ABSTRACT
Teeth consist of 3 mineralized tissues: enamel, dentin, and cementum. Tooth malformation, the most common craniofacial anomaly, arises from complex genetic and environmental factors affecting enamel structure, size, shape, and tooth eruption. Hyaluronic acid (HA), a primary extracellular matrix component, contributes to structural and physiological functions in periodontal tissue. Transmembrane protein 2 (TMEM2), a novel cell surface hyaluronidase, has been shown to play a critical role during embryogenesis. In this study, we demonstrate Tmem2 messenger RNA expression in inner enamel epithelium and presecretory, secretory, and mature ameloblasts. Tmem2 knock-in reporter mice reveal TMEM2 protein localization at the apical and basal ends of secretory ameloblasts. Micro-computed tomography analysis of epithelial-specific Tmem2 conditional knockout (Tmem2-CKO) mice shows a significant reduction in enamel layer thickness and severe enamel deficiency. Enamel matrix protein expression was remarkably downregulated in Tmem2-CKO mice. Scanning electron microscopy of enamel from Tmem2-CKO mice revealed an irregular enamel prism structure, while the microhardness and density of enamel were significantly reduced, indicating impaired ameloblast differentiation and enamel matrix mineralization. Histological evaluation indicated weak adhesion between cells and the basement membrane in Tmem2-CKO mice. The reduced and irregular expressions of vinculin and integrin ß1 suggest that Tmem2 deficiency attenuated focal adhesion formation. In addition, abnormal HA accumulation in the ameloblast layer and weak claudin 1 immunoreactivity in Tmem2-CKO mice indicate impaired tight junction gate function. Irregular actin filament assembly was also observed at the apical and basal ends of secretory ameloblasts. Last, we demonstrated that Tmem2-deficient mHAT9d mouse ameloblasts exhibit defective adhesion to HA-containing substrates in vitro. Collectively, our data highlight the importance of TMEM2 in adhesion to HA-rich extracellular matrix, cell-to-cell adhesion, ameloblast differentiation, and enamel matrix mineralization.
Subject(s)
Dental Enamel Hypoplasia , Mice , Animals , Dental Enamel Hypoplasia/genetics , X-Ray Microtomography , Dental Enamel/metabolism , Ameloblasts/metabolism , Amelogenesis/genetics , Mice, Knockout , Membrane Proteins/genetics , Membrane Proteins/metabolismABSTRACT
INTRODUCTION: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. METHODS: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan-Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. RESULTS: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan-Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. CONCLUSION: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.
Subject(s)
Albumins , Bilirubin , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Albumins/analysis , Bilirubin/analysis , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/drug therapy , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Neoplasm Recurrence, Local , Prognosis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Prospective Studies , Retrospective StudiesABSTRACT
Japan's aging society has an increasing incidence of oral cancer. This study investigated perioperative changes in quality of life (QoL) among 172 oral cancer patients (elderly ≥75 years vs non-elderly <75 years), pre-treatment, at treatment completion, and at 1, 3, and 6 months post-treatment, using the following Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) subscales: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), additional head- and neck-specific concerns (H&N). SWB (P=0.026), H&N (P=0.024), and total FACT-H&N (P=0.009) scores were significantly lower in the elderly group than in the non-elderly group at 6 months post-treatment, especially for mastication items (H&N1, P=0.047; H&N11, P=0.004), but not for swallowing items (H&N5 and H&N7, both P> 0.05). PWB (P= 0.004), EWB (P< 0.001), and FWB (P= 0.022) scores in the non-elderly group were significantly higher at 6 months post-treatment than before treatment. In the elderly group, no subscale showed a better score at 6 months post-treatment. Post-treatment QoL in elderly oral cancer patients did not improve, unlike in non-elderly patients.
