Innovative Percutaneous 3 Stitch Suture Technique for Site Closure in Venoarterial Extracorporeal Membrane Oxygenation Decannulation Without Direct Artery Repair: A Case Series.

No previous studies have reported the use of a percutaneous suture technique performed by bedside intensivists for site closure during decannulation without direct artery repair in venoarterial extracorporeal membrane oxygenation (VA-ECMO) cases. Thus, the objective of this study was to evaluate the safety and effectiveness of this alternative approach. This retrospective study included 26 consecutive patients who underwent percutaneous VA-ECMO decannulation at Maoming People's Hospital. Bedside percutaneous suture technique performed by intensivists facilitated cannula site closure. Primary outcome was successful closure without additional interventions. Secondary outcomes included procedural time, surgical conversion rate, complications (bleeding, vascular/wound complications, neuropathy, lymphocele), procedure-related death. Follow-up ultrasound were conducted within 6 months after discharge. All patients achieved successful site hemostasis with a median procedural time of 28 minutes. Procedure-related complications included minor bleeding (7.7%), acute lower limb ischemia (15.4%), venous thrombus (11.5%), minor arterial stenosis (7.7%), wound infection (4.2%), delayed healing (15.4%), and wound secondary suturing (6.3%). No procedure-related deaths occurred. Follow-up vascular ultrasound revealed two cases (7.7%) of minor arterial stenosis. The perivascular suture technique may offer intensivists a safe and effective alternative method for access site closure without direct artery suture during ECMO decannulation.

Effects of hematite on two types of dissolved organic compounds in lignocellulosic anaerobic hydrolysate: Lignin-derived aromatic compounds and denitrifying carbon sources.

The utilization of anaerobic hydrolysate from agroforestry wastes is limited by dissolved lignin and aromatics, which have received insufficient attention despite their potential as excellent carbon sources for denitrification. This study aims to investigate the influence of hematite on lignin-derived aromatic compounds and denitrifying carbon sources, as well as to identify iron-reducing bacteria that utilize lignin-derived aromatic compounds as electron donors. The findings revealed that hematite facilitated the anaerobic fermentation of plant biomass, resulting in the production of small molecular organic acids. Moreover, biodegradation of lignin-derived aromatic compounds led to the formation of phenolic acids, while an increased generation of denitrifying carbon sources enhanced nitrogen removal efficiency by 13.84 %. Additionally, due to adsorption by hematite and subsequent microbial degradation, there was a significant improvement (40.32%) in color removal rate within denitrification effluent. Notably, Azonexus strains were hypothesized to be involved in Fe(Ⅲ) reduction coupled with aromatic compounds oxidation.

Adjuvant Lipoic acid Injection in Sepsis treatment in China (ALIS study): protocol for a randomised, single-blind, placebo-controlled trial.

INTRODUCTION: Sepsis is a life-threatening immune disorder resulting from an dysregulated host response to infection. Adjuvant therapy is a valuable complement to sepsis treatment. Lipoic acid has shown potential in attenuating sepsis-induced immune dysfunction and organ injury in vivo and in vitro studies. However, clinical evidence of lipoic acid injection in sepsis treatment is lacking. Hence, we devised a randomised controlled trial to evaluate the efficacy and safety of lipoic acid injection in improving the prognosis of sepsis or septic shock patients. METHODS AND ANALYSIS: A total of 352 sepsis patients are planned to be recruited from intensive care units (ICUs) at eight tertiary hospitals in China for this trial. Eligible participants will undergo randomisation in a 1:1 ratio, allocating them to either the control group or the experimental group. Both groups received routine care, with the experimental group also receiving lipoic acid injection and the control group receiving placebo. The primary efficacy endpoint is 28-day all-cause mortality. The secondary efficacy endpoints are as follows: ICU and hospital mortality, ICU and hospital stay, new acute kidney injury in ICU, demand and duration of life support, Sequential Organ Failure Assessment (SOFA)/Acute Physiology and Chronic Health Evaluation II (APACHE II) and changes from baseline (ΔSOFA/ΔApache II), arterial blood lactate (LAC) and changes from baseline (ΔLAC), blood procalcitonin, high-sensitivity C-reactive protein, interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) and changes from baseline on day 1 (D1), D3, D5 and D7. Clinical safety will be assessed through analysis of adverse events. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Maoming People's Hospital (approval no. PJ2020MI-019-01). Informed consent will be obtained from the participants or representatives. The findings will be disseminated through academic conferences or journal publications. TRIAL REGISTRATION: ChiCTR2000039023.

