Influence of adjuvant therapies on organ-specific recurrence of cutaneous melanoma: A multicenter study on 1383 patients of the prospective DeCOG registry ADOReg.

This study investigated whether adjuvant treatments in stage III cutaneous melanoma (CM) influenced patterns of recurrence. Patients with primary (n = 1033) or relapsed CM (n = 350) who received adjuvant therapies with Nivolumab (N), Pembrolizumab (P), or Dabrafenib and Trametinib (D + T) were extracted from the prospective multicenter real-world skin cancer registry ADOReg. Endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), organ-specific DMFS, and overall survival (OS). For primary cases, D + T indicated an improved PFS (1- and 2-year PFS: 90.9%; 82.7%) as compared to P (81.0%, 73.9%; p = .0208), or N (83.8%, 75.2%; p = .0539). BRAF-mutated(mut) CM demonstrated significantly lower PFS (p = .0022) and decreased DMFS (p = .0580) when treated with immune checkpoint inhibitor (ICI) instead of D + T. Besides, NRAS-mut CM tended to perform worse than wt CM upon ICI (PFS: p = .1349; DMFS: p = .0540). OS was similar between the groups. Relapsed cases showed decreased PFS, DMFS, and OS in comparison to primary (all: p < .001), without significant differences between the subgroups. Organ-specific DMFS was significantly altered for primary cases with bone (p = .0367) or brain metastases (p = .0202). In relapsed CM, the frequency of liver (D + T: 1.5%; P: 12%; N: 9%) and LN metastases (D + T: 1.5%; P: 12%; N: 10.2%) was significantly lower with adjuvant D + T than ICI. NRAS-mut CM showed increased recurrence in primary and relapsed cases. These data show that adjuvant D + T is superior to ICI in primary BRAF-mut CM.

The survival benefit of adjuvant trastuzumab with or without chemotherapy in the management of small (T1mic, T1a, T1b, T1c), node negative HER2+ breast cancer.

There is limited data regarding the added benefit of adjuvant systemic therapy in the management of small, node-negative, HER2+ breast cancer. In a multi-institutional retrospective analysis using the American Society of Clinical Oncology CancerLinQ database, we compared survival outcomes among T1a-c N0 HER2+ patients diagnosed between 2010 to 2021 who received locoregional therapy alone or in combination with adjuvant trastuzumab (+/- chemotherapy). Primary outcomes were invasive disease-free survival (iDFS) and overall survival (OS). Of the 1,184 patients, 436 received locoregional therapy alone. We found a statistically significant improvement in iDFS (HR 0.73, P = 0.003) and OS (HR 0.63, P = 0.023) on univariate analysis with adjuvant trastuzumab with or without chemotherapy which remained statistically significant on multivariate analysis. Three-arm univariate analysis found that iDFS was significantly improved with trastuzumab monotherapy (P = 0.003) and combination therapy (P = 0.027) compared to observation. Subgroup data suggests that T1b/c tumors derive the greatest benefit.

Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes.

Recently, we have shown that after partial hepatectomy (PHx), an increased hepatic blood flow initiates liver growth in mice by vasodilation and mechanically-triggered release of angiocrine signals. Here, we use mass spectrometry to identify a mechanically-induced angiocrine signal in human hepatic endothelial cells, that is, myeloid-derived growth factor (MYDGF). We show that it induces proliferation and promotes survival of primary human hepatocytes derived from different donors in two-dimensional cell culture, via activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MYDGF also enhances proliferation of human hepatocytes in three-dimensional organoids. In vivo, genetic deletion of MYDGF decreases hepatocyte proliferation in the regenerating mouse liver after PHx; conversely, adeno-associated viral delivery of MYDGF increases hepatocyte proliferation and MAPK signaling after PHx. We conclude that MYDGF represents a mechanically-induced angiocrine signal and that it triggers growth of, and provides protection to, primary mouse and human hepatocytes.

Hypoxia Attenuates Pressure Overload-Induced Heart Failure.

