HIF-1 Sensor in Detecting Hypoxia Tolerance at High Altitude.

INTRODUCTION: An episode of prolonged exposure to high altitude can cause hypoxia and have significant health consequences. In people with a high-altitude disorder, the body reacts by producing a protein called hypoxia-inducible factor (HIF), which triggers a series of physiological changes and serves a central role in the hypoxia response. Its activity is regulated by the oxygen-dependent degradation of the HIF-1α protein (HIF-1A gene). Therefore, the effects of low oxygen tension in high altitude were explored using fluorescent sensors of hypoxia.METHODS: The development of the sensor provided more sensitivity for detecting hypoxia by generating a calibration of optimized parameters such as reagent concentrations, reagent volumes, and device dimensions.RESULTS: There is a high sensitivity and specificity in detecting the changes of HIF-1α protein hypoxia using the feasibility hypoxia test. This would enable point-of-care (POC) testing and individual self-administration, resulting in faster and more accurate results that can be used for a robust diagnostic approach and enhanced health surveillance, particularly in high-altitude exposure.Shaharuddin S, Rahman NMANA, Masarudin MJ, Alamassi MN, Saad FFA. HIF-1 sensor in detecting hypoxia tolerance at high altitude. Aerosp Med Hum Perform. 2023; 94(6):485-487.

Preparation, Optimisation, and In Vitro Evaluation of [18F]AlF-NOTA-Pamidronic Acid for Bone Imaging PET.

[18F]sodium fluoride ([18F]NaF) is recognised to be superior to [99mTc]-methyl diphosphate ([99mTc]Tc-MDP) and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in bone imaging. However, there is concern that [18F]NaF uptake is not cancer-specific, leading to a higher number of false-positive interpretations. Therefore, in this work, [18F]AlF-NOTA-pamidronic acid was prepared, optimised, and tested for its in vitro uptake. NOTA-pamidronic acid was prepared by an N-Hydroxysuccinimide (NHS) ester strategy and validated by liquid chromatography-mass spectrometry analysis (LC-MS/MS). Radiolabeling of [18F]AlF-NOTA-pamidronic acid was optimised, and it was ensured that all quality control analysis requirements for the radiopharmaceuticals were met prior to the in vitro cell uptake studies. NOTA-pamidronic acid was successfully prepared and radiolabeled with 18F. The radiolabel was prepared in a 1:1 molar ratio of aluminium chloride (AlCl3) to NOTA-pamidronic acid and heated at 100 °C for 15 min in the presence of 50% ethanol (v/v), which proved to be optimal. The preliminary in vitro results of the binding of the hydroxyapatite showed that [18F]AlF-NOTA-pamidronic acid was as sensitive as [18F]sodium fluoride ([18F]NaF). Normal human osteoblast cell lines (hFOB 1.19) and human osteosarcoma cell lines (Saos-2) were used for the in vitro cellular uptake studies. It was found that [18F]NaF was higher in both cell lines, but [18F]AlF-NOTA-pamidronic acid showed promising cellular uptake in Saos-2. The preliminary results suggest that further preclinical studies of [18F]AlF-NOTA-pamidronic acid are needed before it is transferred to clinical research.

Towards efficient Monte Carlo N-Particle simulation of a positron emission tomography (PET) via source volume definition.

Monte Carlo N-Particle (MCNP) simulation has been extensively proven in nuclear medicine imaging systems, most notably in designing and optimizing new medical imaging tools. It enables more complicated geometries and the simulation of particles passing through and interacting with materials. However, a relatively long simulation time is a drawback of Monte Carlo simulation, mainly when complex geometry exists. The current study presents an alternative variance reduction technique for a modeled positron emission tomography (PET) camera by reducing the height of the source volume definition while maintaining the geometry of the simulated model. The National Electrical Manufacturers Association (NEMA) of the International Electrotechnical Commission (IEC) PET's phantom was used with a 1 cm diameter and 7 cm height of line source placed in the middle. The first geometry was fully filled the line source with 0.50 mCi radioactivity. In contrast, the second geometry decreased the source definition to 2.4 cm in height, covering 1 cm above and below the sub-block detector level. The source volume definition approach led to a 71% reduction in the total photons to be simulated. Results showed that the proposed variance reduction strategy could produce spatial resolution as precise as fully filled geometry and sped up the simulation time by approximately 65%. Hence, this strategy can be utilized for further PET optimizing simulation studies.