Subject(s)
Mouth Neoplasms , Quality of Life , Aged , Humans , Japan/epidemiology , Middle Aged , Mouth Neoplasms/surgery , Perioperative Period , Surveys and QuestionnairesABSTRACT
Enterotoxin-based adjuvants including cholera toxin and heat-labile toxin (LT) are powerful manipulators of mucosal immunity; however, past clinical trials identified unacceptable neurological toxicity when LT or mutant AB5 adjuvant proteins were added to intranasal vaccines. Here, we examined the isolated enzymatic A1 domain of LT (LTA1) for intranasal safety and efficacy in combination with influenza (flu) vaccination. LTA1-treated mice exhibited no neurotoxicity, as measured by olfactory system testing and H&E staining of nasal tissue in contrast with cholera toxin. In vaccination studies, intranasal LTA1 enhanced immune responses to inactivated virus antigen and subsequent protection against H1N1 flu challenge in mice (8-week or 24-months). In addition, lung H1N1 viral titers post-challenge correlated to serum antibody responses; however, enhanced protection was also observed in µMT mice lacking B-cells while activation and recruitment of CD4 T-cells into the lung was apparent. Thus, we report that LTA1 protein is a novel, safe and effective enterotoxin adjuvant that improves protection of an intranasal flu vaccination by a mechanism that does not appear to require B-cells.
Subject(s)
Adjuvants, Immunologic/administration & dosage , Aging/immunology , B-Lymphocytes/immunology , Enterotoxins/administration & dosage , Lymphocyte Depletion , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , Adjuvants, Immunologic/pharmacology , Administration, Intranasal , Animals , Antibodies/blood , Antibody Formation/drug effects , B-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Dose-Response Relationship, Immunologic , Enterotoxins/immunology , Enterotoxins/toxicity , Female , Immunity, Mucosal/drug effects , Immunization , Inflammation/pathology , Influenza A Virus, H1N1 Subtype/immunology , Lung/virology , Lymphocyte Activation/drug effects , Mast Cells/drug effects , Mast Cells/pathology , Mice, Inbred C57BL , Orthomyxoviridae Infections/blood , Orthomyxoviridae Infections/virologyABSTRACT
Continuous cell monitoring is very important for the maintenance and control of cell multiplication and differentiation. This paper presents a compact microplate reader that is able to continuously measure a 24-well microplate (6 × 4 wells) using the optical absorption measurement method. The 24-channel plate reader consisted of a spatial filter, light emitting diode light source, and color sensors and was similarly sized with the cell culture microwell plates. A spatial filter was previously fabricated by our group using silicone optical technology (SOT). This SOT-based spatial filter has an excellent noise reduction effect. Light reflection at the optical path interface can be absorbed and only forward light can be transmitted; accordingly, a larger S/N ratio than that of conventional optical systems is expected. The fabricated 24-channel plate reader permits real-time cell monitoring during cultivation on the clean bench and in cell culture conditions by incorporating the SOT spatial filter. Using the device, it was possible to continuously evaluate the concentration and pH of reagents in the 24 wells in real time. Moreover, cell activity and protein production were detectable using the device. These results suggest that the newly fabricated device is a promising tool for the evaluation of cell behaviors for cell management.
ABSTRACT
Although they are known to share pathophysiological processes, the relationship between periodontitis and chronic obstructive pulmonary disease (COPD) is not fully understood. The aim of the present study was to test the hypothesis that periodontitis is associated with a greater risk of development of COPD, when smoking is taken into account. The analysis in a 5-y follow-up population-based cohort study was based on 900 community-dwelling Japanese adults (age: 68.8 ± 6.3 [mean ± SD], 46.0% male) without COPD aged 60 or older with at least 1 tooth. Participants were classified into 3 categories according to baseline periodontitis severity (no/mild, moderate, and severe). COPD was spirometrically determined by a fixed ratio of <0.7 for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and by FEV1/FVC below the lower limit of normal. Poisson regression was used to calculate the relative risk (RR) of developing COPD according to the severity of periodontitis. The population attributable fraction (PAF) was also calculated. During follow-up, 22 (2.4%) subjects developed COPD. Compared with no/mild periodontitis subjects, a significantly increased risk of COPD occurred among severe periodontitis subjects (RR = 3.55; 95% confidence interval [CI], 1.18 to 10.67), but no significant differences were observed between the no/mild and moderate categories (RR = 1.48; 95% CI, 0.56 to 3.90). After adjustment for potential confounders, including smoking intensity, the relationship between severe periodontitis and risk of COPD remained significant (RR = 3.51; 95% CI, 1.15 to 10.74). Likewise, there was a positive association of periodontitis severity with risk of COPD ( P for trend = 0.043). The PAF for COPD due to periodontitis was 22.6%. These data highlight the potential importance of periodontitis as a risk factor for COPD.
