imaging is a powerful approach to study biological processes. Beyond cellular methods,
studies allow for biological stimuli (small molecules or proteins) to be studied in their native environment. ...This has the potential to aid in the discovery of new biology and guide the development of diagnostics and therapies for diseases. To ensure selectivity and an observable readout, the probe development field is shifting towards activity-based sensing (ABS) approaches and near-infrared (NIR) imaging modalities. This perspective will highlight recent
ABS applications that utilize NIR imaging platforms.
Photoacoustic (PA) imaging has emerged as a reliable
technique for diverse biomedical applications ranging from disease screening to analyte sensing. Most contemporary PA imaging agents employ NIR-I ...light (650-900 nm) to generate an ultrasound signal; however, there is significant interference from endogenous biomolecules such as hemoglobin that are PA active in this window. Transitioning to longer excitation wavelengths (i.e., NIR-II) reduces the background and facilitates the detection of low abundance targets (e.g., nitric oxide, NO). In this study, we employed a two-phase tuning approach to develop APNO-1080, a NIR-II NO-responsive probe for deep-tissue PA imaging. First, we performed Hammett and Brønsted analyses to identify a highly reactive and selective aniline-based trigger that reacts with NO via
-nitrosation chemistry. Next, we screened a panel of NIR-II platforms to identify chemical structures that have a low propensity to aggregate since this can diminish the PA signal. In a head-to-head comparison with a NIR-I analogue, APNO-1080 was 17.7-fold more sensitive in an
tissue phantom assay. To evaluate the deep-tissue imaging capabilities of APNO-1080
, we performed PA imaging in an orthotopic breast cancer model and a heterotopic lung cancer model. Relative to control mice not bearing tumors, the normalized turn-on response was 1.3 ± 0.12 and 1.65 ± 0.07, respectively.
Background and Objectives
Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study ...were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels.
Methods
A phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib. Data were analyzed by popPK modeling, and patient demographics contributing to pharmacokinetic variability were explored. Target engagement was evaluated by combining the clinical popPK model with a previously developed pre-clinical pharmacokinetic/pharmacodynamic model.
Results
The pharmacokinetic analysis incorporated 4012 plasma concentrations from 224 patients treated with abemaciclib at doses ranging from 50 to 225 mg every 24 h and 75 to 275 mg every 12 h. A linear one-compartment model with time- and dose-dependent relative bioavailability (
F
rel
) adequately described the pharmacokinetics of abemaciclib. Serum albumin and alkaline phosphatase were the only significant covariates identified in the model, the inclusion of which reduced inter-individual variability in
F
rel
by 10.3 percentage points. By combining the clinical popPK model with the previously developed pre-clinical pharmacokinetic/pharmacodynamic model, the extent of target engagement in skin in cancer patients was successfully predicted.
Conclusion
The proportion of abemaciclib pharmacokinetic variability that can be attributed to patient demographics is negligible, and as such there are currently no dose adjustments recommended for adult patients of different sex, age, or body weight.
Trial registration
NCT01394016 (ClinicalTrials.gov).
The attachment of glucose to drugs and imaging agents enables cancer cell targeting via interactions with GLUT1 overexpressed on the cell surface. While an added benefit of this modification is the ...solubilizing effect of carbohydrates, in the context of imaging agents, aqueous solubility does not guarantee decreased π-stacking or aggregation. The resulting broadening of the absorbance spectrum is a detriment to photoacoustic (PA) imaging since the signal intensity, accuracy, and image quality all rely on reliable spectral unmixing. To address this major limitation and further enhance the tumor-targeting ability of imaging agents, we have taken a biomimetic approach to design a multivalent glucose moiety (mvGlu). We showcase the utility of this new group by developing aza-BODIPY-based contrast agents boasting a significant PA signal enhancement greater than 11-fold after spectral unmixing. Moreover, when applied to targeting cancer cells, effective staining could be achieved with ultra-low dye concentrations (50 nM) and compared to a non-targeted analogue, the signal intensity was >1000-fold higher. Lastly, we employed the mvGlu technology to develop a logic-gated acoustogenic probe to detect intratumoral copper (i.e., Cu(I)), which is an emerging cancer biomarker, in a murine model of breast cancer. This exciting application was not possible using other acoustogenic probes previously developed for copper sensing.
Hymenoptera envenomation with honey bee (Apis mellifera) and paper wasp (Polistes spp.) may cause life-threatening anaphylaxis in dogs. In human patients, clinical history, intradermal testing (IDT) ...and measurement of allergen-specific serological immunoglobulin (Ig)E (sIgE) are used to support a diagnosis of Hymenoptera venom hypersensitivity. The utility of venom allergen-specific sIgE has not yet been evaluated for this purpose in dogs.
The objective of the study was to investigate the sensitivity (sn), specificity (sp) and positive predictive value (PPV) of honey bee and paper wasp serological titres using a commercially available sIgE assay VARL (Veterinary Allergen Reference Laboratory) Liquid Gold against clinical history for a diagnosis of Hymenoptera hypersensitivity in dogs.