Correlation between 18F-FDG dosage and SNR on various BMI patient groups tested in NEMA IEC PET phantom.

The present study was conducted to determine quantitatively the correlation between injected radiotracer and signal-to-noise ratio (SNR) based on differences in physiques and stages of cancer. Eight different activities were evaluated with modelled National Electrical Manufacturers Association (NEMA) of the International Electrotechnical Commission (IEC) PET's phantom with nine different tumour-to-background ratio (TBR). The findings suggest that the optimal value of dosage is required for all categories of patients in the early stages of cancer diagnosis.

Preparation, Characterization, and Radiolabeling of [68Ga]Ga-NODAGA-Pamidronic Acid: A Potential PET Bone Imaging Agent.

Early diagnosis of bone metastases is crucial to prevent skeletal-related events, and for that, the non-invasive techniques to diagnose bone metastases that make use of image-guided radiopharmaceuticals are being employed as an alternative to traditional biopsies. Hence, in the present work, we tested the efficacy of a gallium-68 (68Ga)-based compound as a radiopharmaceutical agent towards the bone imaging in positron emitting tomography (PET). For that, we prepared, thoroughly characterized, and radiolabeled [68Ga]Ga-NODAGA-pamidronic acid radiopharmaceutical, a 68Ga precursor for PET bone cancer imaging applications. The preparation of NODAGA-pamidronic acid was performed via the N-Hydroxysuccinimide (NHS) ester strategy and was characterized using liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectrometry (MSn). The unreacted NODAGA chelator was separated using the ion-suppression reverse phase-high performance liquid chromatography (RP-HPLC) method, and the freeze-dried NODAGA-pamidronic acid was radiolabeled with 68Ga. The radiolabeling condition was found to be most optimum at a pH ranging from 4 to 4.5 and a temperature of above 60 °C. From previous work, we found that the pamidronic acid itself has a good bone binding affinity. Moreover, from the analysis of the results, the ionic structure of radiolabeled [68Ga]Ga-NODAGA-pamidronic acid has the ability to improve the blood clearance and may exert good renal excretion, enhance the bone-to-background ratio, and consequently the final image quality. This was reflected by both the in vitro bone binding assay and in vivo animal biodistribution presented in this research.

A bimodal theranostic nanodelivery system based on [graphene oxide-chlorogenic acid-gadolinium/gold] nanoparticles.

We have synthesized a bimodal theranostic nanodelivery system (BIT) that is based on graphene oxide (GO) and composed of a natural chemotherapeutic agent, chlorogenic acid (CA) used as the anticancer agent, while gadolinium (Gd) and gold nanoparticles (AuNPs) were used as contrast agents for magnetic resonance imaging (MRI) modality. The CA and Gd guest agents were simultaneously loaded on the GO nanolayers using chemical interactions, such as hydrogen bonding and π-π non-covalent interactions to form GOGCA nanocomposite. Subsequently, the AuNPs were doped on the surface of the GOGCA by means of electrostatic interactions, which resulted in the BIT. The physico-chemical studies of the BIT affirmed its successful development. The X-ray diffractograms (XRD) collected of the various stages of BIT synthesis showed the successive development of the hybrid system, while 90% of the chlorogenic acid was released in phosphate buffer solution (PBS) at pH 4.8. This was further reaffirmed by the in vitro evaluations, which showed stunted HepG2 cancer cells growth against the above 90% cell growth in the control cells. A reverse case was recorded for the 3T3 normal cells. Further, the acquired T1-weighted image of the BIT doped samples obtained from the MRI indicated contrast enhancement in comparison with the plain Gd and water references. The abovementioned results portray our BIT as a promising future chemotherapeutic for anticancer treatment with diagnostic modalities.

PET/CT analysis of 21 patients with breast cancer: physiological distribution of 18F-choline and diagnostic pitfalls.

