Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C.

BACKGROUND: KRAS G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy. METHODS: In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response. RESULTS: After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab. CONCLUSIONS: In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.).

Increased Muc5AC and Decreased Ciliated Cells in Severe Asthma Partially Restored by Inhibition of IL-4Rα Receptor.

BACKGROUND: The role of IL-13 on the airway epithelium in severe asthma leading to airway remodeling remains poorly understood. OBJECTIVE: To study IL-13 induced airway remodeling on goblet cells and cilia in the airway epithelium in severe asthma and the impact of an anti-IL4Rα antibody, dupilumab, in vitro. METHODS: Quantitative CT (qCT) lungs and endobronchial biopsies and brushings were obtained in 51 participants (22 severe, 11 non-severe asthma and 18 healthy participants) in the Severe Asthma Research Program (SARPIII) and measured for mucin and cilia related proteins. Epithelial cells were differentiated in air-liquid interphase (ALI) with IL-13 +/-dupilumab and assessed for mucin, cilia, cilia beat frequency (CBF) and epithelial integrity (transepithelial electrical resistance, TEER). RESULTS: Increased Muc5AC (Δ+263.2±92.7 lums/EpiArea) and decreased ciliated cells (Δ-0.07±0.03 Foxj1+cells/EpiArea) were observed in biopsies from severe asthma when compared to healthy (p<0.01 and p=0.047 respectively). RNAseq of epithelial cell brushes confirmed a Muc5AC increase with a decrease in a 5-gene cilia-related mean in severe asthma compared to healthy (all p<0.05). IL-13 (5 ng/mL) differentiated ALI cultures of healthy and asthmatic (severe and non-severe participants) increased Muc5AC, decreased cilia (α-acytl-tubulin) in healthy (Δ+6.5±1.5%, Δ-14.1±2.7%; all p<0.001 respectively) and asthma (Δ+4.4±2.5%, Δ-13.1±2.7%; p=0.084, p<0.001 respectively); decreased epithelial integrity (TEER) in healthy (-140.9±21.3 [ohms], p<0.001) while decreasing CBF in asthma (Δ-4.4±1.7 [Hz], p<0.01). When dupilumab was added to ALI with IL-13, there was no significant decrease in Mu5AC but there was restoration of cilia in healthy and asthma participants (absolute increase of 67.5% and 32.5% cilia, all p<0.05 respectively) while CBF increased (Δ+3.6±1.1 [Hz], p<0.001) and TEER decreased (only in asthma Δ-37.8±16.2 [ohms] p<0.05). CONCLUSIONS: IL-13 drives features of airway remodeling in severe asthma which are partially reversed by inhibiting IL-4Rα receptor in vitro.

Cathode Electrolyte Interphase Engineering for Prussian Blue Analogues in Lithium-Ion Batteries.

The increasing use of low-cost lithium iron phosphate cathodes in low-end electric vehicles has sparked interest in Prussian blue analogues (PBAs) for lithium-ion batteries. A major challenge with iron hexacyanoferrate (FeHCFe), particularly in lithium-ion systems, is its slow kinetics in organic electrolytes and valence state inactivation in aqueous ones. We have addressed these issues by developing a polymeric cathode electrolyte interphase (CEI) layer through a ring-opening reaction of ethylene carbonate triggered by OH- radicals from structural water. This facile approach considerably mitigates the sluggish electrochemical kinetics typically observed in organic electrolytes. As a result, FeHCFe has achieved a specific capacity of 125 mAh g-1 with a stable lifetime over 500 cycles, thanks to the effective activation of Fe low-spin states and the structural integrity of the CEI layers. These advancements shed light on the potential of PBAs to be viable, durable, and efficient cathode materials for commercial use.

The complementary dominance hypothesis: a model for remediating the 'good' hand in stroke survivors.

