Dynamics of the Gut Mycobiome in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Intestinal fungi have been implicated in the pathogenesis of ulcerative colitis (UC). However, it remains unclear if fungal composition is altered during active versus quiescent disease. METHODS: We analyzed clinical and metagenomic data from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD), available via the IBD Plexus Program of the Crohn's & Colitis Foundation. We evaluated the fungal composition of fecal samples from 421 patients with UC during clinical activity and remission. Within a longitudinal subcohort (n = 52), we assessed for dynamic taxonomic changes across alterations in clinical activity over time. We examined if fungal amplicon sequence variants and fungal-bacterial relationships were altered during activity versus remission. Finally, we classified activity in UC using a supervised machine learning random forest model trained on fungal abundance data. RESULTS: During clinical activity, the relative abundance of genus Candida was increased 3.5-fold (P-adj < 1 × 10-4) compared with during remission. Patients with longitudinal reductions in clinical activity demonstrated parallel reductions in Candida relative abundance (P < .05). Candida relative abundance correlated with Parabacteroides diastonis, Faecalibacterium prausnitzii, and Bacteroides dorei relative abundance (P < .05) during remission; however, these correlations were disrupted during activity. Fungal abundance data successfully classified patients with active or quiescent UC (area under the curve ∼0.80), with Candida relative abundance critical to the success of the model. CONCLUSIONS: Clinical activity in UC is associated with an increased relative abundance of Candida, cross-sectionally and dynamically over time. The role of fecal Candida as a target for therapeutics in UC should be evaluated.

Genomic evolution of ST228 SCCmec-I MRSA 10 years after a major nosocomial outbreak.

In this study, we investigated the genomic changes in a major methicillin-resistant Staphylococcus aureus (MRSA) clone following a significant outbreak at a hospital. Whole-genome sequencing of MRSA isolates was utilized to explore the genomic evolution of post-outbreak MRSA strains. The epidemicity of the clone declined over time, coinciding with the introduction of multimodal infection control measures. A genome-wide association study (GWAS) identified multiple genes significantly associated with either high or low epidemic success, indicating alterations in mobilome, virulence, and defense mechanisms. Random Forest models pinpointed a gene related to fibrinogen binding as the most influential predictor of epidemicity. The decline of the MRSA clone may be attributed to various factors, including the implementation of new infection control measures, single nucleotide polymorphisms accumulation, and the genetic drift of a given clone. This research underscores the complex dynamics of MRSA clones, emphasizing the multifactorial nature of their evolution. The decline in epidemicity seems linked to alterations in the clone's genetic profile, with a probable shift towards decreased virulence and adaptation to long-term carriage. Understanding the genomic basis for the decline of epidemic clones is crucial to develop effective strategies for their surveillance and management, as well as to gain insights into the evolutionary dynamics of pathogen genomes.

Antibodies to oral pathobionts and colon cancer risk in the CLUE I cohort study.

Periodontitis has been associated with an increased risk for gastrointestinal cancers. The objective of our study was to investigate the association of antibodies to oral bacteria and the risk of colon cancer in a cohort setting. Using the CLUE I cohort, a prospective cohort initiated in 1974 in Washington County, Maryland, we conducted a nested case-control study to examine the association of levels of IgG antibodies to 11 oral bacterial species (13 total strains) with risk of colon cancer diagnosed a median of 16 years later (range: 1-26 years). Antibody response was measured using checkerboard immunoblotting assays. We included 200 colon cancer cases and 200 controls matched on age, sex, cigarette smoking status, time of blood draw and pipe or cigar smoking status. Controls were selected using incidence density sampling. Conditional logistic regression models were used to assess the association between antibody levels and colon cancer risk. In the overall analysis, we observed significant inverse associations for 6 of the 13 antibodies measured (P-trends <.05) and one positive association for antibody levels to Aggregatibacter actinomycetemcomitans (ATCC 29523; P-trend = .04). While we cannot rule out a role for periodontal disease in colon cancer risk, findings from our study suggest that a strong adaptive immune response may be associated with a lower risk of colon cancer. More studies will need to examine whether the positive associations we observed with antibodies to A. actinomycetemcomitans reflect a true causal association for this bacterium.

