Tuberculous pleural effusion-induced Arg-1+ macrophage polarization contributes to lung cancer progression via autophagy signaling.

BACKGROUND: The association between tuberculous fibrosis and lung cancer development has been reported by some epidemiological and experimental studies; however, its underlying mechanisms remain unclear, and the role of macrophage (MФ) polarization in cancer progression is unknown. The aim of the present study was to investigate the role of M2 Arg-1+ MФ in tuberculous pleurisy-assisted tumorigenicity in vitro and in vivo. METHODS: The interactions between tuberculous pleural effusion (TPE)-induced M2 Arg-1+ MФ and A549 lung cancer cells were evaluated. A murine model injected with cancer cells 2 weeks after Mycobacterium bovis bacillus Calmette-Guérin pleural infection was used to validate the involvement of tuberculous fibrosis to tumor invasion. RESULTS: Increased CXCL9 and CXCL10 levels of TPE induced M2 Arg-1+ MФ polarization of murine bone marrow-derived MФ. TPE-induced M2 Arg-1+ MФ polarization facilitated lung cancer proliferation via autophagy signaling and E-cadherin signaling in vitro. An inhibitor of arginase-1 targeting M2 Arg-1+ MФ both in vitro and in vivo significantly reduced tuberculous fibrosis-induced metastatic potential of lung cancer and decreased autophagy signaling and E-cadherin expression. CONCLUSION: Tuberculous pleural fibrosis induces M2 Arg-1+ polarization, and M2 Arg-1+ MФ contribute to lung cancer metastasis via autophagy and E-cadherin signaling. Therefore, M2 Arg-1+ tumor associated MФ may be a novel therapeutic target for tuberculous fibrosis-induced lung cancer progression.

CK2α-mediated phosphorylation of GRP94 facilitates the metastatic cascade in triple-negative breast cancer.

Distant metastasis is a significant hallmark affecting to the high death rate of patients with triple-negative breast cancer (TNBC). Thus, it is crucial to identify and develop new therapeutic strategies to hinder cancer metastasis. While emerging studies have hinted a pivotal role of glucose-regulated protein 94 (GRP94) in tumorigenesis, the exact biological functions and molecular mechanisms of GRP94 in modulating cancer metastasis remain to be elucidated. Our study demonstrated an increased expression of GRP94 in TNBC correlated with metastatic progression and unfavorable prognosis in patients. Functionally, we identified that GRP94 depletion significantly diminished TNBC tumorigenesis and subsequent lung metastasis. In contrast, GRP94 overexpression exacerbated the invasiveness, migration, and lung metastasis of non-TNBC cells. Mechanistically, we found that casein kinase 2 alpha (CK2α) active in advanced breast cancer phosphorylated GRP94 at a conserved serine 306 (S306) residue. This phosphorylation increased the stability of GRP94 and enhanced its interaction with LRP6, leading to activation of canonical Wnt signaling. From a therapeutic standpoint, we found that benzamidine, a novel CK2α inhibitor, effectively suppressed GRP94 phosphorylation, LRP6 stabilization, and metastasis of TNBC. Our results point to the critical role of CK2α-mediated GRP94 phosphorylation in TNBC metastasis through activation of Wnt signaling, highlighting GRP94 as a therapeutic target to impede TNBC metastasis.

Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones.

High-grade serous ovarian carcinoma (HGSOC) is genetically unstable and characterised by the presence of subclones with distinct genotypes. Intratumoural heterogeneity is linked to recurrence, chemotherapy resistance, and poor prognosis. Here, we use spatial transcriptomics to identify HGSOC subclones and study their association with infiltrating cell populations. Visium spatial transcriptomics reveals multiple tumour subclones with different copy number alterations present within individual tumour sections. These subclones differentially express various ligands and receptors and are predicted to differentially associate with different stromal and immune cell populations. In one sample, CosMx single molecule imaging reveals subclones differentially associating with immune cell populations, fibroblasts, and endothelial cells. Cell-to-cell communication analysis identifies subclone-specific signalling to stromal and immune cells and multiple subclone-specific autocrine loops. Our study highlights the high degree of subclonal heterogeneity in HGSOC and suggests that subclone-specific ligand and receptor expression patterns likely modulate how HGSOC cells interact with their local microenvironment.

