High Uptake Research Articles

Targeted degradation of undruggable proteins using a novel heterobifunctional proteomimetic platform.

47 Background: Of the ~20,000 proteins in the human genome, only a subset can be modulated via traditional pharmacological approaches. “Undruggable” targets currently include proteins with pivotal roles in cancer pathogenesis. Our work aims to introduce a new paradigm for engaging these clinically relevant proteins using a modular platform we term the HYbrid DegRAding Copolymers (HYDRACs). HYDRACs multiplex targeting warheads with degradation inducers and have long circulation times plus high cell uptake. Preliminary studies on MYC and RAS, targets of great pharmaceutical interest, highlight the potential of this platform to revolutionize drug design. Methods: HYDRACs containing MYC or RAS targeting peptides randomly copolymerized with degrons were synthesized using ROMP. Fluorescent and biotin-tags were incorporated for use in uptake and pull-down assays. Viability following treatment with MYC-HYDRACs was performed in multiple cell lines with both cellular (MYC-independent lines) and polymer composition controls. Target engagement was assessed via immunoprecipitation and circular dichroism with protein degradation monitored by WB. Unbiased whole proteome analysis and RNAseq were done to confirm observed effects were selectively on-target. In vivo efficacy and biodistribution was assessed in tumor-bearing mice. Results: HYDRACs show high levels of cell uptake and antiproliferative effects at sub-micromolar concentrations in a formulation- and target-dependent manner. Cells treated with MYC-HYDRACs displayed reduced MYC protein levels, which were rescued by proteasome or neddylation inhibition. Swapping out the degron for various validated E3 ligase recruiters maintained MYC degradation, highlighting the “plug-and-play” nature of this approach. On-target activity was confirmed via RNAseq. Biophysical analysis showed strong HYDRAC-protein interactions, orthogonally supported by the presence of target protein following pull-down of biotin-terminated HYDRACs. Target protein degradation only occurred following treatment with an intact HYDRAC compound. Mice bearing MYC-CaP tumors showed delayed tumor growth following treatment with MYC-HYDRACs, with compound accumulation in the tumor for up to 72 h following a single injection. Generalizability was demonstrated against RAS, with RAS-HYDRACs capable of degrading KRAS across multiple different alleles, acting as a pan-KRAS degrader. Conclusions: We present a novel platform technology that addresses the challenges inherent to peptide delivery approaches. HYDRACs have the potential to dramatically alter the drug discovery landscape, allowing for the development of cancer-relevant target modulators for which there are no current viable therapies. We envision the HYDRAC platform as a generalizable approach to designing degraders of proteins of interest, greatly expanding the therapeutic armamentarium for TPD.

Detection of Hepatocellular Carcinoma in an Orthotopic Patient-Derived Xenograft with an Epithelial Cell Adhesion Molecule-Specific Peptide.

Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We used phage display methods to biopan against the extra-cellular domain of the purified EpCAM protein, and used IRDye800 as a near-infrared (NIR) fluorophore. The 12-mer sequence HPDMFTRTHSHN was identified, and specific binding to EpCAM was validated with HCC cells in vitro. A binding affinity of kd = 67 nM and onset of k = 0.136 min-1 (7.35 min) were determined. Serum stability was measured with a half-life of T1/2 = 2.6 h. NIR fluorescence images showed peak uptake in vivo by human HCC patient-derived xenograft (PDX) tumors at 1.5 h post-injection. Also, the peptide was able to bind to foci of local and distant metastases in liver and lung. Peptide biodistribution showed high uptake in tumor versus other organs. No signs of acute toxicity were detected during animal necropsy. Immunofluorescence staining of human liver showed specific binding to HCC compared with cirrhosis, adenoma, and normal specimens.

