cancer (SCCHN) patients treated with the combination of afatinib and pembrolizumab demonstrated a rate of clinical activity exceeding that of each single agent. Prospective clinical trials evaluating the combination of an EGFR inhibitor and PD-1 blockade should be conducted., (©2018 American Association for Cancer Research.)

Surfactant proteins (SPs)-A and -D are C-type lectins of the collectin family and function in the clearance of infectious particles in the lungs. Some polymorphisms of SPs that give rise to amino acid changes have been found to affect their function. Several SP-A gene polymorphisms have been reported to be associated with respiratory infection diseases, such as tuberculosis (TB). However, the relationship between surfactant proteins D (SP-D) polymorphisms and TB is still unclear. To study the associations between SP-D polymorphisms and TB, the correlations of SP-D polymorphisms with TB were examined in a case-control study, which included 364 patients with TB and 177 control subjects. In addition, we cloned two major SP-D exonic polymorphism C92T (rs721917) and A538G (rs2243639) constructs and used these for in vitro assays. The effects of SP-D polymorphisms on agglutination and other interactions with Mycobacterium bovis bacillus Calmette-Guérin ( M. bovis BCG) were evaluated. In comparison with SP-D 92C (amino acid residue 16, Threonine), our results showed that SP-D 92T (amino acid residue 16, Methionine) had a lower binding ability to M. bovis BCG, a lower capacity to inhibit phagocytosis, lesser aggregation, poorer survival of bacillus Calmette-Guérin (BCG)-infected MH-S cells, and less inhibition of intracellular growth of M. bovis BCG. The case-control association study showed that the 92T homozygous genotype was a risk factor for TB. However, a lesser effect was seen for polymorphism A538G. In conclusion, the results of functional and genetic analyses of SP-D variants consistently showed that the SP-D 92T variant increased susceptibility to TB, which further confirmed the role of SP-D in pulmonary innate immunity against mycobacterial infection.

Background: We examined the risk for Group B streptococcus (GBS)-related diseases in newborns born to mothers who participated in a universal GBS screening program and to determine whether differences are observed in factors affecting the morbidity for neonatal early-onset GBS-related diseases., Methods: This is a retrospective study and the study subjects were women who had undergone GBS screening and who gave birth naturally and their newborns between April 15, 2012 and December 31, 2013. Data from the GBS screening system database and the National Health Insurance database were collected to calculate the GBS prevalence in pregnant women and morbidity of newborns with early-onset GBS-related diseases., Results: The GBS prevalence in pregnant women who gave birth naturally was 19.58%. The rate of early-onset infection caused by GBS in newborns decreased from the original 0.1% to 0.02%, a decrease of as high as 80%. After the implementation of the universal GBS screening program, only three factors, including positive GBS screening result (OR = 2.84), CCI (OR = 2.45), and preterm birth (OR = 4.81) affected the morbidity for neonatal early-onset GBS-related diseases, whereas other factors had no significant impact., Conclusion: The implementation of the universal GBS screening program decreased the infection rate of neonatal early-onset GBS diseases. The effects of socioeconomic factors and high-risk pregnancy on early-onset GBS infections were weakened.