Honeybee and paper wasp IgE serum titres were measured in 15 client-owned dogs with a diagnosis of Hymenoptera venom hypersensitivity based on a history of anaphylaxis, owner observation of Hymenoptera, and positive IDT to bee and/or wasp; and in 10 client-owned dogs with no known history of anaphylaxis or Hymenoptera exposure and a negative IDT to bee and wasp.
Analysis of receiver operating characteristic (ROC) curves demonstrate that a VARL score cut-off of one of six for honeybee yields Sn, Sp and PPV of 40%, 60% and 60%, respectively, and two of six for wasp yields Sn, Sp and PPV of 25%, 78% and 60%, respectively.
Owing to the poor sensitivity and PPV of sIgE assays for both bee and wasp hypersensitivity in dogs with known envenomation and anaphylaxis, the use of sIgE cannot be recommended as a tool for venom identification.
We have developed an optimized protocol for plasma targeted mRNA sequencing in our previous study. Here, we performed plasma targeted mRNA sequencing for 40 colorectal adenoma patients and 39 ...colonoscopy-proven normal controls in order to find potential circulating mRNA markers for colorectal adenoma. Results showed that GSK3A and RHOA were differential expressed genes identified by a cut-off of fold change >2 and adjusted P value < 0.05. More detailed analysis showed that the expression of both GSK3A (0.01-fold with adjusted P < 1 × 10
) and RHOA (0.35-fold with adjusted P < 0.01) in adenoma patients was significantly lower than those in normal healthy subjects. Based on the enrichment analysis of biological process for potential markers, we found that the regulation of programmed cell death (GO: 0043067; GO: 0043069), regulation of cell death (GO: 0010941; GO: 0060548) and cell differentiation (GO: 0021861) were the main processes involved in adenoma formation. In summary, this study is a cutting-edge research on the detection of plasma mRNA in colorectal adenoma patients and normal healthy subjects.
As the COVID-19 pandemic continues to affect the international community, very little is known about its impact on the health and day-to-day activities of people with Parkinson's disease (PwPD). To ...better understand the emotional and behavioral consequences of the public health policies implemented to mitigate the spread of SARS-CoV-2 in PwPD, and to explore the factors contributing to accessing alternative health care mechanisms, such as telehealth, we administered an anonymous knowledge, attitude, and practice survey to PwPD and care partners, via the mailing lists of the Parkinson's Foundation and Columbia University Parkinson's Disease Center of Excellence with an average response rate of 19.3%. Sufficient information was provided by 1,342 PwPD to be included in the final analysis. Approximately half of respondents reported a negative change in PD symptoms, with 45-66% reporting mood disturbances. Telehealth use increased from 9.7% prior to the pandemic to 63.5% during the pandemic. Higher income and higher education were associated with telehealth use. Services were more often used for doctor's appointment than physical, occupational, speech, or mental health therapies. Almost half (46%) of PwPD preferred to continue using telehealth always or sometimes after the coronavirus outbreak had ended. Having received support/instruction for telehealth and having a care partner, friend, or family member to help them with the telehealth visit increased the likelihood of continuous use of telehealth after the pandemic ended. Taken together, PD symptoms and management practices were markedly affected by COVID-19. Given the observed demographic limitations of telehealth, expanding its implementation to include additional physical, occupational, psychological, and speech therapies, increasing support for telehealth, as well as reaching underserved (low income) populations is urgently required.
•Lead exposure was 1.7 times higher among First Nations.•Lead intake increase the risk of high blood pressure.•Traditional food accounted for 73% of dietary intake.•Lead containing ammunition is a ...major source.
Indigenous peoples have elevated risk of lead (Pb) exposure as hunted traditional food can be contaminated with lead-containing ammunition. Recent scientific consensus states that there is no threshold level for Pb exposure. The objective of this study was to estimate dietary exposure to Pb among First Nations living on-reserve in the province of Ontario, Canada. A total diet study was constructed based on a 24-h recall and Pb concentrations for traditional foods from the First Nations Food, Nutrition, and Environment Study (FNFNES) and Pb concentrations in market foods from Health Canada. A probabilistic assessment of annual and seasonal traditional food consumption was conducted. Results indicate that traditional foods, particularly moose and deer meat. are the primary source of dietary Pb intake (73%), despite providing only 1.8% of the average caloric intake. The average dietary Pb exposure (0.21μg/kg/d) in the First Nations population in Ontario was 1.7 times higher than the dietary Pb exposure in the general Canadian population. Pb intake was associated with an estimated average increase in systolic blood pressure of 1.2mmHg. These results indicate that consumption of foods hunted with Pb containing ammunition and shot puts the population at elevated risk of Pb toxicity.