Novel Graphene-Based Reversible Physisorption Materials for High Hydrogen Uptake

Carbon-based nanomaterials (graphene, carbon nanotube, microporous carbon, graphitic carbon etc.) are excellent H2 storage materials due to high molecular H2 uptake at the micropores and large H2 adsorption at the graphene network via the formation of dipoles in H2 molecules through London dispersion forces. On the other hand, incorporation of transition metal nanoparticles within the nanocarbon network facilitates dissociation of H2 molecules into constituents H-atoms over the metal nanoparticles, followed by diffusion into the carbon nano-matrix via ‘spill-over’ effect for polarization/hybridization of metal-hydrogen to create high H2 binding energy for high hydrogen adsorption. Therefore, a nanocomposite of graphene-microporous carbon-metal nanoparticle network is expected to deliver excellent H2 uptake capacity and acts as a novel reversible physisorption material for hydrogen storage applications, which is very important for sustainable renewable energy integration.A simple, cost effective sputtering method is used to fabricate metal incorporated graphitic microporous carbon film and differential resistance measurement showed high H2 uptake. Average number of graphene layer formation is dependent on sputtering parameters, which manifest bi-to-multilayer graphene. With increase in graphene layers, H2 adsorption also increases due to a fourfold effect: higher molecular hydrogen uptake at the graphene layers, more active sites into the micropores, promotion of molecular dissociation into atomic hydrogen by the metal nanoparticles, and the formation of hydrogenated carbon via destruction of the π-bonds.

68Ga/177Lu-Labeled Bivalent Agents for Targeting Hypoxia and PSMA-Binding in Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is an excellent target for cancer detection and therapy. Hypoxia is prevalent in solid tumors, and various nitroimidazole (NI) radioligands can be trapped inside hypoxic cells for diagnosis and therapy. To enhance tumor uptake and retention, we designed bivalent agents (compounds 1-8) incorporating a hypoxia-sensitive NI-moiety and a PSMA-targeting group. Ligands 1-8 were successfully prepared and labeled with 68Ga or 177Lu. Among them, [68Ga]Ga-8 ([68Ga]Ga-AAZTA-NI-PSMA-093) demonstrated significantly higher cellular accumulation under hypoxic conditions than under normoxic conditions, suggesting hypoxia-selective trapping by the introduction of NI group. PET/CT imaging at 60 min postinjection of [68Ga]Ga-8 revealed high tumor uptake (SUVmax: 10.68%ID/mL) in the tumor-bearing mice model. SPECT/CT imaging of [177Lu]Lu-8 at 24 and 48 h postinjection demonstrated excellent accumulation and retention. Preliminary studies indicate that [68Ga]Ga/[177Lu]Lu-8 may be promising bivalent agents targeting hypoxia and PSMA binding for diagnosis and radiotherapy.

Engineering bi-layered skin-like nanopads with electrospun nanofibers and chitosan films for promoting fibroblast infiltration in tissue regeneration and wound healing

This study presents an innovative bi-layered three-dimensional skin-like nanopad (SLN) engineered for skin tissue regeneration. The SLN integrates a mechanically supportive polycaprolactone nanofibrous layer with a functional chitosan hydrogel film, mimicking natural skin. Our SLN exhibits superior flexibility, with a maximum elongation of 751.71 ± 125 % and exceptional porosity of 95 ± 4.5 %, ensuring effective exudate management due to its high water uptake capacity (4393 ± 72 %). FTIR analysis confirmed a distinctive fiber-hydrogel network within the SLN, which serves as a barrier against Staphylococcus aureus and Pseudomonas aeruginosa infiltration. In vitro cell viability assays with the human fibroblast have consistently demonstrated that 3D bi-layered SLN enhances fibroblast attachment, infiltration, and proliferation by 150 ± 20 %. In vivo studies in a rat model demonstrated significantly faster wound closure, with 60 % on day 7 and 87 % on day 10, compared to the 30 % and 60 % in controls, highlighting the efficacy of SLN. By mimicking the architecture of native skin, this biomimetic bi-layered SLN scaffold provides flexibility and support while accelerating in vivo wound closure by promoting fibroblast proliferation and infiltration. Customizable in size, depth, and shape, the engineered SLN has emerged as a promising platform for advanced wound care and tissue engineering.

High uptake of sympagic organic matter by benthos on an Arctic outflow shelf.