Higher serum bilirubin levels are associated with hemorrhagic transformation after intravenous thrombolysis in acute ischemic Stroke.

Background: Bilirubin has both antioxidative and prooxidative properties. The study aimed to explore the relationship between serum bilirubin and hemorrhagic transformation (HT) after intravenous thrombolysis in patients with acute ischemic stroke. Methods: The patients receiving intravenous thrombolysis with alteplase were retrospectively analyzed. HT was defined as new intracerebral hemorrhage in follow-up computed tomography images within 24-36 h after thrombolysis. Symptomatic intracranial hemorrhage (sICH) was defined as HT accompanied by worsening neurological function. Multivariate logistic regression and spline regression models were performed to investigate the relationship between serum bilirubin levels and the risk of HT and sICH. Results: Among 557 included patients, 71 (12.7%) were diagnosed with HT and 28 (5.0%) developed sICH. Patients with HT had significant higher baseline serum total bilirubin, direct bilirubin, and indirect bilirubin levels than those without HT. Multivariable logistic regression analysis indicated that patients with higher serum bilirubin levels, including total bilirubin (OR 1.05, 95% CI 1.01-1.08, p = 0.006), direct bilirubin (OR 1.18, 95% CI 1.05-1.31, p = 0.004), and indirect bilirubin (OR 1.06, 95% CI 1.02-1.10, p = 0.005) had increased risk of HT. Furthermore, multiple-adjusted spline regression models excluded nonlinear association between serum bilirubin levels and HT (p > 0.05 for nonlinearity). Similar results were present between serum bilirubin and sICH. Conclusion: The data showed the positively linearly relationship between serum bilirubin levels and the risk of HT and sICH in patients with acute ischemic stroke undergoing intravenous thrombolysis.

Switchable chiral transport in charge-ordered kagome metal CsV3Sb5.

When electric conductors differ from their mirror image, unusual chiral transport coefficients appear that are forbidden in achiral metals, such as a non-linear electric response known as electronic magnetochiral anisotropy (eMChA)1-6. Although chiral transport signatures are allowed by symmetry in many conductors without a centre of inversion, they reach appreciable levels only in rare cases in which an exceptionally strong chiral coupling to the itinerant electrons is present. So far, observations of chiral transport have been limited to materials in which the atomic positions strongly break mirror symmetries. Here, we report chiral transport in the centrosymmetric layered kagome metal CsV3Sb5 observed via second-harmonic generation under an in-plane magnetic field. The eMChA signal becomes significant only at temperatures below [Formula: see text] 35 K, deep within the charge-ordered state of CsV3Sb5 (TCDW ≈ 94 K). This temperature dependence reveals a direct correspondence between electronic chirality, unidirectional charge order7 and spontaneous time-reversal symmetry breaking due to putative orbital loop currents8-10. We show that the chirality is set by the out-of-plane field component and that a transition from left- to right-handed transport can be induced by changing the field sign. CsV3Sb5 is the first material in which strong chiral transport can be controlled and switched by small magnetic field changes, in stark contrast to structurally chiral materials, which is a prerequisite for applications in chiral electronics.

Quasi-symmetry protected topology in a semi-metal.

The crystal symmetry of a material dictates the type of topological band structures it may host, and therefore symmetry is the guiding principle to find topological materials. Here we introduce an alternative guiding principle, which we call 'quasi-symmetry'. This is the situation where a Hamiltonian has an exact symmetry at lower-order that is broken by higher-order perturbation terms. This enforces finite but parametrically small gaps at some low-symmetry points in momentum space. Untethered from the restraints of symmetry, quasi-symmetries eliminate the need for fine-tuning as they enforce that sources of large Berry curvature will occur at arbitrary chemical potentials. We demonstrate that a quasi-symmetry in the semi-metal CoSi stabilizes gaps below 2 meV over a large near-degenerate plane that can be measured in the quantum oscillation spectrum. The application of in-plane strain breaks the crystal symmetry and gaps the degenerate point, observable by new magnetic breakdown orbits. The quasi-symmetry, however, does not depend on spatial symmetries and hence transmission remains fully coherent. These results demonstrate a class of topological materials with increased resilience to perturbations such as strain-induced crystalline symmetry breaking, which may lead to robust topological applications as well as unexpected topology beyond the usual space group classifications.