The complementary dominance hypothesis is a novel model of motor lateralization substantiated by decades of research examining interlimb differences in the control of upper extremity movements in neurotypical adults and hemisphere-specific motor deficits in stroke survivors. In contrast to earlier ideas that attribute handedness to the specialization of one hemisphere, our model proposes complementary motor control specializations in each hemisphere. The dominant hemisphere mediates optimal control of limb dynamics as required for smooth and efficient movements, whereas the non-dominant hemisphere mediates impedance control, important for countering unexpected mechanical conditions and achieving steady-state limb positions. Importantly, this model proposes that each hemisphere contributes its specialization to both arms (though with greater influence from either arm's contralateral hemisphere) and thus predicts that lesions to one hemisphere should produce hemisphere-specific motor deficits in not only the contralesional arm, but also the ipsilesional arm of stroke survivors - a powerful prediction now supported by a growing body of evidence. Such ipsilesional arm motor deficits vary with contralesional arm impairment, and thus individuals with little to no functional use of the contralesional arm experience both the greatest impairments in the ipsilesional arm, as well as the greatest reliance on it to serve as the main or sole manipulator for activities of daily living. Accordingly, we have proposed and tested a novel intervention that reduces hemisphere-specific ipsilesional arm deficits and thereby improves functional independence in stroke survivors with severe contralesional impairment.

ARBM101 (Methanobactin SB2) Drains Excess Liver Copper via Biliary Excretion in Wilson's Disease Rats.

BACKGROUND & AIMS: Excess copper causes hepatocyte death in hereditary Wilson's disease (WD). Current WD treatments by copper-binding chelators may gradually reduce copper overload; they fail, however, to bring hepatic copper close to normal physiological levels. Consequently, lifelong daily dose regimens are required to hinder disease progression. This may result in severe issues due to nonadherence or unwanted adverse drug reactions and also due to drug switching and ultimate treatment failures. This study comparatively tested bacteria-derived copper binding agents-methanobactins (MBs)-for efficient liver copper depletion in WD rats as well as their safety and effect duration. METHODS: Copper chelators were tested in vitro and in vivo in WD rats. Metabolic cage housing allowed the accurate assessment of animal copper balances and long-term experiments related to the determination of minimal treatment phases. RESULTS: We found that copper-binding ARBM101 (previously known as MB-SB2) depletes WD rat liver copper dose dependently via fecal excretion down to normal physiological levels within 8 days, superseding the need for continuous treatment. Consequently, we developed a new treatment consisting of repetitive cycles, each of ∼1 week of ARBM101 applications, followed by months of in-between treatment pauses to ensure a healthy long-term survival in WD rats. CONCLUSIONS: ARBM101 safely and efficiently depletes excess liver copper from WD rats, thus allowing for short treatment periods as well as prolonged in-between rest periods.

Nucleolar actions in plant development and stress responses.

The nucleolus is conventionally acknowledged for its role in ribosomal RNA (rRNA) synthesis and ribosome biogenesis. Recent research has revealed its multifaceted involvement in plant biology, encompassing regulation of the cell cycle, development, and responses to environmental stresses. This comprehensive review explores the diverse roles of the nucleolus in plant growth and responses to environmental stresses. The introduction delves into its traditional functions in rRNA synthesis and potential participation in nuclear liquid-liquid phase separation. By examining the multifaceted roles of nucleolar proteins in plant development, we highlight the impacts of various nucleolar mutants on growth, development, and embryogenesis. Additionally, we reviewed the involvement of nucleoli in responses to abiotic and biotic stresses. Under abiotic stress conditions, the nucleolar structure undergoes morphological changes. In the context of biotic stress, the nucleolus emerges as a common target for effectors of pathogens for manipulation of host immunity to enhance pathogenicity. The detailed exploration of how pathogens interact with nucleoli and manipulate host responses provides valuable insights into plant stress responses as well as plant growth and development. Understanding these processes may pave the way for promising strategies to enhance crop resilience and mitigate the impact of biotic and abiotic stresses in agricultural systems.

Healthy adults favor stable left/right hand choices over performance at an unconstrained reach-to-grasp task.

