Expenditure and survival of adult patients with intestinal failure due to short bowel syndrome: real-world evidence from Southern Finland.

OBJECTIVES: Comprehensive follow-up data from the largest hospital district in Finland was used to assess hospital-based healthcare resource utilization (HCRU) and expenses, incidence and prevalence, survival, and effect of comorbidities/complications on survival of adult patients with intestinal failure due to short bowel syndrome (SBS-IF). METHODS: This study utilized electronic healthcare data covering all ≥18-year-old patients with SBS-IF at the Hospital District of Helsinki and Uusimaa in Finland between 2010 and 2019. Patients were followed from SBS-IF onset until the end of 2020 or death and compared to birth year and sex-matched control patients without SBS-IF. RESULTS: The study included 77 patients with SBS-IF (cases) and 363 controls. Cases had high HCRU; the cumulative expenses were about tenfold compared to the controls, at the end of the study (€123,000 vs. €14,000 per patient). The expenses were highest during the first year after SBS-IF onset (€53,000 per patient). Of the cases with a median age 62.5 years, 51.9% died during study time. The median survival was 4.4 years from SBS-IF onset and cases died 13.5 times more likely during the follow-up compared to controls. Mortality risk was lower in female cases (hazard ratio (HR) 0.46; 95% confidence intervals (CI) 0.24, 0.9) and higher with presence of comorbidities (Charlson comorbidity index HR 1.55; 95% CI 1.2, 2.0) and mesenteric infarction (HR 4.5; 95% CI 1.95, 10.36). The incidence of adult SBS-IF was 0.6 per 100,000 adults. CONCLUSION: Our study demonstrates a high demand for healthcare support and elevated mortality in adult SBS-IF-patients. Our results suggest that the presence of comorbidities is a key driver for mortality.

Increased α-actinin-1 destabilizes E-cadherin-based adhesions and associates with poor prognosis in basal-like breast cancer.

The controlled formation and stabilization of E-cadherin-based adhesions is vital for epithelial integrity. This requires co-operation between the E-cadherin-based adhesions and the associated actin cytoskeleton. In cancer, this co-operation often fails, predisposing cells to migration through molecular mechanisms that have only been partially characterized. Here, we demonstrate that the actin filament cross-linker α-actinin-1 is frequently increased in human breast cancer. In mammary epithelial cells, the increased α-actinin-1 levels promote cell migration and induce disorganized acini-like structures in Matrigel. This is accompanied by a major reorganization of the actin cytoskeleton and the associated E-cadherin-based adhesions. Increased expression of α-actinin-1 is particularly noted in basal-like breast cancer cell lines, and in breast cancer patients it associates with poor prognosis in basal-like subtypes. Downregulation of α-actinin-1 in E-cadherin expressing basal-like breast cancer cells demonstrate that α-actinin-1-assembled actin fibers destabilize E-cadherin-based adhesions. Taken together, these results indicate that increased α-actinin-1 expression destabilizes E-cadherin-based adhesions, which is likely to promote the migratory potential of breast cancer cells. Furthermore, our results identify α-actinin-1 as a candidate prognostic biomarker in basal-like breast cancer.

Assembly of non-contractile dorsal stress fibers requires α-actinin-1 and Rac1 in migrating and spreading cells.

Cell migration and spreading is driven by actin polymerization and actin stress fibers. Actin stress fibers are considered to contain α-actinin crosslinkers and nonmuscle myosin II motors. Although several actin stress fiber subtypes have been identified in migrating and spreading cells, the degree of molecular diversity of their composition and the signaling pathways regulating fiber subtypes remain largely uncharacterized. In the present study we identify that dorsal stress fiber assembly requires α-actinin-1. Loss of dorsal stress fibers in α-actinin-1-depleted cells results in defective maturation of leading edge focal adhesions. This is accompanied by a delay in early cell spreading and slower cell migration without noticeable alterations in myosin light chain phosphorylation. In agreement with the unaltered myosin II activity, dorsal stress fiber trunks lack myosin II and are resistant to myosin II ATPase inhibition. Furthermore, the non-contractility of dorsal stress fibers is supported by the finding that Rac1 induces dorsal stress fiber assembly whereas contractile ventral stress fibers are induced by RhoA. Loss of dorsal stress fibers either by depleting α-actinin-1 or Rac1 results in a ß-actin accumulation at the leading edge in migrating and spreading cells. These findings molecularly specify dorsal stress fibers from other actin stress fiber subtypes. Furthermore, we propose that non-contractile dorsal stress fibers promote cell migration and early cell spreading through Rac1-induced actin polymerization.

An association between NUAK2 and MRIP reveals a novel mechanism for regulation of actin stress fibers.

Actin stress fiber assembly and contractility in nonmuscle motile cells requires phosphorylation of myosin regulatory light chain (MLC). Dephosphorylation and disassembly are mediated by MLC phosphatase, which is targeted to actin fibers by the association of its regulatory subunit MYPT1 with myosin phosphatase Rho-interacting protein (MRIP). In the present study, we identify the kinase NUAK2 as a second protein targeted by MRIP to actin fibers. Association of NUAK2 with MRIP increases MLC phosphorylation and promotes formation of stress fibers. This activity does not require the kinase activity of NUAK2 but is dependent on both MRIP and MYPT1, indicating that the NUAK2-MRIP association inhibits fiber disassembly and MYPT1-mediated MLC dephosphorylation. NUAK2 levels are strongly induced by stimuli increasing actomyosin fiber formation, and NUAK2 is required for fiber maintenance in exponentially growing cells, implicating NUAK2 in a positive-feedback loop regulating actin stress fibers independently of the MLC kinase Rho-associated protein kinase (ROCK). The identified MRIP-NUAK2 association reveals a novel mechanism for the maintenance of actin stress fibers through counteracting MYPT1 and, together with recent results, implicates the NUAK proteins as important regulators of the MLC phosphatase acting in both a kinase-dependent and kinase-independent manner.