Identifying Variation in Physical Health Behaviors and Depressive Symptoms among Religiosity Clusters of African American Adults in the United States.

Religiosity is an important factor in the lives of many African Americans, who suffer a greater health burden than their White counterparts. In this study, we examined associations between dimensions of religiosity with health behaviors and depressive symptoms in a sample of African American adults in the United States. Participants (N = 2086) completed five measures of religiosity (religious involvement, positive and negative religious coping, scriptural influence, belief in illness as punishment for sin) and measures of several health behaviors, cancer screening behaviors, and depressive symptoms. Using cluster analysis to examine the deep structure of religiosity, three clusters emerged: Positive Religious, Negative Religious, and Low Religious. In general, the Positive Religious group engaged in more healthy behaviors (e.g., fruit and vegetable consumption, fecal occult blood test) and fewer risky health behaviors (e.g., smoke and consume alcohol), and reported fewer depressive symptoms than did the Negative Religious and/or Low Religious groups. Theoretical implications and implications for interventions by clergy and mental health professionals are discussed.

Exploring how military culture shapes veterans' perception of aortic aneurysm repair: A qualitative study.

BACKGROUND: Veterans represent a distinct cultural group whose perceptions of illness and treatment are influenced by military culture. The study explores how prior military service shapes Veterans' assumptions and behaviors in the setting of aneurysm repair surgery. STUDY DESIGN: We conducted content and thematic analysis of a case series of 10 transcripts from telephone interviews with older (76.7 ± 4.3 years) African American and White male Veterans now residing in the Southern U.S. who underwent open or endovascular aneurysm surgery at Veterans Affairs Medical Centers or university affiliates between 2004 and2019. RESULTS: Throughout the continuum of care, Veterans described deferring to authority and not questioning provider's decisions ["I just can't make a judgment on that, because I'm not a doctor"]. Veterans valued commitment and articulated pride in keeping logistically challenging surveillance appointments [I always took them very seriously. . . If I'm scheduled for something by the doctor, I always make it."]. The routine structure of VA care aligned with Veterans military experiences, facilitating compliance with doctor's orders. However, procedural deviations in VA care were disconcerting for patients ["They haven't reached out to me in at least three years, since my surgery; I was being seen once a year and then all of a sudden, they just quit."]. While Veterans praised VA care, they exhibited sensitivity to signs of untoward treatment from clinical and support staff "…my surgeon, he never talked to me before, nor after, no anytime…I thought that maybe that wasn't right". CONCLUSIONS: Military culture embodies rank, order, and respect, and remains a source of strength and stability for Veterans in their medical care late in life. Cultural competency about how military service has shaped Veterans' expectations can enhance providers' awareness of patients' military mindsets and inform surgeons' efforts to engage Veterans in shared decision making.

Modeling epithelial homeostasis and perturbation in three-dimensional human esophageal organoids.

Background: Esophageal organoids from a variety of pathologies including cancer are grown in Advanced Dulbecco's Modified Eagle Medium-Nutrient Mixture F12 (hereafter ADF). However, the currently available ADF-based formulations are suboptimal for normal human esophageal organoids, limiting the ability to compare normal esophageal organoids with those representing a given disease state. Methods: We have utilized immortalized normal human esophageal epithelial cell (keratinocyte) lines EPC1 and EPC2 and endoscopic normal esophageal biopsies to generate three-dimensional (3D) organoids. To optimize ADF-based medium, we evaluated the requirement of exogenous epidermal growth factor (EGF) and inhibition of transforming growth factor-(TGF)-ß receptor-mediated signaling, both key regulators of proliferation of human esophageal keratinocytes. We have modeled human esophageal epithelial pathology by stimulating esophageal 3D organoids with interleukin (IL)-13, an inflammatory cytokine, or UAB30, a novel pharmacological activator of retinoic acid signaling. Results: The formation of normal human esophageal 3D organoids was limited by excessive EGF and intrinsic TGFß receptor-mediated signaling. In optimized HOME0, normal human esophageal organoid formation was improved, whereas IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis. Conclusions: HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media.

Exploring women's bladder self-care practices: A qualitative secondary analysis.