Reach-to-grasp actions are fundamental to the daily activities of human life, but few methods exist to assess individuals' reaching and grasping actions in unconstrained environments. The Block Building Task (BBT) provides an opportunity to directly observe and quantify these actions, including left/right hand choices. Here we sought to investigate the motor and non-motor causes of left/right hand choices, and optimize the design of the BBT, by manipulating motor and non-motor difficulty in the BBT's unconstrained reach-to-grasp task. We hypothesized that greater motor and non-motor (e.g. cognitive/perceptual) difficulty would drive increased usage of the dominant hand. To test this hypothesis, we modulated block size (large vs. small) to influence motor difficulty, and model complexity (10 vs. 5 blocks per model) to influence non-motor difficulty, in healthy adults (n = 57). Our data revealed that increased motor and non-motor difficulty led to lower task performance (slower task speed), but participants only increased use of their dominant hand only under the most difficult combination of conditions: in other words, participants allowed their performance to degrade before changing hand choices, even though participants were instructed only to optimize performance. These results demonstrate that hand choices during reach-to grasp actions are more stable than motor performance in healthy right-handed adults, but tasks with multifaceted difficulties can drive individuals to rely more on their dominant hand.

Microplastic Contamination of a Benthic Ecosystem in a Hydrothermal Vent.

Plastic contamination is a global pervasive issue, extending from coastal areas and open oceans to polar regions and even the deep sea. Microplastic (MP) contamination in hydrothermal vents, which are known for their high biodiversity even under extreme conditions, has remained largely unexplored. Here, we present, for the first time, MP pollution in a deep-sea hydrothermal vent at one of the biodiversity hotspots─the Central Indian Ridge. Not only the environment (seawater: 2.08 ± 1.04 MPs/L, surface sediments: 0.57 ± 0.19 MP/g) but also all six major benthic species investigated were polluted by MPs. MPs mainly consisted of polypropylene, polyethylene terephthalate, and polystyrene fragments ≤100 µm and were characterized as being either transparent or white in color. Remarkably, bioaccumulation and even biomagnification of microplastics were observed in the top predators of the ecosystem, such as squat lobsters (14.25 ± 4.65 MPs/individual) and vent crabs (14.00 ± 2.16 MPs/individual), since they contained more MPs than animals at lower trophic levels (e.g., mussels and snails, 1.75-6.00 average MPs/individuals). These findings reveal MP contamination of an ecosystem in a hydrothermal vent, thereby suggesting that their accumulation and magnification can occur in top-level animals, even within remote and extreme environments.

Flexible Ansatz for N-Body Perturbation Theory.

We propose a new perturbation theory framework that can be used to help with the projective solution of the Schrödinger equation for arbitrary wave functions. This Flexible Ansatz for N-body Perturbation Theory (FANPT) is based on our previously proposed Flexible Ansatz for the N-body Configuration Interaction (FANCI). We derive recursive FANPT expressions, including arbitrary orders in the perturbation hierarchy. We show that the FANPT equations are well-behaved across a wide range of conditions, including static correlation-dominated configurations and highly nonlinear wave functions.

The tale of HORTON: Lessons learned in a decade of scientific software development.

HORTON is a free and open-source electronic-structure package written primarily in Python 3 with some underlying C++ components. While HORTON's development has been mainly directed by the research interests of its leading contributing groups, it is designed to be easily modified, extended, and used by other developers of quantum chemistry methods or post-processing techniques. Most importantly, HORTON adheres to modern principles of software development, including modularity, readability, flexibility, comprehensive documentation, automatic testing, version control, and quality-assurance protocols. This article explains how the principles and structure of HORTON have evolved since we started developing it more than a decade ago. We review the features and functionality of the latest HORTON release (version 2.3) and discuss how HORTON is evolving to support electronic structure theory research for the next decade.

Coupled cluster-inspired geminal wavefunctions.