Making the Brightest Ones Dim: Maximizing the Photothermal Conversion Efficiency of BODIPY-Based Photothermal Agents.

The successful implementation of photothermal therapy (PTT) in cancer treatment hinges on the development of highly effective photothermal agents (PTAs). Boron dipyrromethene (BODIPY) dyes, being well known for their high brightness and quantum efficiencies, are the antithesis of PTAs. Nonetheless, a systematic exploration of the photophysics and photothermal characteristics of a series of π-extended BODIPY dyes with high absorptivity in the near-infrared (NIR) region has achieved superior photothermal conversion efficiencies (>90%), in both monomeric state and nanoparticles after encapsulation in a biocompatible polyethyleneglycol 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000]. Optimal PTA candidates combine strong NIR absorption provided by extended donor-acceptor conjugation and an optimization of the electronic and steric effects of meso-substituents to maximize photothermal conversion performance. The PTT-optimized meso-CF3-BODIPY, TCF3PEn exhibits exceptional efficacy in inducing cancer cell apoptosis and in vivo tumor ablation using low-power NIR laser irradiation (0.3 W cm-2, 808 nm) as well as excellent biological safety, underscoring its potential for advancing light-induced cancer therapies.

Dihydrostilbenes and flavonoids from whole plants of Jacobaea vulgaris.

The isolation of previously undescribed 12 compounds from the MeOH extract of Jacobaea vulgaris whole plants is disclosed, comprising 11 dihydrostilbenes (1-11) and one flavanone (12), and eight known compounds (six flavonoids, one dihydrostilbene, and one caffeoylquinic acid). Structural elucidation employed spectroscopic methods, including 1D and 2D NMR spectroscopy, HRESIMS, and ECD calculations. Evaluation of the compounds' effects on PCSK9 and LDLR mRNA expression revealed that compounds 1 and 3 downregulated PCSK9 mRNA while increasing LDLR mRNA expression, suggesting potential cholesterol-lowering properties.

In situ single-cell profiling sheds light on IFI27 localisation during SARS-CoV-2 infection.

The utilization of single-cell resolved spatial transcriptomics to delineate immune responses during SARS-CoV-2 infection was able to identify M1 macrophages to have elevated expression of IFI27 in areas of infection.

Emerging potentials of Fe-based nanomaterials for chiral sensing and imaging.

Fe-based nanostructures have possessed promising properties that make it suitable for chiral sensing and imaging applications owing to their ultra-small size, non-toxicity, biocompatibility, excellent photostability, tunable fluorescence, and water solubility. This review summarizes the recent research progress in the field of Fe-based nanostructures and places special emphases on their applications in chiral sensing and imaging. The synthetic strategies to prepare the targeted Fe-based structures were also introduced. The chiral sensing and imaging applications of the nanostructures are discussed in details.

Approaches to improve and adapt maternal mortality estimations in low- and middle-income countries: A scoping review.

BACKGROUND: In the absence of robust vital registration systems, many low- and middle-income countries (LMICs) rely on national surveys or routine surveillance systems to estimate the maternal mortality ratio (MMR). Although the importance of MMR estimates in ending preventable maternal deaths is acknowledged, there is limited research on how different approaches are used and adapted, and how these adaptations function. OBJECTIVES: To assess methods for estimating maternal mortality in LMICs and the rationale for these modifications. SEARCH STRATEGY: A literature search with the terms "maternal death", "surveys" and "low- and middle-income countries" was performed in Medline, Embase, Web of Science, Scopus, CINAHL, APA PsycINFO, ERIC, and IBSS from January 2013 to March 17, 2023. SELECTION CRITERIA: Studies were eligible if their main focus was to compare, adapt, or assess methods to estimate maternal mortality in LMICs. DATA COLLECTION AND ANALYSIS: Titles and abstracts were screened using Rayyan. Relevant articles were independently reviewed by two reviewers against inclusion criteria. Data were extracted on mortality measurement methods, their context, and results. MAIN RESULTS: Nineteen studies were included, focusing on data completeness, subnational estimates, and community involvement. Routinely generated MMR estimates are more complete when multiple data sources are triangulated, including data from public and private health facilities, the community, and local authorities (e.g. vital registration, police reports). For subnational estimates, existing (e.g. the sisterhood method and reproductive-age mortality surveys [RAMOS]) and adapted methods (e.g. RAMOS 4 + 2 and Pictorial Sisterhood Method) provided reliable confidence intervals. Community engagement in data collection increased community awareness of maternal deaths, provided local ownership, and was expected to reduce implementation costs. However, most studies did not include a cost-effectiveness analysis. CONCLUSION: Household surveys with community involvement and RAMOS can be used to increase data validity, improve local awareness of maternal mortality estimates, and reduce costs in LMICs.