BACKGROUND: Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)-induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device-mediated mechanical unloading and circulatory support. METHODS AND RESULTS: We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia-inducible factor)-1α-mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia-mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device-mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts. CONCLUSIONS: Hypoxia attenuates LVPO-induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia-mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO-induced heart failure and mediate cardiac recovery following mechanical circulatory support.

Effects of music intervention combined with progressive muscle relaxation on anxiety, depression, stress and quality of life among women with cancer receiving chemotherapy: A pilot randomized controlled trial.

Beneficial effects of music intervention and progressive muscle relaxation alone on psychological issues were reported, however, studies evaluating their combined effects are limited. This study aimed to investigate the feasibility, acceptability and preliminary effects of music intervention combined with progressive muscle relaxation on anxiety, depression, stress, and quality of life among breast and gynaecological cancer patients receiving chemotherapy. METHODS: The study was carried out from March to May 2022 in an oncology hospital in Vietnam. A single-blinded randomized controlled trial was conducted among 24 women with breast and gynaecological cancer undergoing chemotherapy. The intervention group (n = 12) received a face-to-face training program about music listening and progressive muscle relaxation skills. They then performed the self-practice daily at home for three weeks. The control group (n = 12) received standard care, including health assessment, regular health advice and nutrition consultation. Ten participants in the intervention group were interviewed with open-ended questions to explore the acceptability of the intervention. Anxiety, depression and stress were measured using the Depression Anxiety Stress Scale, while The Functional Assessment of Cancer Therapy-General was used to evaluate the quality of life. The outcome measurements were collected at baseline (T0), post-intervention (3rd week, T1) and follow-up (6th week, T2). Appropriate descriptive statistics were used to depict the outcome measures across study time points. RESULTS: A total of 24 patients were eligible to join, and 20 of them completed the study. Greater reductions in anxiety, depression and stress were observed in the intervention group than in the control group at T1 and T2. Greater improvements on quality of life were found in the intervention group than control group at T1 and T2 with respect to T0. The content analysis supported the acceptable intervention of participants through two themes, perceived beneficial effects on psychological and physical health and willingness to keep practising in the future. CONCLUSIONS: Implementing music intervention combined with progressive muscle relaxation is feasible and had a trend in reducing anxiety, depression and stress levels. A larger scale randomized controlled trial is needed to confirm the effect of the intervention on outcomes. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov with ID: NCT05262621.

Pre-emptive iron supplementation prevents myocardial iron deficiency and attenuates adverse remodelling after myocardial infarction.

AIMS: Heart failure (HF) after myocardial infarction (MI) is a major cause of morbidity and mortality. We sought to investigate the functional importance of cardiac iron status after MI and the potential of pre-emptive iron supplementation in preventing cardiac iron deficiency (ID) and attenuating left ventricular (LV) remodelling. METHODS AND RESULTS: MI was induced in C57BL/6J male mice by left anterior descending coronary artery ligation. Cardiac iron status in the non-infarcted LV myocardium was dynamically regulated after MI: non-haem iron and ferritin increased at 4 weeks but decreased at 24 weeks after MI. Cardiac ID at 24 weeks was associated with reduced expression of iron-dependent electron transport chain (ETC) Complex I compared with sham-operated mice. Hepcidin expression in the non-infarcted LV myocardium was elevated at 4 weeks and suppressed at 24 weeks. Hepcidin suppression at 24 weeks was accompanied by more abundant expression of membrane-localized ferroportin, the iron exporter, in the non-infarcted LV myocardium. Notably, similarly dysregulated iron homeostasis was observed in LV myocardium from failing human hearts, which displayed lower iron content, reduced hepcidin expression, and increased membrane-bound ferroportin. Injecting ferric carboxymaltose (15 µg/g body weight) intravenously at 12, 16, and 20 weeks after MI preserved cardiac iron content and attenuated LV remodelling and dysfunction at 24 weeks compared with saline-injected mice. CONCLUSION: We demonstrate, for the first time, that dynamic changes in cardiac iron status after MI are associated with local hepcidin suppression, leading to cardiac ID long term after MI. Pre-emptive iron supplementation maintained cardiac iron content and attenuated adverse remodelling after MI. Our results identify the spontaneous development of cardiac ID as a novel disease mechanism and therapeutic target in post-infarction LV remodelling and HF.