Electron pairs have an illustrious history in chemistry, from powerful concepts to understanding structural stability and reactive changes to the promise of serving as building blocks of quantitative descriptions of the electronic structure of complex molecules and materials. However, traditionally, two-electron wavefunctions (geminals) have not enjoyed the popularity and widespread use of the more standard single-particle methods. This has changed recently, with a renewed interest in the development of geminal wavefunctions as an alternative to describing strongly correlated phenomena. Hence, there is a need to find geminal methods that are accurate, computationally tractable, and do not demand significant input from the user (particularly via cumbersome and often ill-behaved orbital optimization steps). Here, we propose new families of geminal wavefunctions inspired by the pair coupled cluster doubles ansatz. We present a new hierarchy of two-electron wavefunctions that extends the one-reference orbital idea to other geminals. Moreover, we show how to incorporate single-like excitations in this framework without leaving the quasiparticle picture. We explore the role of imposing seniority restrictions on these wavefunctions and benchmark these new methods on model strongly correlated systems.

GBasis: A Python library for evaluating functions, functionals, and integrals expressed with Gaussian basis functions.

GBasis is a free and open-source Python library for molecular property computations based on Gaussian basis functions in quantum chemistry. Specifically, GBasis allows one to evaluate functions expanded in Gaussian basis functions (including molecular orbitals, electron density, and reduced density matrices) and to compute functionals of Gaussian basis functions (overlap integrals, one-electron integrals, and two-electron integrals). Unique features of GBasis include supporting evaluation and analytical integration of arbitrary-order derivatives of the density (matrices), computation of a broad range of (screened) Coulomb interactions, and evaluation of overlap integrals of arbitrary numbers of Gaussians in arbitrarily high dimensions. For circumstances where the flexibility of GBasis is less important than high performance, a seamless Python interface to the Libcint C package is provided. GBasis is designed to be easy to use, maintain, and extend following many standards of sustainable software development, including code-quality assurance through continuous integration protocols, extensive testing, comprehensive documentation, up-to-date package management, and continuous delivery. This article marks the official release of the GBasis library, outlining its features, examples, and development.

Development and validation of the Work Capital Scale.

Vocational psychologists have called for greater attention to different forms of capital, any resource or asset that confers profit and power, to better understand the vocational development process, particularly for those who lack resources and power. However, previous research has had several conceptual and measurement limitations, such as the use of less inclusive frameworks; a focus on more privileged populations; and the overuse of categorical, dummy coded, and objective measures. To address these limitations, the present study aimed to (a) develop an inclusive, subjective, continuous, and multidimensional work capital scale and (b) validate the new scale with representative samples of working adults and job seekers across two studies. We developed a 16-item four-factor Work Capital Scale that consists of Economic Work Capital, Human Work Capital, Social Work Capital, and Cultural Work Capital. Scores from the Work Capital Scale were invariant across household income, social class, gender, race, and employment status. We found that the correlational model fit best to the data and provided evidence for convergent and divergent validity by relating the subscales to subjective social class, objective socioeconomic indicators, and existing measures of capital. The present study advances theory and research in work capital and provides a tool for practitioners to use. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation.

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

The effects of Pycnogenol, a pine bark extract on pulmonary inflammation by Asian sand dust in mice.

Asian sand dust (ASD), also called China dust or yellow dust, mainly occurs in East Asia during spring and autumn. Because ASD enters the body mainly through the respiratory system, it can cause respiratory disorders or worsen underlying diseases. Because of this, it has become an important health concern that threatens the well-being of humans and animals. In this study, we investigated the effects of 15 and 30 mg/kg of Pycnogenol (PYC15 and 30 groups), a pine bark extract, on ASD-induced pulmonary inflammation in mice. We evaluated the inflammatory cell counts, inflammatory cytokines, and matrix-metalloproteinase (MMP)-9 expression in animal models. PYC administration significantly decreased inflammatory cell infiltration into lung tissue; this was accompanied by a reduction in the levels of proinflammatory mediators including interleukin (IL)-1ß (P < 0.01), IL-6 (P < 0.01) and tumour necrosis factor-α (P < 0.01) in bronchoalveolar lavage fluids of ASD-exposed mice (ASD group). Histological analysis revealed that PYC suppressed ASD-induced pulmonary inflammation. Moreover, PYC suppressed the levels of matrix-metalloproteinase (MMP)-9 in the lung tissue of ASD-exposed mice, indicating that PYC reduced ASD-induced pulmonary inflammation by suppressing MMP-9. Together, these results indicate that PYC as the potential to treat ASD-driven pulmonary inflammation.

