Comparing Outcomes Between Standard Mepilex and Mepilex Silver for Tracheotomy Dressings.

OBJECTIVE: The purpose of the study is to compare the incidence of early postoperative tracheotomy stoma wound complications in pediatric patients using a silver-impregnated barrier dressing (Mepilex Ag) versus a standard absorbent foam dressing (standard Mepilex). METHODS: This is a prospective, non-blinded, randomized trial of pediatric patients undergoing tracheotomy at a tertiary care children's hospital. Patients were randomized to receive Mepilex Ag versus standard Mepilex tracheostoma dressings following tracheotomy. All patients received standard postoperative wound care and daily stomal examination. Wound related complications, breakdown, granulation, and infection were recorded for the first 7 days after surgery. A non-inferiority study design was used to test the hypothesis that the Mepilex group had a non-inferior wound complication rate (within 10% margin) compared to the Mepilex Ag group. RESULTS: Eighty-two patients were enrolled; 52 received Mepilex Ag, and 30 received standard Mepilex. There was no difference between the groups with respect to age, sex, race, surgical indication, or postoperative length of stay. Non-inferiority testing demonstrated that the Mepilex standard cohort had no more than 10% greater stomal wound complication rate than that of Mepilex Ag dressing group (p = 0.0108). CONCLUSION: Standard Mepilex was found to be non-inferior to Mepilex Ag in the prevention of tracheotomy stomal wound complications. Standard Mepilex may be used effectively in the postoperative period, potentially reducing costs to caregivers and the institution. Further work is needed to analyze additional factors that could contribute to poor postoperative stoma healing such as bacterial colonization. LEVEL OF EVIDENCE: Randomized Controlled Trial, Level 2 Laryngoscope, 2024.

Kinetics and mechanism of the gas-phase reaction of the hydroxyl radical with meta-aminotoluene compound.

CONTEXT: An ab initio investigation into the potential energy landscape of the meta-aminotoluene + •OH reaction has been conducted in this study. The calculated results reveal that the reaction channel leading to the product (NHC6H4CH3 + H2O) prevails under the 300-1700 K temperature range, while the reaction path forming the product (NH2C6H4CH2 + H2O) dominates in the higher-temperature region (T ≥ 1800 K). Within the specified temperature range, the product branching ratio for the former declines from 48 to 30%, while the latter shows an increase, reaching 29%. The overall second-order rate constants of the titled reaction obtained at the pressure 760 Torr (N2) can be illustrated by the modified Arrhenius expression of ktotal = 1.46 × 10-13 T0.58 exp[(-0.759 kcal.mol-1)/RT] cm3 molecule-1 s-1 and ktotal = 1.86 × 10-22 T3.24 exp[(-5.086 kcal.mol-1)/RT] cm3 molecule-1 s-1, covering the temperature range of T = 300-600 K and T > 600 K, respectively. The total rate constant at the ambient conditions in this work, 1.43 × 10-11 cm3 molecule-1 s-1, has been found to be roughly one order of magnitude lower than the available experimental data, ~ 1.2 × 10-10 cm3 molecule-1 s-1, measured by Atkinson et al., Rinke et al., and Witte et al., or the theoretical value, 4.4 × 10-10 cm3 molecule-1 s-1, and calculated by Abdel-Rahman and co-workers for the aniline + •OH reaction. METHODS: The structures of reactants, transition states, intermediate states, and products of the meta-aminotoluene + •OH reaction are calculated with the aug-cc-pVTZ basis set and the methods DFT/B3LYP and CCSD(T). The rate constants and branching ratios in the 300-2000 K temperature range are calculated with the statistical theoretical TST and RRKM master equation computations including tunneling corrections, with potential energy surface constructed by the CCSD(T)//B3LYP/aug-cc-pVTZ approach.

A facile paper-based chromatography coupled Au nanodendrite on nickel foam for application in separation and SERS measurement.

