Minimal Uptake Research Articles

Prevalence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in Nigeria

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains one of the most challenging pandemics in the world with fewer casualties in Nigeria despite minimal vaccine uptake. This study examines the prevalence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in subjects attending Federal Medical Center, Owo, Ondo State. A questionnaire based descriptive cross-sectional was conducted in 2022 among 100 patients from Federal Medical Centre in Owo, Ondo State .50 of whom had received the COIVD-19 vaccine and 50 of whom had not. For this study, men and women between the ages of 18 and 55 who appeared to be in good health were included. According to the study's findings, the prevalence of SARS-CoV-2 was detected in 5% of the population while it was absent in 95% of the rest. Two (2.00%) men and three (3.00%) women out of the five who confirmed positive for SARS CoV 2. The findings also revealed that, of the 5 participants who were tested positive for SARS CoV 2, 4 (80.00%) had not had a vaccination, while 1 (20.00%) had. Adult Nigerians who have never received the COVID-19 vaccine have a high SARS-CoV-2 antibody seroprevalence rate. Age and gender do not appear to significantly correlate with sero-positivity (p>0.05). Therefore, anti-SARS-CoV-2 antibody testing is required after vaccination since it may be necessary to achieve herd immunity. Keywords: antibody; SARS-CoV-2; Sero-prevalence; vaccine; Covid-19

Noninvasive Quantification of Radiation-Induced Lung Injury Using a Targeted Molecular Imaging Probe

BackgroundRadiation-induced lung injury (RILI) is a progressive inflammatory process seen following irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management. Research QuestionTo noninvasively quantify RILI, utilizing a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI. MethodsUsing a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe to characterize the development of RILI and to assess disease mitigation following losartan treatment. The human analog probe targeted against type 1 collagen, 68Ga-CBP8, was tested on excised human lung tissue containing RILI and quantified via autoradiography. Finally, 68Ga-CBP8 PET was used to assess RILI in vivo in six human subjects. ResultsMurine models demonstrated that probe signal correlated with progressive RILI severity over six-months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding vs unirradiated control tissue and 68Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant 68Ga-CBP8 uptake in areas of RILI and minimal background uptake. InterpretationThese findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI.Clinical trial registered with www.clinicaltrials.gov

High-temperature steam oxidation study of irradiated FeCrAl defueled specimens

Post irradiation examinations (PIE) were performed on irradiated iron-chromium-aluminum (FeCrAl) specimens. These FeCrAl specimens were fabricated at the US Department of Energy's Oak Ridge National Laboratory (ORNL). The experimental setup involved subjecting FeCrAl cladding, along with UO2 pellets, to irradiation in the Idaho National Laboratory Advanced Test Reactor (ATR). In parallel, the FeCrAl alloy tubing without UO2 pellets was irradiated at ORNL's High Flux Isotope Reactor (HFIR). After irradiation, the ATR-irradiated rodlet was transported to an ORNL hot cell, where it was sectioned into multiple samples for the PIE and severe-accident testing. The sectioning process revealed that the fuel was not bonded to the cladding and could be easily detached from sectioned cladding slices. Microstructural analysis of the fuel cross sections demonstrated no significant interaction between the fuel and the cladding. Additionally, high-temperature steam oxidation tests on defueled cladding segments showed minimal oxygen uptake even at 1200 °C. The ATR-irradiated specimens began to exhibit signs of enhanced oxidation upon reaching a temperature of 1300 °C. Furthermore, enhanced oxidation was observed on the inner surface of the ATR-irradiated FeCrAl specimen, which had been subjected to 1300 °C for a duration of 1 min. By contrast, high-temperature steam oxidation experiments indicated that the HFIR-irradiated FeCrAl cladding provided good thermal stability when exposed to 1300 °C for up to 4 h. Comparative analysis encompassing the oxidation behavior of the ATR-irradiated fueled FeCrAl, HFIR-irradiated unfueled FeCrAl, and unirradiated FeCrAl suggests that the fuel–cladding interaction, although not visible via standard microscale electron microscopy measurements, may accelerate the deterioration of FeCrAl cladding in beyond-design-basis accident scenarios.