AIMS: To describe women's experiences with a range of bladder self-care practices. DESIGN: We conducted a secondary, directed content analysis of qualitative data from the Study of Habits, Attitudes, Realities and Experiences, a multisite focus group study designed to explore adolescent and adult women's experiences, perceptions, beliefs, knowledge and behaviours related to bladder health. This study was conducted by the National Institute of Diabetes and Digestive and Kidney Diseases' Prevention of Lower Urinary Tract Symptoms Research Consortium. Study methods were informed by the Consortium's conceptual framework, based on a social ecological model adapted from Glass and McAtee's Society-Behavior-Biology Nexus. METHODS: Participants were recruited at seven geographically diverse United States research centres between July 2017 and April 2018. Data for the current analysis were collected using a semi-structured discussion group with 36 focus groups involving 316 community-dwelling adult women aged 18-93 years. Coded text was re-examined according to eight self-care behavioural domains identified through literature review and expert opinion as potentially influencing bladder health. RESULTS: Participants described many self-care practices they had adopted to prevent bladder problems or manage existing symptoms and conditions. Eight themes were identified: 'Choosing fluids, foods and medications'; 'Dressing for bladder health'; 'Promoting bodily cleanliness'; 'Managing toileting environments'; 'Timing when to void'; 'Exercising pelvic floor muscles for bladder control'; 'Limiting physical activities that challenge the bladder' and 'Staying home and navigating when away'. Thirteen subthemes were derived from five of the eight themes. CONCLUSION: Women use a broad array of self-care practices related to their bladder health. Research is needed to examine the efficacy of self-care behaviours for preventing or managing bladder symptoms and conditions, and to discern potential risks. Results have important implications for development of bladder health promotion interventions and public health messaging around women's bladder health. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This study provides a comprehensive framework for understanding women's bladder self-care practices, which can be used by clinicians and public health professionals in designing interventions to promote bladder health and function. IMPACT: Women with and without lower urinary tract symptoms use a broad range of self-care practices that may affect their bladder health, including some that may be harmful. Because of the high prevalence of bladder symptoms in women, this study may help patient assessment and counselling regarding self-care practices. REPORTING METHOD: This study was reported according to the Standards for Reporting Qualitative Research (SRQR). PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

An all-inclusive model for predicting invasive bacterial infection in febrile infants age 7-60 days.

BACKGROUND: Invasive bacterial infections (IBIs) in febrile infants are rare but potentially devastating. We aimed to derive and validate a predictive model for IBI among febrile infants age 7-60 days. METHODS: Data were abstracted retrospectively from electronic records of 37 emergency departments (EDs) for infants with a measured temperature >=100.4 F who underwent an ED evaluation with blood and urine cultures. Models to predict IBI were developed and validated respectively using a random 80/20 dataset split, including 10-fold cross-validation. We used precision recall curves as the classification metric. RESULTS: Of 4411 eligible infants with a mean age of 37 days, 29% had characteristics that would likely have excluded them from existing risk stratification protocols. There were 196 patients with IBI (4.4%), including 43 (1.0%) with bacterial meningitis. Analytic approaches varied in performance characteristics (precision recall range 0.04-0.29, area under the curve range 0.5-0.84), with the XGBoost model demonstrating the best performance (0.29, 0.84). The five most important variables were serum white blood count, maximum temperature, absolute neutrophil count, absolute band count, and age in days. CONCLUSION: A machine learning model (XGBoost) demonstrated the best performance in predicting a rare outcome among febrile infants, including those excluded from existing algorithms. IMPACT: Several models for the risk stratification of febrile infants have been developed. There is a need for a preferred comprehensive model free from limitations and algorithm exclusions that accurately predicts IBIs. This is the first study to derive an all-inclusive predictive model for febrile infants aged 7-60 days in a community ED sample with IBI as a primary outcome. This machine learning model demonstrates potential for clinical utility in predicting IBI.

Black women's perspectives on bladder health: Social-ecological and life course contexts.

