ABSTRACT
Chromium and arsenic are two of the most problematic water pollutants due to their high toxicity and prevalence in various water streams. While adsorption and ion-exchange processes have been applied for the efficient removal of numerous toxic contaminants, including heavy metals, from water, these technologies display relatively low overall performances and stabilities for the remediation of chromium and arsenic oxyanions. This work presents the use of polyol-functionalized porous aromatic framework (PAF) adsorbent materials that use chelation, ion-exchange, redox activity, and hydrogen-bonding interactions for the highly selective capture of chromium and arsenic from water. The chromium and arsenic binding mechanisms within these materials are probed using an array of characterization techniques, including X-ray absorption and X-ray photoelectron spectroscopies. Adsorption studies reveal that the functionalized porous aromatic frameworks (PAFs) achieve selective, near-instantaneous (reaching equilibrium capacity within 10 s), and high-capacity (2.5 mmol/g) binding performances owing to their targeted chemistries, high porosities, and high functional group loadings. Cycling tests further demonstrate that the top-performing PAF material can be recycled using mild acid and base washes without any measurable performance loss over at least ten adsorption-desorption cycles. Finally, we establish chemical design principles enabling the selective removal of chromium, arsenic, and boron from water. To achieve this, we show that PAFs appended with analogous binding groups exhibit differences in adsorption behavior, revealing the importance of binding group length and chemical identity.
ABSTRACT
Children with chronic illnesses present unique health, psychosocial, and learning challenges. Due to the complexities surrounding their needs, these children and their families often encounter multilayered barriers when accessing educational services and health care management. Medical-family-school interprofessional interagency collaborations (IIC) are needed to facilitate information sharing across institutions, treatment alignment among care partners, and equitable and high-quality school-based service delivery. This article presents a novel hospital-based school consultative liaison service, the Educational Achievement Partnership Program (EAPP), which conducts IIC with the families, schools, hospitals, and community care partners of children with chronic illnesses. We explore disproportionalities in IIC services among low-income and racially/ethnically minoritized children and examine ways to increase IIC service access and utilization. Results demonstrate that systematic changes targeting in-person communication with families significantly increased minoritized and low-income children's EAPP participation. Despite this increase, differences occurred between minoritized and White children's utilization through all stages of EAPP service delivery. These results underscore the importance of ongoing IIC service evaluation to examine the effectiveness of implementation components. We discuss implications and highlight opportunities for similar medical-family-school IIC under a school psychologist-led medical liaison consultative approach. We conclude that IIC is best fostered through innovations in communication models, graduate training, practice, and research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Subject(s)
Poverty , Humans , Chronic Disease , Child , Male , Female , Interprofessional Relations , Adolescent , School Health Services/organization & administration , Cooperative BehaviorABSTRACT
Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.
ABSTRACT
Ecological momentary assessment (EMA) of binge-eating symptoms has deepened our understanding of eating disorders. However, there has been a lack of attention on the psychometrics of EMA binge-eating symptom measures. This paper focused on evaluating the psychometric properties of a four-item binge-eating symptom measure, including multilevel factor structure, reliability, and convergent validity. Forty-nine adults with binge-eating disorder and/or food addiction completed baseline questionnaires and a 10-day EMA protocol. During EMA, participants completed assessments of eating episodes, including four binge-eating symptom items. Analyses included multilevel exploratory factor analysis, computation of omega and intraclass correlation coefficients, and multilevel structural equation models of associations between contextual factors and binge-eating symptoms. A one within-subject factor solution fit the data and showed good multilevel reliability and adequate within-subjects variability. EMA binge-eating symptoms were associated with baseline binge-eating measures as well as relevant EMA eating characteristics: including greater unhealthful food and drink intake; higher perceived taste of food; lower likelihood to be planned eating; and lower likelihood of eating to occur at work/school and other locations and greater likelihood to occur at restaurants compared to home. In conclusion, the study findings support the psychometrics of a 4-item one-factor EMA measure of binge-eating symptoms.