Abstract A068: Site-specific modification of nanobodies for ImmunoPET of Liver Cancer utilizing Self-labeling nanobody-tag pair (SLANT) technology

Abstract Visualization of tumor cells is critical in diagnosing, monitoring, and treating patients with cancer. Liver cancer has an 18 percent 5-year survival rate and is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC), the most common type of liver cancer, only takes up 18F-fluorodeoxyglucose (18F-FDG), the most commonly used clinical positron emission tomography (PET) tracer, 50% of the time. As such, developing an HCC-selective imaging agent could improve our ability for earlier diagnosis, post-treatment surveillance, and ability to increase patient longevity and quality of life. Single domain antibodies (sdAbs), or nanobodies (Nb), are attractive scaffolds for radiopharmaceutical development because of their high target affinity and specificity, ready availability from recombinant expression in bacteria, and small size for rapid clearance, better tumor penetration, and same-day imaging. However, conventional conjugation chemistry that exploits cysteines or lysines found on the native protein can abrogate the binding site of the smaller Nbs. We have previously used sortase A-based site-specific conjugation to address these challenges; however, improvements were still possible. Here, we developed a novel self-labeling Nb-tag pair (SLANT) that allows fast and specific covalent labeling of a Nb based on peptide epitope binding. We used SLANT to engineer a heterodimeric Nb construct consisting of a Nb (HN3) specific for Glypican-3, a heparin sulfate proteoglycan that is overexpressed in 75-90% of all HCCs and our self-labeling Nb. This design allows for site-specific labeling of the heterodimeric (GPC3-specific) construct in a manner that avoids modification of the tumor antigen-specific protomer. Labeling is achieved via exposure of the fusion protein to a crosslinking peptide functionalized with a chelator (DOTA). This methodology produces labeled protein at over 90 percent yields within minutes compared to less than 30 percent yields utilizing enzymatic methods. Biolayer interferometry and radioligand saturation studies were done to determine the binding affinity of the conjugate for GPC3 pre- and post-Indium-111 labeling. SPECT/CT and biodistribution studies were done at 1h, 3hrs, and 24hrs with HepG2 and HepG2-GPC3- xenografts to assess conjugate specificity and ability to accumulate in GPC3+ liver tumors. Our conjugate exhibited a nanomolar affinity for GPC3 in vitro (17-36 nM). SPECT/CT and biodistribution studies showed specificity for GPC3 in HepG2 liver cancer xenografts (~5.5% IA/g at 1-hour post-injection (p.i.)) and minimal uptake in HepG2 GPC3- tumors (~0.62% IA/g at 1-hour p.i.). Our results highlight the development of a new labeling paradigm applied to GPC3+ liver cancer. This approach can be used for same-day imaging and the rapid development of SPECT and PET imaging tracers for different cellular markers on cancer cells, addressing known tumor heterogeneity. Citation Format: Stanley Fayn, Chino C Cabalteja, Woonghee Lee, Divya Nambiar, Kwamena E Baidoo, Freddy E Escorcia, Ross W Cheloha. Site-specific modification of nanobodies for ImmunoPET of Liver Cancer utilizing Self-labeling nanobody-tag pair (SLANT) technology [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A068.

Abstract 16992: Superior Vena Cava Syndrome in a Patient With Metastatic Primary Cardiac Diffuse Large B-cell Lymphoma - Case Report

Introduction: Primary cardiac tumors are uncommon, with an estimated incidence of 0.02%. Primary cardiac lymphomas (PCL), a subtype of non-Hodgkin lymphoma, account for about 10% of malignant and 1% of all primary cardiac tumors. Diffuse large B-cell lymphomas (DLBCLs) emerge as the predominant histological subtype within PCL cases. Case presentation: 54-year-old White male with no medical history presented with a few weeks of exertional dyspnea, nonproductive cough, and neck fullness. Exam was notable for tachycardia, jugular venous distension, bilateral upper extremity edema, and distended chest wall vasculature. Labs showed elevation of alkaline phosphatase and CRP. CT of the chest showed a right atrial mass extending into and obstructing the superior vena cava (SVC) and mediastinal lymphadenopathy (Panel A & B). Coronary CTA performed a few years earlier showed normal interatrial septum (Panel C) and coronary arteries. Transthoracic echo (TTE) confirmed a 7.6 x 5.0cm mass visualized in the interatrial septum extending to both atria. Cardiac MRI redemonstrated a large cardiac mass with malignant features suggestive of cardiac lymphoma vs angiosarcoma (Panel D-F). PET-CT showed enhanced fluorodeoxyglucose (FDG) uptake within cardiac mass, mediastinal, and intraabdominal lymph nodes (Panel G). Lymph node biopsy confirmed DLBCL. Patient underwent three cycles of EPOCH (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) chemotherapy with excellent response. TTE following cycle 2 demonstrated decreased tumor size, and PET-CT after cycle 3 confirmed complete resolution of lymphadenopathy and minimal residual intracardiac FDG uptake. Conclusion: SVC syndrome can be a rare presentation of PCL. Multimodality imaging is important in cardiac mass characterization, diagnosis, treatment planning, and follow-up. Timely diagnosis and initiation of chemotherapy results in improved outcomes.