AIMS: This paper explores Black women's perspectives on bladder health using a social-ecological conceptual framework and life course perspective. METHODS: We conducted a directed content analysis of data from the Study of Habits, Attitudes, Realities, and Experiences (SHARE), a focus group study by the Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium. Analysis was conducted on data from five focus groups and a member-checking session where all participants self-identified as Black or African American. RESULTS: Forty-two participants aged 11-14 or 45+ years reported life course experiences with their bladder. The intersection of race and gender was the lens through which participants viewed bladder health. Participants' accounts of their perspectives on bladder health explicitly and implicitly revealed structural racism as an explanatory overarching theme. Participants described (a) historically-rooted and still pervasive practices of discrimination and segregation, engendering inequitable access to quality medical care and public facilities, (b) institutional barriers to toileting autonomy in educational and occupational settings, promoting unhealthy voiding habits, (c) internalized expectations of Black women's stereotyped role as family caregiver, compromising caregiver health, (d) lack of reliable information on bladder health, leading to unhealthy bladder behaviors, and (e) potentially stress-related comorbid chronic conditions and associated medication use, causing or exacerbating bladder problems. CONCLUSIONS: Bladder health promotion interventions should address social-ecological and life course factors shaping Black women's bladder health, including social and structural barriers to accessing equitable health information and medical care.

The brain, gut, and bladder health nexus: A conceptual model linking stress and mental health disorders to overactive bladder in women.

OBJECTIVE: A small, but growing literature links stressors and mental health disorders (MHDs) across the life course to overactive bladder (OAB) and urinary incontinence symptoms. Mechanisms by which stressors and MHDs may impact bladder health are not fully understood, limiting novel prevention and treatment efforts. Moreover, potential biopsychosocial mechanisms involving the brain and gut have not been considered in an integrated, comprehensive fashion. METHODS: Members of the prevention of lower urinary tract symptoms Research Consortium developed conceptual models to inform research on biopsychosocial mechanisms through which stress and MDHs may impact bladder health among girls and women, focusing on brain and gut physiology. RESULTS: Two conceptual models were developed-one to explain central (brain-based) and peripheral (gut-based) mechanisms linking stressors and MHDs to OAB and bladder health, and one to highlight bidirectional communication between the brain, gut, and bladder. Traumatic events, chronic stressors, and MHDs may lead to a maladaptive stress response, including dysregulated communication and signaling between the brain, gut, and bladder. Gut bacteria produce molecules and metabolites that alter production of neurotransmitters, amino acids, short-chain fatty acids, and inflammatory immune response molecules that mediate communication between the gut and brain. Microbiota signal neurogenesis, microglia maturation, and synaptic pruning; they also calibrate brain-gut-bladder axis communication through neurotransmission and synaptogenesis, potentially influencing bladder symptom development. Life course trajectories of risk may be prevented or interrupted by central and peripheral resources for neuropsychological resilience. CONCLUSIONS: Depicted pathways, including brain-gut-bladder communication, have implications for research and development of novel prevention and treatment approaches.

IL-17 receptor A functions to help maintain barrier integrity and limit activation of immunopathogenic response to H. pylori infection.

Activation of Th17 cell responses, including the production of IL-17A and IL-21, contributes to host defense and inflammatory responses by coordinating adaptive and innate immune responses. IL-17A and IL-17F signal through a multimeric receptor, which includes the IL-17 receptor A (IL-17RA) subunit and the IL-17RC subunit. IL-17RA is expressed by many cell types, and data from previous studies suggest that loss of IL-17 receptor is required to limit immunopathology in the Helicobacter pylori model of infection. Here, an Il17ra-/- mouse was generated on the FVB/n background, and the role of IL-17 signaling in the maintenance of barrier responses to H. pylori was investigated. Generating the Il17ra-/- on the FVB/n background allowed for the examination of responses in the paragastric lymph node and will allow for future investigation into carcinogenesis. While uninfected Il17ra-/- mice do not develop spontaneous gastritis following H. pylori infection, Il17ra-/- mice develop severe gastric inflammation accompanied by lymphoid follicle production and exacerbated production of Th17 cytokines. Increased inflammation in the tissue, increased IgA levels in the lumen, and reduced production of Muc5ac in the corpus correlate with increased H. pylori-induced paragastric lymph node activation. These data suggest that the cross talk between immune cells and epithelial cells regulates mucin production, IgA production, and translocation, impacting the integrity of the gastric mucosa and therefore activating of the adaptive immune response.

CA FIRST (California Febrile Infant Risk Stratification Tool) Algorithm Development in a Learning Health System.