Health Professional- and Volunteer-partnered Self-management Support (COMBO-KEY) to Promote Self-efficacy and Self-management Behaviors in People with Stroke: A Randomized Controlled Trial.

BACKGROUND: Multiple systematic reviews have reported that self-management interventions are associated with positive impacts on self-efficacy and health-related quality of life (HRQoL) of people with stroke. PURPOSE: This article reports the effects of an enhanced stroke self-management program. METHODS: Eligible adults with stroke were recruited from community-based organizations and a support group for a two-arm, assessor-blinded randomized controlled trial. Participants in the control group received usual care, while those in the intervention group also received the 8-week self-management program, Coaching Ongoing Momentum Building On stroKe rEcovery journeY (COMBO-KEY), consisting of four individual home visits and five follow-up phone calls, delivered by healthcare professionals and trained volunteers. Assessments were conducted at baseline and after the intervention, for outcomes of self-efficacy, satisfaction with the performance of self-management behaviors, HRQoL, and community reintegration, which were analyzed using generalized estimating equations (GEEs). RESULTS: 134 Participants were recruited [mean age = 64.1 years, standard deviation (SD) = 12.7]. Over 80% of the participants had a first-ever stroke [mean years after first stroke: 4.2 (SD = 5.1)]. The GEE analysis revealed that the intervention group participants showed significantly greater improvements in self-efficacy, satisfaction with their performance of self-management behaviors, HRQoL, and community reintegration at 8-week follow-up with respect to their baseline levels. CONCLUSIONS: The COMBO-KEY program showed effective improvements in recovery outcomes of people with stroke. Future research should explore the inclusion of virtual/hybrid sessions, strategies to assess health conditions of people with stroke via online modes, and assessment of goal attainment and actual performance of self-management behaviors.

Self-management is the active involvement of a person in managing their overall needs for being able to live well with a chronic condition. Self-management interventions have shown to improve the recovery outcomes of people with stroke. We developed an 8-week long enhanced self-management program "COMBO-KEY" delivered by healthcare professionals and trained volunteers, consisting of individual home visits, follow-up phone calls, peer sharing videos, and enriched resources sharing through a website and a reference guide, aimed at promoting self-efficacy, and self-management behaviors of people with stroke. In this study, 134 adults with stroke were recruited and randomized to either receive the COMBO-KEY program or continue to receiving usual care only. Participants receiving the program showed greater improvements in self-efficacy and self-management behaviors with increased quality of life and reintegrating back to the community after eight weeks compared to the participants receiving usual care. The results highlighted the positive role of a health coaching approach, whereby healthcare professionals, and trained volunteers provide self-management support, to improve the recovery of people with stroke.

Effectiveness of Community Health Worker-Led Interventions in Enhancing Colorectal Cancer Screening Uptake in Racial and Ethnic Minority Populations: A Systematic Review and Meta-analysis.