Tumor gene signatures that correlate with release of extracellular vesicles shape the immune landscape in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) evade immune responses through multiple resistance mechanisms. Extracellular vesicles (EVs) released by the tumor and interacting with immune cells induce immune dysfunction and contribute to tumor progression. This study evaluates the clinical relevance and impact on anti-tumor immune responses of gene signatures expressed in HNSCC and associated with EV production/release. Expression levels of two recently described gene sets were determined in The Cancer Genome Atlas Head and Neck Cancer cohort (n = 522) and validated in the GSE65858 dataset (n = 250) as well as a recently published single-cell RNA sequencing dataset (n = 18). Clustering into HPV(+) and HPV(-) patients was performed in all cohorts for further analysis. Potential associations between gene expression levels, immune cell infiltration, and patient overall survival were analyzed using GEPIA2, TISIDB, TIMER, and the UCSC Xena browser. Compared to normal control tissues, vesiculation-related genes were upregulated in HNSCC cells. Elevated gene expression levels positively correlated (P < 0.01) with increased abundance of CD4(+) T cells, macrophages, neutrophils, and dendritic cells infiltrating tumor tissues but were negatively associated (P < 0.01) with the presence of B cells and CD8(+) T cells in the tumor. Expression levels of immunosuppressive factors NT5E and TGFB1 correlated with the vesiculation-related genes and might explain the alterations of the anti-tumor immune response. Enhanced expression levels of vesiculation-related genes in tumor tissues associates with the immunosuppressive tumor milieu and the reduced infiltration of B cells and CD8(+) T cells into the tumor.

Core genome multilocus sequence typing of Clostridioides difficile to investigate transmission in the hospital setting.

PURPOSE: Traditional epidemiological investigations of healthcare-associated Clostridioides difficile infection (HA-CDI) are often insufficient. This study aimed to evaluate a procedure that includes secondary isolation and genomic typing of single toxigenic colonies using core genome multilocus sequence typing (cgMLST) for the investigation of C. difficile transmission. METHODS: We analyzed retrospectively all toxigenic C. difficile-positive stool samples stored at the Lausanne University Hospital over 6 consecutive months. All isolates were initially typed and classified using a modified double-locus sequence typing (DLST) method. Genome comparison of isolates with the same DLST and clustering were subsequently performed using cgMLST. The electronic administrative records of patients with CDI were investigated for spatiotemporal epidemiological links supporting hospital transmission. A comparative descriptive analysis between genomic and epidemiological data was then performed. RESULTS: From January to June 2021, 86 C. difficile isolates were recovered from thawed samples of 71 patients. Thirteen different DLST types were shared by > 1 patient, and 13 were observed in single patients. A genomic cluster was defined as a set of isolates from different patients with ≤ 3 locus differences, determined by cgMLST. Seven genomic clusters were identified, among which plausible epidemiological links were identified in only 4/7 clusters. CONCLUSION: Among clusters determined by cgMLST analysis, roughly 40% included unexplained HA-CDI acquisitions, which may be explained by unidentified epidemiological links, asymptomatic colonization, and/or shared common community reservoirs. The use of DLST, followed by whole genome sequencing analysis, is a promising and cost-effective stepwise approach for the investigation of CDI transmission in the hospital setting.

Periodontitis and risk of cancer: Mechanistic evidence.

This review aims to critically analyze the pathways of interaction and the pathogenic mechanisms linking periodontitis and oral bacteria with the initiation/progression of cancer at different body compartments. A higher risk of head and neck cancer has been consistently associated with periodontitis. This relationship has been explained by the local promotion of dysbiosis, chronic inflammation, immune evasion, and direct (epi)genetic damage to epithelial cells by periodontal pathobionts and their toxins. Epidemiological reports have also studied a possible link between periodontitis and the incidence of other malignancies at distant sites, such as lung, breast, prostate, and digestive tract cancers. Mechanistically, different pathways have been involved, including the induction of a chronic systemic inflammatory state and the spreading of oral pathobionts with carcinogenic potential. Indeed, periodontitis may promote low-grade systemic inflammation and phenotypic changes in the mononuclear cells, leading to the release of free radicals and cytokines, as well as extracellular matrix degradation, which are all mechanisms involved in carcinogenic and metastatic processes. Moreover, the transient hematogenous spill out or micro-aspiration/swallowing of periodontal bacteria and their virulence factors (i.e., lipopolysaccharides, fimbriae), may lead to non-indigenous bacterial colonization of multiple microenvironments. These events may in turn replenish the tumor-associated microbiome and thus influence the molecular hallmarks of cancer. Particularly, specific strains of oral pathobionts (e.g., Porphyromonas gingivalis and Fusobacterium nucleatum) may translocate through the hematogenous and enteral routes, being implicated in esophageal, gastric, pancreatic, and colorectal tumorigenesis through the modulation of the gastrointestinal antitumor immune system (i.e., tumor-infiltrating T cells) and the increased expression of pro-inflammatory/oncogenic genes. Ultimately, the potential influence of common risk factors, relevant comorbidities, and upstream drivers, such as gerovulnerability to multiple diseases, in explaining the relationship cannot be disregarded. The evidence analyzed here emphasizes the possible relevance of periodontitis in cancer initiation/progression and stimulates future research endeavors.