Subject(s)
Periodontitis , Pulmonary Disease, Chronic Obstructive , Aged , Cohort Studies , Female , Forced Expiratory Volume , Humans , Male , Middle Aged , Risk Factors , SpirometryABSTRACT
Colonic macrophages induce pathogenic inflammation against commensal bacteria, leading to inflammatory bowel disease (IBD). Although the ontogeny of colonic macrophages has been well studied in the past decade, how macrophages gain colitogenic properties during the development of colitis is unknown. Using a chemically induced colitis model, we showed that accumulated Ly6C+ cells consisting of inflammatory monocytes and inflammatory macrophages strongly expressed representative colitogenic mediators such as tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS). The interferon-γ-signal transducer and activator of transcription 1 (IFN-γ-Stat1) pathway was required for generating colitogenic macrophages, given that Stat1-/- mice had less severe colitis and fewer colitogenic macrophages. Notably, IFN-γ induced histone acetylation at the promoter regions of the Tnf and Nos2 loci in the monocyte and macrophage lineage, indicating that IFN-γ-dependent epigenetic regulation instructs the development of the colitogenic monocyte and macrophage lineage in vivo. Collectively, our results provide the essential mechanism by which dysregulated colitogenic monocytes/macrophages develop at the colon mucosa during inflammation, and suggest a new drug target for treating IBD.
Subject(s)
Colitis/immunology , Inflammatory Bowel Diseases/immunology , Macrophages/physiology , Monocytes/physiology , Nitric Oxide Synthase Type II/metabolism , STAT1 Transcription Factor/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Antigens, Ly/metabolism , Cell Differentiation , Cell Lineage , Cells, Cultured , Colitis/chemically induced , Disease Models, Animal , Epigenesis, Genetic , Gene Expression Regulation , Histones/genetics , Histones/metabolism , Humans , Interferon-gamma/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide Synthase Type II/genetics , Promoter Regions, Genetic/genetics , STAT1 Transcription Factor/genetics , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Foxp3+ Regulatory T cells (Tregs) play a critical role in the maintenance of colon homeostasis. Here we utilized photoconvertible KikGR mice to track immune cells from the caecum and ascending (proximal) colon in the steady state and DSS-induced colitis. We found that Tregs from the proximal colon (colonic migratory Tregs) migrated exclusively to the distal part of mesenteric lymph nodes (dMLN) in an S1PR1-dependent process. In the steady state, colonic migratory CD25+ Tregs expressed higher levels of CD103, ICOS, LAG3 and CTLA-4 in comparison with pre-existing LN Tregs. Intestinal inflammation led to accelerated Treg replacement in the colon, bidirectional Treg migration from the colon to dMLN and vice versa, as well as increases in Treg number, proliferation and expression of immunosuppressive molecules. This was especially apparent for CD25 very high Tregs induced in colitis. Furthermore, colonic migratory Tregs from the inflamed colon included more interleukin (IL)-10 producing cells, and demonstrated greater inhibition of T-cell proliferation in comparison with pre-existing LN Tregs. Thus, our results suggest that Tregs with superior immunosuppressive capacity are increased both in the colon and dMLN upon inflammation. These Tregs recirculate between the colon and dMLN, and are likely to contribute to the downregulation of intestinal inflammation.