Abstract 15864: Genetic Findings of Cardiac Sarcoidosis in a Case of Apical Variant Hypertrophic Cardiomyopathy With Recurrent Ventricular Tachyarrhythmias

Background: Genetic sequencing is changing the way physicians practice medicine. Hypertrophic cardiomyopathy (HCM) is one of the most common inheritable cardiac diseases. Sarcoidosis is a multisystem disease involving granulomatous infiltration of the lungs, heart, and other organs thought to be caused by a dysregulated immune system, influenced by genetic factors. Here, we present a case where an individual initially diagnosed with HCM was experiencing frequent episodes of ventricular tachycardia (VT). Further workup, including advanced imaging along with whole genome screening (WGS), revealed an unlikely diagnosis of concurrent cardiac sarcoidosis (CS). Clinical History: A 62-year-old man had ventricular fibrillation with workup notable for an ECG with deeply inverted T-waves, normal coronary angiography, and an echocardiogram and MRI showing apical HCM. An ICD was placed. Six years later, he had VT requiring a shock and was started on sotalol. He has now developed recurrent exercise-induced VT. While VT is seen HCM, the increasing frequency prompted further evaluation. A CT coronary angiogram showed normal coronaries and mediastinal lymphadenopathy. Lymph node biopsy revealed noncaseating granulomas and a PET/CT revealed hypermetabolic basal myocardium meeting HRS criteria for CS. Given minimal apical FDG uptake and a low likelihood that he had CS for 9 years without significant fibrosis, he likely has both HCM and CS. Using WGS, four genetic variants previously described in CS and HCM were identified confirming this diagnosis, HLA-DRB1, HLA-DQA1, ALPK3, and TTN. Discussion: HLA-DRB1 and HLA-DQA1 are both major histocompatibility complexes associated with CS. ALPK3 encodes alpha kinase 3 while TTN encodes titin. Truncating variants of ALPK3 are associated with HCM while pathogenic TTN variants have been described to cause HCM, DCM, and ARVC. This case reflects the potential of WGS in aiding clinicians in confirming an unlikely diagnosis.

SAT487 A Case of Mistaken Identity: A Rare Presentation of Ectopic Thyroid Tissue

Abstract Disclosure: N. Doshi: None. R. Azimzade: None. A. Rajpal: None. Background: Ectopic thyroid tissue (ETT) lateral to the midline is very rare, and its presence at the carotid bifurcation is exceedingly unique. Paraganglioma is the most common primary tumor at the carotid bifurcation, often called a carotid body tumor. We hereby present a case of lateral ETT with radiological features similar to paraganglioma. Case Description: A 72-year-old female with history of GERD was referred to us for evaluation of a well-circumscribed, slightly tender left neck mass. She has had the mass for approximately 15 years with previous evaluation with ultrasound in Yemen, where she was told to undergo surgery to remove it. She did not pursue surgery at that time. She moved to the U.S. one year ago and was re-evaluated for the neck mass. On examination, a firm mass was noted on the left side of the neck, followed by an ultrasound which demonstrated a 4.5 cm mass at the left carotid bifurcation and an enlarged right thyroid lobe of the same echogenicity with no tissue in the left thyroid bed. She had no clinical symptoms suggesting of hypo or hyperthyroidism. Laboratory examination showed suppressed TSH with elevated T3 suggesting thyrotoxicosis. CT neck was obtained for further characterization of the left neck mass which showed a hyper-enhancing, lobular soft tissue mass at the carotid bifurcation extending from the mandible to the level of the thyroid isthmus, concerning for carotid body paraganglioma or schwannoma. An I-123 scan demonstrated 24% (increased) uptake in the right thyroid lobe and minimal uptake in the carotid bifurcation tissue. The patient is currently being treated medically for thyrotoxicosis. Based on its ultrasonographic appearance, mild uptake on the I-123 scan, and no clinical suggestion of paraganglioma, the left neck mass is presumed to be ETT and no surgical intervention is being pursued. It is possible that the right lobe is thyrotoxic, suppressing iodine uptake in the ectopic tissue. Conclusion: This case demonstrates a unique presentation of ETT in the left carotid bifurcation with a thyrotoxic right lobe. It is difficult to distinguish the precise composition of neck masses at the carotid bifurcation, which has important implications for management. Often, an official diagnosis of thyroid tissue is made with histopathology only after the mass is surgically excised. Most ETT is benign in nature, and many times it is the only thyroid tissue available, thus surgery is not indicated. It is especially difficult to distinguish between ETT and paraganglioma on imaging itself. Somatostatin receptor scintigraphy, Ga-68/PET scanning, or iodine uptake scan can be useful to distinguish ETT from paraganglioma. Despite its rarity, lateral ETT must be included in the differential diagnosis of carotid body paraganglioma. Presentation Date: Saturday, June 17, 2023