Fanpy: A python library for prototyping multideterminant methods in ab initio quantum chemistry.

Fanpy is a free and open-source Python library for developing and testing multideterminant wavefunctions and related ab initio methods in electronic structure theory. The main use of Fanpy is to quickly prototype new methods by making it easier to convert the mathematical formulation of a new wavefunction ansätze to a working implementation. Fanpy is designed based on our recently introduced Flexible Ansatz for N-electron Configuration Interaction (FANCI) framework, where multideterminant wavefunctions are represented by their overlaps with Slater determinants of orthonormal spin-orbitals. In the simplest case, a new wavefunction ansatz can be implemented by simply writing a function for evaluating its overlap with an arbitrary Slater determinant. Fanpy is modular in both implementation and theory: the wavefunction model, the system's Hamiltonian, and the choice of objective function are all independent modules. This modular structure makes it easy for users to mix and match different methods and for developers to quickly explore new ideas. Fanpy is written purely in Python with standard dependencies, making it accessible for various operating systems. In addition, it adheres to principles of modern software development, including comprehensive documentation, extensive testing, quality assurance, and continuous integration and delivery protocols. This article is considered to be the official release notes for the Fanpy library.

Nigrosome 1 visibility and its association with nigrostriatal dopaminergic loss in Parkinson's disease.

BACKGROUND: Nigrosome 1 (NG1), a small cluster of dopaminergic cells in the substantia nigra and visible in the susceptibility map-weighted magnetic resonance image (SMwI), is severely affected in Parkinson's disease (PD). However, the degree of nigrostriatal degeneration according to the visibility of NG1 has not yet been well elucidated. METHODS: We consecutively recruited 138 PD and 78 non-neurodegenerative disease (non-ND) patients, who underwent both 18 F-FP-CIT positron emission tomography (PET) and SMwI. Three neurologists and one radiologist evaluated the visibility of NG1 in SMwI. The participants were thereby grouped into visible, intermediate, and non-visible groups. Nigrostriatal dopaminergic input was calculated using the specific binding ratio (SBR) of the 18 F-FP-CIT PET. We determined the threshold of regional SBR for discriminating NG1 visibility and the probability for NG1 visibility according to regional SBR. RESULTS: Visual rating of NG1 showed excellent interobserver agreements as well as high sensitivity and specificity to differentiate the PD group from the non-ND group. NG1 was visible in seven patients (5.1%) in the PD group, who had relatively short disease duration or less severe loss of striatal dopamine. The threshold of putaminal SBR reduction on the more affected side for the disappearance of NG1 was 45.5%, and the probability for NG1 visibility dropped to 50% after the reduction of putaminal SBR to 41% from the normal mean. CONCLUSIONS: Almost half loss of nigrostriatal dopaminergic input is required to dissipate the hyperintensity of NG1 on SMwI, suggesting its utility in diagnosing PD only after the onset of the motor symptoms.

Multiple chronic lacunes predicting early neurological deterioration and long-term functional outcomes according to TOAST classification in acute ischemic stroke.

