AhR promotes phosphorylation of ARNT isoform 1 in human T cell malignancies as a switch for optimal AhR activity.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor present in immune cells as a long and short isoform, referred to as isoforms 1 and 3, respectively. However, investigation into potential ARNT isoform­specific immune functions is lacking despite the well-established heterodimerization requirement of ARNT with, and for the activity of, the aryl hydrocarbon receptor (AhR), a critical mediator of immune homeostasis. Here, using global and targeted transcriptomics analyses, we show that the relative ARNT isoform 1:3 ratio in human T cell lymphoma cells dictates the amplitude and direction of AhR target gene regulation. Specifically, shifting the ARNT isoform 1:3 ratio lower by suppressing isoform 1 enhances, or higher by suppressing isoform 3 abrogates, AhR responsiveness to ligand activation through preprograming a cellular genetic background that directs explicit gene expression patterns. Moreover, the fluctuations in gene expression patterns that accompany a decrease or increase in the ARNT isoform 1:3 ratio are associated with inflammation or immunosuppression, respectively. Molecular studies identified the unique casein kinase 2 (CK2) phosphorylation site within isoform 1 as an essential parameter to the mechanism of ARNT isoform­specific regulation of AhR signaling. Notably, CK2-mediated phosphorylation of ARNT isoform 1 is dependent on ligand-induced AhR nuclear translocation and is required for optimal AhR target gene regulation. These observations reveal ARNT as a central modulator of AhR activity predicated on the status of the ARNT isoform ratio and suggest that ARNT-based therapies are a viable option for tuning the immune system to target immune disorders.

THE 3P MODEL AND ORAL HEALTH IMPACT: DEMONSTRATING THE IMPORTANCE OF BEHAVIORAL AND SOCIAL SCIENCES IN THE FUTURE OF EVIDENCE-BASED DENTISTRY.

Oral health impact or oral health related quality of life is an increasingly important and well-known metric in dental care and research. There have been recent calls for greater integration of the behavioral and social sciences into oral health research and practice, including the need for frameworks and theories to guide this work. One such framework for understanding the role of predisposing, precipitating, and perpetuating biopsychosocial mechanisms in health and disease is the "3P" model. Here, the 3P model is described and applied to case examples to help understand the development and maintenance of oral health impact. Additionally, this paper outlines how this conceptualization using the 3P model and oral health impact makes way for greater integration of behavioral interventions to prevent, mitigate, or treat the negative impact that oral, craniofacial, or dental disease may have on individuals. Doing this allows for a broadening of what evidence-based dentistry means for the future and provides a roadmap going forward.

Surgeon idiosyncrasy is a key driver of cost in arthroscopic rotator cuff repair: a time-driven activity-based costing analysis.

BACKGROUND: Delivering high-value orthopedic care requires optimizing value, defined as health outcomes achieved per dollar spent. Published literature is stippled with inaccurate proxies for cost, including negotiated reimbursement rates, fees paid, or listed prices. Time-driven activity-based costing (TDABC) offers a more robust and accurate approach to calculating cost, including shoulder care. In the present study, we sought to determine the drivers of total cost in arthroscopic rotator cuff repair (aRCR) using TDABC. METHODS: Consecutive patients undergoing aRCR at multiple sites associated with a large urban health care system between January 2019 and September 2021 were identified. Total cost was determined using TDABC methodology. The episode of care was defined by 3 phases: preoperative, intraoperative, and postoperative care. Patient, procedure, rotator cuff tear morphology, and surgeon characteristics were collected. Bivariate analysis was performed across all characteristics between high-cost (top decile) and all other aRCRs. Multivariable linear regression was used to identify the key cost drivers. RESULTS: In total, 625 aRCRs performed by 24 orthopedic surgeons and 572 aRCRs performed by 13 orthopedic surgeons were included in the bivariate and multivariable linear regression analyses, respectively. By TDABC analysis, total aRCR cost varied 6-fold (5.9×) from least to most costly. Intraoperative costs accounted for 91% of average total cost, followed by preoperative costs and postoperative costs (6% and 3%, respectively). Biologic adjuncts (regression coefficient [RC] 0.54, 95% confidence interval [CI] 0.49-0.58, P < .001) and surgeon idiosyncrasy (RC of highest-cost surgeon 0.50, 95% CI 0.26-0.73, P < .001) were the major cost drivers in aRCR. Patient age, comorbidities, number of rotator cuff tendons torn, and revision surgery were not significantly associated with total cost. The amount of tendon retraction (RC 0.0012, 95% CI 0.000020-0.0024, P = .046), average Goutallier grade (RC 0.029, 95% CI 0.0086-0.049, P = .005), and the number of anchors used (RC 0.039, 95% CI 0.032-0.046, P < .001) were also significantly associated with cost, but with far smaller effect sizes. DISCUSSION AND CONCLUSION: Episode of care costs vary nearly 6-fold in aRCR and are almost exclusively dictated by the intraoperative phase. Tear morphology and repair technique contribute to cost, although the largest cost drivers of aRCR are the use of biologic adjuncts and surgeon idiosyncrasy, defined as something a surgeon does or does not do that impacts total cost and is not controlled for in the current analysis. Future work should seek to better delineate what these surgeon idiosyncrasies may represent.

