Publications

BACKGROUND

Epithelial barrier dysfunction and increased permeability may contribute to antigen sensitization and disease progression in asthma. Claudin-18.1 is the only known lung-specific tight junction protein, but its contribution to airway barrier function or asthma is unclear.

OBJECTIVES

We sought to test the hypotheses that claudin-18 is a determinant of airway epithelial barrier function that is downregulated by IL-13 and that claudin-18 deficiency results in increased aeroantigen sensitization and airway hyperresponsiveness.

METHODS

Claudin-18.1 mRNA levels were measured in airway epithelial brushings from healthy controls and patients with asthma. In patients with asthma, claudin-18 levels were compared with a three-gene-mean marker of T2 inflammation. Airway epithelial permeability changes due to claudin-18 deficiency were measured in 16HBE cells and claudin-18 null mice. The effect of IL-13 on claudin expression was determined in primary human airway epithelial cells and in mice. Airway hyperresponsiveness and serum IgE levels were compared in claudin-18 null and wild-type mice following aspergillus sensitization.

RESULTS

Epithelial brushings from patients with asthma (n = 67) had significantly lower claudin-18 mRNA levels than did those from healthy controls (n = 42). Claudin-18 levels were lowest among T2-high patients with asthma. Loss of claudin-18 was sufficient to impair epithelial barrier function in 16HBE cells and in mouse airways. IL-13 decreased claudin-18 expression in primary human cells and in mice. Claudin-18 null mice had significantly higher serum IgE levels and increased airway responsiveness following intranasal aspergillus sensitization.

CONCLUSIONS

These data support the hypothesis that claudin-18 is an essential contributor to the airway epithelial barrier to aeroantigens. Furthermore, T2 inflammation suppresses claudin-18 expression, potentially promoting sensitization and airway hyperresponsiveness.

BACKGROUND/AIM

Palliative care services (PCS) are recommended to enhance quality of care for hospitalized patients.

METHODS

We evaluated the attitudes of liver transplant (LT) providers and perceived barriers to PCS for their patients by conducting a web-based survey of intensive care unit nurses, postgraduate year 1 (PGY1) physician trainees, nurse practitioners, fellows, and attending physicians on the LT service at an academic medical center.

RESULTS

The response rate was 44% (88/200). Providers agreed that LT and PCS are not mutually exclusive (86%, n = 76). Respondents reported confusion regarding criteria and timing for referral to PCS. Most suggested that referral is appropriate when death is imminent (78%, n = 69). Many providers felt that patients' depression (66%, n = 58) was poorly managed, although few identified that PCS were consulted for depression (28%, n = 25). Overall, 84% (n = 74) identified attending physicians as the main barrier to involving PCS, and attendings (93%, n = 82) were more likely than PGY1 (67%, n = 59) and nurses (55%, n = 48) to describe PCS as end-of-life care (p = 0.03). Nearly all LT providers agreed that patients welcomed goals of care discussions (83%, n = 73), were grateful for PCS (96%, n = 85), and received higher quality care with PCS (96%, n = 85).

CONCLUSION

LT providers overwhelmingly report that PCS benefit patients and are consistent with LT goals even while patients are listed for LT. Barriers to PCS include confusion over referral criteria and describing PCS as end-of-life care by attending physicians. PCS teams may expand access for LT patients by establishing clear criteria for PCS referral and targeting educational interventions about palliative care to attendings.

Coordinated gastrointestinal smooth muscle contraction is critical for proper nutrient absorption and is altered in a number of medical disorders. In this work, we demonstrate a critical role for the RGD-binding integrin α8β1 in promoting nutrient absorption through regulation of gastrointestinal motility. Smooth muscle-specific deletion and antibody blockade of α8 in mice result in enhanced gastric antral smooth muscle contraction, more rapid gastric emptying, and more rapid transit of food through the small intestine leading to malabsorption of dietary fats and carbohydrates as well as protection from weight gain in a diet-induced model of obesity. Mechanistically, ligation of α8β1 by the milk protein Mfge8 reduces antral smooth muscle contractile force by preventing RhoA activation through a PTEN-dependent mechanism. Collectively, our results identify a role for α8β1 in regulating gastrointestinal motility and identify α8 as a potential target for disorders characterized by hypo- or hyper-motility.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes.