Disruption of epithelium integrity by inflammation-associated fibroblasts through prostaglandin signaling.

Inflammation-associated fibroblasts (IAFs) are associated with progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial cells is unknown. Here, we developed an in vitro model whereby human colon fibroblasts are induced by specific cytokines and recapitulate key features of IAFs in vivo. When cocultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid expansion and barrier disruption due to swelling and rupture of individual epithelial cells. Colonoids cocultured with IAFs also show increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated by a paracrine pathway involving prostaglandin E2 and its receptor EP4, leading to protein kinase A -dependent activation of the cystic fibrosis transmembrane conductance regulator. EP4-specific chemical inhibitors effectively prevented IAF-induced colonoid swelling and restored normal proliferation and genome stability. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a therapeutic avenue to mitigate inflammation-associated epithelial injury.

Loss of p53 enhances the tumor-initiating potential and drug resistance of clonogenic multiple myeloma cells.

Tumor relapse and drug resistance are major factors that limit the curability of multiple myeloma (MM). New regimens have improved overall MM survival rates, but patients with high-risk features continue to have inferior outcomes. Chromosome 17p13 deletion (del17p) that includes the loss of the TP53 gene is a high-risk cytogenetic abnormality and is associated with poor clinical outcomes owing to relatively short remissions and the development of pan-drug resistant disease. Increased relapse rates suggest that del17p enhances clonogenic growth, and we found that the loss of p53 increased both the frequency and drug resistance of tumor-initiating MM cells (TICs). Subsequent RNA sequencing (RNA-seq) studies demonstrated significant activation of the Notch signaling pathway and upregulation of inhibitor of DNA binding (ID1/ID2) genes in p53-knock out (p53-KO) cells. We found that the loss of ID1 or HES-1 expression or treatment with a gamma-secretase inhibitor (GSI) significantly decreased the clonogenic growth of p53-KO but not p53 wild-type cells. GSI treatment in a small set of MM specimens also reduced the clonogenic growth in del17p samples but not in non-del17p samples. This effect was specific as overexpression of the Notch intracellular domain (NICD) rescued the effects of GSI treatment. Our study demonstrates that the Notch signaling and ID1 expression are required for TIC expansion in p53-KO MM cells. These findings also suggest that GSI may be specifically active in patients with p53 mutant MM.

Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling: IAFs disrupt colon epithelium via PGE2-EP4.

Inflammation-associated fibroblasts (IAFs) are associated with the progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial function and architecture is unknown. In this study, we developed an in vitro model whereby human colon fibroblasts are induced to become IAFs by specific cytokines and recapitulate key features of IAFs in vivo. When co-cultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid swelling and barrier disruption due to swelling and rupture of individual epithelial cells. Epithelial cells co-cultured with IAFs also exhibit increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated through a paracrine pathway involving prostaglandin E2 (PGE2) and the PGE2 receptor EP4, leading to PKA-dependent activation of the CFTR chloride channel. Importantly, EP4-specific chemical inhibitors effectively prevented colonoid swelling and restored normal proliferation and genome stability of IAF-exposed epithelial cells. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a potential treatment to mitigate inflammation-associated epithelial injury.

The aberrant cancer metabolic gene carbohydrate sulfotransferase 11 promotes non-small cell lung cancer cell metastasis via dysregulation of ceruloplasmin and intracellular iron balance.

Aberrant metabolism has been proposed as one of the emerging hallmarks of cancer. However, the interplay between metabolic disorders and cancer metastasis remains to be defined. To explore the sophisticated metabolic processes during metastatic progression, we analyzed differentially expressed metabolic genes during the epithelial-mesenchymal transition (EMT) of lung cancer cells and defined the EMT-associated metabolic gene signature in lung adenocarcinoma patients. We found that the glycosaminoglycan (GAG)-chondroitin sulfate (CS) biosynthesis pathway was upregulated in the mesenchymal state of lung cancer and associated with poor prognosis. Notably, carbohydrate sulfotransferase 11 (CHST11), a crucial CS biosynthetic enzyme, was confirmed as a poor prognosis marker in non-small cell lung cancer (NSCLC) by immunohistochemical analysis. Moreover, forced CHST11 expression promoted invasion and metastasis, which was abolished by depleting the final product of CS biosynthesis by chondroitinase ABC treatment or active-domain negative CHST11. In vivo metastasis mouse models showed that CHST11 increased lung colonies number and sulfated mucosubstance expression. Furthermore, microarray analysis revealed ceruloplasmin (CP), which facilitated iron metabolism, was the downstream effector of CHST11. CP was upregulated by CHST11 through interferon-γ signaling pathway stimulation and related to unfavorable prognosis. Both forced CP expression and long-term iron treatment increased invasion and lung colony formation. Furthermore, we found 3-AP, an iron chelator, hampered the CHST11-induced metastasis. Our findings implicate that the novel CHST11-CP-iron axis enhances EMT and may serve as a new therapeutic target to treat NSCLC patients.