Subject(s)
Colitis/immunology , Colon/immunology , Inflammation/immunology , Lymph Nodes/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Cell Movement , Cells, Cultured , Colitis/chemically induced , Disease Models, Animal , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Homeodomain Proteins/genetics , Humans , Immunosuppression Therapy , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Lysosphingolipid/metabolism , Sodium Dodecyl Sulfate , Sphingosine-1-Phosphate Receptors , Tumor Suppressor Proteins/geneticsSubject(s)
Adrenal Insufficiency/chemically induced , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Substance Withdrawal Syndrome/etiology , Adenocarcinoma/drug therapy , Adenocarcinoma/immunology , Adenocarcinoma/surgery , Adenocarcinoma of Lung , Adrenal Insufficiency/immunology , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/immunology , Clinical Trials, Phase III as Topic , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Lung Neoplasms/surgery , Male , Nivolumab , Randomized Controlled Trials as Topic , Substance Withdrawal Syndrome/immunologyABSTRACT
BACKGROUND: In recent years, installation of bidet toilets within hospitals in Japan has raised concerns regarding potential for cross-contamination by antimicrobial-resistant bacteria from patients who are hospitalized over an extended period. AIM: To investigate the distribution of antimicrobial-resistant bacteria recovered from bidet toilets at a university-affiliated hospital in Japan. METHODS: All 292 electric bidet toilets at a university hospital were sampled for contamination. Swabs for culture were used to sample water-jet nozzles and toilet seats. FINDINGS: Of the 292 toilet seats sampled, warm-water nozzles of 254 (86.9%) were found to be contaminated by one or more of the following organisms: Staphylococcus aureus, Streptococcus spp., Enterococcus spp., Enterobacteriaceae and non-Enterobacteriaceae Gram-negative bacteria. S. aureus was recovered from one water-jet nozzle and nine toilet seats; of these, meticillin-resistant S. aureus was recovered from the water-jet nozzle and from one toilet seat. Both the water-jet nozzle and seat of the same toilet were contaminated with a CTX-M-9 group extended-spectrum ß-lactamase-producing Escherichia coli. Of the Gram-negative isolates recovered from samples, the organism with the highest frequency of isolation was Stenotrophomonas maltophilia, which was recovered from 39 bidet toilets. CONCLUSION: Warm-water nozzles of bidet toilets are contaminated with a wide range of bacteria, making them a potential vehicle for cross-infection. In the hospital setting, shared use of bidet toilets must consider the clinical background of patients. Based on these findings, these devices must be part of the risk management programme, and steps should be included for monitoring and disinfection.
Subject(s)
Environmental Microbiology , Gram-Negative Bacteria/isolation & purification , Gram-Positive Bacteria/isolation & purification , Hospitals, University , Toilet Facilities , Cross Infection/epidemiology , Cross-Sectional Studies , Gram-Negative Bacteria/classification , Gram-Positive Bacteria/classification , Humans , Japan , Risk AssessmentSubject(s)
Antibodies, Monoclonal/therapeutic use , Kidney Neoplasms/drug therapy , Kidney Neoplasms/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Pleurisy/immunology , Thoracic Neoplasms/secondary , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Female , Humans , Kidney Neoplasms/pathology , Nivolumab , Thoracic Neoplasms/drug therapy , Thoracic Neoplasms/immunology , Thoracic Wall/pathologyABSTRACT
Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumour Suppressor homologue kinases, are also tumour suppressors. To investigate MOB1A/B's roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium-specific, null mutations of MOB1A/B in mice (SPC-rtTA/(tetO)7-Cre/Mob1aflox/flox/Mob1b-/-; termed luMob1DKO mice). Most mutants (70%) receiving Dox in utero (luMob1DKO (E6.5-18.5) mice) died of hypoxia within 1 h post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome. Intriguingly, mutant mice that received Dox postnatally (luMob1DKO (P21-41) mice) did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumour formation was decreased (rather than increased). Lungs of luMob1DKO (P21-41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche.