Factors associated with suspected nonmelanoma skin cancers, dysplastic nevus, and cutaneous melanoma among first-time SpotMe screening program participants during 2009-2010.

BACKGROUND: There have been no studies of the American Academy of Dermatology's SpotMe skin cancer screening program to collectively analyze and determine the factors associated with suspected basal cell carcinoma (BCC), squamous cell carcinoma (SCC), dysplastic nevus (DN), and cutaneous melanoma (CM) diagnoses. OBJECTIVE: Describe the demographics, risk factors, and access to care profiles associated with suspected diagnoses of BCC, SCC, DN, and CM among first-time SpotMe screenees during 2009-2010. METHODS: We conducted a cross-sectional analysis of data from the SpotMe skin cancer screenings conducted in 2009 and 2010. We performed multivariable logistic regression analysis for each diagnosis, incorporating standard demographic, access to care, and risk factor variables in the models. RESULTS: Men, those without a regular dermatologist, persons reporting recently changing moles, and those with a personal history of melanoma were at increased risk for each of the suspected diagnoses analyzed. Uninsured persons were at increased risk for suspected malignancies (BCC, SCC, and CM). LIMITATIONS: Lack of histologic confirmation for diagnoses and cross-sectional design. CONCLUSION: Among first-time SpotMe participants, suspected diagnoses of BCC, SCC, DN, and CM shared several associated factors, which may be considered when planning outreach and screening for populations at risk for skin cancer.

CBT for Youth Anxiety: How Does It Fit Within Community Mental Health?

PURPOSE OF REVIEW: We review (1) the empirical literature for cognitive behavioral therapy (CBT) for youth anxiety delivered in community settings, (2) the use of online delivery methods in this process, and (3) identified barriers and facilitators to implementation of CBT for youth anxiety in community mental health clinics (CMHCs). We provide suggestions for future work. RECENT FINDINGS: Meta-analytic reviews of effectiveness studies suggest that outcomes comparable to those of efficacy studies can be achieved in community settings, particularly when in-session exposures occur. Several online programs support delivery of these services, with an evidence base that is promising. The notable barrier to the implementation of services is the cost of implementation and sustainability. Organizational factors such as leadership, culture, and climate are consistently identified as barriers and facilitators depending on their valence and appear to be related to implementation outcomes (e.g., on provider attitudes). The current findings need to be integrated into future studies, with a focus on further identifying facilitators (e.g., champions and online programs) of implementation. There is also the need for efforts to address organizational and individual barriers and to compare ways to reduce costs.

Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study.

AIM: To investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood. MATERIALS AND METHODS: We included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at Visit 4 and had available data on DNA methylation from Visit 2 or 3. DNA methylation levels were compared by periodontal disease severity and edentulism through discovery analyses and subsequent testing of individual CpGs. RESULTS: Our discovery analysis replicated findings from a previous study reporting a region in gene ZFP57 (6p22.1) that was significantly hypomethylated in severe periodontal disease compared with no/mild periodontal disease in European American participants. Higher methylation levels in a separate region in an unknown gene (located in Chr10: 743,992-744,958) was associated with significantly higher odds of edentulism compared with no/mild periodontal disease in African American participants. In subsequent CpG testing, four CpGs in a region previously associated with periodontitis located within HOXA4 were significantly hypermethylated in severe periodontal disease compared with no/mild periodontal disease in African American participants (odds ratio per 1 SD increase in methylation level: cg11015251: 1.28 (1.02, 1.61); cg14359292: 1.24 (1.01, 1.54); cg07317062: 1.30 (1.05, 1.61); cg08657492: 1.25 (1.01, 1.55)). CONCLUSIONS: Our study highlights epigenetic variations in ZPF57 and HOXA4 that are significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci.