SAT530 Use of Tamoxifen and Cabergoline to Suppress Breast Tissue Uptake of Radioactive Iodine Among Differentiated Thyroid Cancer Patients

Abstract Disclosure: A.H. Mohamed: None. M. Basina: None. Background: Radioactive iodine (RAI) has been used in thyroid cancer treatment. Physiologic breast tissue uptake and accumulation of RAI are not desirable due to increased carcinogenesis risk. Case1:31 years old non lactating female diagnosed with stage IVB papillary thyroid cancer and underwent total thyroidectomy and bilateral neck dissection. She had high initial risk with stage of T3N1bM1 and underwent 118 mCi of I-131 treatment with pulmonary foci. One year later, she had biochemical and structural incomplete response and underwent I-123 RAI uptake scan demonstrating residual disease in the right neck and diffuse breast uptake, thus, I-131 treatment was deferred. The patient was started on cabergoline 0.5 mg daily for 2 months. Repeated I-123 uptake scan during day 2 of Cabergoline remained with diffuse breast uptake. Four months later, another repeated RAI uptake scan after 4 months showed minimal breast uptake and RAI I-131 treatment was given. She had normal mammogram screening. Case2: 41 years old non lactating female diagnosed with stage II papillary thyroid cancer and underwent total thyroidectomy with right neck dissection. She had moderate initial risk with stage of T3 N1aM0 and underwent 159 mCI of I-131 treatment. Two years later, she had structural incomplete response and repeated I-123 uptake scan showed thyroid bed foci of avid uptake and diffuse bilateral breast uptake, thus, I-131 therapy was deferred. The patient was started on cabergoline 0.25 mg daily for 4 weeks and Tamoxifen 10 mg twice daily for 10 days prior to repeated I-123 RAI scan that redemonstrated thyroid bed foci without breast tissue uptake. She had normal mammogram screening. DiscussionPotential malignancy risk secondary to non-thyroidal RAI accumulation in tissues was reported. The mechanism of breast RAI uptake involves Na/iodide symporter channel regulated by prolactin and estrogen. Blocking the effect of these hormones prior to I-131 administration are believed to prevent breast uptake. We describe two papillary thyroid cancer cases with breast RAI uptake that was suppressed partially with Cabergoline (prolactin lowering agent) and fully with combination of Cabergoline and Tamoxifen (estrogen receptor blocker). Further studies are needed to evaluate the efficacy of Tamoxifen and cabergoline in suppressing physiologic breast RAI uptake. Presentation Date: Saturday, June 17, 2023

Positron emission tomography assessment of metacarpal/metatarsal condylar fractures post surgical repair: Prospective study in 14 racehorses.

To assess 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) findings associated with metacarpal/metatarsal condylar fractures at the time of fracture repair and through healing. Prospective descriptive study. Fourteen Thoroughbred racehorses. 18F-NaF PET was performed within 4 days of surgical metacarpal/metatarsal condylar fracture repair, on both the injured and contralateral limb. Follow-up PET scans were offered at 3- and 5-months post fracture repair. Areas of abnormal uptake were assessed using a previously validated grading system. Eight fractures were located in the parasagittal groove (PSG) (six lateral and two medial) and six fractures were located abaxial to the PSG (non-PSG) through the palmar/plantar condyle (all lateral). All horses in the latter group had uptake in the lateral palmar condyle of the contralateral limb suggestive of stress remodeling. Three horses with PSG fractures had uptake in a similar location in the contralateral limb. Horses with lateral condylar fracture only presented minimal or mild uptake in the medial condyle, which is considered atypical in the front limbs for horses in full training. Four horses developed periarticular uptake in the postoperative period suggestive of degenerative joint disease, three of these horses had persistent uptake at the fracture site. These four horses did not return to racing successfully. The findings of this study provide evidence of pre-existing lesions and specific uptake patterns in racehorses suffering from metacarpal/metatarsal condylar fractures. PET has a possible role in the prevention, diagnosis, and postoperative monitoring of metacarpal/metatarsal condylar fractures in racehorses.