BACKGROUND: The colorectal cancer (CRC) screening uptake rate is substantially lower in ethnic minority populations than in the general population. Racial and ethnic minority individuals experience more barriers in obtaining a screening test for CRC when compared with the non-Hispanic White population. OBJECTIVE: To examine the effectiveness of community health worker-led interventions in improving the CRC screening uptake rate in racial and ethnic minority populations. METHODS: Five databases, EMBASE, CINAHL, MEDLINE, Scopus, and PubMed, were systematically searched, and reference lists of the identified articles were manually searched for relevant articles in May 2022. Only randomized controlled trials were included. RESULTS: A total of 10 randomized controlled trials conducted in the United States were included in this review. The findings of the meta-analysis showed that CRC screening uptake was enhanced in participants receiving community health worker-led interventions compared with those receiving no intervention (odds ratio, 2.25; 95% confidence interval, 1.48-3.44; P < .001). The subgroup analysis by diverse racial and ethnic groups and number of components (single vs multiple) of the community health worker-led interventions showed that multicomponent interventions were more effective in increasing the CRC uptake rate among all racial and ethnic groups regardless of their background. CONCLUSIONS: Multicomponent community health worker-led interventions can improve CRC screening uptake in racial and ethnic minority populations. IMPLICATIONS FOR PRACTICE: The findings of the present review show that multicomponent community health worker-led interventions are shown to be effective to improve the CRC screening uptake targeting other racial and ethnic minority groups in other countries.

Cardiac Troponin I-Interacting Kinase Affects Cardiomyocyte S-Phase Activity but Not Cardiomyocyte Proliferation.

BACKGROUND: Identifying genetic variants that affect the level of cell cycle reentry and establishing the degree of cell cycle progression in those variants could help guide development of therapeutic interventions aimed at effecting cardiac regeneration. We observed that C57Bl6/NCR (B6N) mice have a marked increase in cardiomyocyte S-phase activity after permanent coronary artery ligation compared with infarcted DBA/2J (D2J) mice. METHODS: Cardiomyocyte cell cycle activity after infarction was monitored in D2J, (D2J×B6N)-F1, and (D2J×B6N)-F1×D2J backcross mice by means of bromodeoxyuridine or 5-ethynyl-2'-deoxyuridine incorporation using a nuclear-localized transgenic reporter to identify cardiomyocyte nuclei. Genome-wide quantitative trait locus analysis, fine scale genetic mapping, whole exome sequencing, and RNA sequencing analyses of the backcross mice were performed to identify the gene responsible for the elevated cardiomyocyte S-phase phenotype. RESULTS: (D2J×B6N)-F1 mice exhibited a 14-fold increase in cardiomyocyte S-phase activity in ventricular regions remote from infarct scar compared with D2J mice (0.798±0.09% versus 0.056±0.004%; P<0.001). Quantitative trait locus analysis of (D2J×B6N)-F1×D2J backcross mice revealed that the gene responsible for differential S-phase activity was located on the distal arm of chromosome 3 (logarithm of the odds score=6.38; P<0.001). Additional genetic and molecular analyses identified 3 potential candidates. Of these, Tnni3k (troponin I-interacting kinase) is expressed in B6N hearts but not in D2J hearts. Transgenic expression of TNNI3K in a D2J genetic background results in elevated cardiomyocyte S-phase activity after injury. Cardiomyocyte S-phase activity in both Tnni3k-expressing and Tnni3k-nonexpressing mice results in the formation of polyploid nuclei. CONCLUSIONS: These data indicate that Tnni3k expression increases the level of cardiomyocyte S-phase activity after injury.

Growth differentiation factor 15 and cardiovascular risk: individual patient meta-analysis.

AIMS: Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown. METHODS AND RESULTS: An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200-1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17-1.31 and HR: 1.16, 95% CI: 1.05-1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90-1.06 and HR: 0.87, 95% CI: 0.39-1.92, respectively). CONCLUSION: Growth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS.

Endothelial Cell GATA2 Modulates the Cardiomyocyte Stress Response through the Regulation of Two Long Non-Coding RNAs.

Capillary endothelial cells modulate myocardial growth and function during pathological stress, but it is unknown how and whether this contributes to the development of heart failure. We found that the endothelial cell transcription factor GATA2 is downregulated in human failing myocardium. Endothelial GATA2 knock-out (G2-EC-KO) mice develop heart failure and defective myocardial signal transduction during pressure overload, indicating that the GATA2 downregulation is maladaptive. Heart failure and perturbed signaling in G2-EC-KO mice could be induced by strong upregulation of two unknown, endothelial cell-derived long non-coding (lnc) RNAs (AK037972, AK038629, termed here GADLOR1 and 2). Mechanistically, the GADLOR1/2 lncRNAs transfer from endothelial cells to cardiomyocytes, where they block stress-induced signalling. Thereby, lncRNAs can contribute to disease as paracrine effectors of signal transduction and therefore might serve as therapeutic targets in the future.