Background: The results showed that the deciding factor is the culture medium in which the bacteria and the graphene oxide (GO) are incubated at the initial manipulation step. These findings allow better use of GO and GO-based materials more and be able to clearly apply them in the field of biomedical nanotechnology., Results: To study the use of GO sheets applied in the field of biomedical nanotechnology, this study determines whether GO-based materials [GO, GO-polyoxyalkyleneamine (POAA), and GO-chitosan] stimulate or inhibit bacterial growth in detail. It is found that it depends on whether the bacteria and GO-based materials are incubated with a nutrient at the initial step. This is a critical factor for the fortune of bacteria. GO stimulates bacterial growth and microbial proliferation for Gram-negative and Gram-positive bacteria and might also provide augmented surface attachment for both types of bacteria. When an external barrier that is composed of GO-based materials forms around the surface of the bacteria, it suppresses nutrients that are essential to microbial growth and simultaneously produces oxidative stress, which causes bacteria to die, regardless of whether they have an outer-membrane-Gram-negative-bacteria or lack an outer-membrane-Gram-positive-bacteria, even for high concentrations of biocompatible GO-POAA. The results also show that these GO-based materials are capable of inducing reactive oxygen species (ROS)-dependent oxidative stress on bacteria. Besides, GO-based materials may act as a biofilm, so it is hypothesized that they suppress the toxicity of low-dose chitosan., Conclusion: Graphene oxide is not an antimicrobial material but it is a general growth enhancer that can act as a biofilm to enhance bacterial attachment and proliferation. However, GO-based materials are capable of inducing ROS-dependent oxidative stress on bacteria. The applications of GO-based materials can clearly be used in antimicrobial surface coatings, surface-attached stem cells for orthopedics, antifouling for biocides and microbial fuel cells and microbial electro-synthesis.

Lactobacilli prevent the early development of allergic diseases in children and experimental asthma in mice. However, the detailed mechanism underlying this action remains unknown. We aimed to explore the activation pathway in the host by Lactobacillus and identify its immunomodulation mechanism in allergic asthma. Continuous administration of 10 7  cfu, but not 10 9  cfu, of L. gasseri for 4 weeks prevented Dermatophagoides pteronyssinus (Der p)-induced airway hypersensitivity and inflammation in a mouse model of allergic asthma. DNA microarray analysis of the mesenteric and lung draining lymph nodes revealed a significant decrease in inflammatory chemokines and increase in gene expression in carbohydrate and lipid metabolism, particularly of PPARγ, in 10 7  cfu L. gasseri-administered mice compared with untreated mice. Compared with WT mice, Der p-sensitized PPARγ L/+ mice showed increased airway hyperresponsiveness to methacholine, inflammatory cell infiltration, and inflammatory cytokine secretion in bronchoalveolar fluid. Moreover, the protective effects of L. gasseri were lost in Der p-induced airway inflammation in PPARγ L/+ mice, and L. gasseri-induced PPARγ activation in BMDCs inhibited the development of allergic airway inflammation in both PPARγ WT and PPARγ L/+ mice. L. gasseri may act via a novel PPARγ activation pathway in DCs to alleviate allergen-induced airway inflammation in allergic asthma., Key Messages: L. gasseri prevents mite allergen (Der p)-induced airway inflammation. Prevention of airway inflammation occurs via activation of PPARγ in dendritic cells. L. gasseri administration does not reverse Der p-induced airway inflammation in PPARγ (+/-) mice. L. gasseri-induced PPARγ activation inhibits development of airway inflammation in WT and PPARγ (+/-) mice.

Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatin-resistant HNSCC cells. Genetic or pharmacologic inhibition of G9a sensitized the resistant cells to cisplatin, increasing cellular apoptosis. Mechanistic investigations indicated that G9a contributes to transcriptional activation of the glutamate-cysteine ligase catalytic subunit (GCLC), which results in upregulation of cellular glutathione (GSH) and drug resistance. In addition, we observed a significant positive correlation between G9a and GCLC expression in tumors of HNSCC patients. Taken together, our findings provide evidence that G9a protects HNSCC cells against chemotherapy by increasing the synthesis of GSH, and imply G9a as a promising target for overcoming cisplatin resistance in HNSCC. Mol Cancer Ther; 16(7); 1421-34. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Reactive oxygen species is the main contributor to photodynamic therapy. The results of this study show that a nitrogen-doped graphene quantum dot, serving as a photosensitizer, was capable of generating a higher amount of reactive oxygen species than a nitrogen-free graphene quantum dot in photodynamic therapy when photoexcited for only 3 min of 670 nm laser exposure (0.1 W cm -2 ), indicating highly improved antimicrobial effects. In addition, we found that higher nitrogen-bonding compositions of graphene quantum dots more efficiently performed photodynamic therapy actions than did the lower compositions that underwent identical treatments. Furthermore, the intrinsically emitted luminescence from nitrogen-doped graphene quantum dots and high photostability simultaneously enabled it to act as a promising contrast probe for tracking and localizing bacteria in biomedical imaging. Thus, the dual modality of nitrogen-doped graphene quantum dots presents possibilities for future clinical applications, and in particular multidrug resistant bacteria., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A graphene quantum dot (GQD) used as the photosensitizer with high two-photon absorption in the near-infrared region, a large absolute cross section of two-photon excitation (TPE), strong two-photon luminescence, and impressive two-photon stability could be used for dual modality two-photon photodynamic therapy (PDT) and two-photon bioimaging with an ultrashot pulse laser (or defined as TPE). In this study, a GQD efficiently generated reactive oxygen species coupled with TPE, which highly increased the effective PDT ability of both Gram-positive and -negative bacteria, with ultralow energy and an extremely short photoexcitation time generated by TPE. Because of its two-photon properties, a GQD could serve as a promising two-photon contrast agent for observing specimens in depth in three-dimensional biological environments while simultaneously proceeding with PDT action to eliminate bacteria, particularly in multidrug-resistant (MDR) strains. This procedure would provide an efficient alternative approach to easily cope with MDR bacteria.

Few studies have investigated the two-photon properties of graphene quantum dots (GQDs) and GQD-conjugated polymers. The results of the present study revealed that conjugated polymers containing nitrogen and sulfur atoms caused higher quantum confinement of emissive energy to be trapped on the surface of nanomaterials, resulting in a high-photoluminescence quantum yield and notable two-photon properties. Additionally, the nanomaterials generated no reactive oxygen species-dependent oxidative stress on cells and served as promising two-photon contrast probes.

Background: The use of salivary biomarkers in stress research is increasing, and the precision and accuracy with which researchers are able to measure these biomarkers have dramatically improved. Chronic psychosocial stress is often linked to the pathogenesis of cardiovascular disease (CVD). Salivary biomarkers represent a noninvasive biological method of characterizing the stress phenomenon that may help to more fully describe the mechanism by which stress contributes to the pathogenesis and outcomes of CVD., Objectives: We conducted a systematic review of 40 research articles to identify the salivary biomarkers researchers have most commonly used to help describe the biological impact of chronic psychosocial stress and explore its associations with CVD risk. We address strengths and weaknesses of specimen collection and measurement., Methods: We used PubMed, CINAHL, EBSCOhost, Web of Science, BIOSIS Previews, Biological Sciences (ProQuest), and Dissertations/Theses (ProQuest) to retrieve 387 initial articles. Once we applied our inclusion/exclusion criteria to specifically target adult human studies dealing with chronic stress rather than acute/laboratory-induced stress, 40 studies remained, which we synthesized using Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria., Results: Cortisol was the biomarker used most frequently. Sources of psychosocial stress included job strain, low socioeconomic status, and environmental factors. Overall, psychosocial stress was associated with CVD risks such as vascular pathology (hypertension, blood pressure fluctuation, and carotid artery plaque) as well as metabolic factors such as abnormal blood glucose, dyslipidemia, and elevated cardiac enzymes., Conclusion: Diverse salivary biomarkers have been useful in stress research, particularly when linked to CVD risks., (© The Author(s) 2015.)

Objective: To examine the associations of psychological strains, salivary biomarkers, and coronary heart disease (CHD) risks in hurricane survivors 2 years after Hurricane Ike in the United States., Background: Hurricane survivors often suffer from long-lasting posttraumatic stress disorder (PTSD) and other forms of psychological strain related to surviving a natural disaster and dealing with its aftermath. Psychological strains may be associated with biomarkers, which, in turn, may be associated with a higher incidence of CHD risks., Methods: Structured interviews were conducted with 19 hurricane survivors to assess psychological strains (PTSD, perceived stress, depression, and anxiety) and measure CHD risks. Saliva samples were collected by the passive drool method and analyzed for inflammatory cytokine (interleukin [IL]-1β, IL-6, and IL-10) and chemokine (monocyte chemotactic protein [MCP]-1) biomarkers., Results: The salivary level of MCP-1 was significantly associated with PTSD symptoms, depression (both p < .01), and anxiety (p < .05). There were significant associations between anxiety and hypertension (p < .01), perceived stress and blood glucose level (p < .05), and perceived stress and obesity (p < .05)., Conclusion: Our findings that long-lasting psychological strains are associated with major CHD risks and salivary MCP-1 levels suggest that the mechanism by which such strains play a role in the development of CHD involves recruitment of monocyte cells in response to chronic endothelial inflammation. Further studies are needed to advance our understanding of the underlying mechanisms by which the PTSD and other psychological strains contribute to the development of CHD., (© The Author(s) 2014.)

Purpose: To evaluate the preventive effects of topical skin disinfection with chlorhexidine on bloodstream infection (BSI) associated with totally implantable venous port (Port-A)., Methods: Two consecutive cohorts of solid cancer patients were prospectively followed for the occurrence of Port-A associated BSI (PABSI). The first cohort used povidone-iodine as topical skin disinfection and the second cohort used chlorhexidine. The primary endpoint was the time to first PABSI. Propensity score analysis was applied. The preventive effects of chlorhexidine were analyzed by Cox proportional hazards models., Results: There were 396 patients (81,752 catheter-days) in the iodine cohort and 497 (99,977 catheter-days) in the chlorhexidine cohort. Gram-negative bacteria were the most common pathogens to cause first episode of PABSI (iodine cohort (I) vs chlorhexidine cohort (C) and 0.404 vs 0.450 per 1,000 catheter-day), followed by Gram-positive bacteria (I vs C and 0.269 vs 0.110 per 1,000 catheter-day), and fungi (I vs C and 0.098 vs 0.070 per 1,000 catheter-day). Three hundred forty-three patients were selected from each cohort by propensity score match analysis. Chlorhexidine use was associated with a significant improvement on time to first PABSI caused by Gram-positive bacteria (log-rank test, p=0.00175; HR=0.35, 95 % CI, 0.14-0.85, p=0.02). No significant preventive effects of chlorhexidine on time to first PABSI caused by Gram-negative bacteria or fungi was found., Conclusions: Chlorhexidine topical skin disinfection may prevent PABSI caused by Gram-positive bacteria in patients with solid cancers. The nonsignificant effect on preventing overall PABSI may be attributed to the high incidence of Gram-negative bacteria related PABSI.

Objectives: Mutation of the exon 3 of CTNNB1, the coding gene of β-catenin, is a crucial molecular mechanism leading to aberrant activation of the Wnt/β-catenin pathway, which is highly associated with the carcinogenesis of hepatocellular carcinoma (HCC). The prevalence and clinical significance of CTNNB1 mutations in advanced HCC remain unclear., Methods: Patients with advanced HCC and available pathologic tissues (either obtained when diagnosed at advanced or early stages) were enrolled in this study. Direct sequencing of exon 3 of CTNNB1 was performed to detect somatic mutations. The associations between CTNNB1 mutations and clinicopathologic features were analyzed., Results: A total of 115 patients were enrolled, among whom 78 (67.8%) had chronic hepatitis B virus infection. Twenty-one (18.3%) patients were found to have CTNNB1 mutations, all of which were missense mutations. The CTNNB1 mutation rates were similar among pathologic tissues obtained at advanced and early stages (17.5 and 20.0%, respectively). Patients aged over 60 years were more likely to have CTNNB1 mutations than patients younger than 60 years (32.6 vs. 8.7%, p = 0.001). The mutations were not associated with survival or other clinicopathologic features., Conclusion: In patients with advanced HCC, CTNNB1 mutations were not prognostically significant. No apparent increase of CTNNB1 mutations occurred during the progression of HCC., (© 2014 S. Karger AG, Basel.)