Regulatory T Cells Induced by Single-Peptide Liposome Immunotherapy Suppress Islet-Specific T Cell Responses to Multiple Antigens and Protect from Autoimmune Diabetes.

Ag-specific tolerizing immunotherapy is considered the optimal strategy to control type 1 diabetes, a childhood disease involving autoimmunity toward multiple islet antigenic peptides. To understand whether tolerizing immunotherapy with a single peptide could control diabetes driven by multiple Ags, we coencapsulated the high-affinity CD4+ mimotope (BDC2.5mim) of islet autoantigen chromogranin A (ChgA) with or without calcitriol (1α,25-dihydroxyvitamin D3) into liposomes. After liposome administration, we followed the endogenous ChgA-specific immune response with specific tetramers. Liposome administration s.c., but not i.v., induced ChgA-specific Foxp3+ and Foxp3- PD1+ CD73+ ICOS+ IL-10+ peripheral regulatory T cells in prediabetic mice, and liposome administration at the onset of hyperglycemia significantly delayed diabetes progression. After BDC2.5mim/calcitriol liposome administration, adoptive transfer of CD4+ T cells suppressed the development of diabetes in NOD severe combined immunodeficiency mice receiving diabetogenic splenocytes. After BDC2.5mim/calcitriol liposome treatment and expansion of ChgA-specific peripheral regulatory T cells. IFN-γ production and expansion of islet-specific glucose-6-phosphatase catalytic subunit-related protein-specific CD8+ T cells were also suppressed in pancreatic draining lymph node, demonstrating bystander tolerance at the site of Ag presentation. Thus, liposomes encapsulating the single CD4+ peptide, BDC2.5mim, and calcitriol induce ChgA-specific CD4+ T cells that regulate CD4+ and CD8+ self-antigen specificities and autoimmune diabetes in NOD mice.

Fear of Pain Across the Adult Life Span.

BACKGROUND: Pain continues to be an important public health concern, especially given the opioid crisis in industrialized countries. It is important to understand the association between emotions such as fear and anxiety and the experience of pain as both a physiological and affective experience. Fear or anxiety about pain is in fact a well-known predictor of and close associate of pain. Nociception and pain history differ depending on age, yet little empirical evidence exists on how fear of pain varies over the life span. The purpose of this study was to provide a cross-sectional examination of the relations between age and fear of pain across the adult life span. METHODS: Using cross-sectional data from 4,122 participants who completed the Fear of Pain Questionnaire-9, structural equation modeling and regression techniques were used to examine the association between fear of pain and age. RESULTS: A positive linear association was discovered between age and fear of severe or minor pain, and a negative association was discovered between age and fear of medical or dental pain. Quadratic and cubic relations were also significant for fear of severe pain, fear of medical and dental pain, and overall fear of pain, but not for fear of minor pain. CONCLUSIONS: Unique trajectories for different components of pain-related fear exist across the adult life span and may be affected by increased exposure to medical and dental experiences over time and by the awareness of a greater likelihood of experiencing pain later in the life span.