A novel strategy sequentially linking mechanical cardiopulmonary resuscitation with extracorporeal cardiopulmonary resuscitation optimizes prognosis of refractory cardiac arrest: an illustrative case series.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) to support cardiopulmonary resuscitation (CPR), also known as extracorporeal cardiopulmonary resuscitation (ECPR), has shown encouraging results in refractory cardiac arrest (RCA) resuscitation. However, its therapeutic benefits are linked to instant and uninterrupted chest compression (CC), besides early implementation. Mechanical CC can overcome the shortcomings of conventional manual CC, including fatigue and labor consumption, and ensure adequate blood perfusion. A strategy sequentially linking mechanical CPR with ECPR may earn extra favorable outcomes. CASE SERIES: We present a four-case series with ages ranging from 8 to 94 years who presented with prolonged absences of return of spontaneous circulation (ROSC) after CA associated with acute fulminant myocarditis (AFM) and myocardial infarction (MI). All the cases received VA-ECMO (ROTAFLOW, Maquet) assisted ECPR, with intra-aortic balloon pump (IABP) or continuous renal replacement treatment (CRRT) appended if persistently low mean blood pressure (MAP) or ischemic kidney injury occurred. All patients have successfully weaned off ECMO and the assistant life support devices with complete neurological recovery. Three patients were discharged, except the 94-year-old patient who died of irreversible sepsis 20 days after ECMO weaning-off. These encouraging results will hopefully lead to more consideration of this lifesaving therapy model that sequentially integrates mechanical CPR with ECPR to rescue RCA related to reversible cardiac causes. CONCLUSIONS: This successful case series should lead to more consideration of an integrated lifesaving strategy sequentially linking mechanical cardiopulmonary resuscitation with ECPR, as an extra favorable prognosis of refractory cardiac arrest related to this approach can be achieved.

Ventilator-associated pneumonia prevention in the Intensive care unit using Postpyloric tube feeding in China (VIP study): study protocol for a randomized controlled trial.

BACKGROUND: Ventilator-associated pneumonia is a challenge in critical care and is associated with high mortality and morbidity. Although some consensuses on preventing ventilator-associated pneumonia are reached, it is still somewhat controversial. Meta-analysis has shown that postpyloric tube feeding may reduce the incidences of ventilator-associated pneumonia, which still desires high-quality evidence. This trial aims to evaluate the efficacy and safety profiles of postpyloric tube feeding versus gastric tube feeding. METHODS/DESIGN: In this multicenter, open-label, randomized controlled trial, we will recruit 924 subjects expected to receive mechanical ventilation for no less than 48 h. Subjects on mechanical ventilation will be randomized (1:1) to receive postpyloric or gastric tube feeding and routine preventive measures simultaneously. The primary outcome is the proportion of patients with at least one ventilator-associated pneumonia episode. Adverse events and serious adverse events will be observed closely. DISCUSSION: The VIP study is a large-sample-sized, multicenter, open-label, randomized, parallel-group, controlled trial of postpyloric tube feeding in China and is well-designed based on previous studies. The results of this trial may help to provide evidence-based recommendations for the prevention of ventilator-associated pneumonia. TRIAL REGISTRATION: Chictr.org.cn ChiCTR2100051593 . Registered on 28 September 2021.

Nomogram to predict survival outcome of patients with veno-arterial extracorporeal membrane oxygenation after refractory cardiogenic shock.

OBJECTIVE: : This study aims to develop a nomogram model to predict the survival of refractory cardiogenic shock (RCS) patients that received veno-arterial extracorporeal membrane oxygenation (VA-ECMO). METHODS: A total of 235 and 209 RCS patients were supported with VA-ECMO from January 2018 to December 2019 in Guangdong Provincial People's Hospital, and from January 2020 to December 2020 in four third-grade and class-A hospitals were a development cohort (DC) and validation cohort (VC), respectively. Finally, 137 and 98 patients were included in the DC and VC. Multivariate logistic regression analysis was used to identify variables, and only these independent risk factors were used to establish the nomogram model. The receiver operating characteristic curve (ROC), calibration plot, decision curve, and clinical impact curves were used to evaluate the nomogram's discriminative ability, predictive accuracy, and clinical application value. RESULTS: Pre-ECMO cardiogenic arrest (pre-ECA), lactate (Lac), inotropic score (IS), and modified nutrition risk in the critically ill score (mNUTRIC score) were incorporated into the nomogram. This showed good discrimination in the DC, with an area under ROC (AUROC) and a 95% confidence interval (CI) of 0.959 (0.911-0.986). The AUROC (95% CI) of the VC was 0.928 (0.858-0.971). The calibration plots of the DC and VC presented good calibration results. The decision curve and clinical impact curve of the nomogram provided improved benefits for RCS patients. CONCLUSIONS: This study established a prediction nomogram composed of pre-ECA, Lac, IS, and mNUTRIC scores that could help clinicians to predict the survival probability at hospital discharge precisely and rapidly for RCS patients that received VA-ECMO.