Introduction There is considerable variation in the approach to infants presenting to the emergency department (ED) with fever. The authors' primary aim was to develop a robust set of algorithms using community ED data to inform modifications of broader clinical guidance. Methods The authors report the development of California Febrile Infant Risk Stratification Tool (CA FIRST) using key components of the Roseville Protocol (ROS) and American Academy of Pediatrics (AAP) Clinical Practice Guideline (CPG). Expanded guidance was derived using a retrospective analysis of a cohort of 3527 febrile infants aged 7-90 days presenting to any Kaiser Permanente Northern California ED between 2010 and 2019 who underwent a core febrile infant evaluation. Results Melding ROS and AAP CPG algorithms in infants 7-60 days old, CA FIRST Algorithms had comparable performance characteristics to ROS and AAP CPG. CA FIRST enhancements included guidance on febrile infants 61-90 days old, high-risk infants, infants with bronchiolitis, and infants who received immunizations within the prior 48 hours. This retrospective analysis revealed that of 235 febrile infants 22-90 days old with respiratory syncytial virus and 221 who had fever in the 48 hours following vaccination, there were no cases of invasive bacterial infection. Discussion CA FIRST is a set of 13 algorithms providing a thoughtful and flexible approach to the febrile infant while minimizing unnecessary interventions. Conclusions CA FIRST Algorithms empower clinicians to manage most febrile infants. Algorithms are being modified as new data become available, imparting useful and ever-current educational information within a learning health care system.

Following Birth Hospitalization: Invasive Bacterial Infections in Preterm Infants Aged 7-90 Days.

OBJECTIVE: To assess the incidence rate of invasive bacterial infections in preterm infants and compare invasive bacterial infection rates and pathogens between preterm and full-term infants at age 7-90 days. STUDY DESIGN: This is a retrospective cohort study of the incidence rate of invasive bacterial infections among all infants born at Kaiser Permanente Northern California (KPNC), with blood and cerebrospinal fluid cultures collected between 7 and 90 days of chronological age from outpatient clinics, from emergency departments, and in the first 24 hours of hospitalization presenting for care between January 1, 2005, and December 31, 2017. Incidence rates of invasive bacterial infection by chronological age and postmenstrual age (PMA) and pathogens were compared between preterm and full-term infants. RESULTS: Between January 1, 2005, and December 31, 2017, a total of 479 729 infants were born at KPNC, including 440 070 full-term infants and 39 659 preterm infants. There were 283 cases of bacteremia in 282 infants. The incidence rate of invasive bacterial infection was significantly higher for preterm infants compared with full-term infants. The highest incidence rates of invasive bacterial infection were in preterm infants at chronological age 7-28 days and/or 37-39 weeks PMA. There was a trend toward lower rates of invasive bacterial infection with increasing PMA in preterm infants aged 61-90 days. Preterm infants aged 29-60 days or at ≥40 weeks PMA and those aged 61-90 days or at ≥43 weeks PMA had a rate of invasive bacterial infection equivalent to the overall rate seen in full-term infants of the same chronological age group. The distribution of pathogens causing bacteremia and meningitis did not differ between preterm and full-term infants. CONCLUSION: PMA and chronological age together were more useful than either alone in informing the incidence rate of invasive bacterial infection in preterm infants during the first 90 days of life.

A longitudinal study of social, religious, and spiritual capital and physical and emotional functioning in a national sample of African-Americans.

The present study builds on prior research by examining the moderating relationships between different types of capital on physical functioning, emotional functioning, and depressive symptoms using a 2.5-year longitudinal design with a national sample of African-American adults. Results indicated a significant T1 social capital × T1 religious capital interaction such that among low T1 religious capital participants, those with high T1 social capital had lower T2 physical functioning than those with lower T1 social capital. There was also a marginally significant T1 social capital × T1 spiritual capital interaction suggesting that among low T1 spiritual capital participants, those with higher T1 social capital reported a decline in depressive symptoms compared to those with lower T1 social capital. Future research and implications for intervention and policy development are discussed.

Using AAP Guidelines for Managing Febrile Infants Without C-Reactive Protein and Procalcitonin.