This report describes a case of sterile pyogranuloma syndrome managed with immunomodulatory therapy and seed skin grafting. Seed skin grafting can be considered as part of a multimodal treatment ...approach for cutaneous defects caused by ulcerative immune‐mediated diseases where secondary intention healing is delayed or contraindicated, and other forms of wound reconstruction may be prohibitive.
Résumé
Cet article décrit un cas de syndrome pyogranulome stérile géré avec un traitement immunomodulateur et une greffe de peau. La greffe de peau peut être considérée comme faisant partie d'une approche de traitement multimodal des défauts cutanés causés par des maladies ulcératives à médiation immunitaire où la cicatrisation secondaire est retardée ou contre‐indiquée, et pour lesquelles d'autres formes de reconstruction de plaies peuvent être prohibitives.
Resumen
Este artículo describe un caso de síndrome de piogranuloma estéril manejado con terapia inmunomoduladora e injerto de piel por ensemillado. El injerto de piel por ensemillado se puede considerar como parte de un enfoque de tratamiento multimodal para los defectos cutáneos causados por enfermedades ulcerativas inmunomediadas en las que la cicatrización por segunda intención se retrasa o está contraindicada, y otras formas de reconstrucción de heridas pueden ser prohibitivas.
Zusammenfassung
Dieser Bericht beschreibt die Behandlung eines sterilen Pyogranulomata Syndroms, dessen kutane Defekte, die durch eine ulzerative immun‐mediierte Erkrankung verursacht waren, mit Immunmodulation, da eine Heilung per secundam intentionem bei dieser Erkrankung verzögert oder kontraindiziert sein könnte und auch andere Formen der Wundrekonstruktion prohibitiv sein könnten.
要約
本報告では，免疫調節療法および種皮移植により治療した無菌性化膿性肉芽腫症候群の1例を示す。二次治癒が遅延するか禁忌である、潰瘍性免疫介在性疾患による皮膚欠損において、他の形態の創傷再建が困難な場合、種皮移植は多剤併用療法アプローチの一部として考慮することが可能である。
摘要
本报告描述了1例通过免疫调节治疗和颗粒皮肤移植治疗的无菌性脓肉芽肿综合征病例。对于由溃疡性免疫介导的疾病引起的皮肤缺损，如果二期愈合延迟或禁忌，可以考虑将颗粒皮肤移植作为多模式治疗方法的一部分，而其他形式的伤口重建可能无法实施。
Resumo
Este relato descreve um caso de síndrome do piogranuloma estéril tratado com terapia imunomoduladora e enxerto de pele. Enxertia de pele pode ser considerada parte da terapia multimodal para defeitos cutâneos causados por doenças imunomediadas ulcerativas em que a cicatrização por segunda intenção é postergada ou contraindicada, e outras formas de reconstrução de feridas são proibitivas.
This report describes a case of sterile pyogranuloma syndrome managed with immunomodulatory therapy and seed skin grafting. Seed skin grafting can be considered as part of a multimodal treatment approach for cutaneous defects caused by ulcerative immune‐mediated diseases where secondary intention healing is delayed or contraindicated, and other forms of wound reconstruction may be prohibitive.
Methyl Mercury (MeHg) exposure is a global environmental health concern. Indigenous peoples around the world are susceptible to MeHg exposure from often higher fish consumption compared to general ...populations. The objective of this study was to estimate dietary exposure to methylmercury (MeHg) among First Nations living on-reserve in the province of Ontario, Canada. A total diet study was constructed based on a 24-h recall from the First Nations Food, Nutrition, and Environment Study (FNFNES), and measured contaminant concentrations from Health Canada for market foods, and FNFNES for traditional foods. A probabilistic assessment of annual and seasonal traditional food consumptions was conducted for 1429 adult participants. Results were compared to exposures in the general Canadian population and reference values from Health Canada for adults and women of childbearing age (ages 19–50). Results indicated traditional foods to be the primary contributor to the dietary total MeHg intake (72%). The average dietary total MeHg exposure in the First Nations population in Ontario (0.039 μg/kg/d) was 1.6 times higher than the general Canadian population; however, the majority (97.8%) of the population was below the reference values. Mercury concentrations in participants’ hair samples (n = 744) ranged from 0.03 to 13.54 µg/g, with an average of 0.64 µg/g (geometric average of 0.27 µg/g). Less than 1% of the population had a hair mercury value above the 6 µg/g level, and 1.3% of women of child bearing age had values greater than 2 µg/g. Fish species contributing to the MeHg intake included pickerel-walleye, pike, perch and trout. Only 7.9% of the population met the recommended fish consumption rate of two, 3.5 oz servings per week from the American Heart Association. Therefore, consumption of lower trophic level fish can be promoted to provide the maximum nutritional benefit with minimal risk of MeHg exposure.
•A total dietary MeHg exposure assessment was conducted for 1429 First Nations participants.•Traditional foods contributed to 72% of the dietary MeHg intake.•The average dietary MeHg was 0.039 μg/kg/d.•The majority (97.8%) of the population was below the reference values.•Only 7.9% of the population ate two servings of fish per week.
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