On Arctic shelves, benthic food-webs are tightly linked to overlying primary production. In the seasonal ice zone, sympagic (ice-associated) primary production can be a major source of carbon for the benthos on productive inflow shelves. However, the role of sympagic organic matter is less well-understood in food webs of heavily ice-covered, less- productive outflow shelves, such as the northeast Greenland shelf. Highly branched isoprenoid biomarkers (HBIs) were used to track the relative distribution of sympagic and pelagic organic matter in the water column, sediments, and benthic fauna of the northeast Greenland shelf and fjords. Low pelagic HBI presence throughout the study area indicated a generally low production by pelagic diatoms (at the time of sampling). This was reflected in the benthos, as ~90% of their assimilated carbon was estimated to come from sympagic sources, indicating a benthic food-web highly reliant on sympagic production. This reliance was higher in coastal areas than on the open shelf, where the potentially higher pelagic productivity and shallower water on banks likely increased contributions of pelagic organic matter. As declining ice cover and reduced production of fast-sinking ice algae projected for Arctic shelves will likely result in weaker coupling between ice algae and the benthos, with possible consequences for future benthic-community structure and function.

Initial clinical experience using 68Ga-FAPI-46 PET/CT for detecting various cancer types.

Numerous studies have shown that gallium-68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) positron emission tomography/computed tomography (PET/CT) scans would yield high intra-tumoral tracer uptake and low uptake in normal tissues as background, thus allowing for excellent visualization of lesions in the cancer microenvironment. This study set out to compare the suitability of novel 68Ga-FAPI-46 PET versus routine fluorine-18-fluorodeoxyglucose (18F-FDG) PET and other few cases of 68Ga-DOTATATE/68Ga-Pentixafor PET/CT for the assessment of different types of cancer. A retrospective analysis of 11 patients (6 males, 5 females; average age: 53 years, range: 10-58 years) with histopathologically confirmed, well-differentiated adenocarcinoma, medullar thyroid cancer (MTC), papillary thyroid carcinoma (PTC), cervical, gastric, glioblastoma multiform (GBM), colon, Ewing's sarcoma, and breast cancer was performed. These patients underwent PET/CT scans using four different radiotracers (9 18F-FDG, 11 68Ga- FAPI, 3 68Ga-DOTATATE, and 1 68Ga-Pentixafor). The patients' PET/CT images were visually evaluated for cancer detection, and analyzed semi-quantitatively through image- derived metrics, such as target-to-background ratio (TBR) and maximum standardized uptake value (SUVmax), for recurrence and metastasis. The study of 11 patients revealed that 68Ga-FAPI-46 was more effective than other tracers for detecting metastases, with 55 vs. 49 metastases in the lymph nodes, 4 vs. 3 in the liver, and 4 vs. 3 in the bones detected in comparison to 18F-FDG. No significant differences were observed in 68Ga-DOTATATE and 68Ga-Pentixafor PET images. In addition, in five patients, the SUVmax and TBR values in 68Ga-FAPI-46 PET images were significantly higher than those in 18F-FDG PET images for lymph nodes and bone metastases. Although the SUVmax in 68Ga-FAPI-46 and 18F-FDG PET images for liver metastases was comparable, 68Ga-FAPI- 46 had a significantly higher TBR than 18F-FDG. Our findings suggest that FAPI PET/CT is not suitable for evaluating GBM and Ewing sarcoma but generally outperforms 18F-FDG PET/CT in various types of breast cancer, gastrointestinal, gynecological, PTC and MTC. However, larger trials are needed to validate these preliminary findings.

Release of natural extracts from PVA and PVA-CMC hydrogel wound dressings: a power law swelling/delivery.