A simple paper-based chromatography coupling with nickel foam decorated Au nanodendrite (PP-AuND/NiF) was fabricated for simultaneous separation and surface-enhanced Raman scattering (SERS) detection of Rhodamine-6G (R6G) from a mixture of analytes. The three-dimensional porous nickel foam (NiF) was employed as a sampling diffusion platform, and AuND with a high surface active area beneficial for SERS efficiency was electro-deposited directly onto the NiF frame. The structure of AuND/NiF was characterized by X-ray diffraction and scanning electron microscopy. The AuND/NiF could detect R6G at 0.1 nM, and the enhancement factor was 1.84 x 106. The AuND/NiF was durable, with a slight signal decrease after 6 m of drop-testing. Also, upon three days of exposure to ambient air, the signal droped only 3.35 %. Subsequently, the PP-AuND/NiF was constructed by directly situating AuND/NiF on a paper strip, serving as a sample in and out to AuND/NiF. A mixture of two SERS active compounds, namely 2-Naphthalenethiol (2-NpSH) and Rhodamine 6G (R6G), was prepared in ethanol: water (1:1) solution to evaluate PP-AuND/NiF separation capability. Raman measurements along different distances of AuND/NiF were performed, and the signal of 2-NpSH was dismissed after 3.0 mm, while R6G's signals were observed throughout AuND/NiF. In general, the PP-AuND/NiF demonstrated effective separation and SERS measurement of analytes in a mixture, which could be applicable for more complex samples in the future, especially in clinical analysis.

Pre-treatment dosimetry in90Y-SIRT: Is it possible to optimise SPECT reconstruction parameters and calculation methods for accurate dosimetry?

PURPOSE: The aim of this study was (a) to optimise the99mTc-SPECT reconstruction parameters for the pre-treatment dosimetry of90Y-selective internal radiation therapy (SIRT) and (b) to compare the accuracy of clinical dosimetry methods with full Monte-Carlo dosimetry (fMCD) performed with Gate. METHODS: To optimise the reconstruction parameters, two hundred reconstructions with different parameters were performed on a NEMA phantom, varying the number of iterations, subsets, and post-filtering. The accuracy of the dosimetric methods was then investigated using an anthropomorphic phantom. Absorbed dose maps were generated using (1) the Partition Model (PM), (2) the Dose Voxel Kernel (DVK) convolution, and (3) the Local Deposition Method (LDM) with known activity restricted to the whole phantom (WP) or to the liver and lungs (LL). The dose to the lungs was calculated using the "multiple DVK" and "multiple LDM" methods. RESULTS: Optimal OSEM reconstruction parameters were found to depend on object size and dosimetric criterion chosen (Dmean or DVH-derived metric). The Dmean of all three dosimetric methods was close (≤ 10%) to the Dmean of fMCD simulations when considering large segmented volumes (whole liver, normal liver). In contrast, the Dmean to the small volume (∅=31) was systemically underestimated (12%-25%). For lungs, the "multiple DVK" and "multiple LDM" methods yielded a Dmean within 20% for the WP method and within 10% for the LL method. CONCLUSIONS: All three methods showed a substantial degradation of the dose-volume histograms (DVHs) compared to fMCD simulations. The DVK and LDM methods performed almost equally well, with the "multiple DVK" method being more accurate in the lungs.

Effectiveness of Opioid Switching in Advanced Cancer Pain: A Prospective Observational Cohort Study.

Opioid switching is a common practice of substituting one opioid for another to improve analgesia or adverse effects; however, it has limited evidence. This study aimed to examine the effectiveness of opioid switching in advanced cancer. This multi-center prospective cohort study recruited patients assessed to switch opioids (opioid switch group) or to continue ongoing opioid treatment (control group). Clinical data (demographics, opioids) and validated instruments (pain and adverse effects) were collected over two timepoints seven days apart. Descriptive analyses were utilized. Non-parametric tests were used to determine differences. Fifty-four participants were recruited (23 control group, 31 switch group). At the follow-up, opioid switching reduced pain (worst, average, and now) (p < 0.05), uncontrolled breakthrough pain (3-fold reduction, p = 0.008), and psychological distress (48% to 16%, p < 0.005). The switch group had a ≥25% reduction in the reported frequency of seven moderate-to-severe adverse effects (score ≥ 4), compared to a reduction in only one adverse effect in the control group. The control group experienced no significant pain differences at the follow-up. Opioid switching is effective at reducing pain, adverse effects, and psychological distress in a population with advanced cancer pain, to levels of satisfactory symptom control in most patients within 1 week.