Intravesical liposomal tacrolimus for hemorrhagic cystitis: a phase 2a multicenter dose-escalation study

BackgroundHemorrhagic cystitis (HC) is an inflammatory disease of the bladder with sustained hematuria for which there is currently no approved drug treatment. We evaluated a liposomal tacrolimus preparation (LP-10) in patients with refractory moderate to severe sterile HC.MethodsThis phase 2a dose-escalation study assessed the safety and efficacy of up to 2 intravesical instillations of LP-10 (2, 4, or 8 mg tacrolimus) in 13 patients with HC. Primary efficacy outcomes were changes from baseline in the number of bleeding sites on cystoscopy, microscopic urine analysis for red blood cells (RBCs), and hematuria on dipstick. Additional efficacy measures included urinary incontinence, frequency, and urgency on a 3-day diary and cystoscopy global response assessment (GRA). Blood samples for pharmacokinetic (PK) assessment were obtained in all patients.ResultsIntravesical LP-10 was well tolerated, with no treatment-related severe or serious adverse events (AEs) and only 3 drug-related AEs (artificial urinary sphincter malfunction, dysuria, and bladder spasms). LP-10 blood levels showed short durations of minimal systemic uptake. Treatment resulted in significant improvements in bleeding on cystoscopy, RBC counts in urine, hematuria on dipstick, and urinary incontinence. Bleeding on cystoscopy and urinary incontinence showed dose-dependent improvements that were more pronounced in the 4 mg and 8 mg dose groups. All dose groups showed a significant improvement in cystoscopy GRA.ConclusionLP-10 was well tolerated, with clinically relevant efficacy seen in improvements in cystoscopic bleeding, hematuria, and urinary incontinence. The benefit-risk profile supports the further clinical development of LP-10 at a tacrolimus dose of 4 mg.

2022 APTA Pediatrics Knowledge Translation Lecture: Clinicians and Researchers Collaborate to Implement a Segmental Approach to Trunk Control.

The aim of this special communication is to describe a clinician/researcher collaboration that supported implementation of the segmental approach to trunk control into physical therapy practice at a large, multisite, pediatric hospital. A 6-phase, multifaceted iterative process including use of educational strategies, the knowledge-to-action (KTA) cycle, the Consolidated Framework for Implementation Research, and the Theoretical Domains Framework was used. The total number of Segmental Assessments of Trunk Control (SATCos) completed increased from 0 to 57. Fifteen of 23 physical therapists representing 7 clinic locations referred a child for a SATCo. Using education alone or education plus the KTA cycle resulted in minimal uptake. Using more formal contextual assessments and mapping of barriers to strategies using implementation frameworks, collaborative goal setting, and planning resulted in more effective strategies and increase in uptake of the segmental approach in later phases.

Combined Amphiphilic Silybin Meglumine Nanosuspension Effective Against Hepatic Fibrosis in Mice Model.

Silybin (SLB) as an effective hepatoprotective phytomedicine has been limited by its hydrophobicity, poor bioavailability and accumulation at lesion sites. Additionally, present drug loading methods are impeded by their low drug loading capacity, potential hazard of materials and poor therapeutic effects. Consequently, there is a pressing need to devise an innovative approach for preparing nanosuspensions loaded with both SLB and Silybin Meglumine salt (SLB-M), as well as to investigate the therapeutic effects of SLB nanosuspensions against hepatic fibrosis. The SLB nanosuspension (NS-SLB) was prepared and further modified with a hyaluronic acid-cholesterol conjugate (NS-SLB-HC) to improve the CD44 targeting proficiency of NS-SLB. To validate the accumulation of CD44 and ensure minimal cytotoxicity, cellular uptake and cytotoxicity assessments were carried out for the nanosuspensions. Western blotting was employed to evaluate the anti-hepatic fibrosis efficacy in LX-2 cells by inhibiting the secretion of collagen I. Hepatic fibrosis mouse models were used to further confirm the effectiveness of NS-SLB and NS-SLB-HC against hepatic fibrosis in vivo. Uniform nanosuspensions were prepared through self-assembly, achieving high drug loading rates of 89.44% and 60.67%, respectively. Both SLB nanosuspensions showed minimal cytotoxicity in cellular environments and mitigated hepatic fibrosis in vitro. NS-SLB-HC was demonstrated to target activated hepatic stellate cells by receptor-ligand interaction between HA and CD44. They can reverse hepatic fibrosis in vivo by downregulating TGF-β and inhibiting the secretion of α-SMA and collagen I. Designed as a medical excipient analogue, SLB-M was aimed to establish an innovative nanosuspension preparation method, characterized by high drug loading capacity and a notable impact against hepatic fibrosis.

