UCSF

Responses to lung injury can vary between individuals with the diet and gut microbiome representing two underappreciated sources for this variability. The gut microbiome can influence lung injury outcomes through the gut‒lung axis, but exactly how diet and its effects on the microbiota are involved remains unclear. We hypothesized that dietary fiber interventions would favor the presence of short-chain fatty acid (SCFA)-producing fermentative bacteria presence in the gut microbiome, thereby influencing the resting lung immunometabolic tone as well as influencing downstream responses to lung injury and infection. To test this hypothesis, we fed mice fiber-rich (FR) and fiber-free (FF) diets, and observed changes in the steady-state transcriptional programming of alveolar macrophages (AM). Next, we examined the effects of the FR and FF diets on murine responses to sterile and infectious lung injury in vivo while simultaneously profiling the gut microbiota and SCFA levels transmitted along the gut‒lung axis. Finally, we validated our in vivo observations with mechanistic studies of the metabolic, signaling, and chromatin-modifying effects of specific SCFAs on lung AM ex vivo and in vitro. Overall, our fiber-rich diet reprogrammed AMs and attenuated lung inflammation after sterile injury while exacerbating lung infection. This effect of FR diets could be transferred to germ-free (GF) mice by fecal microbiome transplantation (FMT) and depended on the ability of the microbiota to produce propionate. Mechanistically, SCFAs altered the metabolic programming of AMs and lung tissue ex vivo without a clear role for free fatty acid receptors (FFAR) or chromatin remodeling. These findings demonstrate that the gut‒lung axis can regulate resting lung metabolic tone through dietary fiber intake and the enrichment of SCFA-producing gut bacteria, as well as influence sterile and non-sterile lung injury responses. These results provide evidence to support the development of therapeutic dietary interventions to preserve or enhance specific aspects of host pulmonary immunity.

Background: Zinc is widely used in oral care products due to its antimicrobial and anti-biofilm properties; however, the molecular mechanisms by which zinc influences Streptococcus mutans (S. mutans) physiology remain incompletely understood. The AdcABC system is the primary high-affinity zinc transporter in S. mutans. We investigated whether loss of adcBC is associated with altered physiological responses in S. mutans. Material and methods: Wild-type (WT), ΔadcBC mutant, and complemented S. mutans UA159 strains were evaluated under zinc-replete and zinc-limited conditions using zinc sulphate (ZnSO₄) at defined concentrations. Growth, carbohydrate utilization, acidogenicity, acid tolerance, aggregation, biofilm formation, and expression of stress response and regulatory genes were assessed. Results: Loss of adcBC impaired growth and reduced utilization of multiple carbohydrates, including key glycolytic substrates, indicating altered metabolism. Zinc supplementation restored growth but did not consistently recover redox-based metabolic activity. Expression of pflA, associated with fermentative metabolism, was reduced in the mutant. Acid tolerance was unaffected by AdcBC. Zinc enhanced aggregation and surface attachment independently of AdcBC, whereas biofilm biomass showed partial dependence on AdcBC-mediated zinc uptake. The ΔadcBC mutant also exhibited altered expression of genes involved in oxidative stress, metal homeostasis, and regulatory pathways. Conclusion: Loss of adcBC is associated with altered physiological responses in S. mutans. Zinc influences bacterial physiology through both uptake-dependent and uptake-independent mechanisms, highlighting its context-dependent role in oral environments.

INTRODUCTION: Treatment indications for oligometastatic/oligoprogressive lung tumors are growing. Safety and lack of detrimental effect on patients' quality of life are critical for novel local therapies. METHODS: We tested that the additive effect of pulsed electric field (PEF) ablation with lower-dose stereotactic body radiation therapy (SBRT) on health-related quality of life (HRQoL) as a secondary endpoint in a prospective clinical trial. FACT-Lung Cancer Subscale (FACT-LCS) and FACT-General domain surveys were collected at screening, 3 months, and 12 months. Functional clinical data included forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and diffusing capacity of the lung for carbon monoxide (DLCO). RESULTS: Six patients with eight tumors were enrolled. Baseline well-being domain scores were: Physical 25.9 (Std Dev 2.3), Social 21.0 (Std Dev 6.9), Emotional 17.3 (Std Dev 4.7), Functional 21.2 (Std Dev 5.8), and LCS 19.4 (Std Dev 5.3). There were no significant changes following combined modality treatment in HRQoL domain scores or pulmonary function metrics after treatment. Lower EWB and SWB were associated with worse FVC and FEV1. CONCLUSION: In this small pilot study, no clinically meaningful declines in pulmonary function or patient-reported quality of life were observed at 3 months following combination therapy.