Biochar Adsorbents for Arsenic Removal from Water Environment: A Review.

Arsenic intake can cause human health disorders to the lungs, urinary tract, kidney, liver, hyper-pigmentation, muscles, neurological and even cancer. Biochar is potent, economical and ecologically sound adsorbents for water purification. After surface modifications, adsorption capacity of biochar significantly increased due to high porosity and reactivity. Adsorption capacities of the biochar derived from the municipal solid waste and KOH mixed municipal solid waste were increased from 24.49 and 30.98 mg/g for arsenic adsorption. Complex formation, electrostatic behavior and ion exchange are important mechanisms for arsenic adsorption. Organic arsenic removal using biochar is a major challenge. Hence, more innovative research should be conducted to achieve one of the 17 sustainable development goals of the United Nations i.e. "providing safe drinking water for all". This review is focused on the arsenic removal from water using pristine and modified biochar adsorbents. Recent advances in production methods of biochar adsorbents and mechanisms of arsenic removal from water are also illustrated.

Gas Phase Reaction of Isocyanic Acid: Kinetics, Mechanisms, and Formation of Isopropyl Aminocarbonyl.

Isocyanic acid, HNCO, mainly emitted by combustion processes, is doubted to be detrimental to human health if its concentration surpasses ∼1 ppbv. Very little information has been found regarding the HNCO loss in the gas phase. This study aims to close this knowledge gap by performing a theoretical kinetic study on the reaction of HNCO with the propargyl radical. The potential energy surface of the HNCO + C3H3 reaction was characterized utilizing high-level CCSD(T)/CBS(TQ5)//B3LYP/6-311++G(3df,2p) quantum-chemical approaches, followed by TST and RRKM/ME kinetic computations. The obtained results reveal that the reaction can proceed via H-abstraction, leading to the C3H4 + NCO bimolecular products with energy barriers of 23-25 kcal/mol, and/or addition, resulting in C4H4NO intermediates with 23-26 kcal/mol barrier heights. The C4H4NO adducts when formed can decompose to products and/or return to HNCO + C3H3 in which the reverse decompositions are found to be dominant with a branching ratio that accounts for nearly 100% at 300 K and 760 Torr. The calculated P-independent rate coefficients indicate that at low temperatures, the H-abstraction channels are insignificant. However, at high temperatures (T > 1500 K), the H-abstraction path leading to H3CCCH + NCO prevails with a branching ratio of ∼50-53% in the descending 1800-1500 K temperature range at 760 Torr, while the H-abstraction leading to H2CCCH2 + NCO is favorable at T > 1800 K, with the yield reaching above 50% at 760 Torr. In contrast to the H-abstraction rate constants, the calculated values for the additions and the C4H4NO decompositions show a positive pressure dependence. Both the total rate constants for the reactions HNCO + C3H3 → products and C4H4NO → products, which are, respectively, k _total_bimo(T) = 3.53 × 10-23 T 3.27 exp[(-21.35 ± 0.06 kcal/mol)/RT] cm3 molecule-1 s-1 and k _total_uni(T) = 1.13 × 1025 T -4.02 exp[(-11.77 ± 0.16 kcal/mol)/RT] s-1, increase with the increasing temperature in the 300-2000 K range at 760 Torr. The rate constant of HNCO + C3H3 → products is about 8 orders of magnitude smaller than the value of HCHO + C3H3 → products, showing that HCHO is more reactive toward the C3H3 free radicals than HNCO. The computed heats of formation for several species agree well with the available literature data with the deviation less than 1.0 kcal/mol, indicating that the methods used in this study are extremely reliable. With the given results, it is vigorously suggested that the predicted rate constants, together with the thermodynamic data of the species involved, can be confidently used for modeling HNCO-related systems under atmospheric and combustion conditions.