Transport evidence of asymmetric spin-orbit coupling in few-layer superconducting 1Td-MoTe2.

Two-dimensional transition metal dichalcogenides MX2 (M = W, Mo, Nb, and X = Te, Se, S) with strong spin-orbit coupling possess plenty of novel physics including superconductivity. Due to the Ising spin-orbit coupling, monolayer NbSe2 and gated MoS2 of 2H structure can realize the Ising superconductivity, which manifests itself with in-plane upper critical field far exceeding Pauli paramagnetic limit. Surprisingly, we find that a few-layer 1Td structure MoTe2 also exhibits an in-plane upper critical field which goes beyond the Pauli paramagnetic limit. Importantly, the in-plane upper critical field shows an emergent two-fold symmetry which is different from the isotropic in-plane upper critical field in 2H transition metal dichalcogenides. We show that this is a result of an asymmetric spin-orbit coupling in 1Td transition metal dichalcogenides. Our work provides transport evidence of a new type of asymmetric spin-orbit coupling in transition metal dichalcogenides which may give rise to novel superconducting and spin transport properties.

Colossal mid-infrared bulk photovoltaic effect in a type-I Weyl semimetal.

Broadband, efficient and fast conversion of light to electricity is crucial for sensing and clean energy. The bulk photovoltaic effect (BPVE) is a second-order nonlinear optical effect that intrinsically converts light into electrical current. Here, we demonstrate a large mid-infrared BPVE in microscopic devices of the Weyl semimetal TaAs. This discovery results from combining recent developments in Weyl semimetals, focused-ion beam fabrication and theoretical works suggesting a connection between BPVE and topology. We also present a detailed symmetry analysis that allows us to separate the shift current response from photothermal effects. The magnitude and wavelength range of the assigned shift current may impact optical detectors, clean energy and topology, and demonstrate the utility of Weyl semimetals for practical applications.

A library of atomically thin metal chalcogenides.

Investigations of two-dimensional transition-metal chalcogenides (TMCs) have recently revealed interesting physical phenomena, including the quantum spin Hall effect1,2, valley polarization3,4 and two-dimensional superconductivity 5 , suggesting potential applications for functional devices6-10. However, of the numerous compounds available, only a handful, such as Mo- and W-based TMCs, have been synthesized, typically via sulfurization11-15, selenization16,17 and tellurization 18 of metals and metal compounds. Many TMCs are difficult to produce because of the high melting points of their metal and metal oxide precursors. Molten-salt-assisted methods have been used to produce ceramic powders at relatively low temperature 19 and this approach 20 was recently employed to facilitate the growth of monolayer WS2 and WSe2. Here we demonstrate that molten-salt-assisted chemical vapour deposition can be broadly applied for the synthesis of a wide variety of two-dimensional (atomically thin) TMCs. We synthesized 47 compounds, including 32 binary compounds (based on the transition metals Ti, Zr, Hf, V, Nb, Ta, Mo, W, Re, Pt, Pd and Fe), 13 alloys (including 11 ternary, one quaternary and one quinary), and two heterostructured compounds. We elaborate how the salt decreases the melting point of the reactants and facilitates the formation of intermediate products, increasing the overall reaction rate. Most of the synthesized materials in our library are useful, as supported by evidence of superconductivity in our monolayer NbSe2 and MoTe2 samples21,22 and of high mobilities in MoS2 and ReS2. Although the quality of some of the materials still requires development, our work opens up opportunities for studying the properties and potential application of a wide variety of two-dimensional TMCs.

High-quality monolayer superconductor NbSe2 grown by chemical vapour deposition.