A Multicenter Retrospective Chart Review on the Effectiveness and Tolerability of Electroconvulsive Therapy in Adolescents and Young Adults With Major Depressive Disorder or Bipolar Depression.

BACKGROUND: Major depressive disorder and bipolar depression in adolescents and young adults are prevalent and major contributors to the global burden of disease, whereas effective interventions are limited. Available evidence is insufficient to assess effectiveness and tolerability of electroconvulsive therapy in depressed adolescents and young adults. METHODS: A retrospective chart review was conducted in patients with major depressive disorder or bipolar depression who underwent electroconvulsive therapy from 2001 to 2021 in 12 centers in the Netherlands. Patients were classified as young (15-25 years) and older adults (26-80 years). Primary outcome was effectiveness, expressed as response (≥50% reduction in rating scale score compared with baseline) and remission. Rating scale scores were cross-sectionally assessed at baseline and at the end of the index course. Outcomes of remitters were included in responders. Secondary outcome was occurrence of subjective cognitive impairment and adverse events. Long-term outcomes were not available. RESULTS: In the young (n = 57) and older adult (n = 41) group, 40.4% and 56.1% (P = 0.153) of patients achieved response and 28.1% and 39.0% (P = 0.281) remission, respectively. Subjective cognitive impairment (80.5% vs 56.3%; P = 0.001) and transient cardiac arrhythmia (14.6% vs 2.8%; P = 0.020) were reported significantly more frequently in the older adult group. CONCLUSIONS: Despite significantly more comorbidity of personality disorders, autism spectrum disorders, and anxiety disorders, effectiveness in the young was similar to the older adults. Tolerability was even superior in the young, despite significantly more bilateral treatment. Electroconvulsive therapy could be considered a viable treatment option in depressed adolescents and young adults.

The oral microbiome in relation to pancreatic cancer risk in African Americans.

BACKGROUND: African Americans have the highest pancreatic cancer incidence of any racial/ethnic group in the United States. The oral microbiome was associated with pancreatic cancer risk in a recent study, but no such studies have been conducted in African Americans. Poor oral health, which can be a cause or effect of microbial populations, was associated with an increased risk of pancreatic cancer in a single study of African Americans. METHODS: We prospectively investigated the oral microbiome in relation to pancreatic cancer risk among 122 African-American pancreatic cancer cases and 354 controls. DNA was extracted from oral wash samples for metagenomic shotgun sequencing. Alpha and beta diversity of the microbial profiles were calculated. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between microbes and pancreatic cancer risk. RESULTS: No associations were observed with alpha or beta diversity, and no individual microbial taxa were differentially abundant between cases and control, after accounting for multiple comparisons. Among never smokers, there were elevated ORs for known oral pathogens: Porphyromonas gingivalis (OR = 1.69, 95% CI: 0.80-3.56), Prevotella intermedia (OR = 1.40, 95% CI: 0.69-2.85), and Tannerella forsythia (OR = 1.36, 95% CI: 0.66-2.77). CONCLUSIONS: Previously reported associations between oral taxa and pancreatic cancer were not present in this African-American population overall.

Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Ribosome-Associated Chloroplast SRP54 Enables Efficient Cotranslational Membrane Insertion of Key Photosynthetic Proteins.