Potential contribution of pineal atrophy and pineal cysts toward vulnerability and clinical characteristics of psychosis.

BACKGROUND: Magnetic resonance imaging (MRI) studies reported pineal gland atrophy in schizophrenia patients and individuals at a clinical high risk of developing psychosis, implicating abnormalities in melatonin secretion in the pathophysiology of psychosis. However, it currently remains unclear whether the morphology of the pineal gland contributes to symptomatology and sociocognitive functions. METHODS: This MRI study examined pineal gland volumes and the prevalence of pineal cysts as well as their relationship with clinical characteristics in 57 at risk mental state (ARMS) subjects, 63 patients with schizophrenia, and 61 healthy controls. The Social and Occupational Functioning Assessment Scale (SOFAS), the Schizophrenia Cognition Rating Scale (SCoRS), and the Brief Assessment of Cognition in Schizophrenia (BACS) were used to assess sociocognitive functions, while the Positive and Negative Syndrome Scale was employed to evaluate clinical symptoms in ARMS subjects and schizophrenia patients. RESULTS: Pineal gland volumes were significantly smaller in the ARMS and schizophrenia groups than in the controls, while no significant differences were observed in the prevalence of pineal cysts. Although BACS, SCoRS, and SOFAS scores were not associated with pineal morphology, patients with pineal cysts in the schizophrenia group exhibited severe positive psychotic symptoms with rather mild negative symptoms. CONCLUSION: The present results indicate the potential of pineal atrophy as a vulnerability marker in various stages of psychosis and suggest that pineal cysts influence the clinical subtype of schizophrenia.

Synthesis and pharmacological evaluation of [18F]PBR316: a novel PET ligand targeting the translocator protein 18 kDa (TSPO) with low binding sensitivity to human single nucleotide polymorphism rs6971.

Radiopharmaceuticals that target the translocator protein 18 kDa (TSPO) have been investigated with positron emission tomography (PET) to study neuroinflammation, neurodegeneration and cancer. We have developed the novel, achiral, 2-phenylimidazo[1,2-a]pyridine, PBR316 that targets the translocator protein 18 kDa (TSPO) that addresses some of the limitations inherent in current TSPO ligands; namely specificity in binding, blood brain barrier permeability, metabolism and insensitivity to TSPO binding in subjects as a result of rs6971 polymorphism. PBR316 has high nanomolar affinity (4.7-6.0 nM) for the TSPO, >5000 nM for the central benzodiazepine receptor (CBR) and low sensitivity to rs6971 polymorphism with a low affinity binders (LABs) to high affinity binders (HABs) ratio of 1.5. [18F]PBR316 was prepared in 20 ± 5% radiochemical yield, >99% radiochemical purity and a molar activity of 160-400 GBq µmol-1. Biodistribution in rats showed high uptake of [18F]PBR316 in organs known to express TSPO such as heart (3.9%) and adrenal glands (7.5% ID per g) at 1 h. [18F]PBR316 entered the brain and accumulated in TSPO-expressing regions with an olfactory bulb to brain ratio of 3 at 15 min and 7 at 4 h. Radioactivity was blocked by PK11195 and Ro 5-4864 but not Flumazenil. Metabolite analysis showed that radioactivity in adrenal glands and the brain was predominantly due to the intact radiotracer. PET-CT studies in mouse-bearing prostate tumour xenografts indicated biodistribution similar to rats with radioactivity in the tumour increasing with time. [18F]PBR316 shows in vitro binding that is insensitive to human polymorphism and has specific and selective in vivo binding to the TSPO. [18F]PBR316 is suitable for further biological and clinical studies.