Minimal mRNA uptake and inflammatory response to COVID-19 mRNA vaccine exposure in human placental explants

Despite universal recommendations for COVID-19 mRNA vaccination in pregnancy, uptake has been lower than desired. There have been limited studies of the direct impact of COVID-19 mRNA vaccine exposure in human placental tissue. Using a primary human placental explants model, we investigated the uptake of two common mRNA vaccines (BNT162b2 Pfizer-BioNTech or mRNA-1273 Moderna), and whether exposure altered villous cytokine responses. Explants derived from second or third trimester chorionic villi were incubated with vaccines at supraphysiologic concentrations and analyzed at two time points. We observed minimal uptake of mRNA vaccines in placental explants by in situ hybridization and quantitative RT-PCR. No specific or global cytokine response was elicited by either of the mRNA vaccines in multiplexed immunoassays. Our results suggest that the human placenta does not readily absorb the COVID-19 mRNA vaccines nor generate a significant inflammatory response after exposure.

Adverse Responses following Exposure to Subtoxic Concentrations of Zinc Oxide and Nickle Oxide Nanoparticles in the Raw 264.7 Cells.

The incorporation of engineered nanomaterials (ENMs) in biomedical and consumer products has been growing, leading to increased human exposure. Previous research was largely focused on studying direct ENM toxicity in unrealistic high-exposure settings. This could result in overlooking potential adverse responses at low and subtoxic exposure levels. This study investigated adverse cellular outcomes to subtoxic concentrations of zinc oxide (ZnONPs) or nickel oxide (NiONPs) nanoparticles in the Raw 264.7 cells, a macrophage-like cell model. Exposure to both nanoparticles resulted in a concentration-dependent reduction of cell viability. A subtoxic concentration of 6.25 µg/mL (i.e., no observed adverse effect level) was used in subsequent experiments. Exposure to both nanoparticles at subtoxic levels induced reactive oxygen species generation. Cellular internalization data demonstrated significant uptake of NiONPs, while there was minimal uptake of ZnONPs, suggesting a membrane-driven interaction. Although subtoxic exposure to both nanoparticles was not associated with cell activation (based on the expression of MHC-II and CD86 surface markers), it resulted in the modulation of the lipopolysaccharide-induced inflammatory response (TNFα and IL6), and cells exposed to ZnONPs had reduced cell phagocytic capacity. Furthermore, subtoxic exposure to the nanoparticles distinctly altered the levels of several cellular metabolites involved in cell bioenergetics. These findings suggest that exposure to ENMs at subtoxic levels may not be devoid of adverse health outcomes. This emphasizes the importance of establishing sensitive endpoints of exposure and toxicity beyond conventional toxicological testing.

PD-L1 Positron Emission Tomography Imaging in Patients With Non-Small Cell Lung Cancer: Preliminary Results of the ImmunoPET Phase 0 Study

ImmunoPET is a multicenter, single arm, phase 0-1 study of 89Zr-DFO-Sq-durvalumab (89Zr-durvalumab), a novel PET tracer, designed to interrogate the expression of PD-L1 in patients with NSCLC. Clinically relevant findings from phase 0 are presented here. Phase 0 was designed to investigate tracer biodistribution and safety in patients with metastatic NSCLC with PD-L1 expression >25%. After 60MBq/70kg 89Zr-durvalumab infusion, PET/CT images were acquired at days 0, 1, 3 or 5 ± 24h. Baseline FDG PET/CT was performed prior to PD-L1 PET imaging. All five patients recruited to phase 0 completed the full imaging protocol. The only reported adverse event was a transient asymptomatic increase in respiratory rate. At the time of PD-L1 imaging, two patients were in complete remission on FDG-PET after treatment with osimertinib and pembrolizumab; neither showed PD-L1 tracer uptake in previous tumor sites. All three patients with active tumor had received radiotherapy to some or all disease sites prior to PD-L1 imaging. With the exception of a single disease site, specific uptake of 89Zr-durvalumab uptake was seen in tumours, with increasing uptake in tumor seen up to Day 5 post-injection. Patient 1, who had multiple metastases, including brain and bone, showed more intense 89Zr-durvalumab uptake in recently irradiated bone lesions than un-irradiated lesions and uptake was also observed in treated brain metastases.. One patient, who experienced rapid growth of a single lung lesion that had acquired resistance to pembrolizumab, showed no significant 89Zr-durvalumab in that lesion, despite recent radiotherapy. In patient 5, 89Zr-durvalumab uptake was observed in the viable rim of a large, recently irradiated adrenal oligometastasis. 89Zr- durvalumab imaging was safe and detected known viable tumor at multiple sites. Recently irradiated tumours showed the highest uptake and in another, a single site of immunotherapy resistant disease showed minimal tracer uptake. PD-L1 imaging may have utility in patients with NSCLC treated with radiotherapy.

