Publications

TGF-β signaling is essential in many processes, including immune surveillance, and its dysregulation controls various diseases, including cancer, fibrosis, and inflammation. Studying the innate host defense, which functions in most cell types, we found that RLR signaling represses TGF-β responses. This regulation is mediated by activated IRF3, using a dual mechanism of IRF3-directed suppression. Activated IRF3 interacts with Smad3, thus inhibiting TGF-β-induced Smad3 activation and, in the nucleus, disrupts functional Smad3 transcription complexes by competing with coregulators. Consequently, IRF3 activation by innate antiviral signaling represses TGF-β-induced growth inhibition, gene regulation and epithelial-mesenchymal transition, and the generation of Treg effector lymphocytes from naive CD4(+) lymphocytes. Conversely, silencing IRF3 expression enhances epithelial-mesenchymal transition, TGF-β-induced Treg cell differentiation upon virus infection, and Treg cell generation in vivo. We present a mechanism of regulation of TGF-β signaling by the antiviral defense, with evidence for its role in immune tolerance and cancer cell behavior.

BACKGROUND

No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS.

METHODS

The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight [PBW]), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774.

FINDINGS

No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related.

INTERPRETATION

A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints.

FUNDING

The National Heart, Lung, and Blood Institute.

CONTEXT

Approximately 30% of the women report pain in the affected breast before breast cancer surgery.

OBJECTIVES

The purpose of this secondary analysis of our prospective study was to determine how women who experienced both preoperative and persistent postsurgical breast pain (n=107) differed from women who did not report preoperative breast pain and did (n=158) or did not (n=122) experience persistent postsurgical breast pain.

METHODS

Differences in demographic and clinical characteristics were evaluated. Linear mixed effects (LME) modeling was used to evaluate for group differences in symptom severity, function, sensation, and quality of life (QOL) over time.

RESULTS

Between-group differences in demographic and clinical characteristics as well as trajectories of shoulder function and QOL were identified. Women with both preoperative and persistent postsurgical breast pain were younger; were more likely to report swelling, strange sensations, hardness, and numbness in the affected breast before surgery; and were more likely to have reconstruction at the time of surgery. Women with both preoperative and persistent postsurgical breast pain had more biopsies in the prior year, more lymph nodes removed, and reported more severe acute postsurgical pain than women without preoperative breast pain. The LME modeling revealed significant group effects for most outcomes evaluated. Over the six months of the study, women with both preoperative and persistent postsurgical pain had persistently poorer shoulder flexion and physical well-being than women without preoperative breast pain.

CONCLUSION

Investigations of the etiology and molecular mechanisms of preoperative breast pain, as well as interventions for this high-risk group, are needed.