Subject(s)
Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Acyltransferases , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Adhesion/physiology , Cell Cycle Proteins , Cell Differentiation/physiology , Cell Line, Tumor , Humans , Intracellular Signaling Peptides and Proteins , Lung Neoplasms/genetics , Mice , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Signal Transduction , Thyroid Nuclear Factor 1 , Trans-Activators , Transcription Factors/genetics , Transcription Factors/metabolism , YAP-Signaling ProteinsABSTRACT
Background: Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness of such liquid biopsy testing with both the digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) during treatment of patients with the epidermal growth factor receptor (EGFR) inhibitor afatinib. Patients and methods: Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations and were treated with afatinib. Plasma samples were collected before and during (4 and 24 weeks) afatinib treatment as well as at disease progression. Tumor and plasma DNA were analyzed by dPCR and NGS. Results: Thirty-five patients were enrolled. The objective response rate and median progression-free survival (PFS) were 77.1% and 13.8 months, respectively. Tumor and plasma DNA were available for 32 patients. dPCR and NGS detected EGFR activating mutations in 81.3% and 71.9% of baseline cfDNA samples, respectively. In 19 patients treated with afatinib for ≥24 weeks, the number of EGFR mutant alleles detected in cfDNA by dPCR declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number (<10 copies per milliliter) at 4 weeks. Median PFS was slightly longer for patients with undetectable EGFR mutant alleles in cfDNA at 4 weeks than for those in whom such alleles were detectable (14.3 versus 10.0 months). A total of 45 somatic mutations was identified in baseline tumor DNA, and 30 (66.7%) of these mutations were identified in cfDNA by NGS. Allele frequency for somatic mutations in cfDNA determined by NGS changed concordantly during afatinib treatment with the number of EGFR mutant alleles determined by dPCR. Conclusions: Monitoring of cfDNA by dPCR is informative for prediction of afatinib efficacy, whereas that by NGS is reliable and has the potential to identify mechanisms of treatment resistance.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Circulating Tumor DNA/genetics , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Quinazolines/therapeutic use , Adenocarcinoma/blood , Adenocarcinoma/enzymology , Adenocarcinoma of Lung , Afatinib , Circulating Tumor DNA/blood , ErbB Receptors/metabolism , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Liquid Biopsy , Lung Neoplasms/blood , Lung Neoplasms/enzymology , Male , Neoplasm Staging , Polymerase Chain Reaction/methods , Prospective Studies , Quinazolines/adverse effectsSubject(s)
Bile Duct Neoplasms/diagnostic imaging , Bile Duct Neoplasms/pathology , Carcinoma, Neuroendocrine/diagnostic imaging , Carcinoma, Neuroendocrine/pathology , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Neoplasm Regression, Spontaneous , Adult , Cholangiopancreatography, Endoscopic Retrograde , Female , Humans , Tomography, X-Ray ComputedABSTRACT
The prevalence of human papillomavirus (HPV)-related oropharyngeal cancers has been increasing in developed countries. We recently demonstrated that members of the apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3, A3) family, which are antiviral factors, can induce hypermutation of HPV DNA in vitro. In the present study, we found numerous C-to-T and G-to-A hypermutations in the HPV16 genome in oropharyngeal cancer (OPC) biopsy samples using differential DNA denaturation PCR and next-generation sequencing. A3s were more abundantly expressed in HPV16-positive OPCs than in HPV-negative, as assessed using immunohistochemistry and reverse transcription quantitative PCR. In addition, interferons upregulated A3s in an HPV16-positive OPC cell line. Furthermore, quantitative PCR analysis of HPV DNA suggests that APOBEC3A (A3A) expression is strongly correlated with the integration of HPV DNA. These results suggest that HPV16 infection may upregulate A3A expression, thereby increasing the chance of viral DNA integration. The role of A3A in HPV-induced carcinogenesis is discussed.
Subject(s)
Cytidine Deaminase/metabolism , Genome, Viral , Oropharyngeal Neoplasms/etiology , Oropharyngeal Neoplasms/metabolism , Papillomaviridae/physiology , Papillomavirus Infections/complications , Papillomavirus Infections/virology , Proteins/metabolism , Cell Line, Tumor , Cytidine Deaminase/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Humans , Mutation , Oncogene Proteins, Viral/genetics , Papillomaviridae/classification , Papillomaviridae/genetics , Proteins/geneticsABSTRACT
As part of the scientific tasks coordinated throughout The 'New Methodologies and Protocols of Forensic Identification by Craniofacial Superimposition (MEPROCS)' project, the current study aims to analyse the performance of a diverse set of CFS methodologies and the corresponding technical approaches when dealing with a common dataset of real-world cases. Thus, a multiple-lab study on craniofacial superimposition has been carried out for the first time. In particular, 26 participants from 17 different institutions in 13 countries were asked to deal with 14 identification scenarios, some of them involving the comparison of multiple candidates and unknown skulls. In total, 60 craniofacial superimposition problems divided in two set of females and males. Each participant follow her/his own methodology and employed her/his particular technological means. For each single case they were asked to report the final identification decision (either positive or negative) along with the rationale supporting the decision and at least one image illustrating the overlay/superimposition outcome. This study is expected to provide important insights to better understand the most convenient characteristics of every method included in this study.