Improved bounds on Lorentz violation from composite pulse Ramsey spectroscopy in a trapped ion.

In attempts to unify the four known fundamental forces in a single quantum-consistent theory, it is suggested that Lorentz symmetry may be broken at the Planck scale. Here we search for Lorentz violation at the low-energy limit by comparing orthogonally oriented atomic orbitals in a Michelson-Morley-type experiment. We apply a robust radiofrequency composite pulse sequence in the 2F7/2 manifold of an Yb+ ion, extending the coherence time from 200 µs to more than 1 s. In this manner, we fully exploit the high intrinsic susceptibility of the 2F7/2 state and take advantage of its exceptionally long lifetime. We match the stability of the previous best Lorentz symmetry test nearly an order of magnitude faster and improve the constraints on the symmetry breaking coefficients to the 10-21 level. These results represent the most stringent test of this type of Lorentz violation. The demonstrated method can be further extended to ion Coulomb crystals.

Biomarker-Based Prediction of Recurrent Ischemic Events in Patients With Acute Coronary Syndromes.

BACKGROUND: In patients with acute coronary syndrome (ACS), there is residual and variable risk of recurrent ischemic events. OBJECTIVES: This study aimed to develop biomarker-based prediction models for 1-year risk of cardiovascular (CV) death and myocardial infarction (MI) in patients with ACS undergoing percutaneous coronary intervention. METHODS: We included 10,713 patients from the PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial in the development cohort and externally validated in 3,508 patients from the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial. Variables contributing to risk of CV death/MI were assessed using Cox regression models, and a score was derived using subsets of variables approximating the full model. RESULTS: There were 632 and 190 episodes of CV death/MI in the development and validation cohorts. The most important predictors of CV death/MI were the biomarkers, growth differentiation factor 15, and N-terminal pro-B-type natriuretic peptide, which had greater prognostic value than all candidate variables. The final model included 8 items: age (A), biomarkers (B) (growth differentiation factor 15 and N-terminal pro-B-type natriuretic peptide), and clinical variables (C) (extent of coronary artery disease, previous vascular disease, Killip class, ACS type, P2Y12 inhibitor). The model, named ABC-ACS ischemia, was well calibrated and showed good discriminatory ability for 1-year risk of CV death/MI with C-indices of 0.71 and 0.72 in the development and validation cohorts, respectively. For CV death, the score performed better, with C-indices of 0.80 and 0.84 in the development and validation cohorts, respectively. CONCLUSIONS: An 8-item score for the prediction of CV death/MI was developed and validated for patients with ACS undergoing percutaneous coronary intervention. The ABC-ACS ischemia score showed good calibration and discrimination and might be useful for risk prediction and decision support in patients with ACS. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872; Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER]; NCT00527943).

Integrated analyses of growth differentiation factor-15 concentration and cardiometabolic diseases in humans.

Growth differentiation factor-15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders, as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across three different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant (rs1058587; p.H202D) in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine mapping identified four independent putative causal signals at the locus. Mendelian randomisation (MR) analysis found evidence of a causal relationship between GDF15 concentration and high-density lipoprotein (HDL) but not body mass index (BMI). Using reverse MR, we identified a potential causal association of BMI on GDF15 (IVW pFDR = 0.0040). Taken together, our data derived from human population cohorts do not support a role for moderately elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.

Rotationally-Resolved Two-Dimensional Infrared Spectroscopy of CO2(g): Rotational Wavepackets and Angular Momentum Transfer.