A Cross-Sectional Study about Knowledge, Awareness and Perception of Risk Factors for Cancer among Cancer-Patients Relatives and Healthy Adults in Ho Chi Minh City, Vietnam.

BACKGROUND AND AIMS: Although cancer is common in Ho Chi Minh city, Vietnam, the community awareness is still unknown. The primary objective of this study was to examine and compare the knowledge and risk perceptions of cancer possessed by cancer patients - relatives and healthy adults in Ho Chi Minh City, Vietnam. METHODS: A cross-sectional study was conducted from June to August 2019. Cancer patients and their relatives were drawn from those who were hospitalized in the Oncology Hospital, Ho Chi Minh City. Healthy individuals were those without a known diagnosis of cancer, and they were drawn from the participants of the Vietnam Osteoporosis Study. A total of 533 participants including 249 patients and relatives (cancerous group) and 284 healthy individuals (healthy group), were asked to respond to a structured questionnaire that was comprised of items concerning cancer knowledge, risk factor perception, and general attitude towards cancer, using Yes, No, or Likert Scale for response. RESULTS: The findings showed that patients hold poorer knowledge of pathology, signs, symptoms, prevention, and treatment and lower awareness of risk factors but more positive attitude towards cancer as compared to their healthy counterparts. Overall, both groups varied in their cancer knowledge, with many areas remain to be improved. CONCLUSIONS: Knowledge about cancer and its risk factors should be improved among the general population as well as among those with direct experiences with cancer.  Practical implications: The findings provided by this study has major implications for the design of an educational program for cancer patients in clinical settings and awareness programs for the general public as a primary preventive measure for mitigating the cancer burden. Future studies with larger and more diverse samples or qualitative studies exploring the personal narratives of people living with cancer could take advantage from the preliminary data provided by this study. 
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ADDING TWO NEW CONTACT CIRCUMSTANCES TO 'MERGED PHANTOM TOOL' AND A TECHNIQUE TO CONVERT STRUCTURE INFORMATION SEGMENTED BY THE CARIMAS SOFTWARE INTO GEANT4 GEOMETRY.

Two new contact circumstances called 'stand-lie' and 'front-rear' are implemented to the merged phantom tool. To allow more flexibility for users when they calculate the dose for a volume of interest (VOI) with arbitrary geometry, an optional utility to convert segmented structure information from the CARIMAS software into parallel geometry of GEANT4 is provided. The effective dose for a person who has been in contact with a male patient being treated for thyroid cancer with 131I is calculated for four circumstances: opposite, side by side, stand-lie and front-rear. The biggest dose is the 'opposite' circumstance and the smallest one is the 'stand-lie' circumstance. Using the dose distribution in the patient's body and applying the right circumstance should be done to optimise the dose calculation for the contact person.

Removal of Lindane from Aqueous Solution Using Aluminum Hydroxide Nanoparticles with Surface Modification by Anionic Surfactant.

In the present study, we investigated the removal of an emerging pesticide lindane from aqueous solution using synthesized aluminum hydroxide Al(OH)3 (bayerite) nanomaterials with surface modification by an anionic surfactant sodium dodecyl sulfate (SDS). The Al(OH)3 nanoparticles were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET) and zeta potential. The lindane removal using SDS-modified nano-aluminum hydroxide nanoparticles (SMNAH) achieved removal of up to 93.68%, which was 3.3 times higher than that of nano-aluminum hydroxide nanoparticles. The adsorptive removal conditions were studied and found to have an adsorption time of 60 min, a pH of 6, an adsorbent dosage of 25 mg/mL and an ionic strength of 10 mM NaCl. After reusing four times, the removal efficiency of lindane using SMNAH still reached 75%. Two-step adsorption can fit adsorption isotherms of lindane onto SMNAH at two salt concentrations. On the basis of the change in zeta potential, surface functional groups and adsorption isotherms, we suggest that the formation of a bilayer micelle induced the removal of lindane.