BACKGROUND AND OBJECTIVES: In 2021, the American Academy of Pediatrics (AAP) published the Clinical Practice Guideline (CPG) for management of well-appearing, febrile infants 8 to 60 days old. For older infants, the guideline relies on several inflammatory markers, including tests not rapidly available in many settings like C-reactive protein (CRP) and procalcitonin (PCT). This study describes the performance of the AAP CPG for detecting invasive bacterial infections (IBI) without using CRP and PCT. METHODS: This retrospective cohort study included infants aged 8 to 60 days old presenting to Kaiser Permanente Northern California emergency departments between 2010 and 2019 with temperatures ≥38°C who met AAP CPG inclusion criteria and underwent complete blood counts, blood cultures, and urinalyses. Performance characteristics for detecting IBI were calculated for each age group. RESULTS: Among 1433 eligible infants, there were 57 (4.0%) bacteremia and 9 (0.6%) bacterial meningitis cases. Using absolute neutrophil count >5200/mm3 and temperature >38.5°C as inflammatory markers, 3 (5%) infants with IBI were misidentified. Sensitivities and specificities for detecting infants with IBIs in each age group were: 8 to 21 days: 100% (95% confidence interval [CI] 83.9%-100%) and 0% (95% CI 0%-1.4%); 22 to 28 days: 88.9% (95% CI 51.8%-99.7%) and 40.4% (95% CI 33.2%- 48.1%); and 29 to 60 days: 93.3% (95% CI 77.9%-99.2%) and 32.1% (95% CI 29.1%- 35.3%). Invasive interventions were recommended for 100% of infants aged 8 to 21 days; 58% to 100% of infants aged 22 to 28 days; and 0% to 69% of infants aged 29 to 60 days. CONCLUSIONS: When CRP and PCT are not available, the AAP CPG detected IBI in young, febrile infants with high sensitivity but low specificity.

Effects of methylene blue photodynamic therapy on oral carcinoma and leukoplakia cells.

Objective: Methylene blue (MB) is a readily available and affordable substrate that can be used as a photosensitizer for photodynamic therapy (PDT). The objective of this study was to determine if PDT with MB can downregulate matrix metalloproteinases (MMPs) related to oral carcinoma. Methods: Cell cultures of oral squamous cell carcinoma (CA-9-22), oral leukoplakia (MSK-Leuk1), and immortalized keratinocytes (Rhek-1A) were photosensitized with MB and treated with PDT. MMP-9 gene expression was interrogated via qRT-PCR. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to confirm the efficacy of MB PDT. Results: MMP-9 gene expression was found to be significantly decreased in oral carcinoma, leukoplakia, and immortalized keratinocytes with use of MB PDT. Conclusion: This work demonstrates that MB-mediated PDT can downregulate MMPs which are critical to the invasion and metastasis of oral cancer. These results suggest that MB PDT could be a clinically significant and cost-effective treatment for oral leukoplakia and carcinoma. Level of Evidence: NA.

Clinical management and outcomes for febrile infants 29-60 days evaluated in community emergency departments.

Objective: Describe emergency department (ED) management and patient outcomes for febrile infants 29-60 days of age who received a lumbar puncture (LP), with focus on timing of antibiotics and type of physician performing LP. Methods: Retrospective observational study of 35 California EDs from January 1, 2010 through December 31, 2019. Primary analysis was among patients with successful LP and primary outcome was hospital length of stay (LOS). Logistic regression analysis included variables associated with LOS of at least 2 days. Secondary outcomes were bacterial meningitis, hospital admission, length of antibiotics, and readmission. Results: Among 2569 febrile infants (median age 39 days), 667 underwent successful LP and 633 received intravenous antibiotics. Most infants (n = 559, 88.3%) had their LP before intravenous antibiotic administration. Pediatricians performed 54% of LPs and emergency physicians 34%. Sixteen infants (0.6% of 2569) were diagnosed with bacterial meningitis, and none died. Five hundred and fifty-eight (88%) infants receiving an LP were hospitalized. Among patients receiving an LP and antibiotics (n = 633), 6.5% were readmitted within 30 days. Patients receiving antibiotics before LP had a longer length of antibiotics (+ 7.9 hours, 95% confidence interval [CI] 3.8-13.4). Primary analysis found no association between timing of antibiotics and LOS (odds ratio [OR] 0.67, 95% CI 0.34-1.30), but shorter LOS when emergency physicians performed the LP (OR 0.66, 95% CI 0.45-0.97). Conclusions: Febrile infants in the ED had no deaths and few cases of bacterial meningitis. In community EDs, where a pediatrician is often not available, successful LP by emergency physician was associated with reduced inpatient LOS.