Key proteins of the photosynthetic complexes are encoded in the chloroplast genome and cotranslationally inserted into the thylakoid membrane. However, the molecular details of this process are largely unknown. Here, we demonstrate by ribosome profiling that the conserved chloroplast signal recognition particle subunit (cpSRP54) is required for efficient cotranslational targeting of several central photosynthetic proteins, such as the PSII PsbA (D1) subunit, in Arabidopsis (Arabidopsis thaliana). High-resolution analysis of membrane-associated and soluble ribosome footprints revealed that the SRP-dependent membrane targeting of PsbA is already initiated at an early translation step before exposure of the nascent chain from the ribosome. In contrast to cytosolic SRP, which contacts the ribosome close to the peptide tunnel exit site, analysis of the cpSRP54/ribosome binding interface revealed a direct interaction of cpSRP54 and the ribosomal subunit uL4, which is not located at the tunnel exit site but forms a part of the internal peptide tunnel wall by a loop domain. The plastid-specific C-terminal tail region of cpSRP54 plays a crucial role in uL4 binding. Our data indicate a novel mechanism of SRP-dependent membrane protein transport with the cpSRP54/uL4 interaction as a central element in early initiation of cotranslational membrane targeting.

[Methicillin-resistant Staphylococcus aureus: 15 years of molecular epidemiology in Western Switzerland]. / Staphylococcus aureus résistant à la méticilline : 15 ans de surveillance moléculaire en Suisse romande.

Since the introduction of antibiotics, successive waves of Staphylococcus aureus clones occurred, each one having characteristic susceptibility pattern to antibiotics and virulence factors. We report here the results of a molecular epidemiological surveillance of methicillin-resistant S. aureus (MRSA) in French-speaking Switzerland between 2006 and 2020 showing the emergence and disappearance of clones known for their international dissemination, and the sporadic appearance of other international clones. Since 2012, a marked decrease in the incidence of cases attributable to the biology of the clones and to the control measures taken in the hospitals has been observed. These results highlight the importance of continuous surveillance in order to better assess the burden of this multi-resistant pathogen in our region.

Depuis l'introduction des antibiotiques, des vagues successives de clones de Staphylococcus aureus sont apparues, chacun avec un profil de susceptibilité aux antibiotiques et de virulence caractéristique. Nous rapportons ici les résultats d'une surveillance épidémiologique moléculaire de S. aureus résistant à la méticilline (MRSA) en Suisse romande entre 2006 et 2020 montrant l'émergence et la disparition de clones connus pour leur dissémination internationale, ainsi que l'apparition sporadique d'autres clones internationaux. Depuis 2012, une diminution marquée de l'incidence des cas attribuable à la biologie des clones et aux mesures de contrôle prises dans les hôpitaux est observée. Ces résultats nous montrent l'importance d'une surveillance continue afin de mieux évaluer le fardeau que représente ce germe multirésistant dans notre région.

Increasing Nitrate-Rich Vegetable Intake Lowers Ambulatory Blood Pressure in (pre)Hypertensive Middle-Aged and Older Adults: A 12-Wk Randomized Controlled Trial.

BACKGROUND: Emerging evidence suggests that increasing dietary nitrate intake may be an effective approach to improve cardiovascular health. However, the effects of a prolonged elevation of nitrate intake through an increase in vegetable consumption are understudied. OBJECTIVE: Our primary aim was to determine the impact of 12 wk of increased daily consumption of nitrate-rich vegetables or nitrate supplementation on blood pressure (BP) in (pre)hypertensive middle-aged and older adults. METHODS: In a 12-wk randomized, controlled study (Nijmegen, The Netherlands), 77 (pre)hypertensive participants (BP: 144 ± 13/87 ± 7 mmHg, age: 65 ± 10 y) either received an intervention with personalized monitoring and feedback aiming to consume ∼250-300 g nitrate-rich vegetables/d (∼350-400 mg nitrate/d; n = 25), beetroot juice supplementation (400 mg nitrate/d; n = 26), or no intervention (control; n = 26). Before and after intervention, 24-h ambulatory BP was measured. Data were analyzed using repeated measures ANOVA (time × treatment), followed by within-group (paired t-test) and between-group analyses (1-factor ANOVA) where appropriate. RESULTS: The 24-h systolic BP (SBP) (primary outcome) changed significantly (P-interaction time × treatment = 0.017) with an increase in the control group (131 ± 8 compared with 135 ± 10 mmHg; P = 0.036); a strong tendency for a decline in the nitrate-rich vegetable group (129 ± 10 compared with 126 ± 9 mmHg; P = 0.051) which was different from control (P = 0.020); but no change in the beetroot juice group (133 ± 11 compared with 132 ± 12 mmHg; P = 0.56). A significant time × treatment interaction was also found for daytime SBP (secondary outcome, P = 0.011), with a significant decline in the nitrate-rich vegetable group (134 ± 10 compared with 129 ± 9 mmHg; P = 0.006) which was different from control (P = 0.010); but no changes in the beetroot juice (138 ± 12 compared with 137 ± 14 mmHg; P = 0.41) and control group (136 ± 10 compared with 137 ± 11 mmHg; P = 0.08). Diastolic BP (secondary outcome) did not change in any of the groups. CONCLUSIONS: A prolonged dietary intervention focusing on high-nitrate vegetable intake is an effective strategy to lower SBP in (pre)hypertensive middle-aged and older adults. This trial was registered at www.trialregister.nl as NL7814.