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Purpose of ReviewTailoring treatment strategies to the biological features of invasive disease and the individual needs and preference of each patient has transformed the way we manage breast cancer. This article calls for a similar shift in the management paradigm of ductal carcinoma in situ (DCIS) from a uniform treatment model toward a risk-stratified stepwise approach that aligns with the heterogeneous nature of the disease to avoid overtreatment.Recent FindingsMost DCIS lesions are hormone receptor positive, and only a subset have a risk for progression to invasive cancer. Early results from observational and clinical studies indicate that active surveillance is a safe and feasible alternative to upfront surgical treatment for low-risk DCIS. Ongoing clinical trials like RECAST will further inform and refine strategies for optimal management of this condition.SummaryThe integration of risk-adapted management strategies, endocrine risk-reducing interventions, and advanced imaging modalities into active surveillance protocols hold significant potential to reduce overtreatment and personalize care for patients with DCIS. Early data from clinical trials support the notion that providing a period of active surveillance is safe and offers a critical assessment window during which DCIS treatment can be individualized. Strengthening the evidence base to support the adoption of active surveillance as an initial approach in the management of DCIS is an important clinical priority.

Introduction: This study aimed to characterize cardiovascular health among U.S. early adolescents using the American Heart Association's Life's Essential 8 metric in a large national cohort. Methods: A cross-sectional analysis of children aged 10-13 years in the Adolescent Brain Cognitive Development Study was conducted, primarily using data from the Year 2 follow-up (2018-2020), with supplemental Year 3 (2019-2021) data to improve completeness of cardiometabolic measures. Life's Essential 8 behavioral factors scores (diet, physical activity, nicotine exposure, sleep) and health factors scores (BMI, blood pressure, blood glucose, blood lipids) as well as overall Life's Essential 8 scores were calculated. Descriptive statistics were generated, and sex (assigned at birth) differences were assessed using Mann-Whitney U tests. Results: Among participants with complete Life's Essential 8 data (n=1,235; mean age 12.0±0.7 years), the mean overall Life's Essential 8 score was 78.1±10.4. Most adolescents had moderate (52.9%) or high (46.4%) cardiovascular health, whereas very few had low (0.4%) or optimal (0.3%) cardiovascular health. The mean behavioral factors score was 66.8±15.9, and the mean health factors score was 88.1±11.8. Overall Life's Essential 8 scores did not significantly differ by sex; however, males had higher (better) physical activity and BMI scores but lower (worse) diet, nicotine exposure, sleep, and blood pressure scores than females. Conclusions: In this national sample of early adolescents, fewer than half demonstrated high cardiovascular health on the basis of Life's Essential 8, and optimal cardiovascular health was rare. Poor diet and low physical activity were prominent contributors to suboptimal cardiovascular health. These findings highlight early adolescence as a critical window for interventions to improve long-term cardiovascular health.

Regulatory T cell (Treg) therapy is an emerging platform for controlling immune overactivation. Persistence of infused Tregs is limited by insufficient IL-2, which is essential for Treg survival and function. IL-2 activates many immune cells, imposing a challenge for the selective provision of IL-2 to infused Tregs. In this study, we found that infusions of orthogonal (ortho) IL-2 failed to enhance Tregs expressing a corresponding orthoIL-2 receptor (IL-2R) in a mouse model of autoimmune diabetes. Engineering Tregs with an orthoIL-2 tethered to its receptor achieved selective autocrine signaling; increased CD25, CTLA-4, and Foxp3 expression; supported Treg persistence without exogenous IL-2 in vivo; and improved the efficacy of Treg prevention of autoimmune diabetes. Inserting the tethered orthoIL-2 construct into the Foxp3 locus enabled Treg-specific self-reinforced expression through the activation of the Foxp3 locus by increased IL-2 signaling. Together, these results illustrate a safe and effective cell-engineering solution for overcoming Tregs' dependency on exogenous IL-2, thereby achieving superior therapeutic efficacy.

Background: Patients with schizophrenia experience gaps in the human immunodeficiency virus (HIV) care continuum. We examined the impact of dual enrollment in Medicare upon HIV testing and retention among Medicaid-enrolled patients with schizophrenia. Methods: Using Medicaid Analytic eXtract and Medicare files from 2008 to 2012, we examined adult participants with schizophrenia enrolled in Medicaid or dually enrolled in Medicare and Medicaid. Our outcomes were (a) HIV testing probability among participants without HIV and (b) retention in HIV care among people living with HIV (PLWH) (two HIV viral loads or CD4+ counts >90 days apart and within 1 year). Results: The average annual HIV testing probability was 4.9% among dually enrolled and 7.4% among Medicaid-enrolled patients (p < 0.001). Compared to Medicaid-only, HIV testing for dually enrolled patients were highest among those with opioid use disorder or sexually transmitted infection (STI); and lowest among study sample aged 50-59 years, Asian or White race. Among PLWH, the average retention probability in care was 54.7% for dually enrolled and 44.7% for Medicaid-enrolled patients (p < 0.001). Compared to Medicaid-only, retention probability for dually enrolled patients were highest among those with an STI or dyslipidemia, and lowest among younger sample. Conclusions and Relevance: Dual Medicare enrollment for Medicaid-enrolled patients benefitted HIV retention efforts more than HIV testing efforts. Differences in public insurance coverage between HIV care retention and testing among patients with schizophrenia, emphasizes the need for ongoing evaluation of the HIV care continuum as payor coverage and policies continue to evolve.