Determining mechanisms of resistance to aPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), aPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8 þ T cells from tumors (not CD4 þ T cells or macrophages); CD8 þ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8 þ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8 þ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFb1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 "normalized" CAF to a quiescent phenotype and promoted intratumoral CD8 þ T-cell infiltration, overcoming the exclusion effect; TGFb1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAFrich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. Significance: NOX4 is critical for maintaining the immunesuppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAFmediated CD8 þ T-cell exclusion.

Background. Intestinal parasitic infections (IPIs) are a public health problem in developing countries such as Sao Tome and Principe (STP) although the pregnancy burden of IPIs is unknown in this endemic country. Thus, the aim of this study was to determine the prevalence of IPIs, prescribed anthelmintics, and associated factors among pregnant women admitted to Hospital Dr. Ayres de Menezes (HAM). Methods. A hospital-based cross-sectional study was conducted among pregnant women admitted to the HAM who had undergone antenatal copro-parasitological screening. Data were abstracted from antenatal care (ANC) cards regarding parasitological results and anthelmintic prescriptions. A structured questionnaire face-to-face interview was also applied. Pregnant women with an IPI (210) were compared to noninfected women (151). Data analysis was performed using SPSS version 25.0. Odds ratios (ORs) with 95% confidence intervals (CIs) for factors associated with IPIs were estimated using multiple logistic regression models. A p value <0.05 was considered statistically significant. Results. A total of 361 participants (210 IPI and 151 no-IPI) with a mean age of 26.96 (SD: 7.00) were included. The overall prevalence of IPI was 58.2% (95% CI 52.9 to 63.3), mainly due to helminthiasis, with a 55.9% (95% CI 50.7–61.2%) rate. Ascaris lumbricoides (90.9%) was the most predominant parasite species identified followed by Trichuris trichiura (13.8%). Polyparasitism was observed in 25 cases (11.9%). Anthelmintics were prescribed to 23% of pregnant women. S intercalatum (11) and E histolytica (7) infections were not adequately treated. IPI was significantly associated with primary education (AOR 1.73 (95% CI: 1.10–2.71)), unemployment (AOR 1.94 (95% CI: 1.20–3.13)), and parity of five or above (AOR 3.82 (95% CI: 1.32–11.08)). Conclusion. This study highlights the IPI burden, associated factors, and missing treatment opportunities among pregnant women with STP. This study is a useful tool for policymakers in STP to enhance the health of women and their unborn babies.

Introduction To investigate the combined performance of quantitative CT (qCT) following a computer algorithm analysis (IMBIO) and 18 F-FDG PET/CT to assess survival in patients with idiopathic pulmonary fibrosis (IPF). Methods A total of 113 IPF patients (age 70 ± 9 years) prospectively and consecutively underwent 18 F-FDG PET/CT and high-resolution CT (HRCT) at our institution. During a mean follow-up of 29.6 ± 26 months, 44 (48%) patients died. As part of the qCT analysis, pattern evaluation of HRCT (using IMBIO software) included the total extent (percentage) of the following features: normal-appearing lung, hyperlucent lung, parenchymal damage (comprising ground-glass opacification, reticular pattern and honeycombing), and the pulmonary vessels. The maximum (SUV max ) and minimum (SUV min ) standardized uptake value (SUV) for 18 F-FDG uptake in the lungs, and the target-to-background (SUV max /SUV min ) ratio (TBR) were quantified using routine region-of-interest (ROI) analysis. Pulmonary functional tests (PFTs) were acquired within 14 days of the PET/CT/HRCT scan. Kaplan–Meier (KM) survival analysis was used to identify associations with mortality. Results Data from 91 patients were available for comparative analysis. The average ± SD GAP [gender, age, physiology] score was 4.2 ± 1.7 (range 0–8). The average ± SD SUV max , SUV min , and TBR were 3.4 ± 1.4, 0.7 ± 0.2, and 5.6 ± 2.8, respectively. In all patients, qCT analysis demonstrated a predominantly reticular lung pattern (14.9 ± 12.4%). KM analysis showed that TBR ( p = 0.018) and parenchymal damage assessed by qCT ( p = 0.0002) were the best predictors of survival. Adding TBR and qCT to the GAP score significantly increased the ability to differentiate between high and low risk ( p < 0.0001). Conclusion 18 F-FDG PET and qCT are independent and synergistic in predicting mortality in patients with IPF.

The use of saline 0.9% was associated with a lower incidence of electrolyte disturbances.