Disparities in Health and Economic Burdens of Cancer Attributable to Suboptimal Diet in the United States, 2015‒2018.

Objectives. To quantify disparities in health and economic burdens of cancer attributable to suboptimal diet among US adults. Methods. Using a probabilistic cohort state-transition model, we estimated the number of new cancer cases and cancer deaths, and economic costs of 15 diet-related cancers attributable to suboptimal intake of 7 dietary factors (a low intake of fruits, vegetables, dairy, and whole grains and a high intake of red and processed meats and sugar-sweetened beverages) among a closed cohort of US adults starting in 2017. Results. Suboptimal diet was estimated to contribute to 3.04 (95% uncertainty interval [UI] = 2.88, 3.20) million new cancer cases, 1.74 (95% UI = 1.65, 1.84) million cancer deaths, and $254 (95% UI = $242, $267) billion economic costs among US adults aged 20 years or older over a lifetime. Diet-attributable cancer burdens were higher among younger adults, men, non-Hispanic Blacks, and individuals with lower education and income attainments than other population subgroups. The largest disparities were for cancers attributable to high consumption of sugar-sweetened beverages and low consumption of whole grains. Conclusions. Suboptimal diet contributes to substantial disparities in health and economic burdens of cancer among young adults, men, racial/ethnic minorities, and socioeconomically disadvantaged groups. (Am J Public Health. 2021;111(11):2008-2018. https://doi.org/10.2105/AJPH.2021.306475).

Neutrophils: fast and furious-the nucleotide pathway.

Nucleotide signaling is a key element of the neutrophil activation pathway. Neutrophil recruitment and migration to injured tissues is guided by purinergic receptor sensitization, mostly induced by extracellular adenosine triphosphate (ATP) and its hydrolysis product, adenosine (ADO), which is primarily produced by the CD39-CD73 axis located at the neutrophil cell surface. In inflammation unrelated to cancer, neutrophil activation via purinergic signaling aims to eliminate antigens and promote an immune response with minimal damage to healthy tissues; however, an antagonistic response may be expected in tumors. Indeed, alterations in purinergic signaling favor the accumulation of extracellular ATP and ADO in the microenvironment of solid tumors, which promote tumor progression by inducing cell proliferation, angiogenesis, and escape from immune surveillance. Since neutrophils and their N1/N2 polarization spectrum are being considered new components of cancer-related inflammation, the participation of purinergic signaling in pro-tumor activities of neutrophils should also be considered. However, there is a lack of studies investigating purinergic signaling in human neutrophil polarization and in tumor-associated neutrophils. In this review, we discussed the human neutrophil response elicited by nucleotides in inflammation and extrapolated its behavior in the context of cancer. Understanding these mechanisms in cancerous conditions may help to identify new biological targets and therapeutic strategies, particularly regarding tumors that are refractory to traditional chemo- and immunotherapy.

Repeated prolonged moderate-intensity walking exercise does not appear to have harmful effects on inflammatory markers in patients with inflammatory bowel disease.