Drugs that target the EGFR have a major impact on the treatment of advanced non-small-cell lung cancer (NSCLC). EGFR mutations in NSCLC are associated with a dramatic and sustained response to EGFR tyrosine kinase inhibitors (TKIs). This review summarizes the results of randomized trials using EGFR TKIs or EGFR monoclonal antibodies with chemotherapy in the first-line setting, and discusses several unresolved issues regarding the use of the EGFR TKIs as the first-line therapy in advanced NSCLC.

By 2050, Mexican Americans (MAs) will become the largest aged minority subgroup in the United States. Although older MAs often depend on family for care, no standard instrument is available to scale the motive for filial obligation. Building on previous work, the purpose of this study is to establish psychometric properties of the bilingual Mutuality Scale (MS) for use with MA family caregivers of older adults. A methodological design with a convenience sample is used. Through Principal Axis Factoring with Oblimin(©) rotation, a two-factor structure emerge--interaction between the caregiving dyad and reaction from the care recipient--which accounted for 63% of the variance in MS scores. Cronbach's alphas are .87 in both cases and test-retest estimates across three weeks are r = .93 and .94, respectively. Despite needing further refinement, the MS shows potential to measure the motive involved in older adult care, which may be useful in designing culturally relevant interventions for the MA population.

Emerging evidence suggests that the transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) may contribute to airway remodeling in severe asthma and fibrotic lung diseases. Studies have shown that extracts from propolis protect chemical-induced cardiac and liver fibrosis in animals. This study assesses the inhibitory effect of propolis on TGF-β1-induced EMT in serum-deprived A549 cells (human AECs). Experimental results show progressive cell morphological changes, decreased E-cadherin, increased N-cadherin production, intracellular F-actin rearrangement, increased reactive oxygen species (ROS) production, and increased cell motility with increasing TGF-β1 concentration. A549 cells pretreated with propolis and then treated with TGF-β1 for 24 h regained epithelial cell morphology, decreased the production of N-cadherin and ROS, and had reduced motility. Propolis prevents the effects of TGF-β1-induced Smad2 and AKT activation pathways and Snail expression. Moreover, propolis pretreatment may prevent the TGF-β1-induced down-regulation of nuclear hormone receptors and peroxisome proliferator-activated receptor gamma (PPARγ) protein in A549 cells, whose effect was blocked by adding PPARγ antagonist, GW9662. Two active components of propolis, caffeic acid phenethyl ester (CAPE) and pinocembrin (PIN), only had partial effects on TGF-β1-induced EMT in A549 cells. The results of this study suggest that natural propolis extracts may prevent TGF-β1-induced EMT in immortalized type II AECs via multiple inhibitory pathways, which may be clinically applied in the prevention and/or treatment of EMT-related fibrotic diseases as well as airway remodeling in chronic asthma., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: Infection is believed to be one of frequent and important causes of preterm labor. We attempted to evaluate whether the level of inflammatory markers, e.g. interleukin-16 (IL-16), interleukin-18 (IL-18), and ferritin, in amniotic fluid at early second trimester can predict preterm birth., Methods: Amniotic fluid (AF) samples were collected from 350 pregnant women who had trans-abdominal amniocentesis for genetic indications at 16 to 20 weeks of gestation. AF levels of IL-16, IL-18 and ferritin levels were measured by immunoassay and were correlated with pregnancy outcomes., Results: Among the 350 pregnant women, 58 (16.6%) had preterm birth (<37 weeks gestation). AF levels of IL-16, IL-18, and ferritin were significantly higher in pregnant women with subsequent preterm birth. Multivariate analyses showed that a quartile higher of AF IL-16 level was significantly associated with preterm birth (OR: 3.09, 95% CI 1.52-6.27, p = 0.002). A receiver operating characteristic analysis revealed that an IL-16 cutoff value of 105 pg/ml was a reliable predictor of preterm birth (sensitivity, 90.2%; specificity, 52.7%; negative predictive value, 84.3%)., Conclusion: It is feasible to predict preterm birth by measuring the AF levels of IL-16 especially for the pregnant women requiring genetic amniocentesis during early second trimester.