The discovery of monolayer superconductors bears consequences for both fundamental physics and device applications. Currently, the growth of superconducting monolayers can only occur under ultrahigh vacuum and on specific lattice-matched or dangling bond-free substrates, to minimize environment- and substrate-induced disorders/defects. Such severe growth requirements limit the exploration of novel two-dimensional superconductivity and related nanodevices. Here we demonstrate the experimental realization of superconductivity in a chemical vapour deposition grown monolayer material-NbSe2. Atomic-resolution scanning transmission electron microscope imaging reveals the atomic structure of the intrinsic point defects and grain boundaries in monolayer NbSe2, and confirms the low defect concentration in our high-quality film, which is the key to two-dimensional superconductivity. By using monolayer chemical vapour deposited graphene as a protective capping layer, thickness-dependent superconducting properties are observed in as-grown NbSe2 with a transition temperature increasing from 1.0 K in monolayer to 4.56 K in 10-layer.Two-dimensional superconductors will likely have applications not only in devices, but also in the study of fundamental physics. Here, Wang et al. demonstrate the CVD growth of superconducting NbSe2 on a variety of substrates, making these novel materials increasingly accessible.

Large-Area and High-Quality 2D Transition Metal Telluride.

Large-area and high-quality 2D transition metal tellurides are synthesized by the chemical vapor deposition method. The as-grown WTe2 maintains two different stacking sequences in the bilayer, where the atomic structure of the stacking boundary is revealed by scanning transmission electron microscopy. The low-temperature transport measurements reveal a novel semimetal-to-insulator transition in WTe2 layers and an enhanced superconductivity in few-layer MoTe2 .

Mechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis.

Matrix stiffening is a prominent feature of pulmonary fibrosis. In this study, we demonstrate that matrix stiffness regulates the ability of fibrotic lung myofibroblasts to invade the basement membrane (BM). We identify α6-integrin as a mechanosensing integrin subunit that mediates matrix stiffness-regulated myofibroblast invasion. Increasing α6-expression, specifically the B isoform (α6B), couples ß1-integrin to mediate MMP-2-dependent pericellular proteolysis of BM collagen IV, leading to myofibroblast invasion. Human idiopathic pulmonary fibrosis lung myofibroblasts express high levels of α6-integrin in vitro and in vivo. Genetic ablation of α6 in collagen-expressing mesenchymal cells or pharmacological blockade of matrix stiffness-regulated α6-expression protects mice against bleomycin injury-induced experimental lung fibrosis. These findings suggest that α6-integrin is a matrix stiffness-regulated mechanosensitive molecule which confers an invasive fibroblast phenotype and mediates experimental lung fibrosis. Targeting this mechanosensing α6(ß1)-integrin offers a novel anti-fibrotic strategy against lung fibrosis.

Development of a radiofrequency ablation platform in a clinically relevant murine model of hepatocellular cancer.

RFA is used in treatment of patients with hepatocellular cancer (HCC); however, tumor location and size often limit therapeutic efficacy. The absence of a realistic animal model and a radiofrequency ablation (RFA) suitable for small animals presents significant obstacles in developing new strategies. To establish a realistic RFA platform that allows the development of effective RFA-integrated treatment in an orthotopic murine model of HCC, a human cardiac radiofrequency generator was modified for murine use. Parameters were optimized and RFA was then performed in normal murine livers and HCCs. The effects of RFA were monitored by measuring the ablation zone and transaminases. The survival of tumor-bearing mice with and without RFA was monitored, ablated normal liver and HCCs were evaluated macroscopically and histologically. We demonstrated that tissue-mimicking media was able to optimize RFA parameters. Utilizing this information we performed RFA in normal and HCC-bearing mice. RFA was applied to hepatic parenchyma and completely destroyed small tumors and part of large tumors. Localized healing of the ablation and normalization of transaminases occurred within 7 days post RFA. RFA treatment extended the survival of small tumor-bearing mice. They survived at least 5 months longer than the controls; however, mice with larger tumors only had a slight therapeutic effect after RFA. Collectively, we performed RFA in murine HCCs and observed a significant therapeutic effect in small tumor-bearing mice. The quick recovery of tumor-bearing mice receiving RFA mimics observations in human subjects. This platform provides us a unique opportunity to study RFA in HCC treatment.

Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis.

Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic fibrotic diseases involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase (Rho/ROCK), actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 (MKL1), that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic pulmonary fibrosis (IPF), we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung fibrosis. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.

Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction.