Theoretical Study of the Kinetics of the Gas-Phase Reaction between Phenyl and Amino Radicals.

The potential energy surface (PES) of the C6H5 + NH2 reaction has been investigated by using ab initio CCSD(T)//B3LYP/6-311++G(3df,2p) calculations. The conventional transition-state theory (TST) and the variable reaction coordinate-TST (VRC-TST) have been used to predict the rate constants for the channels possessing tight and barrierless transition states, respectively. The Rice-Ramsperger-Kassel-Marcus/Master equation (RRKM/ME) theory has been utilized to determine the pressure-dependent rate constants for these reactions. The PES shows that the reaction begins with an exothermic barrierless addition of NH2 to C6H5 producing the vital intermediate state, namely, aniline (C6H5NH2, IS1). Once IS1 is generated, it can further isomerize to various intermediate states, which can give rise to different products, including PR4 (4,5,6-trihydro-1-amino phenyl + H2), PR5 (3,4,5,6-tetrahydro phenyl + NH3), PR6 (2,3,5,6-tetrahydro-1-imidogen phenyl + H2), PR9 (3,4,5,6-tetrahydro-1-imidogen phenyl + H2), and PR10 (2,5,6-trihydro-1-amino phenyl + H2), of which the most stable product, PR5, was formed by the most favorable channel going through the two advantageous transition states T1/11 (-28.9 kcal/mol) and T11P5 (-21.5 kcal/mol). The calculated rate constants for the low-energy channel, 1.37 × 10-9 and 2.16 × 10-11 cm3 molecule-1 s-1 at T = 300, P = 1 Torr and T = 2000 K, P = 760 Torr, respectively, show that the title reaction is almost pressure- and temperature-dependent. The negative temperature-dependent rate coefficients can be expressed in the modified Arrhenius form of k 1 = 8.54 × 1013 T -7.20 exp (-7.07 kcal·mol-1/RT) and k 2 = 2.42 × 1015 T -7.61 exp (-7.75 kcal·mol-1/RT) at 1 and 10 Torr, respectively, and in the temperature range of 300-2000 K. The forward and reverse rate coefficients as well as the high-pressure equilibrium constants of the C6H5 + NH2 ↔ IS1 process were also predicted; their values revealed that its kinetics do not depend on pressure at low temperature but strongly depend on pressure at high temperature. Moreover, the predicted formation enthalpies of reactants and the enthalpy changes of some channels are in good agreement with the experimental results.

Radiosynthesis and 'click' conjugation of ethynyl-4-[(18)F]fluorobenzene--an improved [(18)F]synthon for indirect radiolabeling.

Reproducible methods for [(18)F]radiolabeling of biological vectors are essential for the development of new [(18)F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi-step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [(18)F]radiolabeling of such molecules, our group has synthesized ethynyl-4-[(18)F]fluorobenzene ([(18)F]2, [(18)F]EYFB) in a single step (14 ± 2% non-decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne-functionalized synthon [(18)F]2 was then conjugated to two azido-functionalized vector molecules via CuAAC reactions. The first 'proof of principle' conjugation of [(18)F]2 to 1-azido-1-deoxy-ß-D-glucopyranoside (3) gave the desired radiolabeled product [(18)F]4 in excellent radiochemical yield (76 ± 4% ndc RCY (11% overall)). As a second example, the conjugation of [(18)F]2 to matrix-metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [(18)F]6 in very good radiochemical yield (56 ± 12% ndc RCY (8% overall)). Total preparation time for [(18)F]4 and [(18)F]6 including [(18)F]F(-) drying, two-step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [(18)F]2 and the conjugated products, [(18)F]4 and [(18)F]6, were all greater than 98%. The specific activities of [(18)F]2 and [(18)F]6 were low, 5.97 and 0.17 MBq nmol(-1), respectively.

Synthesis and in Vivo Evaluation of [123I]Melanin-Targeted Agents.