Liver Lipoma in a Dog: Case Report and Literature Review

ABSTRACT Lipoma of the liver has not been reported in dogs. An 8 yr old spayed female Great Dane was referred for diagnostic workup of abdominal distention. Computed tomography showed fat-attenuating masses with negative attenuation values (variable between −60 to −40 Hounsfield units) and minimal contrast uptake within the left cranial abdomen. Left lateral and right medial liver lobectomies were performed to remove two liver masses. Histopathology showed large lipomas arising from within the hepatic parenchyma. Immunohistochemistry for smooth muscle actin was negative, consistent with true lipomas. The dog was euthanized 8 mo later because of causes likely unrelated to the liver lipoma. This is the first case report of lipoma in the liver of a dog. The purpose of this case report and brief literature review is to provide evidence that surgical excision of fat-attenuating masses within the liver that are consistent with lipoma using immunohistochemistry can be curative.

Biosynthesis and properties of polyhydroxyalkanoates synthesized from mixed C5 and C6 sugars obtained from hardwood hydrolysis

Glucose and xylose are fermentable sugars readily available from lignocellulosic biomass, and are a sustainable carbon substrate supporting industrial biotechnology. Three strains were assessed in this work – Paraburkholderia sacchari, Hydrogenophaga pseudoflava, and Bacillus megaterium – for their ability to uptake both C5 and C6 sugars contained in a hardwood hydrolysate produced via a thermomechanical pulping-based process with concomitant production of poly(3-hydroxyalkanoate) (PHA) biopolymers. In batch conditions, B. megaterium showed poor growth after 12 h, minimal uptake of xylose throughout the cultivation, and accumulated a maximum of only 25 % of the dry biomass as PHA. The other strains simultaneously utilized both sugars, although glucose uptake was faster than xylose. From hardwood hydrolysate, P. sacchari accumulated 57 % of its biomass as PHA within 24 h, whereas H. pseudoflava achieved an intracellular PHA content of 84 % by 72 h. The molecular weight of the PHA synthesized by H. pseudoflava (520.2 kDa) was higher than that of P. sacchari (265.5 kDa). When the medium was supplemented with propionic acid, the latter was rapidly consumed by both strains and incorporated as 3-hydroxyvalerate subunits into the polymer, demonstrating the potential for production of polymers with improved properties and value. H. pseudoflava incorporated 3-hydroxyvalerate subunits with at least a 3-fold higher yield, and produced polymers with higher 3-hydroxyvalerate content than P. sacchari. Overall, this work has shown that H. pseudoflava can be an excellent candidate for bioconversion of lignocellulosic sugars to PHA polymers or copolymers as part of an integrated biorefinery.

Intravenous and oral whole body ketone dosimetry, biodistribution, metabolite correction and kinetics studied by (R)-[1-11C]β-hydroxybutyrate ([11C]OHB) PET in healthy humans