Disability and Health in African Americans: Population Research and Implications for Occupational Therapy Community-Based Practice.

Background: Population-based research and community-based interventions are integral to occupational therapy's scope of practice, yet they are underdeveloped in actual implementation. Therefore, this paper focuses on some health challenges facing the African American population, guided by the Person-Environment-Occupation-Performance Model. Method: Using data from an observational cross-sectional nationwide telephone survey of African American adults, we examined differences between African Americans who are receiving disability payments (RDP) and those who are employed full time (FTE) on several physical health behaviors and psychosocial health indicators. We further compared the differences between African Americans RDP versus those FTE on those physical health behaviors and psychosocial health indicators across five US regions. Results: Findings suggest that African Americans RDP are engaging in fewer positive physical health behaviors and experiencing worse psychosocial health compared to their counterparts FTE. There are also nuanced regional variations in the differences between African Americans RDP and FTE in physical health behaviors and psychosocial health indicators. Conclusion: This research highlighted some health challenges of African Americans RDP and FTE using a regional lens, demonstrating the value of OT population-based research. There is a need for OT population-specific community-based practice to address the health disparities of underserved and minority populations, such as African Americans.

Assessing the Clinical Utility of a Wearable Device for Physiological Monitoring of Heart Rate Variability in Military Service Members with Traumatic Brain Injury.

Introduction: Autonomic dysfunction has been implicated as a consequence of traumatic brain injury (TBI). Heart rate variability (HRV) may be a viable measure of autonomic dysfunction that could enhance rehabilitative interventions for individuals with TBI. This pilot study sought to assess the feasibility and validity of using the Zeriscope™ platform system in a real-world clinical setting to measure HRV in active-duty service members with TBI who were participating in an intensive outpatient program. Methods: Twenty-five service members with a history of mild, moderate, or severe TBI were recruited from a military treatment facility. A baseline assessment was conducted in the cardiology clinic where point validity data were obtained by comparing a 5-min recording of a standard 12-lead electrocardiogram (ECG) output against the Zeriscope platform data. Results: Compared with the ECG device, the Zeriscope device had a concordance coefficient (rc) of 0.16, falling below the standard deemed to represent acceptable accuracy in HR measurement (i.e., 0.80). Follow-up analyses excluding outliers did not significantly improve the concordance coefficient to an acceptable standard for the total participant sample. System Usability Survey responses showed that participants rated the Zeriscope system as easy to use and something that most people would learn to use quickly. Conclusions: This study demonstrated promise in ambulatory HRV measurement in a representative military TBI sample. Future research should include further refinement of such ambulatory devices to meet the specifications required for use in a military active-duty TBI population.

IL-17 Receptor Signaling through IL-17A or IL-17F Is Sufficient to Maintain Innate Response and Control of Helicobacter pylori Immunopathogenesis.

IL-17R signaling is required for control of extracellular pathogens and is also implicated in development of chronic inflammatory processes. The response to the human pathogen Helicobacter pylori results in Th1 and Th17 cell activation and a chronic inflammatory process that can lead to adverse outcomes, such as gastric cancer. Previously, we identified IL-17RA as a requirement for the recruitment of neutrophils and control of H. pylori colonization in the gastric mucosa. Unexpectedly, H. pylori-infected Il17ra -/- mice had significantly more chronic inflammation than H. pylori-infected wild-type mice. In this study, human epithelial cell lines and murine models were used to investigate differential roles for IL-17A, IL-17F, and IL-17A/F during H. pylori infection. Moreover, the hypothesis that IL-17RA signaling, specifically in lymphocytes, provides an autocrine feedback loop that downregulates Th17 cytokine production was investigated. The data indicate that epithelial cells exhibit a stronger response to IL-17A and IL-17A/F than IL-17F, and that IL-17A and IL-17A/F can synergize with TNF and IL-22 to induce antimicrobial genes of gastric epithelial cells. In vivo deficiencies of IL-17A or IL-17F alone did not significantly change the immunopathological response to H. pylori, but if both cytokines were absent, a hyperinflammatory lymphocytic response developed. Using a cre/flox targeting approach for IL-17RA combined with infection, our findings demonstrate that increased chronic inflammation in Il17ra -/- mice was not attributed to a T cell-intrinsic defect. These data imply that IL-17A and IL-17F may have overlapping roles in maintenance of the gastric mucosal response to infection.