BACKGROUND AND OBJECTIVES: The role of exercise in the management of inflammatory bowel disease (IBD) is inconclusive as most research focused on short or low-intensity exercise bouts and subjective outcomes. We assessed the effects of repeated prolonged moderate-intensity exercise on objective inflammatory markers in IBD patients. METHODS: In this study, IBD patients (IBD walkers, n = 18), and a control group (non-IBD walkers, n = 19), completed a 30, 40 or 50 km walking exercise on four consecutive days. Blood samples were taken at baseline and every day post-exercise to test for the effect of disease on exercise-induced changes in cytokine concentrations. A second control group of IBD patients who did not take part in the exercise, IBD non-walkers (n = 19), was used to test for the effect of exercise on faecal calprotectin. Both IBD groups also completed a clinical disease activity questionnaire. RESULTS: Changes in cytokine concentrations were similar for IBD walkers and non-IBD walkers (IL-6 p = .95; IL-8 p = .07; IL-10 p = .40; IL-1ß p = .28; TNF-α p = .45), with a temporary significant increase in IL-6 (p < .001) and IL-10 (p = .006) from baseline to post-exercise day 1. Faecal calprotectin was not affected by exercise (p = .48). Clinical disease activity did not change in the IBD walkers with ulcerative colitis (p = .92), but did increase in the IBD walkers with Crohn's disease (p = .024). CONCLUSION: Repeated prolonged moderate-intensity walking exercise led to similar cytokine responses in participants with or without IBD, and it did not affect faecal calprotectin concentrations, suggesting that IBD patients can safely perform this type of exercise.

The association of clinically determined periodontal disease and edentulism with total cancer mortality: The National Health and Nutrition Examination Survey III.

Increasing evidence supports a positive association between periodontal disease and total cancer risk. We evaluated the association of clinically assessed periodontal disease and a consequence, edentulism with total cancer mortality in participants without a prior cancer diagnosis in a U.S. nationally representative population. Included were 6,034 participants aged ≥40 years without a prior cancer diagnosis who participated in the National Health and Nutrition Examination Survey III. Periodontal health was measured by trained dentists. Cancer deaths (n = 702) were ascertained during a median of 21.3 years of follow-up. Cox proportional hazards regression was used to estimate the association of periodontal disease and edentulism with total cancer mortality using no periodontal disease/dentate as the reference and adjusting for potential demographic, lifestyle including smoking and social factor confounders. Fifteen percent had periodontitis and 17% were edentulous. Periodontitis was not statistically significantly associated with risk of total cancer death after multivariable adjustment. Edentulism was associated with an increased risk of cancer mortality (hazard ratio = 1.50, 95% confidence interval = 1.12-2.00) after multivariable adjustment, including in men and women and in each racial/ethnic group studied. The positive association was observed in overweight/obese participants but not participants with normal body mass index, more strongly in prediabetic/diabetic participants than in participants without diabetes and in ever cigarette smokers but not in never cigarette smokers. In this U.S. nationally representative population, those with edentulism, but not periodontal disease, had a higher risk of total cancer death, especially in those with shared risk factors for periodontal disease and cancer.

Ccm1p is a 15S rRNA primary transcript processing factor as elucidated by a novel in vivo system in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, the mitoribosomal RNA of the minor subunit, 15S rRNA, is transcribed as a bicistronic transcript along with tRNAW. 5' and 3' sequences flanking the mature transcript must be removed by cleavage at the respective junctions before incorporating it into the mitoribosome. An in vivo dose-response triphasic system was created to elucidate the role of Ccm1p in the processing of 15S rRNA: Ccm1p supply ("On"), deprivation ("Off"), and resupply ("Back on"). After 72 h under "Off" status, the cells started to exhibit a complete mutant phenotype as assessed by their lack of growth in glycerol medium, while keeping their mitochondrial DNA integrity (ρ+). Full functionality of mitochondria was reacquired upon "Back on." 15S rRNA levels and phenotype followed the Ccm1p intramitochondrial concentrations throughout the "On-Off-Back on" course. Under "Off" status, cells gradually accumulated unprocessed 5' and 3' junctions, which reached significant levels at 72-96 h, probably due to a saturation of the mitochondrial degradosome (mtEXO). The Ccm1p/mtEXO mutant (Δccm1/Δdss1) showed a copious accumulation of 15S rRNA primary transcript forms, which were cleaved upon Ccm1p resupply. The gene that codes for the RNA component of RNase P was conserved in wild-type and mutant strains. Our results indicate that Ccm1p is crucial in processing the 15S rRNA primary transcript and does not stabilize the already mature 15S rRNA. Consequently, failure of this function in Δccm1 cells results, as it happens to any other unprocessed primary transcripts, in total degradation of 15S rRNA by mtEXO, whose mechanism of action is discussed.