Chlorophyll a and novel synthetic derivatives alleviate atopic dermatitis by suppressing Th2 cell differentiation via IL-4 receptor modulation.

Atopic dermatitis (AD) treatment has largely relied on non-specific broad immunosuppressants despite their long-term toxicities until the approval of dupilumab, which blocks IL-4 signaling to target Th2 cell responses. Here, we report the discovery of compound 4aa, a novel compound derived from the structure of chlorophyll a, and the efficacy of chlorophyll a to alleviate AD symptoms by oral administration in human AD patients. 4aa downregulated GATA3 and IL-4 in differentiating Th2 cells by potently blocking IL-4 receptor dimerization. In the murine model, oral administration of 4aa reduced the clinical severity of symptoms and scratching behavior by 76% and 72%, respectively. Notably, the elevated serum levels of Th2 cytokines reduced to levels similar to those in the normal group after oral administration of 4aa. Additionally, the toxicological studies showed favorable safety profiles and good tolerance. In conclusion, 4aa may be applied for novel therapeutic developments for patients with AD.

Preventive Effect of Ecklonia cava Extract on DSS-Induced Colitis by Elevating Intestinal Barrier Function and Improving Pathogenic Inflammation.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a complex gastrointestinal disorder with a multifactorial etiology, including environmental triggers, autoimmune mechanisms, and genetic predisposition. Despite advancements in therapeutic strategies for IBD, its associated mortality rate continues to rise, which is often attributed to unforeseen side effects of conventional treatments. In this context, we explored the potential of Ecklonia cava extract (ECE), derived from an edible marine alga known for its anti-inflammatory and antioxidant properties, in mitigating IBD. This study investigated the effectiveness of ECE as a preventive agent in a murine model of dextran sulfate sodium (DSS)-induced colitis. Our findings revealed that pretreatment with ECE significantly ameliorated colitis severity, as evidenced by increased colon length, reduced spleen weight, and histological improvements demonstrated by immunohistochemical analysis. Furthermore, ECE significantly attenuated the upregulation of inflammatory cytokines and mediators and the infiltration of immune cells known to be prominent features of colitis in mice. Notably, ECE alleviated dysbiosis of intestinal microflora and aided in the recovery of damaged intestinal mucosa. Mechanistically, ECE exhibited protective effects against pathogenic colitis by inhibiting the NLRP3/NF-κB pathways known to be pivotal regulators in the inflammatory signaling cascade. These compelling results suggest that ECE holds promise as a potential candidate for IBD prevention. It might be developed into a functional food for promoting gastrointestinal health. This research sheds light on the preventive potential of natural compounds like ECE in the management of IBD, offering a safer and more effective approach to combating this challenging disease.

Role of School Quality and Neighborhood Disadvantage in Educational Attainment: Do They Vary by Race?