Background: The purpose of this study is to characterize the risk factors of bloodstream infection (BSI) associated with the use of permanent implantable venous ports (Port-A) in solid cancer patients., Methods: Solid cancer patients implanted with a Port-A were prospectively observed for the occurrence of Port-A-associated BSI (PABSI), defined as BSI without other identifiable infection foci. A PABSI risk score was developed using the Cox proportional hazards model., Results: A total of 415 patients were registered; 88 PABSI episodes occurred in 58 patients (incidence1.05 per 1000 catheter-days). All but one patient had stage IV cancer. Independent predictors of PABSI occurrence included neutropenia, total parenteral nutrition (TPN), chronic steroid use, invasive procedures, postoperative antibiotics, and preoperative antibiotics. A PABSI risk score with a cut-off value of 0 (sensitivity 88.5%, specificity 64.3%) was defined for stage IV cancer patients as follows: neutropenia, +1.350; TPN, +1.256; chronic steroid use, +1.947; preoperative antibiotics, -0.970; postoperative antibiotics, +0.959; and invasive procedures, +1.098. The median PABSI-free survival was 4.47 months for patients with scores ≥ 0 but not reached for patients with scores <0 (P < 0.0001)., Conclusion: The PABSI risk score can assist in identifying high-risk solid cancer patients and may assist in designing future preventive strategies.

Background: Acute occlusion of internal carotid artery (ICA) is a clinical catastrophic entity with mortality as high as 50%. With innovative devices and technology, we want to clarify the benefit and risk of interventional treatment for those patients., Methods and Results: From 2005 to 2009, 62 patients were enrolled and 7 patients were diagnosed as total ICA occlusion with severe neurological deficit and poor collateral circulation received endovascular interventions. Intra-arterial thrombolysis was performed in all the 7 patients. Besides, angioplasty was done in 2 patients, stenting in 3, and thrombosuction in 1. The average NIHSS was 23.3 (standard deviation=3.6) before revascularization, was 14.2(standard deviation=6.8) on day 7. Three patients had symptomatically hemorrhagic transformation and one developed severe brain edema after procedure. Decompressive craniotomy has been conducted in 3, who survived thereafter. One patient died for refusal of decompressive craniotomy. The 30-day modified Rankin scale was 1 in 1, 2 in 1, 3 in 1, and 4 in 3. All of our patients had distal residual lesions at anterior or middle cerebral artery area, and delayed recanalization was noted in 4., Conclusions: Endovascular therapy was promising as a hyperacute management for patients of ICA total occlusion leading to survival rate more than 80% and significant neurological recovery in 50% of our patients. Distal residual lesions were common in patients of total carotid occlusion after aggressive revascularization. Although the mechanism was not clear, delayed re-canalization was common in such patients., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

We develop a 16-band atomic bond-orbital model (16ABOM) to compute the spin splitting induced by bulk inversion asymmetry in zincblende materials. This model is derived from the linear combination of atomic-orbital (LCAO) scheme such that the characteristics of the real atomic orbitals can be preserved to calculate the spin splitting. The Hamiltonian of 16ABOM is based on a similarity transformation performed on the nearest-neighbor LCAO Hamiltonian with a second-order Taylor expansion k at the Γ point. The spin-splitting energies in bulk zincblende semiconductors, GaAs and InSb, are calculated, and the results agree with the LCAO and first-principles calculations. However, we find that the spin-orbit coupling between bonding and antibonding p-like states, evaluated by the 16ABOM, dominates the spin splitting of the lowest conduction bands in the zincblende materials.