PVA hydrogels present many characteristics of the ideal dressing, although without antimicrobial properties. The present work aims to study the physical, mechanical and release characteristics of hydrogel wound dressings loaded with either of two natural herbal products, sage extract and dragon's blood. Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and tensile mechanical testing were used to investigate the structure and properties of the gels. Swelling and degradation tests were conducted according to ISO 10993-9. Release characteristics were studied using UV Spectrophotometry. PVA matrices incorporating sage extract or dragon's blood (DB) present hydrogen bonding between these components. PVA-CMC hydrogels containing sage present similar spectra to PVA-CMC alone, probably indicating low miscibility or interaction between the matrix and sage. The opposite is found for DB, which exhibits more pronounced interference with crystallinity than sage. DB and NaCMC negatively affect Young's modulus and failure strength. All samples appear to reach equilibrium swelling degree (ESD) in 24 h. The addition of DB and sage to PVA increases the gels' swelling capacity, indicating that the substances likely separate PVA chains. The inclusion of CMC contributes to high media uptake. The kinetics profile of media uptake for 4 days is described by a power-law model, which is correlated to the drug delivery mechanism. A PVA-CMC gel incorporating 15% DB, the highest amount tested, shows the most favorable characteristics for flavonoid delivery, as well as flexibility and swelling capacity.

Interrogating the Role of Endocytosis Pathway and Organelle Trafficking for Doxorubicin-Based Combination Ionic Nanomedicines.

We have studied the endocytic mechanisms that determine subcellular localization for three carrier-free chemotherapeutic-photothermal (chemo-PTT) combination ionic nanomedicines (INMs) composed of doxorubicin (DOX) and an near-infrared (NIR) dye (ICG, IR820, or IR783). This study aims to understand the cellular basis for previously published enhanced toxicity results of these combination nanomedicines toward MCF-7 breast cancer cells. The active transport mechanism of INMs, unlike free DOX, which is known to employ passive transport, was validated by conducting temperature-dependent cellular uptake of the drug in MCF-7 cells using confocal microscopy. The internalization pathway of these INMs was further probed in the presence and absence of different endocytosis inhibitors. Detailed examination of the mode of entry of the carrier-free INMs in MCF-7 cells revealed that they are primarily internalized through clathrin-mediated endocytosis. In addition, time-dependent subcellular localization studies were also investigated. Examination of time-dependent confocal images indicated that the INMs targeted multiple organelles, in contrast to free DOX that primarily targets the nucleus. Collectively, the high cellular endocytic uptake in cancerous cells (EPR effect) and the multimode targeting ability demonstrated the main reason for the low half-maxima inhibitory concentration (IC50) value (the high cytotoxicity) of these carrier-free INMs as compared to their respective parent chemo and PTT drugs.

Enhanced breast cancer therapy using multifunctional lipid-coated nanoparticles combining curcumin chemotherapy and nitric oxide gas delivery

The limitations associated with conventional cancer treatment modalities, particularly for breast cancer, underscore the imperative for developing safer and more productive drug delivery systems. A promising strategy that has emerged is the combination of chemotherapy with gas therapy. We synthesized curcumin-loaded amorphous calcium carbonate nanoparticles (Cur-CaCO3) via a gas diffusion reaction in the present study. Subsequently, a "one-step" ethanol injection method was employed to fabricate lipid-coated calcium carbonate nanoparticles (Cur-CaCO3@LA-Lip) loaded with L-arginine, aimed at harnessing the synergistic effects of chemotherapy and nitric oxide to enhance antitumor efficacy. Transmission electron microscopy analysis revealed that Cur-CaCO3@LA-Lip nanoparticles were subspherical with a distinct lipid layer encapsulating the periphery. Fourier transform infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry results confirmed the successful synthesis of Cur-CaCO3@LA-Lip. The nanoparticles exhibited significant drug loading capacities of 8.89% for curcumin and 3.1% for L-arginine. In vitro and in vivo assessments demonstrated that Cur-CaCO3@LA-Lip nanoparticles facilitated sustained release of curcumin and exhibited high cellular uptake, substantial tumor accumulation, and excellent biocompatibility. Additionally, the nanoparticles showed robust cytotoxicity and potent antitumor efficacy, suggesting their potential as a formidable candidate for breast cancer therapy.

Association of serum lactate dehydrogenase with prognosis and tumor metabolism in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy.