BackgroundKetones are increasingly recognized as an important and possibly oxygen sparing source of energy in vital organs such as the heart, the brain and the kidneys. Drug treatments, dietary regimens and oral ketone drinks designed to deliver ketones for organ and tissue energy production have therefore gained popularity. However, whether ingested ketones are taken up by various extra-cerebral tissues and to what extent is still largely unexplored. It was therefore the aim of this study to use positron emission tomography (PET) to explore the whole body dosimetry, biodistribution and kinetics of the ketone tracer (R)-[1-11C]β-hydroxybutyrate ([11C]OHB). Six healthy subjects (3 women and 3 men) underwent dynamic PET studies after both intravenous (90 min) and oral (120 min) administration of [11C]OHB. Dosimetry estimates of [11C]OHB was calculated using OLINDA/EXM software, biodistribution was assessed visually and [11C]OHB tissue kinetics were obtained using an arterial input function and tissue time-activity curves.ResultsRadiation dosimetry yielded effective doses of 3.28 upmuSv/MBq (intravenous administration) and 12.51 upmuSv/MBq (oral administration). Intravenous administration of [11C]OHB resulted in avid radiotracer uptake in the heart, liver, and kidneys, whereas lesser uptake was observed in the salivary glands, pancreas, skeletal muscle and red marrow. Only minimal uptake was noted in the brain. Oral ingestion of the tracer resulted in rapid radiotracer appearance in the blood and radiotracer uptake in the heart, liver and kidneys. In general, [11C]OHB tissue kinetics after intravenous administration were best described by a reversible 2-tissue compartmental model.ConclusionThe PET radiotracer [11C]OHB shows promising potential in providing imaging data on ketone uptake in various physiologically relevant tissues. As a result, it may serve as a safe and non-invasive imaging tool for exploring ketone metabolism in organs and tissues of both patients and healthy individuals.Trial registrationClinical trials, NCT0523812, Registered February 10th 2022, https://clinicaltrials.gov/ct2/show/NCT05232812?cond=NCT05232812&draw=2&rank=1.

Novel peptide binder to Glypican-3 for targeted radiopharmaceutical therapy of hepatocellular carcinoma.

e16131 Background: Glypican-3 (GPC3) is a membrane-associated heparan sulfate proteoglycan primarily involved in embryonic development, and is barely detectable in normal adult tissues. Significant upregulation of GPC3 protein in hepatocellular carcinomas (HCC) has been observed in multiple immunohistochemistry (IHC) studies with up to 75% positivity rate, and is associated with poor prognosis. GPC3 is not expressed in healthy or non-malignant liver tissue. Targeting GPC3 could fulfill an unmet medical need for HCC, a leading cause of cancer-related deaths worldwide for which efficacious therapies are lacking. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for GPC3-targeted radiopharmaceutical therapy (RPT) to treat HCC. Methods: RAYZ-8009 is comprised of a novel macrocyclic peptide binder to GPC3, a linker, and chelator DOTA that can be complexed with different radioisotopes. The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR), as well as a radioligand binding assay in human HCC cell line HepG2. The cross-species binding was assessed by radioligand binding using recombinant mouse, cynomolgus monkey, and human GPC3 proteins. Target-mediated internalization in HepG2 cells was measured using Microbeta at various time points. In vivo biodistribution with 177Lu, and anti-tumor efficacy studies using 225Ac were performed in HepG2 tumor-bearing athymic nude mice. Results: RAYZ-8009 showed high binding affinity to human GPC3 with a KD of 0.7 nM as determined by SPR. Binding affinity was maintained across mouse, cynomolgus monkey and human GPC3. Potent cellular binding was confirmed in GPC3+ HepG2 cells, and was independent of choice of isotope. 177Lu-RAYZ-8009 showed fast and efficient internalization with 42% internalized by 20 minutes in HepG2 cells. In vivo biodistribution of 177Lu-RAYZ-8009 showed tumor uptake of 19.8, 16.6, 16.4, and 8.8 %ID/g at 2, 24, 48, and 96 hours, respectively. Renal uptake was 16.1, 4.7, 1.6, and 0.7 %ID/g at the same timepoints, with tumor/kidney ratios of 1.3, 3.7, 11.3, and 15.0, respectively. Minimal uptake was observed in other normal tissues. Tumor-specific uptake and retention were also observed when tumors were implanted orthotopically with no uptake in non-malignant liver tissue. Furthermore, significant tumor growth inhibition and survival benefit were achieved with 225Ac-RAYZ-8009 in GPC3+ HCC xenografts. Conclusions: Preclinical pharmacodynamic, pharmacokinetic, biodistribution and efficacy data demonstrate the potential of RAYZ-8009 as a RPT agent for the treatment of patients with GPC3-positive HCC.

Myocardial Perfusion Scintigraphy in a Patient With Transposition of Great Arteries Post-Atrial Switch Surgery.

We report a case of a 33-year-old woman who underwent stress and rest myocardial perfusion scintigraphy (MPS) to exclude coronary artery disease. MPS images showed an apparent dextrocardia with a right-sided septal wall uptake. The electrocardiograph showed a right axis deviation with dominant R waves at leads aVR and V1. Upon retrieval of the patient's medical records, she had an underlying transposition of great arteries and underwent a Senning atrial switch surgery. Hence, the MPS images demonstrated a prominent right ventricular wall due to its function as the "systemic" ventricle with minimal uptake in the "pulmonary" left ventricle.