Schools and neighborhoods are adolescents' primary environments, and each has a significant influence on their academic success. The majority of studies on educational attainment have examined the impact of a single context-either the school or the neighborhood-suggesting mixed findings on school and neighborhood effects as well as potential disparities across racial groups. To address this gap, the present study examined the roles of school quality and neighborhood disadvantage on educational attainment for White and Black adolescents. This study used the National Longitudinal Study of Adolescent to Adult Health data collected from a nationally representative sample of U.S. adolescents, merging multiple data sources including in-home surveys, school administrator surveys, student-level educational records, and contextual data. Educational attainment was measured using college enrollment and graduation status. School quality was a significant predictor of college enrollment and graduation for both White and Black adolescents. Neighborhood disadvantage is significantly associated with college enrollment for both racial groups; however, college graduation is significant only for White adolescents. These findings suggest that improving school quality is particularly important for educational attainment regardless of racial background. The article concludes with a discussion on the differential roles of school quality and neighborhood disadvantage in relation to White and Black adolescents.

J-Aggregate-Triggering BODIPYs: an Ultrasensitive Chromogenic and Fluorogenic Sensing Platform for Perfluorooctanesulfonate.

Contamination of water supplies by polyfluoroalkyl substances, notably perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA), has serious health and environmental consequences. Therefore, the development of straightforward and effective means of monitoring and removing PFASs is urgently required. In this study, we report a rapid and sensitive method for the detection of PFOS and PFOA in water that rely on the J-aggregate formation of meso-ester-BODIPY dyes. The dye C10-mim, which contains a hydrophilic methylimidazolium group and a hydrophobic alkylated BODIPY, self-assembles in water into weakly green-emissive micellar assemblies. Upon binding to PFOS or PFOA, a spontaneous disassembly and reorganization forms orange-emissive J-aggregates. The rapid formation (≤5 s) of J-aggregates and the accompanying spectral shifts provide a superior sensing performance, with excellent sensitivity (limit of detection=0.18 ppb for PFOS) and distinct chromogenic and fluorogenic "turn-on" responses.

Stereochemical assignment of clerodane-type diterpenes from the fruits of Casearia grewiifolia and their ability to inhibit PCSK9 expression.

More than 20 natural products have been reported to modulate PCSK9-mediated cholesterol regulation, and small-molecule-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors continue to be developed and identified. Here, twelve undescribed clerodane-type diterpenes (1-9 and 12-14) and two known compounds were isolated from the chloroform-soluble extract of the dried fruits of Casearia grewiifolia Vent. using a PCSK9 mRNA expression monitoring assay. Among the undescribed compounds, the stereochemistry of two diastereomeric grewiifolins A and B (1 and 2) were extensively elucidated using 2D Nuclear Overhauser Effect Spectroscopy (NOESY) experiments, excitation-sculptured indirect detection experiments (EXSIDE), interproton distance analyses, and computational calculations that included quantum chemical shift calculations combined with DP4+ analysis. All isolates were assessed for their inhibitory activity against PCSK9 and IDOL mRNA expression. Among the compounds tested, compound 3 inhibited PCSK9 and IDOL mRNA expression.

miR-429 Suppresses Endometrial Cancer Progression and Drug Resistance via DDX53.

(1) Background: To examine miR-429-meditated DEAD (Asp-Glu-Ala-Asp) box polypeptide 53 (DDX53) function in endometrial cancer (EC). (2) Methods: DDX53 and miR-429 levels were measured using quantitative real-time polymerase chain reaction and western blotting assays, cell invasion and migration using Transwell invasion and wound healing assays, and cell proliferation using colony-forming/proliferation assays. A murine xenograft model was also generated to examine miR-429 and DDX53 functions in vivo. (3) Results: DDX53 overexpression (OE) promoted key cancer phenotypes (proliferation, migration, and invasion) in EC, while in vivo, DDX53 OE hindered tumor growth in the murine xenograft model. Moreover, miR-429 was identified as a novel miRNA-targeting DDX53, which suppressed EC proliferation and invasion. (4) Conclusions: DDX53 and miR-429 regulatory mechanisms could provide novel molecular therapies for EC.

An information theoretic approach to detecting spatially varying genes.