Angular momentum transfer and wavepacket dynamics of CO2(g) were measured on the picosecond time scale using polarization-resolved two-dimensional infrared (2D-IR) spectroscopy. The dynamics of rotational levels up to Jmax ≈ 50 are observed simultaneously at room temperature. Rotational wavepackets launched by the pump pulses cause oscillations in the intensity of individual peaks and beating patterns in the 2D-IR spectra. The structure of the rotationally resolved 2D-IR spectrum is explained using nonlinear response function theory. Spectral diffusion of the rotationally resolved 2D-IR peaks reveals information about angular momentum transfer. We demonstrate the ability to directly measure inelastic angular momentum dynamics simultaneously across the ∼50 thermally excited rotational levels over several hundred picoseconds.

pH Jumps in a Protic Ionic Liquid Proceed by Vehicular Proton Transport.

The dynamics of excess protons in the protic ionic liquid (PIL) ethylammonium formate (EAF) have been investigated from femtoseconds to microseconds using visible pump mid-infrared probe spectroscopy. The pH jump following the visible photoexcitation of a photoacid (8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt, HPTS) results in proton transfer to the formate of the EAF. The proton transfer predominantly (∼70%) occurs over picoseconds through a preformed hydrogen-bonded tight complex between HPTS and EAF. We investigate the longer-range and longer-time-scale proton-transport processes in the PIL by obtaining the ground-state conjugate base (RO-) dynamics from the congested transient-infrared spectra. The spectral kinetics indicate that the protons diffuse only a few solvent shells from the parent photoacid before recombining with RO-. A kinetic isotope effect of nearly unity (kH/kD ≈ 1) suggests vehicular transfer and the transport of excess protons in this PIL. Our findings provide comprehensive insight into the complete photoprotolytic cycle of excess protons in a PIL.

Meteorin-like promotes heart repair through endothelial KIT receptor tyrosine kinase.

Effective tissue repair after myocardial infarction entails a vigorous angiogenic response, guided by incompletely defined immune cell-endothelial cell interactions. We identify the monocyte- and macrophage-derived cytokine METRNL (meteorin-like) as a driver of postinfarction angiogenesis and high-affinity ligand for the stem cell factor receptor KIT (KIT receptor tyrosine kinase). METRNL mediated angiogenic effects in cultured human endothelial cells through KIT-dependent signaling pathways. In a mouse model of myocardial infarction, METRNL promoted infarct repair by selectively expanding the KIT-expressing endothelial cell population in the infarct border zone. Metrnl-deficient mice failed to mount this KIT-dependent angiogenic response and developed severe postinfarction heart failure. Our data establish METRNL as a KIT receptor ligand in the context of ischemic tissue repair.

Skeletal muscle derived Musclin protects the heart during pathological overload.

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.

Interactions between poloxamer, PEOx-PPOy-PEOx, and non-ionic surfactant, sucrose monolaurate: A study on potential allergenic effect using model phospholipid membrane.

Sugar-based surfactants are involved in skin related allergy cases in the past decade. Skin irritation starts with the interaction of the surfactant with the skin lipids leading to lipid emulsification and eventual barrier damage. Polymers or co-surfactants can be used to mitigate the allergenic effect but the mechanism of formulation mildness on skin remains unclear. We have used the quartz crystal microbalance (QCM) together with dissipative particle dynamics (DPD) simulation, small angle x-ray scattering (SAXS) as well as cell viability tests to decipher the interactions between poloxamers and sucrose monolaurate (SML), and how these interactions could prevent the disruption of a model supported phospholipid bilayer (SLB). Poloxamer addition to the SML solution can delay or totally prevent the disruption of the SLB depending on poloxamer type and concentration. Poloxamer P407 (Pluronic® F127) delays the onset of disruption while poloxamer P188 (Pluronic® F68) does not preserve the bilayer integrity even at high concentration of up to 15% w/w. Preservation of the SLB is likely due to the differences in the aggregates formation between SML-F127 and SML-F68 mixtures with corresponding retarded motion of SML micelles through the SML-F127 polymer matrix that improved cell viability.