Preclinical evidence for pioglitazone and bexarotene combination in oral cancer chemoprevention.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) requires new treatments and targeted approaches to improve survival. The peroxisome proliferator-activated receptor γ (PPARγ) and retinoic X receptor alpha (RXRα) nuclear receptor pathways may be targetable with repurposed Food and Drug Administration (FDA)-approved agents for prevention and treatment. METHODS: Oral cancer and leukoplakia cell lines were treated with the PPARγ agonist (pioglitazone) and RXRα activator (bexarotene). PPARγ activation, cellular proliferation, apoptosis activity and phenotype, including the pharmacodynamic marker, involucrin (IVL), were subsequently analyzed using a reporter gene assay, genomic data, MTT assay and western blot. RESULTS: Microarray analysis of HNSCC tumor versus normal tissue shows IVL expression is significantly increased in normal tissue compared to HNSCC tumors (p < 0.0001). In MSK Leuk1 and CA 9-22 cell lines, pioglitazone increases PPARγ DNA binding activity and IVL promoter activity in a dose dependent manner (p < 0.01 and p < 0.0001). Combination treatment with pioglitazone and bexarotene increases PPARγ DNA binding activity and IVL promoter activity (p < 0.01 and p < 0.0001). MTT analysis shows decreases in cell proliferation when cells are treated with pioglitazone and bexarotene. Decreases in cell proliferation are significant to at least p < 0.05 for all combination versus single agent treatments. Western blot on whole-cell lysate from cells treated with pioglitazone and bexarotene alone or in combination for IVL showed increased protein levels with combination treatment. CONCLUSIONS: Targeting the PPARγ/RXRα heterodimer with pioglitazone and bexarotene was effective in this preclinical project. This was functional in both preneoplastic and oral cancer cell lines. A better understanding of the molecular mechanism on downstream effects on cellular proliferation could potentially have implications clinically, both in oral preneoplasia and possibly head and neck cancer; however, more research needs to be done to explore the potential these medications have in chemoprevention.

Loss of Corpus-Specific Lipids in Helicobacter pylori-Induced Atrophic Gastritis.

Helicobacter pylori colonization of the stomach is a strong risk factor for the development of stomach cancer and peptic ulcer disease. In this study, we tested the hypothesis that H. pylori infection triggers alterations in gastric lipid composition. Mongolian gerbils were experimentally infected with H. pylori for 3 months. Conventional histologic staining revealed mucosal inflammation in stomachs from the H. pylori-infected animals but not in stomachs from uninfected control animals. Atrophic gastritis (a premalignant condition characterized by loss of corpus-specific parietal and chief cells), gastric mucosal hyperplasia, dysplasia, and/or gastric cancer were detected in stomachs from several infected animals. We then used imaging mass spectrometry to analyze the relative abundance and spatial distribution of gastric lipids. We detected ions corresponding to 36 distinct lipids that were differentially abundant when comparing gastric tissues from H. pylori-infected animals with tissues from uninfected animals. Liquid chromatography-tandem mass spectrometry analysis of lipid extracts from homogenized gastric tissues provided additional supportive evidence for the identification of several differentially abundant lipids. Sixteen of the differentially abundant lipids were localized mainly to the gastric corpus in stomachs from uninfected animals and were markedly reduced in abundance in stomachs from H. pylori-infected animals with severe disease (atrophic gastritis and dysplasia or gastric cancer). These findings indicate that H. pylori infection can lead to alterations in gastric lipid composition and constitute a new approach for identifying biomarkers of gastric atrophy and premalignant changes. IMPORTANCE H. pylori colonization of the stomach triggers a cascade of gastric alterations that can potentially culminate in stomach cancer. The molecular alterations that occur in gastric tissue prior to development of stomach cancer are not well understood. We demonstrate here that H. pylori-induced premalignant changes in the stomach are accompanied by extensive alterations in gastric lipid composition. These alterations are predicted to have important functional consequences relevant to H. pylori-host interactions and the pathogenesis of gastric cancer.

Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions.

BACKGROUNDThe aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention.METHODSIndividuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3-12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing.RESULTSTwenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses (P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological (P = 0.04) and clinical (P = 0.01) responses.CONCLUSIONTo our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent.TRIAL REGISTRATIONNCT02581137FUNDINGNIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870.