A key step in spatial transcriptomics is identifying genes with spatially varying expression patterns. We adopt an information theoretic perspective to this problem by equating the degree of spatial coherence with the Jensen-Shannon divergence between pairs of nearby cells and pairs of distant cells. To avoid the notoriously difficult problem of estimating information theoretic divergences, we use modern approximation techniques to implement a computationally efficient algorithm designed to scale with in situ spatial transcriptomics technologies. In addition to being highly scalable, we show that our method, which we call maximization of spatial information (Maxspin), improves accuracy across several spatial transcriptomics platforms and a variety of simulations when compared with a variety of state-of-the-art methods. To further demonstrate the method, we generated in situ spatial transcriptomics data in a renal cell carcinoma sample using the CosMx Spatial Molecular Imager and used Maxspin to reveal novel spatial patterns of tumor cell gene expression.

Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease.

Ulcerative colitis and Crohn's disease are chronic inflammatory intestinal diseases with perplexing heterogeneity in disease manifestation and response to treatment. While the molecular basis for this heterogeneity remains uncharacterized, single-cell technologies allow us to explore the transcriptional states within tissues at an unprecedented resolution which could further understanding of these complex diseases. Here, we apply single-cell RNA-sequencing to human inflamed intestine and show that the largest differences among patients are present within the myeloid compartment including macrophages and neutrophils. Using spatial transcriptomics in human tissue at single-cell resolution (CosMx Spatial Molecular Imaging) we spatially localize each of the macrophage and neutrophil subsets identified by single-cell RNA-sequencing and unravel further macrophage diversity based on their tissue localization. Finally, single-cell RNA-sequencing combined with single-cell spatial analysis reveals a strong communication network involving macrophages and inflammatory fibroblasts. Our data sheds light on the cellular complexity of these diseases and points towards the myeloid and stromal compartments as important cellular subsets for understanding patient-to-patient heterogeneity.

Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis.

In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with specific malignant subtypes and neoadjuvant chemotherapy/radiotherapy. We developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid co-culture system. Overall, this study demonstrates that characterization of the tumor microenvironment using high-plex single-cell spatial transcriptomics allows for identification of molecular interactions that may play a role in the emergence of chemoresistance and establishes a translational spatial biology paradigm that can be broadly applied to other malignancies, diseases, and treatments.

Pellino 3 promotes the colitis-associated colorectal cancer through suppression of IRF4-mediated negative regulation of TLR4 signalling.

The incidence of colitis-associated colorectal cancer (CAC) has increased due to a high-nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin-protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING-type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3-deficient mice in an azoxymethane/dextran sulphate sodium-induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll-like receptor 4 (TLR4)-mediated inflammation through ubiquitination-dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation-mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC.

Provider and client perspectives on the use of maternity waiting homes in rural Rwanda.

BACKGROUND: The World Health Organization recommends the implementation of maternity waiting homes (MWH) to reduce delays in access to obstetric care, particularly for high-risk pregnancies and mothers living far from health facilities, and as a result, several countries have rolled out MWHs. However, Rwanda has not implemented this recommendation on a large scale. There is only one MWH in the country, hence a gap in knowledge regarding the potential utilisation and benefits of MWHs. OBJECTIVE: To explore providers' and clients' perspectives on facilitators and barriers to the use of MWH in rural Rwanda. METHODS: We conducted a qualitative study to explore health providers' and clients' perspectives on facilitators and barriers to the use of MWH in Rwanda, between December 2020 and January 2021. We used key informant interviews and focus group discussions to collect data. Data were analysed using NVivo qualitative analysis software version 11. RESULTS: Facilitators included perceptions that the MWH offered either a peaceful and home-like environment, good-quality services, or timely obstetric services, and was associated with good maternal and neonatal outcomes. Barriers included limited awareness of the MWH among pregnant women, fear of health providers to operate the MWH at full capacity, women's lack of autonomy, uncertainty over funding for the MWH, and perceived high user fees. CONCLUSION: The Ruli MWH offers a peaceful environment for pregnant women while providing quality and timely obstetric care, resulting in positive maternal and neonatal outcomes for women. However, its existence and benefits are not widely known, and its use is limited due to inadequate resources. There is a need for increased awareness of the MWH among healthcare providers and the community, and lessons from this MWH could inform the scale up of MWHs in Rwanda.