Probiotics are normal inhabitants of the gastrointestinal tract of man and are widely considered to exert a number of beneficial effects in many diseases. But the mechanism by which they modulate the immune system is poorly understood. The present study was planned to explore the anti-allergic effect of Lactobacillus gasseri on a mouse model of allergic asthma. Dermatophoides pteronyssinus (Der p) sensitised and challenged BALB/c mice were orally administered via oral administration with three different doses of L. gasseri (low, 1 × 10(6) colony-forming units (CFU); medium, 2 × 10(6) CFU; high, 4 × 10(6) CFU), in 700 μl of PBS daily, starting from 2 weeks before Der p sensitisation for 4 weeks. After the allergen challenge, airway responsiveness to methacholine, influx of inflammatory cells to the lung, and cytokine levels in bronchoalveolar lavage (BAL) fluids and splenocytes culture were assessed. Our results showed that oral administration of a high dose of L. gasseri (4 × 10(6) CFU) decreased airway responsiveness to methacholine, attenuated the influx of inflammatory cells to the airways and reduced the levels of TNF-α, thymus and activation-regulated chemokine (TARC) and IL-17A in BAL fluids of Der p-sensitised and -challenged mice. Moreover, L. gasseri decreased IL-17A production in transforming growth factor-α and IL-6 stimulated splenocytes and cell numbers of IL-17 producing alveolar macrophages in L. gasseri-treated mice as compared to non-treated, Der p-sensitised and -challenged mice. In conclusion, oral administration with L. gasseri can attenuate major characteristics of allergen-induced airway inflammation and IL-17 pro-inflammatory immune response in a mouse model of allergic asthma, which may have clinical implication in the preventive or therapeutic potential in allergic asthma.

Purpose: Informal family care for elders is conventional in Mexican American communities despite increasing intergenerational gaps in filial values. In our study, we explored whether acculturation and dyadic mutuality, as perceived by Mexican American family caregivers, explain the caregivers' expectations of family loyalty toward elderly relatives., Design: A nonexperimental, correlational design with convenience sampling was used in El Paso, Texas, from October 2007 to January 2008., Methods: Three bilingual promotoras collected data from 193 Mexican American adult caregivers of community-dwelling elders using three scales designed for Mexican Americans: the Acculturation Rating Scale for Mexican Americans II-Short Form, the Mutuality Scale, and the Expectations of Family Loyalty of Children Toward Elderly Relatives Scale. Confirmatory factor analysis was used to analyze the data., Findings: Acculturation had a marginal effect (r = .21, p < .05), but mutuality presented a strong correlation (r = .45, p < .001) with the expectations of family loyalty toward elderly relatives. There was no significant correlation between acculturation and mutuality (r = .05)., Conclusions: Although Mexican American caregivers with strong Mexican orientation may have high expectations of family loyalty toward elderly relatives, mutuality exhibits more significant effects on expectations. Among Mexican Americans, mutuality between the caregiving dyad, as perceived by caregivers, may be a better predictor of filial values than caregivers' acculturation alone., Clinical Relevance: It may be useful to incorporate the dual paradigm of acculturation and mutuality into immigrant family care for elderly relatives., (© 2012 Sigma Theta Tau International.)

House dust mites (HDMs) induce allergic asthma in sensitized individuals, although how HDMs activate immature mucosal dendritic cells (DCs) to render the T helper cell type 2 (Th2)-mediated immune response is unclear. In this study, our results showed a significant calcium-dependent lectin binding of Dermatophagoides pteronyssinus (Der p) extracts to DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), the C-type lectin receptors (CLRs) of DCs. Moreover, monocyte-derived DCs (MDDCs) of Der p-sensitized asthmatics (AS) exhibited decreased expression of DC-SIGN, increased endocytosis, and impaired differentiation of DC precursors. The Der p-induced downregulation of DC-SIGN expression in the differentiation of immature MDDCs may be because of the internalization of Der p-DC-SIGN complex. MDDCs of AS produced more interleukin (IL)-6 and less IL-12p70 cytokines when stimulated with lipopolysaccharide (LPS) or Der p than those of nonallergic controls (NC). In the co-culture experiments, MDDCs pretreated with Der p induced GATA-3 expression and IL-4 cytokine productions in naive CD4(+) T cells. These effects of Der p on the differentiation and function of MDDCs could be partially blocked by anti-DC-SIGN antibodies. In conclusion, our results suggest a critical step of allergen sensitization that involves CLRs in the innate immune response of DCs, which may provide a therapeutic or preventive potential for allergic asthma.