Objectives 18F-choline is a useful tracer for detecting tumours with high lipogenesis. Knowledge of its biodistribution pattern is essential to recognise physiological variants. The aim of this study was to describe the physiologic distribution of 18F-choline and pitfalls in patients with breast cancer. Methods Twenty-one consecutive patients with breast cancer (10 premenopausal and 11 postmenopausal women; mean age, 52.82 ± 10.71 years) underwent 18F-choline positron emission tomography (PET)/computed tomography (CT) for staging. Whole-body PET/CT was acquired after 40 minutes of 18F-choline uptake. Acquired PET images were measured semiquantitatively. Results All patients showed pitfalls unrelated to breast cancer. These findings were predominantly caused by physiological glandular uptake in the liver, spleen, pancreas, bowels, axial skeleton (85%-100%), inflammation and benign changes (4.76%), appendicular skeleton (4.76%-19.049%), and site contamination (61.9%). In <1%, a concomitant metastatic neoplasm was found. The breast showed higher physiological uptake in premenopausal compared with postmenopausal woman (18F-choline maximum standardised uptake values [g/dL] of the right breast = 2.04 ± 0.404 vs 1.59 ± 0.97 and left breast = 2.00 ± 0.56 vs 1.93 ± 1.28, respectively). Conclusion 18F-choline uptake was higher in premenopausal women. Physiological 18F-choline uptake was observed in many sites, representing possible pathologies.

Graphene Oxide as a Nanocarrier for a Theranostics Delivery System of Protocatechuic Acid and Gadolinium/Gold Nanoparticles.

We have synthesized a graphene oxide (GO)-based theranostic nanodelivery system (GOTS) for magnetic resonance imaging (MRI) using naturally occurring protocatechuic acid (PA) as an anticancer agent and gadolinium (III) nitrate hexahydrate (Gd) as the starting material for a contrast agent,. Gold nanoparticles (AuNPs) were subsequently used as second diagnostic agent. The GO nanosheets were first prepared from graphite via the improved Hummer's protocol. The conjugation of the GO and the PA was done via hydrogen bonding and π-π stacking interactions, followed by surface adsorption of the AuNPs through electrostatic interactions. GAGPA is the name given to the nanocomposite obtained from Gd and PA conjugation. However, after coating with AuNPs, the name was modified to GAGPAu. The physicochemical properties of the GAGPA and GAGPAu nanohybrids were studied using various characterization techniques. The results from the analyses confirmed the formation of the GOTS. The powder X-ray diffraction (PXRD) results showed the diffractive patterns for pure GO nanolayers, which changed after subsequent conjugation of the Gd and PA. The AuNPs patterns were also recorded after surface adsorption. Cytotoxicity and magnetic resonance imaging (MRI) contrast tests were also carried out on the developed GOTS. The GAGPAu was significantly cytotoxic to the human liver hepatocellular carcinoma cell line (HepG2) but nontoxic to the standard fibroblast cell line (3T3). The GAGPAu also appeared to possess higher T1 contrast compared to the pure Gd and water reference. The GOTS has good prospects of serving as future theranostic platform for cancer chemotherapy and diagnosis.

Gadolinium-based layered double hydroxide and graphene oxide nano-carriers for magnetic resonance imaging and drug delivery.

Gadolinium (Gd)-based contrasts remain one of the most accepted contrast agents for magnetic resonance imaging, which is among the world most recognized noninvasive techniques employed in clinical diagnosis of patients. At ionic state, Gd is considered toxic but less toxic in chelate form. A variety of nano-carriers, including gadolinium oxide (Gd2O3) nanoparticles have been used by researchers to improve the T1 and T2 contrasts of MR images. Even more recently, a few researchers have tried to incorporate contrast agents simultaneously with therapeutic agents using single nano-carrier for theranostic applications. The benefit of this concept is to deliver the drugs, such as anticancer drugs and at the same time to observe what happens to the cancerous cells. The delivery of both agents occurs concurrently. In addition, the toxicity of the anticancer drugs as well as the contrast agents will be significantly reduced due to the presence of the nano-carriers. The use of graphene oxide (GO) and layered double hydroxides (LDH) as candidates for this purpose is the subject of current research, due to their low toxicity and biocompatibility, which have the capacity to be used in theranostic researches. We review here, some of the key features of LDH and GO for simultaneous drugs and diagnostic agents delivery systems for use in theranostics applications.

Gadolinium-Doped Gallic Acid-Zinc/Aluminium-Layered Double Hydroxide/Gold Theranostic Nanoparticles for a Bimodal Magnetic Resonance Imaging and Drug Delivery System.