Treatment outcomes are predicted by analyzing peripheral blood markers such as serum lactate dehydrogenase (LDH). We conducted this study to investigate whether serum LDH levels can predict the prognosis of patients treated with atezolizumab plus bevacizumab (ATZ/BEV) therapy for hepatocellular carcinoma (HCC) and whether LDH levels correlate with metabolic changes. We enrolled 66 HCC patients treated with ATZ/BEV. Based on the change in serum LDH levels before and after treatment, the patients were divided into two groups, and the prognosis of each group was examined. Moreover, the association of LDH levels with tumor metabolism was analyzed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). There were 32 patients categorized as the LDH-decrease group. Kaplan-Meier survival analysis indicated worse progression-free survival (PFS) in the LDH-increase group than in the LDH-decrease group (p = 0.0029). Multivariate analysis showed that an increase in the LDH level was an independent risk factor for worse PFS (p = 0.0045). The baseline LDH level correlated significantly with a high maximum standardized uptake value of 18F-FDG, according to the PET/CT findings. Transcriptomic analyses of specimens resected after ATZ/BEV therapy showed downregulated mitochondria-related pathways. Serum LDH levels are a potential prognostic marker and an indicator of tumor metabolism.

Newly synthesised diglycolamide functionalised silica gel with terminal 2-ethylhexyl alkyl chain, Silica-DGA (2EH) having high ligand density for adsorption of trivalent actinide and lanthanide from acidic medium

A novel diglycolamide resin with 2-ethylhexyl terminal alkyl chain functionalised to silica gel was synthesised and characterised by ATR-FTIR, SEM, TG/DSC, &13C (CP/MAS) solid state NMR techniques. Effective functionalization of the organic ligand upon silica gel was confirmed from the two carbonyl stretching frequencies at 1735 cm−1 and 1619 cm−1 in the FTIR spectrum and carbonyl carbon atom signal at 170 ppm in 13C (CP/MAS) solid state NMR spectrum. Thermo gravimetric measurement showed 17.3 ± 0.2 % (W/W) weight loss corresponding to the ligand loading value of 425 µmol/g. The resin showed very high uptake of trivalent lanthanide and actinide ions from 4.0 M HNO3 medium and very low distribution of Cs & Sr; Kd ∼ 1.1×103 mL/g for Am(III), ∼ 1.41×103 mL/g for Eu(III), ∼2.5 mL/g for Sr and 1.53 mL/g for Cs. FTIR spectroscopic study of the Eu3+ adsorbed resin showed single carbonyl stretching frequency at 1654 cm−1, instead of the two carbonyl stretching frequencies in fresh silica-DGA(2EH) resin indicating complexation through carbonyl oxygen. Very low Kd of ∼1.2–5.1 mL/g for lanthanides/actinides from 4.0 M HNO3 containing water soluble DGA namely N, N, N, N, Tetraethyldiglycolamide (TEDGA) in the concentration range 0.3–0.1 M indicates 99 % back adsorption feasibility.

Hierarchically porous carbon foams coated with carbon nitride: Insights into adsorbents for pre-combustion and post-combustion CO2 separation

Adsorption is fundamental to many industrial processes, including separation of carbon dioxide from other gases in pre- or post-combustion gas mixtures. Adsorbents should have high capacity and selectivity, which are both intimately linked with surface area, pore size distribution, and surface energy. Porous carbons are cheap and scalable adsorbents, but greater understanding of how their textural properties and surface chemistry affects their performance is needed. Here, we investigate the effect of nitrogen doping on CO2 adsorption. Microporous carbon foams with large surface area (>2500 m2 g−1) and pore volume (1.6 cm3 g−1) are synthesized, then coated with varying amounts of carbon nitride (up to 17 at% nitrogen) to achieve high CO2 uptake (25.5 mmol g−1) and selectivity (CO2:N2 = 21), whilst also giving insights into the relationship between structure and function. At low pressure (relevant to post-combustion capture), moderate carbon nitride loading leads to enhanced uptake and selectivity by combining large ultramicropore volume with the introduction of Lewis base sites, leading to high isosteric heat of adsorption. Higher carbon nitride loading further increases selectivity but lowers uptake by blocking micropores. Conversely, at high pressure (relevant to pre-combustion capture) the uncoated carbon foam displays superior uptake, because mesoporosity is the dominant factor in this regime, rather than the presence of ultramicropores. Finally, the samples displayed excellent regeneration under repeated adsorption–desorption cycles, and breakthrough curves were measured. These results underscore the delicate balance required for optimal material design when applying porous carbon adsorbents to CO2 separation processes. Moving forward, improved adsorbents will contribute to the proliferation of carbon capture and storage (CCS) and carbon capture and utilisation (CCU) technologies, ultimately contributing reduced anthropogenic CO2 emissions.