Medications as a Risk Factor for Fragility Hip Fractures: A Systematic Review and Meta-analysis.

Fragility hip fractures and their associated morbidity and mortality pose a global healthcare problem. Several pharmaceutical products have been postulated to alter bone architecture and contribute to fragility hip fractures. We searched four electronic databases from inception to September 2017. Inclusion criteria were the following: (1) adult patients with fragility hip fractures, (2) full text in English, (3) minimum one-year follow-up, and (4) reporting of at least one risk factor. To minimize heterogeneity among the studies, we performed subgroup analyses. Whenever heterogeneity remained significant, we employed random effect meta-analysis for data pooling. Thirty-eight studies were included, containing 1,244,155 subjects and 188,966 cases of fragility hip fractures. Following medications were significantly associated with fragility hip fractures: Antidepressants (OR 2.07, 95% CI 1.98-2.17), antiparkinsonian drugs (OR 2.21, 95% CI 1.15-4.24), antipsychotic drugs (OR 2.0, 95% CI 1.50-2.66), anxiolytic drugs (OR 1.44, 95% CI 1.19-1.75), benzodiazepines (OR 1.84, 95% CI 1.26-2.69), sedatives (OR 1.33, 95% CI 1.14-1.54), systemic corticosteroids (OR 1.65, 95% CI 1.37-1.99), H2 antagonists (OR 1.21, 95% CI 1.18-1.24), proton pump inhibitors (OR 1.41, 95% CI 1.16-1.71), and thyroid hormone (OR 1.29, 95% CI 1.13-1.47). Hormone replacement therapy with estrogen (HRT) was associated with decreased risk of hip fracture (OR 0.80, 95% CI 0.65-0.98). There are several medications associated with sustaining a fragility hip fracture. Medical interventions should be considered for patients on these medications, including information about osteoporosis and fracture prevention.

The Role of Distress Tolerance as a Potential Mechanism Between Anxiety Sensitivity and Gut-Specific Anxiety.

BACKGROUND: The link between anxiety/fear and gut dysfunction has been robustly documented in both physical and mental health literatures. The current study explored distress tolerance as a potential mechanism in the relation between anxiety sensitivity and gut-specific anxiety. METHOD: A cross-sectional sample of 828 adults completed measures of distress tolerance, gut-specific anxiety, and anxiety sensitivity. Multiple linear regression analyses were conducted to determine variable associations, including potential mediating factors. RESULTS: The results demonstrated a bidirectional relation between anxiety sensitivity and gut-specific anxiety (ß = 0.23, p < 0.001; ß = 0.22, p < 0.001). Findings suggest distress tolerance is a significant mediator that may partially explain the relation between gut-specific anxiety and anxiety sensitivity more broadly (ß = 0.11, CI [0.07-0.14]). Mediation results were consistent when individual subscales of distress tolerance or anxiety sensitivity were incorporated. CONCLUSION: The outcome of the present study merits additional examination of the psychosomatic nature of distress tolerance as a potential clinical target for individuals with both anxiety and gut-related disorders.

Genomic Deletion of BAP1 and CDKN2A Are Useful Markers for Quality Control of Malignant Pleural Mesothelioma (MPM) Primary Cultures.

Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of CDNK2A and BAP1 is common in MPM and has potential diagnostic value. Changes in CDKN2A and BAP1 genomic expression were confirmed in MPM samples in the current study using Fluorescence In situ Hybridization (FISH) analysis or copy number variation (CNV) analysis with digital droplet PCR (ddPCR). To determine whether MPM tissue and cell lines were comparable in terms of molecular alterations, IHC marker expression was analyzed in both sample types. The percentage of MPM biomarker levels showed variation between original tissue and matched cells established in culture. Genomic deletions of BAP1 and CDKN2A, however, showed consistent levels between the two. The data from this study suggest that genomic deletion analysis may provide more accurate biomarker options for MPM diagnosis.

Progenitor genotyping reveals a complex clonal architecture in a subset of CALR-mutated myeloproliferative neoplasms.