We have developed gadolinium-based theranostic nanoparticles for co-delivery of drug and magnetic resonance imaging (MRI) contrast agent using Zn/Al-layered double hydroxide as the nanocarrier platform, a naturally occurring phenolic compound, gallic acid (GA) as therapeutic agent, and Gd(NO3)3 as diagnostic agent. Gold nanoparticles (AuNPs) were grown on the system to support the contrast for MRI imaging. The nanoparticles were characterized using techniques such as Hi-TEM, XRD, ICP-ES. Kinetic release study of the GA from the nanoparticles showed about 70% of GA was released over a period of 72 h. The in vitro cell viability test for the nanoparticles showed relatively low toxicity to human cell lines (3T3) and improved toxicity on cancerous cell lines (HepG2). A preliminary contrast property test of the nanoparticles, tested on a 3 Tesla MRI machine at various concentrations of GAGZAu and water (as a reference) indicates that the nanoparticles have a promising dual diagnostic and therapeutic features to further develop a better future for clinical remedy for cancer treatment.

Incremental Role of Fluorine 18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Assessment of Computed Tomography-Inconspicuous Pancreatic Lesions.

Background: Pancreatic malignancies encompass a heterogenous group of disorders, with poor prognosis at diagnosis. Traditionally, conventional computed tomography (CT) has been used for diagnosis, staging, and follow up. However, this technique lacks functional information; and is limited in diagnosis of occult pancreatic disease. Hybrid imaging in the form of positron emission tomography (PET)/CT provides a potential avenue for early detection and subsequent appropriate therapy. Case Presentation: A 60-year-old male, with a history of abdominal aortic aneurysm which was repaired, came with a complaint of 2 months history of back pain, radiating to the front. The pain was relieved on leaning forward, and aggravated by lying on his back. CT angiography of the abdomen was done, which revealed a concealed aortic aneurysm and a significant atrophy of the pancreatic tail. The serum cancer antigen (CA) 19-9 was elevated (50.0 U/mL, reference range 0.0-37.0 U/mL). At this juncture, the PET scan done revealed no discernible abnormalities. Patient was put on close follow-up in view of the rising trend of CA 19-9 levels. Three months following the initial scans, a repeat 18F-FDG (fluorine 18 fluorodeoxyglucose) PET/CT revealed an FDG-avid lesion at the neck of the pancreas on PET without perceptible changes on the correlated CT. A Whipple's procedure ensued, with histopathological examination findings of pancreatic adenocarcinoma. Conclusion: This article discusses the role of PET/CT in the early diagnosis of inconspicuous pancreatic lesions; which could have averted immediate medical therapy.

Impacts of biological and procedural factors on semiquantification uptake value of liver in fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging.

BACKGROUND: Increased metabolic activity of fluorodeoxyglucose (FDG) in tissue is not only resulting of pathological uptake, but due to physiological uptake as well. This study aimed to determine the impacts of biological and procedural factors on FDG uptake of liver in whole body positron emission tomography/computed tomography (PET/CT) imaging. METHODS: Whole body fluorine-18 ((18)F) FDG PET/CT scans of 51 oncology patients have been reviewed. Maximum standardized uptake value (SUVmax) of lesion-free liver was quantified in each patient. Pearson correlation was performed to determine the association between the factors of age, body mass index (BMI), blood glucose level, FDG dose and incubation period and liver SUVmax. Multivariate regression analysis was established to determine the significant factors that best predicted the liver SUVmax. Then the subjects were dichotomised into four BMI groups. Analysis of variance (ANOVA) was established for mean difference of SUVmax of liver between those BMI groups. RESULTS: BMI and incubation period were significantly associated with liver SUVmax. These factors were accounted for 29.6% of the liver SUVmax variance. Statistically significant differences were observed in the mean SUVmax of liver among those BMI groups (P<0.05). CONCLUSIONS: BMI and incubation period are significant factors affecting physiological FDG uptake of liver. It would be recommended to employ different cut-off value for physiological liver SUVmax as a reference standard for different BMI of patients in PET/CT interpretation and use a standard protocol for incubation period of patient to reduce variation in physiological FDG uptake of liver in PET/CT study.

Improving the (18)F-fluoromethylcholine ((18)F-FCH) radiochemical yield via optimising the azeotropic drying of non-carrier-added (18)F-fluorine.

(18)F-Fluoromethylcholine ((18)F-FCH) has been suggested as one of the reputable imaging tracers for diagnosis of prostate tumour in PET/CT examination. Nevertheless, it has never been synthesised in Malaysia. We acknowledged the major problem with (18)F-FCH is due to its relatively low radiochemical yield at the end of synthesis (EOS). Therefore, this technical note presents improved (18)F-FCH radiochemical yields after carrying out optimisation on azeotropic drying of non-carrier-added (18)F-Fluorine.