ABSTRACT
Diamine-appended Mg2(dobpdc) (dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) metal-organic frameworks are promising candidates for carbon capture that exhibit exceptional selectivities and high capacities for CO2. To date, CO2 uptake in these materials has been shown to occur predominantly via a chemisorption mechanism involving CO2 insertion at the amine-appended metal sites, a mechanism that limits the capacity of the material to â¼1 equiv of CO2 per diamine. Herein, we report a new framework, pip2-Mg2(dobpdc) (pip2 = 1-(2-aminoethyl)piperidine), that exhibits two-step CO2 uptake and achieves an unusually high CO2 capacity approaching 1.5 CO2 per diamine at saturation. Analysis of variable-pressure CO2 uptake in the material using solid-state nuclear magnetic resonance (NMR) spectroscopy and in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) reveals that pip2-Mg2(dobpdc) captures CO2 via an unprecedented mechanism involving the initial insertion of CO2 to form ammonium carbamate chains at half of the sites in the material, followed by tandem cooperative chemisorption and physisorption. Powder X-ray diffraction analysis, supported by van der Waals-corrected density functional theory, reveals that physisorbed CO2 occupies a pocket formed by adjacent ammonium carbamate chains and the linker. Based on breakthrough and extended cycling experiments, pip2-Mg2(dobpdc) exhibits exceptional performance for CO2 capture under conditions relevant to the separation of CO2 from landfill gas. More broadly, these results highlight new opportunities for the fundamental design of diamine-Mg2(dobpdc) materials with even higher capacities than those predicted based on CO2 chemisorption alone.
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BACKGROUND: Language in nonmedical data sets is known to transmit human-like biases when used in natural language processing (NLP) algorithms that can reinforce disparities. It is unclear if NLP algorithms of medical notes could lead to similar transmissions of biases. RESEARCH QUESTION: Can we identify implicit bias in clinical notes, and are biases stable across time and geography? STUDY DESIGN AND METHODS: To determine whether different racial and ethnic descriptors are similar contextually to stigmatizing language in ICU notes and whether these relationships are stable across time and geography, we identified notes on critically ill adults admitted to the University of California, San Francisco (UCSF), from 2012 through 2022 and to Beth Israel Deaconess Hospital (BIDMC) from 2001 through 2012. Because word meaning is derived largely from context, we trained unsupervised word-embedding algorithms to measure the similarity (cosine similarity) quantitatively of the context between a racial or ethnic descriptor (eg, African-American) and a stigmatizing target word (eg, nonco-operative) or group of words (violence, passivity, noncompliance, nonadherence). RESULTS: In UCSF notes, Black descriptors were less likely to be similar contextually to violent words compared with White descriptors. Contrastingly, in BIDMC notes, Black descriptors were more likely to be similar contextually to violent words compared with White descriptors. The UCSF data set also showed that Black descriptors were more similar contextually to passivity and noncompliance words compared with Latinx descriptors. INTERPRETATION: Implicit bias is identifiable in ICU notes. Racial and ethnic group descriptors carry different contextual relationships to stigmatizing words, depending on when and where notes were written. Because NLP models seem able to transmit implicit bias from training data, use of NLP algorithms in clinical prediction could reinforce disparities. Active debiasing strategies may be necessary to achieve algorithmic fairness when using language models in clinical research.