The identification of acquired CALR mutations in patients with essential thrombocythaemia (ET) or myelofibrosis (MF) has meant that disease-initiating mutations can now be detected in about 90% of all patients with a myeloproliferative neoplasm (MPN). Here, we show that only those CALR mutations that cause a +1 frameshift, thereby altering the carboxy-terminus of calreticulin, promote cytokine independence in vitro; in-frame deletions were not functional, and are unlikely to be the pathogenetic mutation underlying some MPN cases. Expression of the thrombopoietin receptor, MPL, was also necessary for factor-independence. Although the CALR mutations are considered to occur only in JAK2 V617F-negative cases and in a heterozygous state, progenitor genotyping revealed that this is not always true. Notably, CALR mutation-positive MPNs can be polyclonal: in one case, two distinct CALR mutation-positive subpopulations could be identified; in another, separate populations of JAK2 V617F-positive and CALR-mutated cells were present. Mitotic recombination involving chromosome 19 in a third instance resulted in the emergence of a CALR mutation-homozygous subclone. Collectively, our studies demonstrate that occasional patients with CALR mutation-positive ET or MF carry other MPN-initiating genetic mutations (including JAK2 V617F), acquire "secondary mutations" before or after the CALR mutation, or evolve over time to being CALR mutation-homozygous.

CD11a/ICAM-1 blockade combined with IL-2 targeting therapy causes a paradoxical acceleration of type 1 diabetes.

Enhancement of regulatory T-cell (Treg) function is the goal of many immunotherapies aimed at treating type 1 diabetes (T1D). The use of interleukin (IL)-2 is hindered by its effects on other populations such as effector T cells and NK cells. Combination therapies aimed at suppressing effector T cells while using IL-2 to expand Tregs could be beneficial and have been trialed in T1D patients. We have investigated a combination therapy using IL-2 and αCD11a blocking antibody to simultaneously expand Tregs and suppress the activation and migration of autoreactive T cells. When non-obese diabetic mice were treated with low-dose IL-2/anti-IL-2 complexes (IL-2c) and αCD11a, significant Treg expansion occurred in both the spleen and pancreas. Activation and IFNγ production by islet-specific T cells was robustly suppressed in the periphery following IL-2c/αCD11a treatment. Surprisingly, combination therapy accelerated diabetes onset compared with control treatments. Analysis of IL-2 responsive populations found that combination therapy increased the activation of CD8+ T cells and natural killer (NK) cells specifically within the pancreas despite concomitant Treg expansion. Blocking effector T-cell migration with the inhibitor FTY720 together with IL-2c treatment also resulted in intra-pancreatic expansion of effector cell populations. Thus, inhibiting effector T-cell migration into the islets unleashes islet-resident pathogenic effectors in the presence of low doses of exogenous IL-2.

KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets. METHODS: Utilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy. RESULTS: We identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epithelioid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the (normal) mesothelial line MeT-5A, and was also upregulated in patient tumor samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration. CONCLUSION: These functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and potentially druggable targets.

A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma.

BACKGROUND: We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM). METHODS: Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts. RESULTS: Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC. CONCLUSIONS: Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.

Nuclear factor-κB-inducing kinase (NIK) contains an amino-terminal inhibitor of apoptosis (IAP)-binding motif (IBM) that potentiates NIK degradation by cellular IAP1 (c-IAP1).

Activation of the noncanonical NF-κB pathway hinges on the stability of the NF-κB-inducing kinase (NIK), which is kept at low levels basally by a protein complex consisting of the E3 ubiquitin ligases cellular inhibitor of apoptosis 1 and 2 (c-IAP1/2) proteins and the tumor necrosis factor receptor-associated factors 2 and 3 (TRAF2/3). NIK is brought into close proximity to the c-IAPs through a TRAF2-TRAF3 bridge where TRAF2 recruits c-IAP1/2 and TRAF3 binds to NIK. However, it is not clear how the c-IAPs specifically recognize and ubiquitylate NIK in the complex. We have identified an IAP-binding motif (IBM) at the amino terminus of NIK. IBMs are utilized by a number of proapoptotic proteins to antagonize IAP function. Here, we utilize mutational studies to demonstrate that wild-type NIK is destabilized in the presence of c-IAP1, whereas the NIK IBM mutant is stable. NIK interacts with the second baculovirus IAP repeat (BIR2) domain of c-IAP1 via the IBM, and this interaction, in turn, provides substrate recognition for c-IAP1 mediated ubiquitylation and degradation of NIK. Furthermore, in the presence of the NIK IBM mutant, we observed an elevated processing of p100 to p52 followed by increased expression of NF-κB target genes. Together, these findings reveal the novel identification and function of the NIK IBM, which promotes c-IAP1-dependent ubiquitylation of NIK, resulting in optimal NIK turnover to ensure that noncanonical NF-κB signaling is off in the absence of an activating signal.

