VA Nebraska Western Iowa Health Care System

Cervical cancer (CVC) is classically understood as an HPV-driven disease in which high-risk HPV infects cervical basal epithelial cells, induces neoplastic transformation, and drives upward epithelial expansion, pathogenic events underlying the success of cytology- and HPV-based screening. With widespread HPV vaccination and screening, the WHO has launched the CVC elimination initiative and believes that CVC will be the first cancer that would be eliminated as a public health problem. However, statistics showed that CVC remains the most common gynecologic malignancy worldwide, and in the United States, where HPV testing and Pap smears have reached near-maximal implementation, the CVC mortality rate has plateaued for more than two decades. These epidemiologic trends suggest the existence of a subset of CVC that can escape current screening strategies. Here, we demonstrate that hyperactivation of YAP1 caused by disruption of Hippo-YAP signaling is sufficient to induce a subtype of HPV-independent invasive CVC that lacks surface lesions and therefore evades HPV- and cytology-based detection. Using single-cell RNA sequencing combined with high-resolution spatial transcriptomics, we define the cellular architecture, molecular pathways, and immune microenvironment underlying this invasive subtype. We show that YAP1-driven tumors adopt an EMT-high transcriptional state and selectively recruit immunosuppressive myeloid-derived suppressor cells that functionally interact with cancer cells to promote invasion and progression. Our findings suggest that targeting the disrupted Hippo signaling may offer a new strategy to prevent the subset of invasive CVC that current HPV- and Pap-based programs cannot detect, an essential step toward achieving global CVC elimination.

We assessed whether circulating adipokines are associated with incident fractures in patients with rheumatoid arthritis (RA). Three adipokines (adiponectin, leptin, and fibroblast growth factor [FGF]-21) were measured using banked enrollment serum from participants in a longitudinal RA cohort. Adipokine levels were dichotomized as high/low using median values. Incident osteoporotic fracture was defined based on published algorithms using diagnostic codes and confirmed by chart review. Cox proportional hazard models evaluated adipokines and incident fracture risk adjusting for age, sex, race, smoking status, body mass index (BMI), prednisone use, disease activity, comorbidity score, calendar year, osteoporosis history, and previous fracture. A total of 2,527 participants were included (89% male, mean age 72 years). There were 228 incident fractures over 27,540 person-years of follow-up (8.3 fractures per 1,000 person-years). After adjustment, the risk of incident fracture was increased for high levels of leptin (hazard ratio [HR] = 1.47; 95% confidence interval [CI] 1.15-1.90; P = 0.003), FGF-21 [HR = 1.39; 95% CI 1.16-1.67; P < 0.001), and adiponectin (HR = 1.21; 95% CI 0.94-1.55), with the latter not achieving significance (P = 0.13). Participants who had elevated levels of all three adipokines experienced twice the risk of fracture compared with those in whom none was elevated (HR = 2.17; 95% CI 1.27-3.70; P = 0.005). Elevations in adipokines are associated with an increased risk of fracture in patients with RA, independent of other established risk factors including BMI, smoking, and prednisone use. This supports further investigation to understand whether this association is related to altered body composition or disrupted metabolic pathways.

