Role of MIF1/MIF2/CD74 interactions in bladder cancer.

Macrophage migration inhibitory factor (MIF1) is a pleiotropic cytokine involved in inflammation and cancer. Genetic knockout of Mif1 in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) model of bladder cancer (BCa) resulted in stage arrest at non-muscle-invasive disease in prior studies. Small-molecule inhibition of MIF1 reduced cancer-associated outcomes, but it did not fully recapitulate genetic models. D-dopachrome tautomerase (gene symbol DDT), commonly referred to as MIF2, is a functional homolog of MIF1, and both MIF1 and MIF2 can bind the cell surface receptor CD74 on multiple cell types to initiate a signaling cascade. It has been proposed that this interaction mediates part of the protumorigenic effects of MIF1 and MIF2 and may explain the discordance in prior studies. We hypothesized that MIF2 functions redundantly with MIF1 in BCa development and progression. The Cancer Genome Atlas (TCGA) analysis indicated MIF and DDT expression were increased in BCa patients compared to control. 4-Iodopyridine (4-IPP), a combined MIF1/MIF2 inhibitor, was more efficacious than ISO-1, a MIF1-only inhibitor, in preventing cellular proliferation in BCa cell lines. To evaluate these findings in vivo, wild-type (WT) and Mif1-/- animals were exposed to 0.05% BBN in drinking water for 16 weeks to initiate tumorigenesis and then evaluated over the subsequent 4 weeks for tumor formation and progression in the presence or absence of 4-IPP. 4-IPP reduced bladder weights in WT animals and bladder weights/tumor stage in Mif1-/- animals. To determine whether MIF1/MIF2 functioned through CD74 in BCa, WT or Cd74-/- animals were used in the same BBN model. Although these animals were partially protected against BBN-induced BCa, 4-IPP did not enhance this effect. In conclusion, our data suggest that MIF2 mechanistically functions in a similar protumorigenic manner to MIF1, and this is at least partially through CD74. Dual inhibition of MIF homologs is more efficacious at reducing tumor burden in this model of BCa. © 2022 The Pathological Society of Great Britain and Ireland.

Development of a Sitting MicroEnvironment Simulator for wheelchair cushion assessment.

STUDY AIM: Pressure ulcers (PU) are a common comorbidity among wheelchair users. An appropriate wheelchair cushion is essential to relieve pressure and reduce PU development during sitting. The microenvironment, specifically excessive heat and moisture, impacts risk for PU development. An effective wheelchair cushion should maintain a healthy microenvironment at the seating interface. Measurement of heat and moisture can characterize microenvironmental conditions at the wheelchair cushion interface under load. We describe the development of a Sitting MicroEnvironment Simulator (SMES) for the reliable assessment of wheelchair cushion microenvironments. MATERIALS: The prototype SMES was developed for use mounted on a Materials Testing Systems (MTS) 810(®) uniaxial servo-hydraulic loading rig and used to assess microenvironmental conditions for Jay Medical Jay 2(®), Roho High Profile Dry Floatation(®) and Low Profile Dry Floatation(®) cushions and a novel modular gel cushion. METHODS: Each cushion was assessed for two hours in triplicate. The SMES was used to load the cushions to 300N ± 10N, with an interface surface temperature of 37 °C±1 °C and fluid delivery of 13 mL/h±1 mL/h of water. Interface temperature and humidity were measured at the left ischial tuberosity (IT) region every five minutes. RESULTS: Heat and moisture responses were similar for the three commercial cushions. The modular gel cushion stayed cooler for at least 15 min longer than any commercial cushion. CONCLUSIONS: The SMES maintained performance to technical specifications for over one hundred hours of total testing and is a reliable tool for characterizing the microenvironmental conditions of wheelchair cushions.

Urologist Access for the Male Population: An 18-Year Study on Population Trends.

INTRODUCTION: Our study examines the factors associated with urologist availability for younger and older men across the country over a period of 18 years from 2000 to 2018. METHODS: The Area Health Resource Files and US Census Data were analyzed from 2000, 2010, and 2018. The younger male population was defined as men aged 20 to 49, and the older male population was defined as ages 50 to 79. Urologist availability was determined by county at all time points. Logistic regression analysis and geographically weighted regression was completed. RESULTS: Over an 18-year period, overall urologist availability decreased for men by 19.6%. Access to urologist availability for men in metropolitan and rural counties decreased by 9.4% and 29.5%, respectively. Among the younger male cohort, urologist availability increased in metropolitan counties by 4%, but decreased by 16% in rural counties. There was an overall decrease in urologist availability of 28% and 43% in metropolitan and rural counties in the older male population. Multiple logistic regression analysis demonstrated that metropolitan status was the most significant factor associated with urologist availability for both male populations. The odds of each independent factor predicting urologist availability for the younger and older male population is dependent on geography. CONCLUSIONS: The majority of the male population has seen a decline in urologist availability. This is especially true for the older male residing in a rural county. Predictors of urologist availability depend on geographical regions, and understanding these regional drivers may allow us to better address disparities in urological care.

Candidate Heterotaxy Gene FGFR4 Is Essential for Patterning of the Left-Right Organizer in Xenopus.

Congenital heart disease (CHD) is the most common birth defect, yet its genetic causes continue to be obscure. Fibroblast growth factor receptor 4 (FGFR4) recently emerged in a large patient exome sequencing study as a candidate disease gene for CHD and specifically heterotaxy. In heterotaxy, patterning of the left-right (LR) body axis is compromised, frequently leading to defects in the heart's LR architecture and severe CHD. FGF ligands like FGF8 and FGF4 have been previously implicated in LR development with roles ranging from formation of the laterality organ [LR organizer (LRO)] to the transfer of asymmetry from the embryonic midline to the lateral plate mesoderm (LPM). However, much less is known about which FGF receptors (FGFRs) play a role in laterality. Here, we show that the candidate heterotaxy gene FGFR4 is essential for proper organ situs in Xenopus and that frogs depleted of fgfr4 display inverted cardiac and gut looping. Fgfr4 knockdown causes mispatterning of the LRO even before cilia on its surface initiate symmetry-breaking fluid flow, indicating a role in the earliest stages of LR development. Specifically, fgfr4 acts during gastrulation to pattern the paraxial mesoderm, which gives rise to the lateral pre-somitic portion of the LRO. Upon fgfr4 knockdown, the paraxial mesoderm is mispatterned in the gastrula and LRO, and crucial genes for symmetry breakage, like coco, xnr1, and gdf3 are subsequently absent from the lateral portions of the organizer. In summary, our data indicate that FGF signaling in mesodermal LRO progenitors defines cell fates essential for subsequent LR patterning.