MicroRNA-34c is associated with emphysema severity and modulates SERPINE1 expression.

BACKGROUND: MicroRNAs (MiRNA) are small non-coding RNAs that regulate gene expression. The aim of this study was to identify miRNAs differentially expressed between mild and moderately emphysematous lung, as well as their functional target mRNAs. Resected lung from patients with COPD undergoing lung cancer surgery was profiled using miRNA (Agilent Human miRNA profiler G4470 V1.01) and mRNA (OperonV2.0) microarrays. Cells of lung origin (BEAS-2B and HFL1) were profiled using mRNA microarrays (Illumina HumanHT-12 V3) after in vitro manipulation. RESULTS: COPD patients had mean (SD) age 68 (6) years, FEV1 72 (17)% predicted and gas transfer (KCO) 70 (10)% predicted. Five miRNAs (miR-34c, miR-34b, miR-149, miR-133a and miR-133b) were significantly down-regulated in lung from patients with moderate compared to mild emphysema as defined by gas transfer (p < 0.01). In vitro upregulation of miR-34c in respiratory cells led to down-regulation of predicted target mRNAs, including SERPINE1, MAP4K4, ZNF3, ALDOA and HNF4A. The fold change in ex-vivo expression of all five predicted target genes inversely correlated with that of miR-34c in emphysematous lung, but this relationship was strongest for SERPINE1 (p = 0.05). CONCLUSION: Differences in miRNA expression are associated with emphysema severity in COPD patients. MiR-34c modulates expression of its putative target gene, SERPINE1, in vitro in respiratory cell lines and ex vivo in emphysematous lung tissue.

The role of postnatal neurogenesis in supporting remote memory and spatial metric processing.

In this study, we determined the contribution of juvenile neurogenesis to the performance of mice on a remote memory for temporally based association task and in a novelty based spatial pattern separation task. This was accomplished by mating homozygous DNMT1-loxP mice with heterozygous GFAP-Cre mice and comparing Cre+ (no postnatal neurogenesis) to Cre- (wild type) littermate offspring. The results indicate that Cre+ mice are impaired relative to Cre- mice in the remote memory for a temporal based association task and in a novelty based spatial pattern separation task. These results support the temporal integration model of Aimone et al., [(2006) Nat Neurosci 9:723-727] and provide further support for an important role for postnatally born neurons in spatial pattern separation. In contrast, Cre+ mice are not impaired relative to Cre- mice in an object-context recognition task and a spatial location recognition task. These latter data suggest that postnatally derived neurons in the dentate gyrus (DG) do not support all spatial and object recognition functions of the DG.

Exploring and describing current behavioral and social sciences curricula in predoctoral dental programs.

PURPOSE: To maintain accreditation status, predoctoral dental programs in the United States and Canada are required to train future dentists in the fundamentals of behavioral sciences. Each program independently determines how to fulfill this task, and little information exists on the consistency of training across programs. The purpose of this study was to identify the range of topics currently taught in predoctoral dental programs in the United States and Canada, who teaches them, and the modes of instruction and assessment. METHODS: Invitations to complete an online survey were emailed to faculty responsible for, or familiar with, the behavioral sciences curricula at 75 predoctoral dental programs in the United States and Canada. Questions elicited information on behavioral sciences education at each program, including instructor background, topics taught, instructional and assessment methods, and sources of content. RESULTS: Of those invited, 27 (36%) completed surveys. Per the responses, prototypical behavioral sciences programs usually consist of didactic/lecture format teaching, mostly during the first 2 years of the predoctoral program, by a dentist who assesses students using multiple-choice or true/false exams. The results indicated, however, substantial variation in what is taught, how it is taught, who teaches it, and how it is assessed. CONCLUSIONS: While being a requirement for accreditation, this study demonstrated how behavioral and social sciences topics, teaching strategies, and assessments, along with the individuals teaching those topics varied across predoctoral programs. Consistency, coordination, and clinical integration are possible ways of enhancing behavioral science instruction.

