Stromal mediated DNA damage promotes high grade serous ovarian cancer initiation.

The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear, thus providing critical barriers to the development of prevention or early detection strategies for this deadly disease. Increasing evidence demonstrates most HGSOC starts in the fallopian tube epithelium (FTE). Current models propose HGSOC initiates when FTE cells acquire increasing numbers of mutations allowing cells to evolve into serous tubal intraepithelial carcinoma (STIC) precursors and then to full blown cancer. Here we report that epigenetically altered mesenchymal stem cells (termed high risk MSC-hrMSCs) can be detected prior to the formation of ovarian cancer precursor lesions. These hrMSCs drive DNA damage in the form of DNA double strand breaks in FTE cells while also promoting the survival of FTE cells in the face of DNA damage. Indicating the hrMSC may actually drive cancer initiation, we find hrMSCs induce full malignant transformation of otherwise healthy, primary FTE resulting in metastatic cancer in vivo . Further supporting a role for hrMSCs in cancer initiation in humans, we demonstrate that hrMSCs are highly enriched in BRCA1/2 mutation carriers and increase with age. Combined these findings indicate that hrMSCs may incite ovarian cancer initiation. These findings have important implications for ovarian cancer detection and prevention.

Latent class analysis of emotions experienced during compulsive hair-pulling episodes.

BACKGROUND AND OBJECTIVES: Reasons for compulsive hair pulling are heterogeneous and not fully understood. Given that many people who experience compulsive hair pulling do not respond to treatment, identifying subgroups can inform potential mechanisms and treatment design. METHODS: We sought to identify empirical subgroups among participants in an online treatment program for trichotillomania (N = 1728). A latent class analysis was used to identify patterns of emotions associated with compulsive hair-pulling episodes. RESULTS: Six classes of participants were found which reflected three predominant themes. One theme reflected expected patterns, where emotional changes were seen following pulling. Two other themes were more surprising, where one reflected high overall emotional activation that did not show consistent change in response to pulling, and another showed low emotional activation overall. These results suggest that there are multiple types of hair-pulling and a sizeable group of people may benefit from treatment adjustments. LIMITATIONS: Participants did not receive semi-structured diagnostic assessment. A majority of participants were Caucasian, and future research would benefit from increased participant diversity. Emotions associated with compulsive hair-pulling were measured across an entire treatment program, but the relationship between specific intervention components and change in specific emotions was not systematically collected. CONCLUSIONS: While previous research has addressed overall phenomenology and comorbidity, the present study is the first to identify empirical subgroups of people who experience compulsive hair-pulling at the level of individual pulling episodes. Identified participant classes had distinguishing features that can aid in personalizing treatment to individual symptom presentations.

Effect of Dietary Berry Supplementation on Antioxidant Biomarkers in Adults with Cardiometabolic Risks: A Systematic Review of Clinical Trials.

Cardiometabolic conditions are closely associated with inflammation and oxidative stress. Dietary berries may serve as a beneficial nutrition intervention to address the features of cardiometabolic dysfunction and associated oxidative stress. The high antioxidant status of dietary berries may increase antioxidant capacity and reduce biomarkers of oxidative stress. This systematic review was conducted to investigate these effects of dietary berries. The search was conducted using PubMed, Cochrane Library, Web of Science, and citation searching. Through this search we identified 6309 articles and 54 were included in the review. Each study's risk of bias was assessed using the 2019 Cochrane Methods' Risk of Bias 2 tool. Antioxidant and oxidative stress outcomes were evaluated, and the magnitude of effect was calculated using Cohen's d. A range of effectiveness was reported in the included studies and the quality of the studies differed between the parallel and crossover trials. Considering the inconsistency in reported effectiveness, future investigations are warranted to determine the acute and sustained reductions of oxidative stress biomarkers from dietary berry intake (PROSPERO registration# CRD42022374654).

Indwelling Pleural Catheter: Management of Complications.

Multiple randomized clinical trials have established the advantages of indwelling pleural catheter (IPC) in the management of malignant pleural effusions, resulting in its widespread adoption in clinical practice. Complications can occur with IPC use and must be recognized and managed effectively. This review provides a comprehensive overview of IPC complications and their best care. Pain postinsertion or during drainage of IPC is easily manageable and must be distinguished from tumor-related chest wall pain. IPC-related infections require systemic antibiotics and often intrapleural fibrinolytic/deoxyribonuclease therapy. The removal of IPC for infection is usually unnecessary. Symptomatic loculation usually responds to fibrinolytics but may recur. Catheter tract metastases are common in mesothelioma patients and usually respond to radiotherapy without inducing damages to the IPC. Less common complications include dislodgement, irreversible blockage, and fractures (upon removal) of the catheter. Recommendations on the management of IPC complications by recent consensus statement/guideline are discussed. Expert opinions on management approaches are included in areas where evidence is lacking to guide care.