ABSTRACTDyspnea, a debilitating symptom of COPD, worsens health‐related quality of life (HRQL), reduces daily physical activity, increases health care utilization, and is more closely associated with survival than airflow limitation. Thus, having treatments that reduce dyspnea in COPD is important. Pulmonary hypertension (PH) is a common complication of COPD that is associated with severe dyspnea, more frequent COPD exacerbations, and increased mortality. Multiple causes of PH, including a reduction in bioavailable vasodilator nitric oxide (NO), are associated with COPD (COPD‐PH). Phosphodiesterase type‐5 inhibitor (PDE5i) therapy restores NO signaling and improves hemodynamics and dyspnea in patients with Group 1 Pulmonary Arterial Hypertension, but has not been proven effective in COPD‐PH. In a prior study (ClinicalTrials. gov identifier: NCT01862536), we investigated effects of 12 months of oral PDE5i therapy with tadalafil on 6‐min walk distance (6MWD) in a multi‐center, randomized, placebo‐controlled trial funded by the Department of Veterans Affairs. While tadalafil did not change 6MWD at 12 months, the treatment group experienced clinically meaningful improvements in patient‐reported dyspnea and HRQL at 6 months. Because of the importance of mitigating dyspnea in COPD‐PH, we developed a new study protocol examining the effect of PDE‐5i therapy in COPD‐PH, with a reduction in dyspnea the primary outcome. In the current study (NCT05937854), we will conduct a prospective, randomized, double‐blind, multi‐center clinical trial to evaluate the effects of 6 months of maximally tolerated therapy with tadalafil (target dose 40 mg/day) versus placebo on dyspnea, as measured by University of California San Diego Shortness of Breath Questionnaire.

Mitochondria are increasingly recognized as important contributors to immune function, in addition to energy production. They exert this influence through modulation of various signaling pathways that regulate cellular metabolism and immune function in response to pathogens. Peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PGC-1α) is the primary transcription factor and regulator involved in mitochondrial biogenesis. Long known to be involved in immune function, zinc (Zn) is also required for proper mitochondrial function. It is increasingly recognized that many cellular immunometabolic activities are also Zn-dependent. Taken together, we investigated the role of Zn deficiency, both dietary and genetically induced, and Zn supplementation in PGC-1α-mediated macrophage mitochondrial biogenesis and immune function following infection with Mycobacterium avium complex (MAC). Our novel findings show that Zn is an important regulator of PGC-1α, TFAM and mitochondrial biogenesis, leading to enhanced bacterial phagocytosis and bacterial killing in macrophages. Mechanistically, we show that the Zn importer ZIP8 (Zrt/Irt-like protein) orchestrates Zn-mediated effects on PGC-1α and mitochondrial function. Taken together, defective Zn biodistribution may increase susceptibility to infection, whereas Zn supplementation may provide a tractable host-directed therapy to enhance the innate immune response in patients vulnerable to MAC infection.

The field of rheumatoid arthritis (RA) is moving towards identification of and intervention in people at risk of RA, but a validated risk stratification method is lacking. This work was undertaken to develop a risk stratification method for persons presenting with arthralgia considered to be at risk of RA. A joint European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) expert committee was established. Risk factor and outcome data from 10 arthralgia cohorts (including clinically suspect arthralgia and autoantibody-positive arthralgia) were studied. The work focused on differentiating the risk of progression to clinically apparent inflammatory arthritis (IA) within 1 year, using clinical and serologic variables, without and with subclinical joint inflammation detected by ultrasound (US) or magnetic resonance imaging (MRI). Developing RA according to the 2010 EULAR/ACR criteria within 1 year was a secondary outcome. A set of validated risk stratification criteria was developed. Using data from 2293 symptomatic at-risk individuals, a stratification method was derived consisting of 6 clinical and serologic variables (morning stiffness, patient-reported joint swelling, difficulty making a fist, C-reactive protein, rheumatoid factor, and anti-citrullinated peptide antibody) yielding an area under the curve (AUC) of 0.80 (95% CI, 0.77-0.83) for IA development. The inclusion of US variables did not increase the discriminative ability. When MRI-detected subclinical inflammation variables were included, the AUC was 0.87 (95% CI, 0.82-0.90). In the presence of clinical, serologic, and MRI variables, a sensitivity and specificity of >75% was achieved. For RA development, the AUC of the criteria with MRI was 0.93 (95% CI, 0.90-0.97). EULAR/ACR risk stratification criteria have been developed for people with arthralgia in secondary care who are considered at risk for RA. They can be applied in the absence or presence of imaging data and have been developed to define homogeneous risk groups for future prevention trials.

16.5%), and speaker/faculty compensation (8.5%) (Figure 1).