Pain, Fear, Anxiety, and Stress: Relations to the Endogenous Opioid System.

Pain, fear, stress, and anxiety are separate yet interrelated phenomena. Each of these concepts has an extensive individual body of research, with some more recent work focusing on points of conceptual overlap. The role of the endogenous opioid system in each of these phenomena is only beginning to be examined and understood. Research examining the ways in which endogenous opioids (e.g., beta-endorphin; ßE) may mediate the relations among pain, fear, stress, and anxiety is even more nascent. This chapter explores the extant evidence for endogenous opioid activity as an underpinning mechanism of these related constructs, with an emphasis on research examining ßE.

Dental anxiety and oral health in American Indian and Alaska natives.

OBJECTIVE: American Indian and Alaska native (AI/AN) individuals report distrust of the healthcare system. This study explored associations between having either high levels of dental distrust or high levels of dental care-related fear and anxiety ("dental anxiety") and oral health outcomes in AI/AN adults. METHODS: The 2022 State of Oral Health Equity in America survey included the Modified Dental Anxiety Scale and asked to what extent respondents agreed with the statement, "At my last oral health visit, I trusted the oral health provider I saw", and asked about self-rated oral health and presence of a dental home. RESULTS: AI/AN individuals (N = 564) who reported low dental trust (n = 110) or with high dental anxiety (MDAS≥19; n = 113) reported significantly worse overall and oral health and were significantly less likely to have a dental home (p < 0.05 used for each analysis). CONCLUSION: Dental distrust and dental anxiety can significantly impact oral health and dental utilization in AI/AN communities and are important intervention targets to improve AI/AN oral health.

Genome-wide CpG island methylation analyses in non-small cell lung cancer patients.

DNA methylation is part of the epigenetic gene regulation complex, which is relevant for the pathogenesis of cancer. We performed a genome-wide search for methylated CpG islands in tumors and corresponding non-malignant lung tissue samples of 101 stages I-III non-small cell lung cancer (NSCLC) patients by combining methylated DNA immunoprecipitation and microarray analysis. Overall, we identified 2414 genomic positions differentially methylated between tumor and non-malignant lung tissue samples. Ninety-seven percent of them were found to be tumor-specifically methylated. Annotation of these genomic positions resulted in the identification of 477 tumor-specifically methylated genes of which many are involved in regulation of gene transcription and cell adhesion. Tumor-specific methylation was confirmed by a gene-specific approach. In the majority of tumors, methylation of certain genes was associated with loss of their protein expression determined by immunohistochemistry. Treatment of NSCLC cells with epigenetically active drugs resulted in upregulated expression of many tumor-specifically methylated genes analyzed by gene expression microarrays suggesting that about one-third of these genes are transcriptionally regulated by methylation. Moreover, comparison of methylation results with certain clinicopathological characteristics of the patients suggests that methylation of HOXA2 and HOXA10 may be of prognostic relevance in squamous cell carcinoma (SCC) patients. In conclusion, we identified a large number of tumor-specifically methylated genes in NSCLC patients. Expression of many of them is regulated by methylation. Moreover, HOXA2 and HOXA10 methylation may serve as prognostic parameters in SCC patients. Overall, our findings emphasize the impact of methylation on the pathogenesis of NSCLCs.

New insights into the function of IAP proteins: modulation of the MYC/MAX/MAD network.

A growing number of studies have revealed that the inhibitor of apoptosis (IAP) proteins play a variety of cellular roles in addition to suppression of apoptosis. A recent study in Molecular Cell demonstrates that one IAP member, c-IAP1, functions to potentiate the activity of Myc by triggering the ubiquitination and proteasomal degradation of the Myc inhibitory protein Mad1.