Development of GTP-responsive liposomes by exchanging the metal-DPA binding site in a synthetic lipid switch.

We report stimuli-responsive liposomes that selectively release encapsulated contents upon treatment with guanosine triphosphate (GTP) over a wide variety of phosphorylated metabolites, validated by fluorescence-based leakage assays. Significant changes in liposome self-assembly properties were also observed. Our results showcase the potential of this platform for triggered release applications.

Cardiovascular outcomes in obstructive sleep apnoea and implications of clinical phenotyping on effect of CPAP treatment.

BACKGROUND: There is a growing awareness of the heterogeneity of obstructive sleep apnoea (OSA). Clinical trials of CPAP treatment on cardiovascular protection have been mostly negative. We aimed to assess the association between polysomnographic parameters and incident major adverse cardiovascular events (MACEs), and to investigate if the CPAP effect could be better delineated among clinical subgroups. METHODS: This sleep cohort study was conducted using a clinical database and territory-wide electronic health administration data in Hong Kong. Cox regressions were used to calculate HRs. Latent class analysis was used to cluster patients with OSA according to clinical and polysomnographic features. RESULTS: Of 1860 eligible Chinese subjects who underwent polysomnography (2006-2013), 1544 (83%) had OSA. Over median follow-up of 8.3 years, 278 (14.9%) experienced MACEs. Apnoea-hypopnoea index (AHI) did not predict MACEs (HR: 0.95; 95% CI 0.76 to 1.17), whereas sleep time with oxygen saturation <90% (TST90) (HR: 1.41; 95% CI 1.10 to 1.81) was an independent predictor of MACEs, as were wake and nocturnal heart rate. In moderate-severe OSA (n=1108) who were indicated for CPAP treatment, regular CPAP was not associated with reduction of incident MACEs. Further cluster analysis identified a subgroup (n=333) who was younger, more obese, had more severe OSA (higher AHI and TST90) and more cardiovascular risks, in whom regular CPAP was associated with a lower risk of MACEs (HR:0.49, 95% CI 0.25 to 0.95). CONCLUSIONS: OSA-related TST90 and mean heart rate, but not AHI, were robust predictors of MACEs. A clinical phenotype subgroup who demonstrated beneficial effect of CPAP treatment was identified.

Spindly is a nucleocytosolic O-fucosyltransferase in Dictyostelium and related proteins are widespread in protists and bacteria.

O-GlcNAcylation is a prominent modification of nuclear and cytoplasmic proteins in animals and plants and is mediated by a single O-GlcNAc transferase (OGT). Spindly (Spy), a paralog of OGT first discovered in higher plants, has an ortholog in the apicomplexan parasite Toxoplasma gondii, and both enzymes are now recognized as O-fucosyltransferases (OFTs). Here we investigate the evolution of spy-like genes and experimentally confirm OFT activity in the social amoeba Dictyostelium-a protist that is more related to fungi and metazoa. Immunofluorescence probing with the fucose-specific Aleuria aurantia lectin (AAL) and biochemical cell fractionation combined with western blotting suggested the occurrence of nucleocytoplasmic fucosylation. The absence of reactivity in mutants deleted in spy or gmd (unable to synthesize GDP-Fuc) suggested monofucosylation mediated by Spy. Genetic ablation of the modE locus, previously predicted to encode a GDP-fucose transporter, confirmed its necessity for fucosylation in the secretory pathway but not for the nucleocytoplasmic proteins. Affinity capture of these proteins combined with mass spectrometry confirmed monofucosylation of Ser and Thr residues of several known nucleocytoplasmic proteins. As in Toxoplasma, the Spy OFT was required for optimal proliferation of Dictyostelium under laboratory conditions. These findings support a new phylogenetic analysis of OGT and OFT evolution that indicates their occurrence in the last eukaryotic common ancestor but mostly complementary presence in its eukaryotic descendants with the notable exception that both occur in red algae and plants. Their generally exclusive expression, high degree of conservation, and shared monoglycosylation targets suggest overlapping roles in physiological regulation.

Nutrition-Education-Based Interventions in Gestational Diabetes: A Scoping Review of Clinical Trials.

Cases of diabetes mellitus have seen a global increase in prevalence, but there are inherent differences in the pathology and management of different types of diabetes. Type 2 and gestational diabetes have the most similar pathophysiology. For that reason, many similar management strategies exist between type 2 and gestational diabetes, including nutrition-based interventions. Diabetes self-management education and medical nutrition therapy have been advanced as cost-effective interventions to manage hyperglycemia. Many of these interventions, however, were designed for type 2 diabetes and adapted for diabetes in gestation. Nutrition-education-based interventions in gestational diabetes have not been fully elucidated. We scrutinized this gap by conducting a scoping review of recently published peer-reviewed studies that evaluated clinical endpoints in cases of gestational diabetes with nutrition-education-based interventions. The search yielded 621 articles, and the 12 articles included were published between 2012 and 2022. The nutrition information varied across the heterogeneous diabetes self-management education, whereas the medical nutrition therapy studies were more consistent. Our literature search revealed similar outcomes across self-management education and medical nutrition therapy interventions implemented during the third trimester of pregnancies with diabetes. These results suggest that both generalized and personalized approaches to nutrition education in gestational diabetes can manage hyperglycemia and offset its adverse consequences.

Implementation of evidence on management of pleural diseases: insights from a territory-wide survey of clinicians in Hong Kong.

BACKGROUND: Major advances in management of common pleural diseases have taken place in the past decade. However, pleural diseases are often managed by physicians of diverse training background and research on implementation of new knowledge is scanty. We aim to evaluate the practice pattern in pleural medicine among physicians in Hong Kong, for identification of possible gaps for clinical service improvement. METHODS: The Hong Kong Thoracic Society undertook a cross-sectional questionnaire survey in 2019, targeting clinicians of various subspecialties in internal medicine and levels of experience (basic and higher trainees, specialists) from twelve regional hospitals of diverse service scopes throughout Hong Kong. Respondents were selected by non-probability quota sampling. The questionnaire tool consisted of 46 questions covering diagnostic and therapeutic aspects of common pleural diseases. The responses were anonymous, and analysed independently using SPSS statistics software. RESULTS: The survey collected 129 responses, 47(36%) were from clinicians specialized in respiratory medicine. Majority of the respondents (98%) managed pleural diseases, including performing pleural procedures in their practice. Fifty-five percent of all the respondents had not received any formal training in transthoracic ultrasonography. A significant proportion of clinicians were unaware of pleuroscopy for investigation of exudative pleural effusion, indwelling pleural catheter for recurrent malignant pleural effusion, and combined intra-pleural Alteplase plus DNase for treatment of pleural infection (30%, 15% and 70% of non-respiratory clinicians respectively). Significant heterogeneity was found in the management of pleural infection, malignant pleural effusion and pneumothorax among respiratory versus non-respiratory clinicians. Contributing factors to the observed heterogeneity included lack of awareness or training, limited accessibility of drugs, devices, or dedicated service support. CONCLUSION: Significant heterogeneity in management of pleural diseases was observed among medical clinicians in Hong Kong. Continuous medical education and training provision for both specialists and non-specialists has to be strengthened to enhance the implementation of advances, improve quality and equity of healthcare provision in pleural medicine.

Iron-Based Magnetic Nanosystems for Diagnostic Imaging and Drug Delivery: Towards Transformative Biomedical Applications.

The advancement of biomedicine in a socioeconomically sustainable manner while achieving efficient patient-care is imperative to the health and well-being of society. Magnetic systems consisting of iron based nanosized components have gained prominence among researchers in a multitude of biomedical applications. This review focuses on recent trends in the areas of diagnostic imaging and drug delivery that have benefited from iron-incorporated nanosystems, especially in cancer treatment, diagnosis and wound care applications. Discussion on imaging will emphasise on developments in MRI technology and hyperthermia based diagnosis, while advanced material synthesis and targeted, triggered transport will be the focus for drug delivery. Insights onto the challenges in transforming these technologies into day-to-day applications will also be explored with perceptions onto potential for patient-centred healthcare.

Biomaterials-Enabled Antithrombotics: Recent Advances and Emerging Strategies.

Antithrombotic and thrombolytic therapies are used to prevent, treat, and remove blood clots in various clinical settings, from emergent to prophylactic. While ubiquitous in their healthcare application, short half-lives, off-target effects, overdosing complications, and patient compliance continue to be major liabilities to the utility of these agents. Biomaterials-enabled strategies have the potential to comprehensively address these limitations by creating technologies that are more precise, durable, and safe in their antithrombotic action. In this review, we discuss the state of the art in anticoagulant and thrombolytic biomaterials, covering the nano to macro length scales. We emphasize current methods of formulation, discuss how material properties affect controlled release kinetics, and summarize modern mechanisms of clot-specific drug targeting. The preclinical efficacy of these technologies in an array of cardiovascular applications, including stroke, pulmonary embolism, myocardial infarction, and blood contacting devices, is summarized and performance contrasted. While significant advances have already been made, ongoing development efforts look to deliver bioresponsive "smart" biomaterials that will open new precision medicine opportunities in cardiology.

Solvent Anions Enable Photoinduced Borylation and Phosphonation of Aryl Halides via EDA Complexes.

We report the synthesis of aryl boronic esters and aryl phosphonate esters promoted by visible-light in the absence of transition-metals or photoredox catalysts. The transformation proceeds at room temperature using sodium hydride, as a non-nucleophilic base, and exhibits functional group tolerance for anilines, amides, and esters. UV-vis spectroscopy, radical trapping experiments, and computational (TD-DFT) calculations suggest an electron-donor-acceptor (EDA) complex between solvent anions and aryl halides as the species responsible for this reactivity.

Reactive Oxygen Species (ROS) Activated Liposomal Cell Delivery using a Boronate-Caged Guanidine Lipid.

We report boronate-caged guanidine-lipid 1 that activates liposomes for cellular delivery only upon uncaging of this compound by reactive oxygen species (ROS) to produce cationic lipid products. These liposomes are designed to mimic the exceptional cell delivery properties of cell-penetrating peptides (CPPs), while the inclusion of the boronate cage is designed to enhance selectivity such that cell entry will only be activated in the presence of ROS. Boronate uncaging by hydrogen peroxide was verified by mass spectrometry and zeta potential (ZP) measurements. A microplate-based fluorescence assay was developed to study the ROS-mediated vesicle interactions between 1-liposomes and anionic membranes, which were further elucidated via dynamic light scattering (DLS) analysis. Cellular delivery studies utilizing fluorescence microscopy demonstrated significant enhancements in cellular delivery only when 1-liposomes were incubated with hydrogen peroxide. Our results showcase that lipid 1 exhibits strong potential as an ROS-responsive liposomal platform for targeted drug delivery applications.

Glyco-nanotechnology: A biomedical perspective.

Glycans govern cellular signaling through glycan-protein and glycan-glycan crosstalk. Disruption in the crosstalk initiates 'rogue' signaling and pathology. Nanomaterials supply platforms for multivalent displays of glycans, mediate 'rogue' signal correction, and provide disease treatment modalities (therapeutics). The decorated glycans also target overexpressed lectins on unhealthy cells and direct metal nanoparticles such as gold, iron oxide, and quantum dots to the site of infection. The nanoparticles inform us about the state of the disease (diagnosis) through their distinct optical, magnetic, and electronic properties. Glyco-nanoparticles can sense disease biomarkers, report changes in protein-glycan interactions, and safeguard quality control (analysis). Here we review the current state of glyco-nanotechnology focusing on diagnosis, therapeutics, and analysis of human diseases. We highlight how glyco-nanotechnology could aid in improving diagnostic methods for the detection of disease biomarkers with magnetic resonance imaging (MRI) and fluorescence imaging (FLI), enhance therapeutics such as anti-adhesive treatment of cancer and vaccines against pneumonia, and advance analysis such as the rapid detection of pharmaceutical heparin contaminant and recombinant SARS-COV-2 spike protein. We illustrate these progressions and outline future potentials of glyco-nanotechnology in advancing human health.

Transition-Metal-Free Photoredox Phosphonation of Aryl C-N and C-X Bonds in Aqueous Solvent Mixtures.

Herein, we present an efficient and mild methodology for the synthesis of aromatic phosphonate esters in good to excellent yields using 10H-phenothiazine, an inexpensive commodity chemical, as a photoredox catalyst. The reaction exhibits wide functional group compatibility enabling the transformation in the presence of ketone, amide, ester, amine, and alcohol moieties. Importantly, the reaction proceeds using a green solvent mixture primarily composed of water, thus lowering the environmental footprint of this transformation compared to current methods. The transformation also proceeds under atmospheric conditions, which further differentiates it from current methods that require inert atmosphere. Mechanistic work using fluorescence quenching experiments and radical trapping approaches support the proposed mechanism.

Naxitamab: a humanized anti-glycolipid disialoganglioside (anti-GD2) monoclonal antibody for treatment of neuroblastoma.

Therapy for high-risk neuroblastoma (HR NBL) is comprised of multimodal therapy including chemotherapy, surgery, radiation therapy, myeloablative therapy followed by autologous hematopoietic stem cell transplant, and immunotherapy. GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells, with limited expression on normal tissues, which makes it an attractive target for immunologic therapy. The combination of immunotherapy with murine and chimeric anti-GD2 antibody formulations has improved outcomes compared with standard therapy in HR NBL patients. Naxitamab (Danyelza), a fully humanized anti-GD2 antibody, was developed at Memorial Sloan Kettering Cancer Center (MSKCC) to mitigate adverse reactions related to intolerance of foreign murine and chimeric antigens. Phase I and II studies demonstrating the tolerability and efficacy of naxitamab in patients with relapsed/refractory (r/r) HR NBL prompted its approval by the U.S. Food and Drug Administration (FDA) in 2020 for HR NBL with bone or bone marrow involvement. Initial outcomes with naxitamab are encouraging; however, future trials to maximize drug tolerance and elucidate its optimal role in neuroblastoma therapy in conjunction with other treatment strategies are needed. This review discusses the use of naxitamab in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of r/r HR NBL.

Single Cell and Plasma RNA Sequencing for RNA Liquid Biopsy for Hepatocellular Carcinoma.

BACKGROUND: Human plasma contains RNA transcripts released by multiple cell types within the body. Single-cell transcriptomic analysis allows the cellular origin of circulating RNA molecules to be elucidated at high resolution and has been successfully utilized in the pregnancy context. We explored the application of a similar approach to develop plasma RNA markers for cancer detection. METHODS: Single-cell RNA sequencing was performed to decipher transcriptomic profiles of single cells from hepatocellular carcinoma (HCC) samples. Cell-type-specific transcripts were identified and used for deducing the cell-type-specific gene signature (CELSIG) scores of plasma RNA from patients with and without HCC. RESULTS: Six major cell clusters were identified, including hepatocyte-like, cholangiocyte-like, myofibroblast, endothelial, lymphoid, and myeloid cell clusters based on 4 HCC tumor tissues as well as their paired adjacent nontumoral tissues. The CELSIG score of hepatocyte-like cells was significantly increased in preoperative plasma RNA samples of patients with HCC (n = 14) compared with non-HCC participants (n = 49). The CELSIG score of hepatocyte-like cells declined in plasma RNA samples of patients with HCC within 3 days after tumor resection. Compared with the discriminating power between patients with and without HCC using the abundance of ALB transcript in plasma [area under curve (AUC) 0.72)], an improved performance (AUC: 0.84) was observed using the CELSIG score. The hepatocyte-specific transcript markers in plasma RNA were further validated by ddPCR assays. The CELSIG scores of hepatocyte-like cell and cholangiocyte trended with patients' survival. CONCLUSIONS: The combination of single-cell transcriptomic analysis and plasma RNA sequencing represents an approach for the development of new noninvasive cancer markers.

Impact of Nutrition-Based Interventions on Athletic Performance during Menstrual Cycle Phases: A Review.

Despite the steady increase in female participation in sport over the last two decades, comprehensive research on interventions attenuating the influence of female menstrual physiology on performance remains scarce. Studies involving eumenorrheic women often only test in one menstrual phase to limit sex hormone variance, which may restrict the application of these findings to the rest of the menstrual cycle. The impacts of nutrition-based interventions on athletic performance throughout the menstrual cycle have not been fully elucidated. We addressed this gap by conducting a focused critical review of clinical studies that reported athletic outcomes as well as menstrual status for healthy eumenorrheic female participants. In total, 1443 articles were identified, and 23 articles were included. These articles were published between 2011 and 2021, and were retrieved from Google Scholar, Medline, and PubMed. Our literature search revealed that hydration-, micronutrient-, and phytochemical-based interventions can improve athletic performance (measured by aerobic capacity, anaerobic power, and strength performance) or attenuate exercise-induced damage (measured by dehydration biomarkers, muscle soreness, and bone resorption biomarkers). Most performance trials, however, only assessed these interventions in one menstrual phase, limiting the application throughout the entire menstrual cycle. Improvements in athletic performance through nutrition-based interventions may be contingent upon female sex hormone variation in eumenorrheic women.