This study reports the synthesis, [(123)I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [(131)I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60-90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [(123)I]4 (ICF01012). The most favorable compounds ([(123)I]20, [(123)I]23, [(123)I]41, and [(123)I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [(123)I]20 and [(123)I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [(123)I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [(123)I]41 and [(123)I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [(123)I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [(131)I] therapeutic evaluation.

SPECT imaging of glioma with radioiodinated CLINDE: evidence from a mouse GL26 glioma model.

BACKGROUND: Recent research has demonstrated the potential of 18-kDa translocator protein (TSPO) to serve as a target for nuclear imaging of gliomas. The aim of this study was to evaluate SPECT imaging of GL26 mouse glioma using radioiodinated CLINDE, a TSPO-specific tracer. METHODS: GL26 cells, previously transfected with an enhanced green fluorescent protein (EGFP)-expressing lentivirus, were stereotactically implanted in the striatum of C57/Bl6 mice. At 4 weeks post-injection, dynamic SPECT scans with [(123)I]CLINDE were performed. A displacement study assessed specificity of tracer binding. SPECT images were compared to results of autoradiography, fluorescence microscopy, in situ nucleic acid hybridization, histology, and immunohistochemistry. Western blotting was performed to verify TSPO production by the tumor. RESULTS: Specific uptake of tracer by the tumor is observed with a high signal-to-noise ratio. Tracer uptake by the tumor is indeed 3.26 ± 0.32 times higher than that of the contralateral striatum, and 78% of the activity is displaceable by unlabeled CLINDE. Finally, TSPO is abundantly expressed by the GL26 cells. CONCLUSIONS: The present study demonstrates the feasibility of [(123)I]CLINDE SPECT in translational studies and underlines its potential for clinical glioma SPECT imaging.

Positron emission tomography and functional characterization of a complete PBR/TSPO knockout.

The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer's disease to anxiety. Here we show that global C57BL/6-Tspo(tm1GuWu(GuwiyangWurra))-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from (GuwiyangWurra)TSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of (GuwiyangWurra)TSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs.

Optimization of nucleophilic ¹8F radiofluorinations using a microfluidic reaction approach.

Microfluidic techniques are increasingly being used to synthesize positron-emitting radiopharmaceuticals. Several reports demonstrate higher incorporation yields, with shorter reaction times and reduced amounts of reagents compared with traditional vessel-based techniques. Microfluidic techniques, therefore, have tremendous potential for allowing rapid and cost-effective optimization of new radiotracers. This protocol describes the implementation of a suitable microfluidic process to optimize classical (18)F radiofluorination reactions by rationalizing the time and reagents used. Reaction optimization varies depending on the systems used, and it typically involves 5-10 experimental days of up to 4 h of sample collection and analysis. In particular, the protocol allows optimization of the key fluidic parameters in the first tier of experiments: reaction temperature, residence time and reagent ratio. Other parameters, such as solvent, activating agent and precursor concentration need to be stated before the experimental runs. Once the optimal set of parameters is found, repeatability and scalability are also tested in the second tier of experiments. This protocol allows the standardization of a microfluidic methodology that could be applied in any radiochemistry laboratory, in order to enable rapid and efficient radiosynthesis of new and existing [(18)F]-radiotracers. Here we show how this method can be applied to the radiofluorination optimization of [(18)F]-MEL050, a melanoma tumor imaging agent. This approach, if integrated into a good manufacturing practice (GMP) framework, could result in the reduction of materials and the time required to bring new radiotracers toward preclinical and clinical applications.

Synthesis and biological characterisation of 18F-SIG343 and 18F-SIG353, novel and high selectivity σ2 radiotracers, for tumour imaging properties.

