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Alveolar epithelial cell (AEC) injury is central to the pathogenesis of pulmonary fibrosis. Epithelial FGF (fibroblast growth factor) signaling is essential for recovery from hyperoxia- and influenza-induced lung injury, and treatment with FGFs is protective in experimental lung injury. The cell types involved in the protective effect of FGFs are not known. We hypothesized that FGF signaling in type II AECs (AEC2s) is critical in bleomycin-induced lung injury and fibrosis. To test this hypothesis, we generated mice with tamoxifen-inducible deletion of FGFR1–3 (fibroblast growth factor receptors 1, 2, and 3) in surfactant protein C–positive (SPC+) AEC2s (SPC triple conditional knockout [SPC-TCKO]). In the absence of injury, SPC-TCKO mice had fewer AEC2s, decreased Sftpc (surfactant protein C gene) expression, increased alveolar diameter, and increased collagen deposition. After intratracheal bleomycin administration, SPC-TCKO mice had increased mortality, lung edema, and BAL total protein, and flow cytometry and immunofluorescence revealed a loss of AEC2s. To reduce mortality of SPC-TCKO mice to less than 50%, a 25-fold dose reduction of bleomycin was required. Surviving bleomycin-injured SPC-TCKO mice had increased collagen deposition, fibrosis, and ACTA2 expression and decreased epithelial gene expression. Inducible inactivation of individual Fgfr2 or Fgfr3 revealed that Fgfr2, but not Fgfr3, was responsible for the increased mortality and lung injury after bleomycin administration. In conclusion, AEC2-specific FGFR2 is critical for survival in response to bleomycin-induced lung injury. These data also suggest that a population of SPC+ AEC2s require FGFR2 signaling for maintenance in the adult lung. Preventing epithelial FGFR inhibition and/or activating FGFRs in alveolar epithelium may therefore represent a novel approach to treating lung injury and reducing fibrosis.

Limited data describe the epidemiology and risk factors of acral lentiginous melanoma (ALM). In this retrospective analysis, we examined trends in incidence and mortality of ALM among racial and ethnic minoritized populations. We queried 22 Surveillance, Epidemiology, and End Results registries for cases of ALM among Hispanics, non-Hispanic Asians or Pacific Islanders (NHAPIs), non-Hispanic Blacks (NHBs), and non-Hispanic Whites (NHWs) from 2000 through 2020. Age-adjusted incidence and annual percentage changes (APCs) were estimated. Kaplan–Meier curves were stratified by race and ethnicity and compared with log-rank tests. Cox proportional hazard regression models were adjusted for age, sex, race, ethnicity, income, urban–rural residence, stage, and treatment. Of 4188 total cases of ALM with complete data, our study cohort was comprised of 792 (18.9%) Hispanics, 274 (6.5%) NHAPIs, 336 (8.0%) NHBs, and 2786 (66.5%) NHWs. The age-adjusted incidence of ALM increased by 2.48% ( P  < 0.0001) annually from 2000 to 2020, which was driven by rising rates among Hispanics (APC 2.34%, P  = 0.001) and NHWs (APC 2.69%, P  < 0.0001). Incidence remained stable among NHBs (APC 1.15%, P  = 0.1) and NHAPIs (APC 1.12%, P  = 0.4). From 2000 through 2020, 765 (18.3%) patients died from ALM. Compared to NHWs, Hispanics, NHAPIs, and NHBs had significantly increased ALM-specific mortality (all P  < 0.0001). Unadjusted and adjusted cause-specific mortality modeling revealed significantly elevated risk of ALM-specific mortality among Hispanics (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.22–1.75; adjusted hazard ratio [aHR] 1.38, 95% CI 1.14–1.66), NHAPIs (HR 1.80, 95% CI 1.41–2.32; aHR 1.58, 95% CI 1.23–2.04), and NHBs (HR 1.98, 95% CI 1.59–2.47; aHR 2.19, 95% CI 1.74–2.76) (all P  < 0.001). Our study finds rising incidence of ALM among Hispanics and NHWs along with elevated risk of ALM-specific mortality among racial and ethnic minoritized populations. Future strategies to mitigate health inequities in ALM are warranted.