Prognostic Value of Bone Scintigraphy in Cardiac Amyloidosis: A Systematic Review and Meta-analysis.

The prognostic value of bone scintigraphy in cardiac amyloidosis (CA) remains undetermined. We conducted a systematic review and meta-analysis on the association of cardiac uptake on bone scintigraphy with mortality in known or suspected CA. PubMed, Embase, and Cochrane library databases were searched up to November 2023 for studies that evaluated cardiac uptake on bone scintigraphy as a prognostic factor in the workup of CA. Hazards ratios (HRs) of high cardiac uptake for outcomes of all-cause or cardiac death were pooled and analyzed with stratifications according to the study populations, analytical methodologies, and radiotracers. Fourteen studies (3325 patients) were finally included. In studies regarding known or suspected CA, visual grades were not prognostically significant, regardless of the threshold used, with pooled HRs of 2.25 (95% confidence interval [CI], 0.93-5.48), 1.55 (95% CI, 0.89-2.68), and 1.53 (95% CI, 0.95-2.47) for visual grades ≥1, ≥2, and ≥3, respectively. By contrast, high cardiac uptake on semiquantitative measurements (heart-to-contralateral lung ratio, n = 6; heart-to-whole-body ratio, n = 1) was associated with increased mortality (pooled HR = 2.27 [95% CI, 1.87-2.76] for all semiquantitative measurements; 2.26 [1.86-2.74] for heart-to-contralateral lung ratio only). No difference in prognostic significance was found across 3 different 99mTc-radiotracers (P = 0.619). However, high cardiac uptake was not predictive of mortality in aortic stenosis-related CA (pooled HR = 1.13 [95% CI, 0.96-1.32]). High semiquantitative cardiac uptake on bone scintigraphy is associated with an increased risk of mortality in patients with known or suspected CA.

Synthesis of 64Cu-, 55Co-, and 68Ga-Labeled Radiopharmaceuticals Targeting Neurotensin Receptor-1 for Theranostics: Adjusting InVivo Distribution Using Multiamine Macrocycles.

The development of theranostic radiotracers relies on their binding to specific molecular markers of a particular disease and the use of corresponding radiopharmaceutical pairs thereafter. This study reports the use of multiamine macrocyclic moieties (MAs), as linkers or chelators, in tracers targeting the neurotensin receptor-1 (NTSR-1). The goal is to achieve elevated tumor uptake, minimal background interference, and prolonged tumor retention in NTSR-1-positive tumors. Methods: We synthesized a series of neurotensin antagonists bearing MA linkers and metal chelators. The MA unit is hypothesized to establish a strong interaction with the cell membrane, and the addition of a second chelator may enhance water solubility, consequently reducing liver uptake. Small-animal PET/CT imaging of [64Cu]Cu-DOTA-SR-3MA, [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, [64Cu]Cu-NT-CB-DOTA, and [64Cu]Cu-NT-Sarcage was acquired at 1, 4, 24, and 48 h after injection using H1299 tumor models. [55Co]Co-NT-CB-NOTA was also tested in HT29 (high NTSR-1 expression) and Caco2 (low NTSR-1 expression) colorectal adenocarcinoma tumor models. Saturation binding assay and internalization of [55Co]Co-NT-CB-NOTA were used to test tracer specificity and internalization in HT29 cells. Results: In vivo PET imaging with [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, and [55Co]Co-NT-CB-NOTA revealed high tumor uptake, high tumor-to-background contrast, and sustained tumor retention (≤48 h after injection) in NTSR-1-positive tumors. Tumor uptake of [64Cu]Cu-NT-CB-NOTA remained at 76.9% at 48 h after injection compared with uptake 1 h after injection in H1299 tumor models, and [55Co]Co-NT-CB-NOTA was retained at 60.2% at 24 h compared with uptake 1 h after injection in HT29 tumor models. [64Cu]Cu-NT-Sarcage also showed high tumor uptake with low background and high tumor retention 48 h after injection Conclusion: Tumor uptake and pharmacokinetic properties of NTSR-1-targeting radiopharmaceuticals were greatly improved when attached with different nitrogen-containing macrocyclic moieties. The study results suggest that NT-CB-NOTA labeled with either 64Cu/67Cu, 55Co/58mCo, or 68Ga (effect of 177Lu in tumor to be determined in future studies) and NT-Sarcage labeled with 64Cu/67Cu or 55Co/58mCo may be excellent diagnostic and therapeutic radiopharmaceuticals targeting NTSR-1-positive cancers. Also, the introduction of MA units to other ligands is warranted in future studies to test the generality of this approach.