BACKGROUND: Sigma2 (σ2) receptors are highly expressed in cancer cell lines and in tumours. Two novel selective 18F-phthalimido σ2 ligands, 18F-SIG343 and 18F-SIG353, were prepared and characterised for their potential tumour imaging properties. METHODS: Preparation of 18F-SIG343 and 18F-SIG353 was achieved via nucleophilic substitution of their respective nitro precursors. In vitro studies including radioreceptor binding assays in the rat brain membrane and cell uptake studies in the A375 cell line were performed. In vivo studies were carried out in mice bearing A375 tumours including positron emission tomography (PET) imaging, biodistribution, blocking and metabolite studies. RESULTS: In vitro studies showed that SIG343 and SIG353 displayed excellent affinity and selectivity for σ2 receptors (Ki(σ2) = 8 and 3 nM, σ2:σ1 = 200- and 110-fold, respectively). The σ2 selectivity of 18F-SIG343 was further confirmed by blocking studies in A375 cells, however, not noted for 18F-SIG353. Biodistribution studies showed that both radiotracers had similar characteristics including moderately high tumour uptake (4%ID/g to 5%ID/g); low bone uptake (3%ID/g to 4%ID/g); and high tumour-to-muscle uptake ratios (four- to sevenfold) up to 120 min. Although radiotracer uptake in organs known to express σ receptors was significantly blocked by pre-injection of competing σ ligands, the blocking effect was not observed in the tumour. PET imaging studies indicated major radioactive localisation in the chest cavity for both ligands, with approximately 1%ID/g uptake in the tumour at 120 min. Metabolite studies showed that the original radiotracers remained unchanged 65% to 80% in the tumour up to 120 min. CONCLUSIONS: The lead ligands showed promising in vitro and in vivo characteristics. However, PET imaging indicated low tumour-to-background ratios. Furthermore, we were unable to demonstrate that uptake in the A375 tumour was σ2-specific. 18F-SIG343 and 18F-SIG343 do not display ideal properties for imaging the σ2 receptor in the A375 tumour model. However, since the radiotracers show promising in vitro and in vivo characteristics, longer scans using appropriate half-life isotopes and alternative tumour models will be carried out in future studies to fully validate the imaging characteristics of these radiotracers.

Central nervous system expression and PET imaging of the translocator protein in relapsing-remitting experimental autoimmune encephalomyelitis.

UNLABELLED: Glial neuroinflammation is associated with the development and progression of multiple sclerosis. PET imaging offers a unique opportunity to evaluate neuroinflammatory processes longitudinally in a noninvasive and clinically translational manner. (18)F-PBR111 is a newly developed PET radiopharmaceutical with high affinity and selectivity for the translocator protein (TSPO), expressed on activated glia. This study aimed to investigate neuroinflammation at different phases of relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) in the brains of SJL/J mice by postmortem histologic analysis and in vivo by PET imaging with (18)F-PBR111. METHODS: RR EAE was induced by immunization with PLP(139-151) peptide in complete Freund's adjuvant. Naive female SJL/J mice and mice immunized with saline-complete Freund's adjuvant were used as controls. The biodistribution of (18)F-PBR111 was measured in 13 areas of the central nervous system and compared with PET imaging results during different phases of RR EAE. The extents of TSPO expression and glial activation were assessed with immunohistochemistry, immunofluorescence, and a real-time polymerase chain reaction. RESULTS: There was significant TSPO expression in all of the central nervous system areas studied at the peak of the first clinical episode and, importantly, at the preclinical stage. In contrast, only a few TSPO-positive cells were observed at the second episode. At the third episode, there was again an increase in TSPO expression. TSPO expression was associated with microglial cells or macrophages without obvious astrocyte labeling. The dynamics of (18)F-PBR111 uptake in the brain, as measured by in vivo PET imaging and biodistribution, followed the pattern of TSPO expression during RR EAE. CONCLUSION: PET imaging with the TSPO ligand (18)F-PBR111 clearly reflected the dynamics of microglial activation in the SJL/J mouse model of RR EAE. The results are the first to highlight the discrepancy between the clinical symptoms of EAE and TSPO expression in the brain, as measured by PET imaging at the peaks of various EAE episodes. The results suggest a significant role for PET imaging investigations of neuroinflammation in multiple sclerosis and allow for in vivo follow-up of antiinflammatory treatment strategies.