Organ fibrosis, including idiopathic pulmonary fibrosis, is associated with significant morbidity and mortality. Because currently available therapies have limited effect, there is a need to better understand the mechanisms by which organ fibrosis occurs. We have recently reported that transforming growth factor (TGF)-β, a key cytokine that promotes fibrogenesis, induces the expression of the enzymes of the de novo serine and glycine synthesis pathway in human lung fibroblasts, and that phosphoglycerate dehydrogenase (PHGDH; the first and rate-limiting enzyme of the pathway) is required to promote collagen protein synthesis downstream of TGF-β. In this study, we investigated whether inhibition of de novo serine and glycine synthesis attenuates lung fibrosis in vivo. We found that TGF-β induces mRNA and protein expression of PHGDH in murine fibroblasts. Similarly, intratracheal administration of bleomycin resulted in increased expression of PHGDH in mouse lungs, localized to fibrotic regions. Using a newly developed small molecule inhibitor of PHGDH (NCT-503), we tested whether pharmacologic inhibition of PHGDH could inhibit fibrogenesis both in vitro and in vivo. Treatment of murine and human lung fibroblasts with NCT-503 decreased TGF-β–induced collagen protein synthesis. Mice treated with the PHGDH inhibitor beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung fibrosis. These results indicate that the de novo serine and glycine synthesis pathway is necessary for TGF-β–induced collagen synthesis and bleomycin-induced pulmonary fibrosis. PHGDH and other enzymes in the de novo serine and glycine synthesis pathway may be a therapeutic target for treatment of fibrotic diseases, including idiopathic pulmonary fibrosis.

BackgroundThe utilization of MRI to risk stratify elevated PSA prior to prostate biopsy has been inconsistently adopted and varies considerably by practice setting. This study aims to evaluate the usage and performance of MRI as an advanced risk stratification tool of elevated PSA prior to biopsy and identify factors associated with differential utilization of MRI at a large academic setting with ready access to 3T multiparametric MRI of the prostate.MethodsA retrospective single-center study of 2900 men presenting with elevated PSA 2–20 ng/mL from 2018 through 2021 was conducted. We analyzed trends in MRI utilization and outcomes of prostate biopsy by MRI usage. Univariate and multivariate logistic regressions were performed to calculate odds ratios to identify patient- and provider-level predictors of MRI usage.ResultsRates of prebiopsy MRI utilization increased from 56% in 2018 to 89% in 2021 (p < 0.001). Prebiopsy MRI led to biopsy avoidance in 31% of men. MRI usage enhanced detection of clinically significant prostate cancer by 13% and reduced identification of Gleason Grade Group 1 disease by 3% and negative biopsies by 10% (p < 0.001). Men who received MRI were more likely to be younger than 75 years in age and have private or Medicare insurance, PSA >4 ng/mL, and PHI >27. In both univariate and multivariate analysis, black race and Medicaid insurance were associated with reduced MRI utilization (all p < 0.001). Urologic provider was an independent predictor of MRI usage (p < 0.001).ConclusionsUse of MRI as a risk stratification tool for elevated PSA rose during this 4-year study period. Men who self-identify as black or men with Medicaid coverage have diminished rates of MRI usage. Considerable provider-level variability in MRI use was observed. Future research aimed at identifying factors affecting implementation of MRI as a routine risk assessment tool is warranted.

PurposeTo develop nomograms that predict the detection of clinically significant prostate cancer (csPCa, defined as ≥GG2 [Grade Group 2]) at diagnostic biopsy based on multiparametric prostate MRI (mpMRI), serum biomarkers, and patient clinicodemographic features.Materials and methodsNomograms were developed from a cohort of biopsy-naïve men presenting to our 11-hospital system with prostate specific antigen (PSA) of 2–20 ng/mL who underwent pre-biopsy mpMRI from March 2018-June 2021 (n = 1494). The outcomes were the presence of csPCa and high-grade prostate cancer (defined as ≥GG3 prostate cancer). Using significant variables on multivariable logistic regression, individual nomograms were developed for men with total PSA, % free PSA, or prostate health index (PHI) when available. The nomograms were both internally validated and evaluated in an independent cohort of 366 men presenting to our hospital system from July 2021-February 2022.Results1031 of 1494 men (69%) underwent biopsy after initial evaluation with mpMRI, 493 (47.8%) of whom were found to have ≥GG2 PCa, and 271 (26.3%) were found to have ≥GG3 PCa. Age, race, highest PIRADS score, prostate health index when available, % free PSA when available, and PSA density were significant predictors of ≥GG2 and ≥GG3 PCa on multivariable analysis and were used for nomogram generation. Accuracy of nomograms in both the training cohort and independent cohort were high, with areas under the curves (AUC) of ≥0.885 in the training cohort and ≥0.896 in the independent validation cohort. In our independent validation cohort, our model for ≥GG2 prostate cancer with PHI saved 39.1% of biopsies (143/366) while only missing 0.8% of csPCa (1/124) with a biopsy threshold of 20% probability of csPCa.ConclusionsHere we developed nomograms combining serum testing and mpMRI to help clinicians risk stratify patients with elevated PSA of 2–20 ng/mL who are being considered for biopsy. Our nomograms are available at https://rossnm1.shinyapps.io/MynMRIskCalculator/ to aid with biopsy decisions.