Subject(s)
Decision Making , Face/anatomy & histology , Forensic Anthropology/methods , Skull/anatomy & histology , Datasets as Topic , Female , Humans , Imaging, Three-Dimensional , Male , Photography , Reproducibility of Results , SoftwareABSTRACT
Treatment with an epidermal growth factor receptor inhibitor (egfri) in patients having non-small-cell lung cancer can cause frequent and diverse skin toxicities, an acneiform rash being one of the commonest. Although the exact pathophysiology of this rash and its development mechanisms remain unknown, investigators have noted that egfri-induced skin toxicity might be partly associated with sebaceous gland function. Sebum is composed mainly of the lipids squalene (sq), wax ester (we), triglyceride, free fatty acid, and cholesterol, which are secreted mostly from the sebaceous glands and by keratinocytes. We therefore investigated the lipid composition of sebum before and after administration of egfri and whether sebum composition was associated with the development of acneiform rash. To investigate any associated changes in sebum gland activity, we focused especially on alterations in the amounts of sq and we, which are secreted solely from the sebaceous glands. In contrast to our expectations, we observed no substantial changes in the lipid composition of sebum before and after administration of egfri. Composition varies with the individual; however, the proportion of sq and we derived from the sebaceous glands was significantly lower in regions that did not develop acneiform rash than in regions that did. Our results suggest that development of an acneiform rash after administration of egfri could be related to sebaceous gland activity. Measurement of the lipid composition of sebum before therapy with egfri might predict which patients will be prone to acneiform rash.
ABSTRACT
This paper presents a microfluidic device that can automatically transport a droplet on a plastic plate. This device consists of a Cyclo Olefin Polymer (COP) plate and a SiO2 membrane and has wettability gradient surface. Lithographic patterns of hydrophilic SiO2 permitted wettability modification of a hydrophobic COP surface. A series of alternate hydrophobic and hydrophilic wedge-shaped patterns generated a required gradient in wettability. When we dropped a droplet on the wettability gradient surface, it moved along the wettability gradient due to an imbalance between surface tension forces acting on the opposite sides of the droplet edge. The droplet transportation test was carried out using water of 5 µl. As a result, we succeeded in automatically transporting the droplet on the SiO2/COP wettability gradient pattern. We also carried out droplet transportation in an enclosed microchannel for preventing droplet evaporation using DI (Deionized) water of 5 µl. In this case, the droplet was automatically transported by forming the wettability gradient pattern at the top and bottom in an enclosed microchannel without evaporation.
Subject(s)
Microfluidic Analytical Techniques/instrumentation , Microfluidic Analytical Techniques/methods , Plastics/chemistry , Wettability , Automation , Equipment Design , Silicon Dioxide/chemistry , Surface Tension , Water/chemistryABSTRACT
Breakdown of the intestinal epithelial layer's barrier function results in the inflow of commensal flora and improper immune responses against the commensal flora, leading to inflammatory bowel disease (IBD) development. Using a mouse dextran sodium sulfate (DSS)-induced colitis model, we show here that commensal Gram-positive bacteria trigger the mobilization of inflammatory monocytes and macrophages into the colon. Monocytes/macrophages are major producers of tumor necrosis factor-α (TNF-α), a representative cytokine that aggravates colitis. Notably, pretreating mice with vancomycin, which eliminated Gram-positive bacteria, particularly the Lachnospiraceae family, significantly reduced the severity of the colitis by selectively blocking the recruitment of monocytes/macrophages, but not of other cells. Importantly, vancomycin treatment specifically downregulated the colonic epithelial cell (cEC) expression of C-C chemokine receptor type-2 (CCR2) ligands, which are critical chemokines for monocyte/macrophage mobilization into the inflamed colon. Collectively, these results provide previously undiscovered evidence that Gram-positive commensal bacteria induce colitis by recruiting colitogenic monocytes and macrophages. Our findings may lead to new avenues of treatment for IBD.