Subject(s)
Intensive Care Units , Natural Language Processing , Neural Networks, Computer , Humans , Algorithms , Critical Illness/psychology , Bias , Electronic Health Records , Male , FemaleABSTRACT
It has been proposed that cerebrospinal fluid (CSF) can enter and leave the retina and optic nerve along perivascular spaces surrounding the central retinal vessels as part of an aquaporin-4 (AQP4) dependent ocular 'glymphatic' system. Here, we injected fluorescent dextrans and antibodies into the CSF of mice at the cisterna magna and measured their distribution in the optic nerve and retina. We found that uptake of dextrans in the perivascular spaces and parenchyma of the optic nerve is highly sensitive to the cisternal injection rate, where high injection rates, in which dextran disperses fully in the sub-arachnoid space, led to uptake along the full length of the optic nerve. Accumulation of dextrans in the optic nerve did not differ significantly in wild-type and AQP4 knockout mice. Dextrans did not enter the retina, even when intracranial pressure was greatly increased over intraocular pressure. However, elevation of intraocular pressure reduced accumulation of fluorescent dextrans in the optic nerve head, and intravitreally injected dextrans left the retina via perivascular spaces surrounding the central retinal vessels. Human IgG distributed throughout the perivascular and parenchymal areas of the optic nerve to a similar extent as dextran following cisternal injection. However, uptake of a cisternally injected AQP4-IgG antibody, derived from a seropositive neuromyelitis optica spectrum disorder subject, was limited by AQP4 binding. We conclude that large molecules injected in the CSF can accumulate along the length of the optic nerve if they are fully dispersed in the optic nerve sub-arachnoid space but that they do not enter the retina.
Subject(s)
Dextrans , Neuromyelitis Optica , Mice , Humans , Animals , Dextrans/metabolism , Optic Nerve/metabolism , Retina/metabolism , Neuromyelitis Optica/metabolism , Aquaporin 4/metabolism , Autoantibodies/metabolismABSTRACT
Recent measurements [Xu, J.; J. Phys. Chem. Lett. 2019, 10 (22), 7044-7049] have reported temperature-dependent rates of detachment of diamine from Mg sites in diamine-appended Mg2(dobpdc) [dobpdc4- = 4,4'-dihydroxy(1,1'-biphenyl)-3,3'-dicarboxylic] metal-organic frameworks, a process hypothesized to be a precursor for cooperative CO2 adsorption, leading to step-shaped isotherms or isobars. Here, we compute the rate of diamine exchange in this system for different diamines using metadynamics simulations based on a density functional theory-derived neural network potential. Reanalyzing recent measurements accounting for entropic effects, we find a positive correlation between the previously reported CO2 adsorption step pressure and the free energy at room temperature and show that the experiments and simulations are in good qualitative and quantitative agreement. The rates obtained here provide new insight into the chemical dynamics of CO2 adsorption in a class of materials that are promising for carbon capture and a lower bound on the time scale of cooperative adsorption.
ABSTRACT
BACKGROUND: Immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) to peanut and its components may influence the clinical reactivity to peanut. Allergen-specific immunotherapy is known for modifying both IgE and IgG4. Peanut oral immunotherapy may influence these serological parameters. METHODS: Exploratory analyses of serological data from participants receiving peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) and placebo in the double-blind, randomized, phase 3 PALISADE trial were conducted to evaluate potential relationships between peanut-specific and peanut component-specific (Ara h 1, Ara h 2, Ara h 3, Ara h 6, Ara h 8, and Ara h 9) IgE and IgG4 levels and clinical outcomes. RESULTS: A total of 269 participants (PTAH, n = 202; placebo, n = 67) were analyzed. No relationship was observed between specific IgE and IgG4 levels at screening and maximum tolerated peanut protein dose during screening or response status during exit double-blind placebo-controlled food challenge (DBPCFC). In PTAH-treated participants, no relationship was observed between IgE and IgG4 levels at screening and maximum symptom severity during exit DBPCFC. Postscreening ratios (ie, postscreening/screening) in the PTAH group were significant at the end of updosing and exit visit for most components. Postscreening changes in specific IgE levels were more pronounced with PTAH versus placebo for most components. CONCLUSIONS: Specific IgE and IgG4 levels at screening are not correlated with screening or exit DBPCFC results, and are not predictive of clinical response to PTAH. Peanut (Arachis hypogaea) allergen powder-dnfp contains the relevant and immunodominant allergens, inducing immunological changes with the treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02635776.