Novel Predictive Models for High-Value Care Outcomes Following Glioblastoma Resection.

BACKGROUND: Treating patients with glioblastoma (GBM) requires extensive medical infrastructure. Individualized risk assessment for extended length of stay (LOS), nonroutine discharge disposition, and increased total hospital charges is critical to optimize delivery of care. Our study sought to develop predictive models identifying independent risk factors for these outcomes. METHODS: We retrospectively reviewed patients undergoing GBM resection at our institution between January 2017 and September 2020. Extended LOS and elevated hospital charges were defined as values in the upper quartile of the cohort. Nonroutine discharge was defined as any disposition other than to home. Multivariate models for each outcome included covariates demonstrating P ≤ 0.10 on bivariate analysis. RESULTS: We identified 265 patients undergoing GBM resection, with an average age of 58.2 years. 24.5% of patients experienced extended LOS, 22.6% underwent nonroutine discharge, and 24.9% incurred elevated total hospital charges. Decreasing Karnofsky Performance Status (KPS) (P = 0.004), increasing modified 5-factor frailty (mFI-5) index (P = 0.012), lower surgeon experience (P = 0.005), emergent surgery (P < 0.0001), and larger tumor volume (P < 0.0001) predicted extended LOS. Independent predictors of nonroutine discharge included older age (P = 0.02), decreasing KPS (P < 0.0001), and emergent surgery (P = 0.048). Nonprivate insurance (P = 0.011), decreasing KPS (P = 0.029), emergent surgery (P < 0.0001), and larger tumor volume (P = 0.004) predicted elevated hospital charges. These models were incorporated into an open-access online calculator (https://neurooncsurgery3.shinyapps.io/gbm_calculator/). CONCLUSIONS: Several factors were independent predictors for at least 1 high-value care outcome, with lower KPS and emergent admission associated with each outcome. These models and our calculator may help clinicians provide individualized postoperative risk assessment to glioblastoma patients.

Person- and Incident-Level Predictors of Blame, Disclosure, and Reporting to Authorities in Rape Scenarios.

Rapes perpetrated during college are both common and underreported. Research highlights that several person- and incident-level factors relating to gender and sexuality may diminish reporting, by themselves and as they pertain to attributions of blame for the assault. In this study, male and female college students (N = 916) read vignettes describing a rape perpetrated by a man against a woman, a man against a man, or a woman against a man. Participants rated the blameworthiness of both perpetrator and victim and rated the likelihood that they would disclose the rape to social ties or health services or report it to authorities if they were in the victim's position. We found that male gender and heterosexual orientation predicted higher victim blame, lower perpetrator blame, and lower likelihood of disclosure, although relative endorsement of masculine gender ideology seemed to be driving these associations, as well as predicted lower likelihood of reporting to authorities. Controlling for other factors, vignettes portraying a woman raping a man led to a lower likelihood of disclosing or reporting the assault, compared with a male-on-female rape. We also found that the effects of female-on-male rape and traditional masculine ideologies tied to rape disclosure partially by decreasing blame to the perpetrator, which itself carried a unique influence on decisions to report. Our findings overall indicate that factors related to gender, sexuality, and blame have myriad influences and may contribute to low rates of disclosing rape to important outlets.

Predictors of Academic Neurosurgical Career Trajectory among International Medical Graduates Training Within the United States.

BACKGROUND: Within the literature, there has been limited research tracking the career trajectories of international medical graduates (IMGs) following residency training. OBJECTIVE: To compare the characteristics of IMG and US medical school graduate (USMG) neurosurgeons holding academic positions in the United States and also analyze factors that influence IMG career trajectories following US-based residency training. METHODS: We collected data on 243 IMGs and 2506 USMGs who graduated from Accreditation Council for Graduate Medical Education (ACGME)-accredited neurosurgery residency programs. We assessed for significant differences between cohorts, and a logistic regression model was used for the outcome of academic career trajectory. RESULTS: Among the 2749 neurosurgeons in our study, IMGs were more likely to pursue academic neurosurgery careers relative to USMGs (59.7% vs 51.1%; P = .011) and were also more likely to complete a research fellowship before beginning residency (odds ratio [OR] = 9.19; P < .0001). Among current US academic neurosurgeons, USMGs had significantly higher pre-residency h-indices relative to IMGs (1.23 vs 1.01; P < .0001) with no significant differences between cohorts when comparing h-indices during (USMG = 5.02, IMG = 4.80; P = .67) or after (USMG = 14.05, IMG = 13.90; P = .72) residency. Completion of a post-residency clinical fellowship was the only factor independently associated with an academic career trajectory among IMGs (OR = 1.73, P = .046). CONCLUSION: Our study suggests that while IMGs begin their US residency training with different research backgrounds and achievements relative to USMG counterparts, they attain similar levels of academic productivity following residency. Furthermore, IMGs are more likely to pursue academic careers relative to USMGs. Our work may be useful for better understanding IMG career trajectories following US-based neurosurgery residency training.