In order to take their medications at home, elders rely increasingly on their family, but little is known about the factors influencing this task. This study explored the effects of acculturation and social exchange on the hassles that Mexican American (MA) family caregivers face in administering medication to their elders. A descriptive, correlational design, with a convenience sample of 239 MA adult caregivers of elders who were on a daily prescription that was recruited in Dallas, Texas and San Diego, California, USA, was used. The caregivers' scores on the medication administration hassles scale were significantly affected by acculturation and social exchange factors that explained 36% of the variance in the scores; the social exchange block had a larger influence than did the acculturation block. Caregiving might be an outcome of dynamic family exchange relationships between the caregiving dyad. The results can help healthcare professionals to detect potentially at-risk MA families and provide them with culturally appropriate nursing interventions., (© 2011 Blackwell Publishing Asia Pty Ltd.)

Given the fast-growing Mexican American (MA) population, it is common for investigators to be pressured into using Spanish translated instruments developed for English-speaking populations. However, these translated instruments may have limited relevance for data collection without adequate assessment and vetting. The purpose of this paper is to present lessons learned from the pilot testing of instruments designed for use with Mexican Americans. Pilot testing of two instruments was conducted with 22 Mexican American family caregivers of older adults. Issues that emerged were classified into three categories-instrumentation, methodology, and demographic data. Within the area of instrumentation, six issues were identified-level of abstraction, concreteness, pronoun use, clarity, exclusiveness, and response format. Methodological concerns were focused on test-retest administration and inclusion criteria. Issues within the demographic data were concerned with marital status, country of birth, household size and income, and validity of self-rated scales. By addressing those concerns, investigators may be more likely to have culturally sensitive measures and greater generalization to relevant MA populations.

Aims and Objectives: This study builds on earlier work on medication administration hassles, minor daily irritants experienced by family caregivers of older relatives, by investigating the feasibility of using the Family Caregiver Medication Administration Hassles Scale (FCMAHS) for use with Mexican American caregivers., Background: Appropriate medication administration is a critical factor in the effective management of chronic illness. When medication regimens are managed on behalf of an older care recipient, especially those with numerous medications for a variety of conditions, the caregiving task is even more complex. Relying on family support is common for older Mexican Americans. Despite this, there is little known about how Mexican Americans are handling their caregiving duties at home., Design: A non-experimental methodological design was used to assess the psychometric properties of the FCMAHS with Mexican Americans, chosen because they are a rapidly growing population in the US., Methods: A purposive sample of 239 Mexican American adult caregivers, recruited in Dallas and San Diego, completed a brief biographical survey and the version of the FCMAHS created for Mexican Americans, i.e., the FCMAHS-MA., Results: Principal axis factoring with orthogonal rotation was used to extract six factors which accounted for 53% of the variance in total scores - initial information seeking, safety issues, advanced information acquisition, scheduling, daily routine and prescription filling. Reliability estimates for the factors (alpha) ranged from 0.70-0.90. Test-retest reliability across a three-week interval was r = 0.64., Conclusions: The FCMAHC-MA shows promise as a guide for future caregiving intervention studies on family medication management for older relatives; however, it would benefit from refinement in future studies., Relevance to Clinical Practice: Understanding family caregivers' hassles with medication administration is important because these hassles can accumulate and lead to caregiver strain. Culturally relevant intervention depends on accurate measurement of the hassles experienced by these caregivers.