The mechanical properties of the extracellular matrix have recently been shown to promote myofibroblast differentiation and lung fibrosis. Mechanisms by which matrix stiffness regulates myofibroblast differentiation are not fully understood. The goal of this study was to determine the intrinsic mechanisms of mechanotransduction in the regulation of matrix stiffness-induced myofibroblast differentiation. A well established polyacrylamide gel system with tunable substrate stiffness was used in this study. Megakaryoblastic leukemia factor-1 (MKL1) nuclear translocation was imaged by confocal immunofluorescent microscopy. The binding of MKL1 to the α-smooth muscle actin (α-SMA) gene promoter was quantified by quantitative chromatin immunoprecipitation assay. Normal human lung fibroblasts responded to matrix stiffening with changes in actin dynamics that favor filamentous actin polymerization. Actin polymerization resulted in nuclear translocation of MKL1, a serum response factor coactivator that plays a central role in regulating the expression of fibrotic genes, including α-SMA, a marker for myofibroblast differentiation. Mouse lung fibroblasts deficient in Mkl1 did not respond to matrix stiffening with increased α-SMA expression, whereas ectopic expression of human MKL1 cDNA restored the ability of Mkl1 null lung fibroblasts to express α-SMA. Furthermore, matrix stiffening promoted production and activation of the small GTPase RhoA, increased Rho kinase (ROCK) activity, and enhanced fibroblast contractility. Inhibition of RhoA/ROCK abrogated stiff matrix-induced actin cytoskeletal reorganization, MKL1 nuclear translocation, and myofibroblast differentiation. This study indicates that actin cytoskeletal remodeling-mediated activation of MKL1 transduces mechanical stimuli from the extracellular matrix to a fibrogenic program that promotes myofibroblast differentiation, suggesting an intrinsic mechanotransduction mechanism.

Relaxin regulates myofibroblast contractility and protects against lung fibrosis.

Myofibroblasts are specialized contractile cells that participate in tissue fibrosis and remodeling, including idiopathic pulmonary fibrosis (IPF). Mechanotransduction, a process by which mechanical stimuli are converted into biochemical signals, regulates myofibroblast differentiation. Relaxin is a peptide hormone that mediates antifibrotic effects through regulation of collagen synthesis and turnover. In this study, we demonstrate enhanced myofibroblast contraction in bleomycin-induced lung fibrosis in mice and in fibroblastic foci of human subjects with IPF, using phosphorylation of the regulatory myosin light chain (MLC(20)) as a biomarker of in vivo cellular contractility. Compared with wild-type mice, relaxin knockout mice express higher lung levels of phospho-MLC(20) and develop more severe bleomycin-induced lung fibrosis. Exogenous relaxin inhibits MLC(20) phosphorylation and bleomycin-induced lung fibrosis in both relaxin knockout and wild-type mice. Ex vivo studies of IPF lung myofibroblasts demonstrate decreases in MLC(20) phosphorylation and reduced contractility in response to relaxin. Characterization of the signaling pathway reveals that relaxin regulates MLC(20) dephosphorylation and lung myofibroblast contraction by inactivating RhoA/Rho-associated protein kinase through a nitric oxide/cGMP/protein kinase G-dependent mechanism. These studies identify a novel antifibrotic role of relaxin involving the inhibition of the contractile phenotype of lung myofibroblasts and suggest that targeting myofibroblast contractility with relaxin-like peptides may be of therapeutic benefit in the treatment of fibrotic lung disease.

KLF6 induces apoptosis in prostate cancer cells through up-regulation of ATF3.

KLF6 (Kruppel-like factor 6) is a zinc finger transcription factor and a tumor suppressor that is frequently mutated in prostate cancer. KLF6 suppresses tumor growth and induces apoptosis in cancer cells through mechanisms still not defined. Here we show that KLF6 induces apoptosis in prostate cancer cells by ATF3 (activating transcription factor 3) expression. KLF6 binds directly to and activates the ATF3 promoter. ATF3 induced apoptosis when ectopically expressed in cells, whereas knockdown of ATF3 by small interference RNA blocked KLF6-induced apoptosis. KLF6 mutants derived from clinical prostate cancers failed to activate the ATF3 promoter and were unable to induce apoptosis. Furthermore, stress conditions (exposure to staurosporine and hypoxia induced by sodium azide) caused significant increase in ATF3 expression and induced apoptosis, whereas knockdown of KLF6 by small interference RNA blocked the increase of ATF3 as well as the induction of apoptosis in these conditions. Thus, ATF3 is a key mediator of KLF6-induced apoptosis in prostate cancer cells.