ABSTRACT
Lung cancer is the leading global cause of cancer-related deaths. Although smoking cessation is the best prevention, 50% of lung cancer diagnoses occur in people who have quit smoking. Research into treatment options for high-risk patients is constrained to rodent models, which are time-consuming, expensive, and require large cohorts. Embedding precision-cut lung slices (PCLS) within an engineered hydrogel and exposing this tissue to vinyl carbamate, a carcinogen from cigarette smoke, creates an in vitro model of lung cancer premalignancy. Hydrogel formulations are selected to promote early lung cancer cellular phenotypes and extend PCLS viability to six weeks. Hydrogel-embedded PCLS are exposed to vinyl carbamate, which induces adenocarcinoma in mice. Analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content after six weeks reveals that vinyl carbamate induces premalignant lesions with a mixed adenoma/squamous phenotype. Putative chemoprevention agents diffuse through the hydrogel and induce tissue-level changes. The design parameters selected using murine tissue are validated with hydrogel-embedded human PCLS and results show increased proliferation and premalignant lesion gene expression patterns. This tissue-engineered model of human lung cancer premalignancy is the foundation for more sophisticated ex vivo models that enable the study of carcinogenesis and chemoprevention strategies.
Subject(s)
Lung Neoplasms , Precancerous Conditions , Humans , Mice , Animals , Hydrogels , Lung Neoplasms/pathology , Lung/pathology , UrethaneABSTRACT
BACKGROUND: The role of neuroinflammation in psychiatric disorders is not well-elucidated. A noninvasive technique sensitive to low-level neuroinflammation may improve understanding of the pathophysiology of these conditions. PURPOSE: To test the ability of quantitative magnetization transfer (QMT) MR at 3 T for detection of low-level neuroinflammation induced by typhoid vaccine within a clinically reasonable scan time. STUDY TYPE: Randomized, crossover, placebo-controlled. SUBJECTS: Twenty healthy volunteers (10 males; median age 34 years). FIELD STRENGTH/SEQUENCE: Magnetization prepared rapid gradient-echo and MT-weighted 3D fast low-angle shot sequences at 3 T. ASSESSMENT: Participants were randomized to either vaccine or placebo first with imaging, then after a washout period received the converse with a second set of imaging. MT imaging, scan time, and blood-based inflammatory marker concentrations were assessed pre- and post-vaccine and placebo. Mood was assessed hourly using the Profile of Mood States questionnaire. QMT parameter maps, including the exchange rate from bound to free pool (kba) were generated using a two-pool model and then segmented into tissue type. STATISTICAL TESTS: Voxel-wise permutation-based analysis examined inflammatory-related alterations of QMT parameters. The threshold-free cluster enhancement method with family-wise error was used to correct voxel-wise results for multiple comparisons. Region of interest averages were fed into mixed models and Bonferroni corrected. Spearman correlations assessed the relationship between mood scores and QMT parameters. Results were considered significant if corrected P < 0.05. RESULTS: Scan time for the MT-weighted acquisition was approximately 11 minutes. Blood-based analysis showed higher IL-6 concentrations post-vaccine compared to post-placebo. Voxel-wise analysis found three clusters indicating an inflammatory-mediated increase in kba in cerebellar white matter. Cerebellar kba for white matter was negatively associated with vigor post-vaccine but not post-placebo. DATA CONCLUSION: This study suggested that QMT at 3 T may show some sensitivity to low-level neuroinflammation. Further studies are needed to assess the viability of QMT for use in inflammatory-based disorders. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.
