Natural history of the distal aorta following elective root replacement in patients with Marfan syndrome.

OBJECTIVE: It is unclear if the addition of a prophylactic arch operation is beneficial at the time of root replacement in patients with Marfan syndrome (MFS). This project aims to understand the fate of the distal aorta following elective root replacement in patients with MFS. METHODS: Between 2000 and 2019, 124 adult patients with MFS were identified as having undergone elective aortic root replacement with a clamped distal aortic anastomosis during their lifetime. Serial axial imaging was analyzed. The primary outcome was a composite of subsequent type B aortic dissection (TBAD), aneurysmal degeneration (>4 cm), and aortic reintervention. Secondary outcomes included subsequent TBAD and mortality. RESULTS: Mean age at root replacement was 33.3 years. Median follow-up was 11.3 years. Thirty-one patients (25%) experienced the primary outcome, with no survival difference (P = .9). The crossclamp and aortic cannulation sites were stable (growth rate, 0.33 mm/year), and 2 patients (1.6%) required reintervention there. Twenty-three patients (19.8%) experienced subsequent TBAD. Patients with TBAD had a higher rate of distal degeneration (P < .001), but no significant change in survival (P = .2). Preoperative hypertension (odds ratio, 3.96; P < .05) and younger age at root replacement (odds ratio, 1.05; P < .05) increased the risk of TBAD, based on regression analysis. CONCLUSIONS: The distal aorta (including the clamp and cannulation site) overall appears stable in patients with MFS following elective root replacement without prophylactic arch operation. Development of TBAD seems to be the primary driver of distal degeneration. Factors associated with TBAD development included hypertension, underscoring the importance of strict blood pressure control in these patients.

MEK1 regulates pulmonary macrophage inflammatory responses and resolution of acute lung injury.

The MEK1/2-ERK1/2 pathway has been implicated in regulating the inflammatory response to lung injury and infection, and pharmacologic MEK1/2 inhibitor compounds are reported to reduce detrimental inflammation in multiple animal models of disease, in part through modulation of leukocyte responses. However, the specific contribution of myeloid MEK1 in regulating acute lung injury (ALI) and its resolution remain unknown. Here, the role of myeloid Mek1 was investigated in a murine model of LPS-induced ALI (LPS-ALI) by genetic deletion using the Cre-floxed system (LysMCre × Mekfl), and human alveolar macrophages from healthy volunteers and patients with acute respiratory distress syndrome (ARDS) were obtained to assess activation of the MEK1/2-ERK1/2 pathway. Myeloid Mek1 deletion results in a failure to resolve LPS-ALI, and alveolar macrophages lacking MEK1 had increased activation of MEK2 and the downstream target ERK1/2 on day 4 of LPS-ALI. The clinical significance of these findings is supported by increased activation of the MEK1/2-ERK1/2 pathway in alveolar macrophages from patients with ARDS compared with alveolar macrophages from healthy volunteers. This study reveals a critical role for myeloid MEK1 in promoting resolution of LPS-ALI and controlling the duration of macrophage proinflammatory responses.

Matrix metalloproteinase 28 is regulated by TRIF- and type I IFN-dependent signaling in macrophages.

Matrix metalloproteinases (MMPs) are transcriptionally regulated proteases that have multiple roles in modifying the extracellular matrix (ECM) and inflammatory response. Our previous work identified Mmp28 as a key regulator of inflammation and macrophage polarization during experimental models of pulmonary infection, fibrosis, and chronic smoke exposure. However, the signaling pathways responsible for regulation of macrophage Mmp28 expression remain undefined. This study utilized murine macrophages obtained from wild type, Tlr2-/-, Tlr4-/-, MyD88-/-, Ticam1 Lps2 ( Trifmutant), and Ifnar1-/- mice to test the hypothesis that macrophage Mmp28 expression was dependent on TRIF and type I IFN. Our results support the hypothesis, demonstrating that increased macrophage Mmp28 expression was dependent on type I IFN after LPS and poly(I:C) stimulation. To gain further insight into the function of MMP28, we explored the inflammatory response of macrophages derived from wild type or Mmp28-/- mice to stimulation with poly(I:C). Our data support a role for MMP28 in regulating the macrophage inflammatory response to poly(I:C) because expression of Ccl2, Ccl4, Cxcl10, and Il6 were increased in Mmp28-/- macrophages. Together, these data support a model in which macrophages integrate TRIF- and type I IFN-dependent signaling to coordinate regulation of proteins with the capacity to modify the ECM.

Xenopus TACC1 is a microtubule plus-end tracking protein that can regulate microtubule dynamics during embryonic development.

Microtubule plus-end dynamics are regulated by a family of proteins called plus-end tracking proteins (+TIPs). We recently demonstrated that the transforming acidic coiled-coil (TACC) domain family member, TACC3, can function as a +TIP to regulate microtubule dynamics in Xenopus laevis embryonic cells. Although it has been previously reported that TACC3 is the only TACC family member that exists in Xenopus, our examination of its genome determined that Xenopus, like all other vertebrates, contains three TACC family members. Here, we investigate the localization and function of Xenopus TACC1, the founding member of the TACC family. We demonstrate that it can act as a +TIP to regulate microtubule dynamics, and that the conserved C-terminal TACC domain is required for its localization to plus-ends. We also show that, in Xenopus embryonic mesenchymal cells, TACC1 and TACC3 are each required for maintaining normal microtubule growth speed but exhibit some functional redundancy in the regulation of microtubule growth lifetime. Given the conservation of TACC1 in Xenopus and other vertebrates, we propose that Xenopus laevis is a useful system to investigate unexplored cell biological functions of TACC1 and other TACC family members in the regulation of microtubule dynamics.

Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study.

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0.1 mg/kg p.o.), ATO (0.25 mg/kg i.v.) and AA (1 g i.v) on days 1-4 of week 1, ATO and AA twice weekly during weeks 2-5 and no treatment during week 6 of cycle 1; during cycles 2-6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression-free survival and overall survival were 7 and 19 months respectively. Twenty-two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non-haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid-free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM.