"Clicking" trimeric peptides onto hybrid T8POSS nanocages and identifying synthesis limitations.

Macromolecule branching upon polyhedral oligomeric silsesquioxanes (POSS) via "click" chemistry has previously been reported for promoting natural biological responses in vitro, particularly when regarding their demonstrated biocompatibility and structural robustness as potential macromolecule anchoring points. However, "clicking" of large molecules around POSS structures uncovers two main challenges: (1) a synthetic challenge encompassing multi-covalent attachment of macromolecules to a single nanoscale-central position, and (2) purification and separation of fully adorned nanocages from those that are incomplete due to their similar physical characteristics. Here we present peptide decoration to a T8POSS nanocage through the attachment of azido-modified trimers. Triglycine- and trialanine-methyl esters "clicked" to 97% and 92% completion, respectively, resulting in 84% and 68% yields of the fully-adorned octamers. The "clicks" halt within 27-h of the reaction time, and efforts to further increase the octamer yield were of negligible benefit. Exploration of reaction conditions reveals multiple factors preventing full octa-arm modification to all available POSS nanocages, and offers insights into macromolecule attachment between both peptides and small inorganic-organic structures, all of which require consideration for future work of this nature.

Dietary intake, obesity, and physical activity in association with biliary tract cancer risk: Results from meta-analyses of individual-level data from prospective cohort studies of 723,326 adults.

Biliary tract cancer (BTC) is a rare and aggressive malignancy with increasing incidence. Most BTC cases are diagnosed with metastatic disease which carries a 5-year survival rate of <5%. Physical activity, diet, and obesity might be associated with BTC risk, but studies have been limited particularly in African descendants. We addressed this knowledge gap by evaluating associations of BTC risk with obesity, physical activity, and dietary intakes in 723,326 adult participants in four cohort studies conducted in China, the United Kingdom, and the United States. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) in each cohort; results were combined using meta-analysis. All cohorts had ≥11 median follow-up years with 839 incident BTC cases combined. BTC risk was positively associated with body mass index (BMI) and waist-to-hip ratio (WHR) whereas physical activity, fruit intake, and fish intake were inversely associated. HR and (95% CI) comparing BMI >35.0 to 18.5-24.9: 1.71 (1.26, 2.31), p-trend <.0001; comparing BMI-adjusted WHR top to bottom quartile: 1.20 (0.94, 1.53), p-trend = .05; comparing ≥15-0 metabolic equivalent task-hours/week 0.76 (0.61, 0.94), p-trend = .009; comparing highest to lowest intake tertile for fruit and fish 0.79 (0.66, 0.95), p-trend = .01; 0.82 (0.68, 0.98), p-trend = .04, respectively. Associations were, in general, similar across ancestry groups. Our study provides strong evidence for important roles of obesity, diet, and physical activity in BTC etiology and stresses the need for lifestyle modification to combat the rising incidence of this fatal malignancy.

Expression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response.

Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

Utility of methylated DNA markers for the diagnosis of malignant biliary strictures.

BACKGROUND AND AIMS: Early identification of malignant biliary strictures (MBSs) is challenging, with up to 20% classified as indeterminants after preliminary testing and tissue sampling with endoscopic retrograde cholangiopancreatography. We aimed to evaluate the use of methylated DNA markers (MDMs) from biliary brushings to enhance MBS detection in a prospective cohort. APPROACH: Candidate MDMs were evaluated for their utility in MBS diagnosis through a series of discovery and validation phases. DNA was extracted from biliary brushing samples, quantified, bisulfite-converted, and then subjected to methylation-specific droplet digital polymerase chain reaction.  Patients were considered to have no malignancy if the sampling was negative and there was no evidence of malignancy after 1 year or definitive negative surgical histopathology. RESULTS: Fourteen candidate MDMs were evaluated in the discovery phase, with top-performing and new markers evaluated in the technical validation phase. The top 4 MDMs were TWIST1, HOXA1, VSTM2B, and CLEC11A, which individually achieved AUC values of 0.82, 0.81, 0.83, and 0.78, respectively, with sensitivities of 59.4%, 53.1%, 62.5%, and 50.0%, respectively, at high specificities for malignancy of 95.2%-95.3% for the final biologic validation phase. When combined as a panel, the AUC was 0.86, achieving 73.4% sensitivity and 92.9% specificity, which outperformed cytology and fluorescence in situ hybridization (FISH). CONCLUSIONS: The selected MDMs demonstrated improved performance characteristics for the detection of MBS compared to cytology and FISH. Therefore, MDMs should be considered viable candidates for inclusion in diagnostic testing algorithms.

Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma.

Background & Aims: Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA. Methods: Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case-control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels. Results: Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA. Conclusions: The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis. Impact and implications: Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.

Effect of Sustainably Sourced Protein Consumption on Nutrient Intake and Gut Health in Older Adults: A Systematic Review.

Diet is integral to the healthy ageing process and certain diets can mitigate prolonged and deleterious inflammation. This review aims to assess the impact of diets high in sustainably sourced proteins on nutrient intake, gut, and age-related health in older adults. A systematic search of the literature was conducted on 5 September 2023 across multiple databases and sources. Studies assessing sustainably sourced protein consumption in community dwelling older adults (≥65 years) were included. Risk of bias (RoB) was assessed using 'RoB 2.0' and 'ROBINS-E'. Narrative synthesis was performed due to heterogeneity of studies. Twelve studies involving 12,166 older adults were included. Nine studies (n = 10,391) assessed habitual dietary intake and had some RoB concerns, whilst three studies (n = 1812), two with low and one with high RoB, conducted plant-based dietary interventions. Increased adherence to sustainably sourced diets was associated with improved gut microbial factors (n = 4640), healthier food group intake (n = 2142), and increased fibre and vegetable protein intake (n = 1078). Sustainably sourced diets positively impacted on gut microbiota and healthier intake of food groups, although effects on inflammatory outcomes and health status were inconclusive. Future research should focus on dietary interventions combining sustainable proteins and fibre to evaluate gut barrier function and consider inflammatory and body composition outcomes in older adults.

Valuing the health benefits of nature-based recreational physical activity in England.

Physical activity (PA) reduces the risk of several non-communicable diseases (NCDs). Natural environments support recreational PA. Using data including a representative cross-sectional survey of the English population, we estimated the annual value of nature-based PA conducted in England in 2019 in terms of avoided healthcare and societal costs of disease. Population-representative data from the Monitor of Engagement with the Natural Environment (MENE) survey (n = 47,580; representing 44,386,756) were used to estimate the weekly volume of nature-based recreational PA by adults in England in 2019. We used epidemiological dose-response data to calculate incident cases of six NCDs (ischaemic heart disease (IHD), ischaemic stroke (IS), type 2 diabetes (T2D), colon cancer (CC), breast cancer (BC) and major depressive disorder (MDD)) prevented through nature-based PA, and estimated associated savings using published costs of healthcare, informal care and productivity losses. We investigated additional savings resulting from hypothetical increases in: (a) visitor PA and (b) visitor numbers. In 2019, 22million adults > 16 years of age in England visited natural environments at least weekly. At reported volumes of nature-based PA, we estimated that 550 cases of IHD, 168 cases of IS, 1,410 cases of T2D, 41 cases of CC, 37 cases of BC and 10,552 cases of MDD were prevented, creating annual savings of £108.7million (95 % uncertainty interval: £70.3million; £150.3million). Nature-based recreational PA in England results in reduced burden of disease and considerable annual savings through prevention of priority NCDs. Strategies that increase nature-based PA could lead to further reductions in the societal burden of NCDs.

Trends in the Use and Discussion of Race in Pediatrics Articles Over 75 Years.

BACKGROUND AND OBJECTIVES: Race-based medicine, which falsely assumes that race is biological, is common in the published medical literature. We analyzed trends in the use of race in Pediatrics articles over a 75-year period. METHODS: We analyzed a random sample of 50 original research articles published each decade in Pediatrics from 1948 to 2022. RESULTS: Of 375 articles, 39% (n = 147) included race. Among articles, 85% (n = 116) used race only to describe study subjects, 7% (n = 9) described race as a social construct, and 11% (n = 15) described race as a biological construct. Only 7% (n = 10) of studies provided a reason for including race. Statements reflective of racial bias or discrimination were identified in 22% (n = 30) of the articles that mentioned race. Although statements concerning for explicit racial bias were uncommon, with none identified in the most recent decade, statements suggestive of implicit racial bias still occurred (22%, 5 of 23). Race was presented as a dichotomy, such as "white/nonwhite," in 9% of studies (n = 12). Regarding currently nonrecommended terminology, the term "minorities" was used in 13% of studies (n = 18); 25% of studies used the term "others" (n = 34), and among these, 91% (n = 31 of 34) did not provide any definition, an occurrence that increased over time at a rate of 0.9%/year. CONCLUSIONS: Although there has been improvement over the past 75 years in the reporting of race in published studies in Pediatrics, significant opportunities for further improvement remain.

A review of the mesotheliogenic potency of cleavage fragments found in talc.

It has long been recognized that amphibole minerals, such as cleavage fragments of tremolite and anthophyllite, may exist in some talc deposits. We reviewed the current state of the science regarding the factors influencing mesotheliogenic potency of cleavage fragments, with emphasis on those that may co-occur in talc deposits, including dimensional and structural characteristics, animal toxicology, and the most well-studied cohort exposed to talc-associated cleavage fragments. Based on our review, multiple lines of scientific evidence demonstrate that inhaled cleavage fragments associated with talc do not pose a mesothelioma hazard.

Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts.

Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

Conceptualizing Sexual Wellbeing: A Qualitative Investigation to Inform Development of a Measure (Natsal-SW).

Despite increasing scientific and policy interest in sexual wellbeing, it remains poorly conceptualized. Many studies purporting to measure it instead measure related but distinct concepts, such as sexual satisfaction. This lack of conceptual clarity impedes understanding, measuring, and improving sexual wellbeing. We present qualitative research from multi-stage, mixed-methods work to develop a new measure of sexual wellbeing (Natsal-SW) for the fourth British National Survey of Sexual Attitudes & Lifestyles. Literature review and discussion generated a conceptual framework with seven proposed domains: respect, self-esteem, comfort, self-determination, safety and security, forgiveness, and resilience. Semi-structured interviews with 40 adults aged 18-64 then explored whether and how these domains aligned with participants' own understandings, experiences, and language of sexual wellbeing. Data were analyzed thematically. Participants conceptualized sexual wellbeing as distinct from sexual satisfaction and sexual health and as multidimensional, dynamic, and socially and structurally influenced. All seven proposed domains resonated with accounts of sexual wellbeing as a general construct. The personal salience of different domains and their dimensions varied between individuals (especially by gender and sexual orientation) and fluctuated individually over time. This study clarifies dimensions of domains that participants considered important, providing an empirical basis to inform development of a new measure of sexual wellbeing.

Synthesis and Derivatives of Beryllium Triflate.

Various pathways for the synthesis of beryllium triflate were investigated. The reaction of triflic acid or trimethylsilyl triflate with beryllium metal in liquid ammonia led to the formation of mono-, di-, and tetra-nuclear beryllium ammine complexes. Utilization of SMe2 as a solvent gave homoleptic Be(OTf)2. Various beryllium triflate complexes with N- and O-donor ligands as well as the complex anions [Be(OTf)4]2- and [Be2(OTf)6]2- were synthesized to evaluate the reactivity and solution properties of beryllium triflate. This showed that OTf- is not a weakly coordinating anion for Be2+ cations and that it exhibits good bridging properties.

Mono-Ortho-Beryllated Carbodiphosphoranes: Synthesis, Structure, Bonding and Reactivity.

The reaction of organoberyllium compounds with hexaphenylcarbodiphosphorane yields mono-ortho-beryllated complexes, which feature a double dative Be=C bond. The bonding situation in these compounds together with a simple carbodiphosphorane and an N-heterocyclic carbene adduct was analysed with energy decomposition analysis in combination with natural orbital for chemical valence as well as with quantum theory of atoms-in-molecules. Furthermore, the driving forces accountable for mono-ortho-beryllation were elucidated along with the reactivity of the Be=C bond.

Considerations for the development of guidance on dose level selection for developmental and reproductive toxicity studies.

In 2022, the European Chemicals Agency issued advice on the selection of high dose levels for developmental and reproductive toxicity (DART) studies indicating that the highest dose tested should aim to induce clear evidence of reproductive toxicity without excessive toxicity and severe suffering in parental animals. In addition, a recent publication advocated that a 10% decrease in body weight gain should be replaced with a 10% decrease in bodyweight as a criterion for dose adequacy. Experts from the European Centre for Ecotoxicology and Toxicology of Chemicals evaluated these recent developments and their potential impact on study outcomes and interpretation and identified that the advice was not aligned with OECD test guidelines or with humane endpoints guidance. Furthermore, data analysis from DART studies indicated that a 10% decrease in maternal body weight during gestation equates to a 25% decrease in body weight gain, which differs from the consensus of experts at a 2010 ILSI/HESI workshop. Dose selection should be based on a biological approach that considers a range of other factors. Excessive dose levels that cause frank toxicity and overwhelm homeostasis should be avoided as they can give rise to effects that are not relevant to human health assessments.

Terahertz Vibrational Dynamics and DFT Calculations for the Quantum Spin Chain Linarite, PbCuSO4(OH)2.

The low-dimensional quantum-magnet, linarite, PbCuS4(OH)2, has been investigated using terahertz (THz) spectroscopy coupled with detailed density functional theory (DFT) calculations in order to explore the effects of the temperature on its lattice vibrations. Linarite is characterized by largely isolated CuO chains propagating along the crystallographic b-axis, which at very low temperatures are responsible for exotic, quasi-1D magnetism in this material. To better understand the synergy between the structural bonds and lattice oscillations that contribute to these chains, polarized THz spectroscopic measurements were performed. Consolidating these results with detailed DFT calculations has revealed that the anisotropic vibrational motion for the THz modes is correlated with extreme motion associated with the crystallographic b-axis. An unexpected feature observed in the infrared spectrum is attributed to subtle lattice distortions which break the centro-symmetry in linarite at high temperatures. This phenomenon has not previously been observed in linarite and likely results from anharmonicity in lattice oscillations.

The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance: a single-arm pilot study.

BACKGROUND: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. METHODS: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. RESULTS: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. CONCLUSIONS: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). REGISTRATION: https://www.isrctn.com/ISRCTN65527208 (14/05/2018).