Subject(s)
Mental Disorders , Typhoid-Paratyphoid Vaccines , Male , Humans , Adult , Cross-Over Studies , Neuroinflammatory Diseases , Magnetic Resonance Imaging/methodsABSTRACT
BACKGROUND: Somatic mutations are frequently reported in individuals with cytopenia but without a confirmed haematological diagnosis (clonal cytopenia of undetermined significance; CCUS). These patients have an increased risk of progression to a myeloid malignancy and worse overall survival than those with no such mutations. To date, studies have been limited by retrospective analysis or small patient numbers. We aimed to establish the natural history of CCUS by prospectively investigating outcome in a large, well defined patient cohort. METHODS: This prospective cohort study was conducted at the Haematological Malignancy Diagnostic Service, a diagnostic laboratory in Leeds, UK. Patients aged at least 18 years who were referred for investigation of cytopenia were eligible for inclusion; those with a history of myeloid malignancy were not eligible. Targeted sequencing was conducted alongside routine clinical testing. Baseline mutation analysis was then correlated with the main study outcomes: longitudinal blood counts, disease progression to a myeloid malignancy, and overall survival with a median follow-up of 4·54 years (IQR 4·03-5·04). Data were collected manually from hospital records or extracted from laboratory or clinical outcome databases. FINDINGS: Bone marrow samples from 2348 patients were received at the Haematological Malignancy Diagnostic Service between July 1, 2014, and July 31, 2016. Of these, 2083 patients (median age 72 years [IQR 63-80, range 18-99]; 854 [41·0%] female and 1229 [59·0%] male) met the inclusion criteria and had samples of sufficient quality for further analysis. 598 (28·7%) patients received a diagnosis on the basis of their biopsy sample, whereas 1485 (71·3%) samples were classified as non-diagnostic; of these, CCUS was confirmed in 400 (26·9%) patients (256 [64·0%] male and 144 [36·0%] female). TET2, SRSF2, and DNMT3A were the most frequently mutated genes in patients with CCUS, with 320 (80%) of 400 patients harbouring a mutation in at least one of these genes. Age (p<0·0001), sex (p=0·0027), and mutations in ASXL1 (p=0·0009), BCOR (p=0·0056), and TP53 (p=0·0055) correlated with a worse overall survival; however, the number of mutations was the strongest predictor for progression to a myeloid malignancy (two mutations, p=0·0024; three or more mutations, p=0·0004). Extended sequencing of samples from a subgroup of patients with sequential samples and no mutations in the initial myeloid gene panel showed recurrent mutations in both DDX41 and UBA1, suggesting that these genes should be included in clinical test panels. INTERPRETATION: Mutation analysis is advised in patients who have undergone bone marrow examination and have an otherwise-unexplained cytopenia. High-risk genetic mutations and increased numbers of mutations are predictive of both survival and progression within 5 years of presentation, warranting clinical surveillance and, when necessary, intervention. FUNDING: MDS Foundation.
Subject(s)
Cytopenia , Hematologic Neoplasms , Myelodysplastic Syndromes , Myeloproliferative Disorders , Humans , Male , Female , Adolescent , Adult , Aged , Myelodysplastic Syndromes/pathology , Retrospective Studies , Prospective Studies , Mutation , Hematologic Neoplasms/geneticsABSTRACT
In the second century CE the Roman Empire had increasing contact with Sarmatians, nomadic Iranian speakers occupying an area stretching from the Pontic-Caspian steppe to the Carpathian mountains, both in the Caucasus and in the Danubian borders of the empire.1,2,3 In 175 CE, following their defeat in the Marcomannic Wars, emperor Marcus Aurelius drafted Sarmatian cavalry into Roman legions and deployed 5,500 Sarmatian soldiers to Britain, as recorded by contemporary historian Cassius Dio.4,5 Little is known about where the Sarmatian cavalry were stationed, and no individuals connected with this historically attested event have been identified to date, leaving its impact on Britain largely unknown. Here we document Caucasus- and Sarmatian-related ancestry in the whole genome of a Roman-period individual (126-228 calibrated [cal.] CE)-an outlier without traceable ancestry related to local populations in Britain-recovered from a farmstead site in present-day Cambridgeshire, UK. Stable isotopes support a life history of mobility during childhood. Although several scenarios are possible, the historical deployment of Sarmatians to Britain provides a parsimonious explanation for this individual's extraordinary life history. Regardless of the factors behind his migrations, these results highlight how long-range mobility facilitated by the Roman Empire impacted provincial locations outside of urban centers.