Synthesis and Preclinical Evaluation of [18F]AlF-NOTA-Asp2-PEG2-Folate as a Novel Folate-Receptor-Targeted Tracer for PET Imaging.

Recently, the folate receptor (FR) has become an exciting target for the diagnosis of FR-positive malignancies. Nevertheless, suboptimal invivo pharmacokinetic properties, particularly high uptake in the renal and hepatobiliary systems, are important limiting factors for the clinical translation of most FR-based radiotracers. In this study, we developed a novel 18F-labeled FR-targeted positron emission tomography (PET) tracer [18F]AlF-NOTA-Asp2-PEG2-Folate modified with a hydrophilic linker (-Asp2-PEG2) to optimize its pharmacokinetic properties and conducted a comprehensive preclinical assessment. The [18F]AlF-NOTA-Asp2-PEG2-Folate was manually synthesized within 30 min with a non-decay-corrected radiochemical yield of 16.3 ± 2.0% (n = 5). Among KB cells, [18F]AlF-NOTA-Asp2-PEG2-Folate exhibited high specificity and affinity for FR. PET/CT imaging and biodistribution experiments in KB tumor-bearing mice showed decent tumor uptake (1.7 ± 0.3% ID/g) and significantly decreased uptake in kidneys and liver (22.2 ± 2.1 and 0.3 ± 0.1% ID/g at 60 min p.i., respectively) of [18F]AlF-NOTA-Asp2-PEG2-Folate, compared to the known tracer [18F]AlF-NOTA-Folate (78.6 ± 5.1 and 5.3 ± 0.5 % ID/g at 90 min p.i., respectively). The favorable properties of [18F]AlF-NOTA-Asp2-PEG2-Folate, including its efficient synthesis, decent tumor uptake, relatively low renal uptake, and rapid clearance from most normal organs, portray it as a promising PET tracer for FR-positive tumors.

The Use of Pictorial Recall Aids Modifies Dietary Assessment Results: Experiences from Quantitative 24-hour Dietary Recalls of Young Children in Nepal and Senegal

BackgroundRecall bias or memory error is a known limitation of recall-based dietary assessment methods and can lead to substantial misrepresentation of diets. Pictorial recall aids have been used by various studies to mitigate recall bias, but their effect on quantitative, 4-pass 24-h dietary recall (24HR) results has not yet been measured. ObjectivesThis article examines uptake of pictorial recall aids among caregivers of young children in Kathmandu Valley, Nepal, and Guédiawaye Department, Senegal; describes what foods/beverages are subject to recall bias in these contexts; and assesses the effect of these recall aids on estimated dietary outcomes. MethodsWe used cross-sectional data from 24HR surveys that provided a recall aid to reduce caregiver recall bias. Young children’s dietary outcomes were calculated from the 24HR data. Logistic regressions were used to compare characteristics and estimated dietary outcomes of children by recall aid uptake. McNemar’s test and paired t-tests were used to compare estimated dietary outcomes in initial 24HR data with revised 24HR data that incorporated omitted items identified by the recall aid. ResultsPictorial recall aids had relatively high uptake by caregivers in both contexts. Beverages, unhealthy snacks, and fruit were most subject to recall bias. Adding omitted items identified by recall aids resulted in statistically significant changes in most dietary outcomes assessed. Children of caregivers who chose to use the recall aid had significantly different estimated dietary outcomes than children of caregivers who did not use the recall aid. ConclusionsThe use of pictorial recall aids modifies 24HR results in these 2 contexts. Rigorous research is needed to fully understand the impact of recall aids on 24HR methodology and results, with an aim to improve the accuracy of dietary assessment and ultimately inform evidence-based nutrition programming, policy, and recommendations.