INTRODUCTION: Studies regarding multiple chronic lacunes (MCLs) and clinical outcome according to stroke etiology are scarce. We sought to evaluate the association between MCL and short-term/long-term clinical outcomes according to stroke etiology. PATIENTS AND METHODS: We analyzed a prospectively collected stroke registry of acute ischemic stroke patients over 4 years. The enrolled patients were classified as having large artery atherosclerosis (LAA), small vessel occlusion (SVO), cardioembolic (CE) stroke, and other etiology. The early neurological deterioration (END) and favorable outcome at 3 months were assessed. RESULTS: A total of 1070 patients were enrolled. Patients with MCL had significantly more END compared to those without MCL both in total population (adjusted odds ratio (OR), 1.7; 95% confidence interval [CI], 1.1-2.5; p = 0.013*) and in the LAA group (adjusted OR, 2.3; 95% CI, 1.3-4.2, p < 0.006). Patients with MCL had a significantly lower OR for favorable outcome at 3 months compared to those without MCL both in total population (adjusted OR, 0.7; 95% CI, 0.5-1.0, p = 0.035) and in the LAA group (adjusted OR, 0.6; 95% CI, 0.3-1.0, p = 0.043). However, MCL was not associated with END or long-term functional outcome in patients with SVO, CE, or other etiology. CONCLUSIONS: The presence of MCL was an independent predictive factor for END as well as long-term poor functional outcome in acute ischemic stroke patients. These associations were only observed in patients with LAA, not in those with SVO, CE, or other etiology.

Untreated hypertension and prognosis paradox in acute ischemic stroke.

INTRODUCTION: This study is to explore the long-term functional outcome of antihypertensive medication-naïve, untreated hypertension (HTN) patients with acute ischemic stroke compared to those with no prior HTN and those with treated HTN. PATIENTS AND METHODS: We analyzed a prospectively collected stroke registry of all patients with acute ischemic stroke consecutively admitted to Incheon St. Mary's Hospital. Patients who received reperfusion therapy were excluded. Long-term functional outcomes were assessed at a 3-month follow-up visit using the modified Rankin Scale. RESULTS: A total of 1044 patients was enrolled. Compared to patients with no or treated HTN, those with untreated HTN had higher odds for more favorable outcomes (adjusted odds ratio (OR): 1.7 [95% CI: 1.0-2.7, p = 0.050*] and 1.7 [95% CI: 1.0-2.8, p = 0.047*], respectively) when the stroke was large vessel atherosclerosis (LAA)/cardioembolic (CE) with large vessel occlusion/stenosis. However, no such association was observed when there was no large vessel occlusion or stenosis, in total patients, or if the index stroke was related to SVO. In untreated HTN patients with LAA/CE and large vessel occlusion/stenosis compared to patients in the lowest mean arterial pressure quartile (< 96.7 mmHg), patients in the second and third highest quartiles had higher odds of favorable outcomes. CONCLUSIONS: Patients with untreated HTN had significantly more favorable outcomes at 3 months after ischemic stroke compared to those with no or treated HTN when the stroke was LAA/CE with large vessel occlusion/stenosis. Untreated HTN patients also showed an association between higher MAP and favorable outcomes.

Green tea extract ameliorates macrophage-driven emphysematous lesions in chronic obstructive pulmonary disease induced by cigarette smoke condensate.

Chronic obstructive pulmonary disease (COPD) is an important lung disease characterized by complicated symptoms including emphysema. We aimed to explore the mechanisms underlying the protective effect of green tea extract (GTE) on cigarette smoke condensate (CSC)-induced emphysema by demonstrating the reduction of macrophage-induced protease expression through GTE treatment in vivo and in vitro. Mice were intranasally administered 50 mg/kg CSC once a week for 4 weeks, and doses of 100 or 300 mg/kg GTE were administered orally once daily for 4 weeks. GTE significantly reduced macrophage counts in bronchoalveolar lavage fluid and emphysematous lesions in lung tissues in CSC-exposed mice. In addition, GTE suppressed CSC-induced extracellular signal-regulated kinase (ERK)/activator protein (AP)-1 phosphorylation followed by matrix metalloproteinases (MMP)-9 expression as revealed by western blotting, immunohistochemistry, and zymography in CSC-instilled mice. These underlying mechanisms related to reduced protease expression were confirmed in NCI-H292 cells stimulated by CSC. Taken together, GTE effectively inhibits macrophage-driven emphysematous lesions induced by CSC treatment, and these protective effects of GTE are closely related to the ERK/AP-1 signaling pathway, followed by a reduced protease/antiprotease imbalance. These results suggest that GTE can be used as a supplementary agent for the prevention of emphysema progression in COPD patients.