Subject(s)
Isotopes , Roman World , Humans , United Kingdom , Iran , Roman World/historyABSTRACT
Importance: Periviable and previable premature rupture of membranes (pPPROM) occurs in <1% of pregnancies but can have devastating consequences for the mother and the fetus. Understanding risk factors, possible interventions, and both maternal and neonatal outcomes will improve the counseling and care provided for these patients. Objective: The aim of this review is to describe the etiology, risk factors, management strategies, neonatal and maternal outcomes, and recurrence risk for patients experiencing pPPROM. Evidence Acquisition: A PubMed, Web of Science, and CINAHL search was undertaken with unlimited years searched. The search terms used included "previable" OR "periviable" AND "fetal membranes" OR "premature rupture" OR "PROM" OR "PPROM." The search was limited to English language. Results: There were 181 articles identified, with 41 being the basis of review. Multiple risk factors for pPPROM have been identified, but their predictive value remains low. Interventions that are typically used once the fetus reaches 23 to 24 weeks of gestation have not been shown to improve outcomes when used in the previable and periviable stage. Neonatal outcomes have improved over time, but survival without severe morbidity remains low. Later gestational age at the time of pPPROM and longer latency period have been shown to be associated with improved outcomes. Conclusions and Relevance: Periviable and previable premature rupture of membranes are uncommon pregnancy events, but neonatal outcomes remain poor, and routine interventions for PPROM >24 weeks of gestation have not proven beneficial. The 2 most reliable prognostic indicators are gestational age at time of pPPROM and length of the latency period.
Subject(s)
Fetal Membranes, Premature Rupture , Premature Birth , Pregnancy , Infant, Newborn , Female , Humans , Pregnancy Outcome , Retrospective Studies , Fetal Membranes, Premature Rupture/therapy , Gestational AgeABSTRACT
Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A by Zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages towards an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that Zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon response uniformly across models. The induction of an interferon response is partially due to the inhibition of Sox4 translation by Zotatifin. A similar induction of interferon-stimulated genes was observed in breast cancer patient biopsies following Zotatifin treatment. Surprisingly, Zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened interferon response resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for Zotatifin, and provide a rationale for new combination regimens comprising Zotatifin and chemotherapy or immunotherapy as treatments for TNBC.
ABSTRACT
OBJECTIVES: The aim of the present study was to investigate whether diagnostic assessment methods used on radiographs in humans with slipped capital femoral epiphysis (SCFE) can be used in cats. METHODS: The ventrodorsal (VD) extended-leg and VD frog-leg pelvic radiographs of 20 cats with SCFE without fully displaced femoral capital epiphyses (FCE), eight cats with fully displaced FCE and five control cats with normal pelvic anatomy were assessed by five observers on two separate occasions 3 months apart. The Klein's line and modified Klein's line were assessed on each VD extended-leg radiograph, and the S-sign was assessed on each VD extended-leg and VD frog-leg radiograph. RESULTS: Excluding cases of fully displaced FCE, the S-sign on the VD frog-leg radiographs more accurately diagnosed SCFE than the S-sign on the VD extended-leg radiographs and the Klein's line (92.4% vs 88.8% vs 60.6%, respectively), and had the greatest sensitivity (93.9% vs 79.2% vs 30.6%, respectively). The S-sign on the VD extended-leg radiographs had greater specificity than the Klein's line and S-sign on the VD frog-leg radiographs (99.2% vs 97.9% vs 90.9%, respectively). The modified Klein's line detected SCFE in 40.2% of cases that were negative for the Klein's line. CONCLUSIONS AND RELEVANCE: The S-sign in both VD extended-leg and VD frog-leg views successfully detected SCFE in cats and can be used to increase early diagnosis and treatment in cats with SCFE that have only subtle radiographic changes.
Subject(s)
Cat Diseases , Slipped Capital Femoral Epiphyses , Humans , Cats , Animals , Slipped Capital Femoral Epiphyses/diagnostic imaging , Slipped Capital Femoral Epiphyses/veterinary , Femur , Radiography , Early Diagnosis , Epiphyses , Retrospective Studies , Cat Diseases/diagnostic imagingABSTRACT
Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon (IFN) response uniformly across models. The induction of an IFN response is partially due to the inhibition of Sox4 translation by zotatifin. A similar induction of IFN-stimulated genes was observed in breast cancer patient biopsies following zotatifin treatment. Surprisingly, zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened IFN response, resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for zotatifin, and provide a rationale for new combination regimens consisting of zotatifin and chemotherapy or immunotherapy as treatments for TNBC.
Subject(s)
Antineoplastic Agents , Triple Negative Breast Neoplasms , Animals , Mice , Humans , Interferons , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Cell Proliferation , Tumor MicroenvironmentABSTRACT
Introduction: Lower-limb physical function declines with age and contributes to a greater difficulty in performing activities of daily living. Existing assessments of lower-limb function assess one dimension of movement in isolation or are not time-efficient, which discourages their use in community and clinical settings. We aimed to address these limitations by assessing the inter-rater reliability and convergent validity of a new multimodal functional lower-limb assessment (FLA). Methods: FLA consists of five major functional movement tasks (rising from a chair, walking gait, stair ascending/descending, obstacle avoidance, and descending to a chair) performed consecutively. A total of 48 community-dwelling older adults (32 female participants; age: 71 ± 6 years) completed the FLA as well as timed up-and-go, 30-s sit-to-stand, and 6-min walk tests. Results: Slower FLA time was correlated with a slower timed up-and-go test (ρ = 0.70), less sit-to-stand repetitions (ρ = -0.65), and a shorter distance in the 6-min walk test (ρ = -0.69; all, p < 0.001). Assessments by two raters were not different (12.28 ± 3.86 s versus 12.29 ± 3.83 s, p = 0.98; inter-rater reliability ρ = 0.993, p < 0.001) and were statistically equivalent (via equivalence testing). Multiple regression and relative weights analyses demonstrated that FLA times were most predicted by the timed up-and-go performance [adjusted R 2 = 0.75; p < 0.001; raw weight 0.42 (95% CI: 0.27, 0.53)]. Discussion: Our findings document the high inter-rater reliability and moderate-strong convergent validity of the FLA. These findings warrant further investigation into the predictive validity of the FLA for its use as an assessment of lower-limb physical function among community-dwelling older adults.
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An efficient synthesis of cyclohexenes has been achieved from easily accessible tetrahydropyrans via a tandem 1,5-hydride shift-aldol condensation. We discovered that readily available aluminium reagents, e.g. Al2 O3 or Al(Ot Bu)3 are essential for this process, promoting the 1,5-hydride shift with complete regio- and enantiospecificity (in stark contrast to results obtained under basic conditions). The mild conditions, coupled with multiple methods available to access the tetrahydropyran starting materials makes this a versatile method with exceptional functional group tolerance. A wide range of cyclohexenes (>40 examples) have been prepared, many in enantiopure form, showing our ability to selectively install a substituent at each position around the newly forged cyclohexene ring. Experimental and computational studies revealed that aluminium serves a dual role in facilitating the hydride shift, activating both the alkoxide nucleophile and the electrophilic carbonyl group.
ABSTRACT
Research developing and testing interventions that address the social determinants of liver disease are urgently needed; however, this cannot be achieved using conventional clinical research designs. A different approach is needed to conduct widely applicable, inclusive, and community-based research that addresses upstream factors driving liver morbidity. Natural experimental studies encompass a well-established field of research methodology that is less familiar to clinical hepatologists than conventional research methods such as the randomized control trial. The key strength of natural experiments is that, when robustly designed, they can be used to imply causality from routinely collected data. As such, they are well placed to test the impact of community interventions that aim to address social determinants of liver disease that cannot feasibly be assessed in a randomized control trial. In this review, we define natural experiments and their potential utility. We then work through examples of where they have already been used in clinical hepatology to highlight a range of research designs, analytical approaches, and best practices regarding their conduct and reporting. In doing so, we hope to equip clinical hepatologists with another tool to ensure the hepatology community can meet the global liver disease epidemic with evidence-based interventions.