Factors associated with COVID-19 vaccine uptake among South African health care workers

BackgroundIdentifying factors associated with vaccine uptake among health care workers (HCWs) remains crucial to generating evidence aimed at guiding national COVID-19 vaccination and future infectious disease outbreak strategies. This study aimed to elucidate these factors, focusing on the interplay between socio-demographic, health, knowledge, beliefs and attitudinal indicators. MethodsThis was a cross-sectional online survey administered to HCWs across South Africa between August and October 2022. Bivariate and Multivariate logistic regressions identified associations between COVID-19 vaccine uptake and demographics, occupational characteristics, general knowledge of and attitudes towards vaccination, perceived COVID-19 risk and perceived importance of COVID-19 vaccine attributes. ResultsAnalysis revealed high vaccine uptake rates among the sample of 5564 HCWs, with 87.6% of the sample vaccinated at the time of the study. Demographic measures significantly associated with vaccine uptake were age (P-value = 0.001), race (P-value = 0.021), religion (P-value = 0.004), and having a chronic illness (P-value <0.001). Belief and attitude measures significantly associated with vaccine uptake included: need for vaccines (P-value <0.001), perceived risk of infection (P-value = 0.001), perceived patient risk (P-value <0.001), and perceived vaccine knowledge (P-value <0.001). Multivariate analysis revealed that HCWs who listed their religion as African Spirituality (OR = 0.4; 95% CI = 0.2–0.7; P-value = 0.002) and had any occupation other than nurse or doctor (OR = 0.6; 95% CI = 0.4–0.8; P-value <0.001), were less likely to vaccinate, while HCWs who had a chronic condition (OR = 1.5; 95% CI = 1.2–2.0; P-value <0.001) were more likely to have been vaccinated. ConclusionThis study provides useful insights into the factors associated with and possibly driving COVID-19 vaccine uptake among HCWs in South Africa. These results add to a limited body of knowledge on contextual dynamics associated with vaccination programmes in Africa.

Stepwise tuning carbon slits at sub-angstrom scale for dynamical separation of hydrogen isotope

Heavier hydrogen isotope is indispensable for many applications such as isotope tracing and labeling, neutron scattering, and nuclear fusion reaction. Thus it calls for efficient hydrogen isotope separation. Cryogenic adsorptive separation is an energy-efficient way for deuterium/protium (D2/H2) separation, requiring nanopores with precisely tuned pore size and suitable geometry to induce the quantum sieving effect. Herein, we report on the stepwise tuned slit-shaped ultramicropores at sub-angstrom (Å) scale for highly efficient D2/H2 separation. The opening width of carbon nanoslits was precisely tuned by the devised thermal-induced molecularly imprinting method. The adsorbent with 4.0 Å centered nanoslits showed an excellent D2/H2 uptake ratio of 1.9 with a high D2 uptake of 10.1mmol/g at 40 K and 100 kPa. Column breakthrough experiments revealed a high D2/H2 selectivity of 10.1 at 40 K. It evidenced that the 4.0 Å centered slits enable an optimal balance between the barrier induced by zero-point energy and the adsorption potential at 40 K, thereby reaching a selectively quantized configurational diffusion of D2/H2. Programmed thermal desorption experiments indicated that a 0.1 Å alteration of the slit size enhanced the quantum sieving effect of D2/H2 by 180 %. These results would benefit the understanding of D2/H2 separation behavior, and the design principle may inspire other isotope separations.

Haemorrhage after thrombectomy with adjuvant thrombolysis in unknown onset stroke depends on high early lesion water uptake

Background and purposeIn wake-up stroke, CT-based quantitative net water uptake (NWU) might serve as an alternative tool to MRI to guide intravenous thrombolysis with alteplase (IVT). An important complication after...