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BackgroundThe programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells’ immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors’ immunotherapy landscape.MethodsBy immunizing an alpaca with recombinant human PD-L1, three clones of the variable domain of the heavy chain of heavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC).ResultsWhile RW102 has a high binding affinity to PD-L1 with an excellent KD value of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KD value of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have different in vivo circulation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies.ConclusionsWe developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments.Trial registration numberNCT06165874.

Introduction: Neurotensin receptor 1 (NTSR1) is an emerging target for imaging and therapy of many types of cancer. Nuclear imaging of NTSR1 allows for noninvasive assessment of the receptor levels of NTSR1 on the primary tumor, as well as potential metastases. This work focuses on a the neurotensin peptide analogue NT-20.3 conjugated to the chelator NOTA for radiolabeling for use in noninvasive positron emission tomography (PET). NOTA-NT-20.3 was radiolabeled with gallium-68, copper-64, and cobalt-55 to determine the effect that modification of the radiometal has on imaging and potential therapeutic properties of NOTA-NT-20.3. Methods: In vitro assays investigating cell uptake and subcellular localization of the radiolabeled peptides were performed using human colorectal adenocarcinoma HT29 cells. In vivo PET/CT imaging was used to determine the distribution and clearance of the peptide in mice bearing NTSR1 expressing HT29 tumors. Results: Cell uptake studies showed that the highest uptake was obtained with [55Co] Co-NOTA-NT-20.3 (18.70 ± 1.30%ID/mg), followed by [64Cu] Cu-NOTA-NT-20.3 (15.46 ± 0.91%ID/mg), and lastly [68Ga] Ga-NOTA-NT-20.3 (10.94 ± 0.46%ID/mg) (p < 0.001). Subcellular distribution was similar across the three constructs, with the membranous fraction containing the highest amount of radioactivity. In vivo PET/CT imaging of the three constructs revealed similar distribution and tumor uptake at the 1 h imaging timepoint. Tumor uptake was receptor-specific and blockable by co-injection of non-radiolabeled NOTA-NT-20.3. SUV ratios of tumor to heart at the 24 h imaging timepoint show that [55Co] Co-NOTA-NT-20.3 (20.28 ± 3.04) outperformed [64Cu] Cu-NOTA-NT-20.3 (6.52 ± 1.97). In conclusion, our studies show that enhanced cell uptake and increasing tumor to blood ratios over time displayed the superiority of [55Co] Co-NOTA-NT-20.3 over [68Ga] Ga-NOTA-NT-20.3 and [64Cu] Cu-NOTA-NT-20.3 for the targeting of NTSR1.

Using research from brand roles and goal pursuit as our theoretical framework, we find that the type of goal pursuit influences how consumers respond to the brand role of leader (i.e., leader brand) vs. servant (i.e., servant brand). Two experiments show that consumers in the goal attainment condition prefer a leader brand rather than a servant brand. In contrast, consumers in the goal progress condition show no difference in their preference for a leader brand or a servant brand. Mediation analyses show that the level of motivation mediates the effect of goal pursuit on consumers’ preference for leader brands. Theoretical and managerial implications are discussed.

Purpose This paper aims to investigate the influence of implicit self-theories and the change in CEO of a firm after product failure on consumers’ preference of the enhanced product. Design/methodology/approach Three experiments were conducted involving product failure and CEO change scenarios. Findings Studies demonstrate that incremental theorists prefer the enhanced product after the CEO change (vs no change), whereas entity theorists do not prefer the enhanced product after the CEO change. This effect is mediated by consumers’ perception of the likelihood of success of the firm after the CEO change. Furthermore, entity theorists prefer the enhanced product only when the CEO change is external (vs internal). Research limitations/implications Future research could investigate if the impact of CEO change on product perception depends on the severity of the situation, and identify boundary conditions under which the CEO change is not beneficial. Practical implications The results suggest that organizations can take advantage of the leadership change by introducing new products strategically around the period of leadership change. Marketers can induce incremental mindset in their advertisement material during the period of leadership change to ensure that all consumers have a positive perception of the enhanced products. Originality/value This is the first research to investigate how consumers respond to leadership changes made by organizations. The findings show that different signals (internal vs external CEO change) can generate different reactions across different receivers (incremental vs entity theorists).

Background Promising developments in Pb-212 radiopharmaceutical therapies have increased demand for Pb-203 diagnostic agents. Building on previous work from various isotope production facilities, this study optimized Pb-203 production from electrodeposited Tl targets at Brookhaven National Laboratory (BNL). The additional supply of Pb-203 may help meet growing preclinical and clinical demands. Results Two Tl targets were irradiated at the Brookhaven Linac Isotope Producer facility with 30 ± 1 MeV protons, measured using previously published cross section data. Distribution coefficients for Pb Resin in acetate media were investigated for both Na + and K + cations, where potassium acetate was ~ 4 times more effective at stripping Pb from the Pb Resin. The Tl electrodeposition was optimized to deposit 350 mg of Tl (~ 60 mg/cm 2 ) on Au backing in under 6 h. The proposed separation process was completed in < 1.5 h and achieved > 98% and 92 ± 3% recovery of Tl and Pb, respectively, with an overall Tl-Pb separation factor of 6 × 10 5 . The experimentally measured half-life of Pb-203 was 52.4 ± 0.7 h, agreeing with 51.93 ± 0.02 h reported by the National Nuclear Data Center. The radioisotopic purity of the Pb fraction at 24 h post end of bombardment (EOB) from a 24 h irradiation was 66% Pb-203, 28% Pb-201, and 6% Pb-200. Following chemical separation, the Pb-203 produced in this work (21 MBq Pb-203 EOB) achieved apparent molar activities of 10 ± 5 and 0.9 ± 0.5 GBq/µmol for [ 203 Pb]Pb-DOTAM and [ 203 Pb]Pb-DO3A, respectively, decay corrected to EOB. Data derived from this work suggests BNL can produce > 10’s GBq Pb-203 with > 99% radiochemical and radioisotopic purity from Tl-205 for worldwide distribution. Conclusions The production and separation of Pb-203 from natural Tl target material was successfully demonstrated at BNL. Existing methods were adapted and optimized for the facilities at BNL. Results from this work will guide future large-scale Pb-203 production opportunities at BNL for clinical applications.

The emerging success of [68Ga/177Lu]Ga/Lu-DOTATATE as a theranostic pair has spurred interest in other isotopes as potential theranostic combinations. Here, we review cobalt-55 and cobalt-58m as a potential theranostic pair. Radionuclidically pure cobalt-55 and cobalt-58m have been produced on small cyclotrons with high molar activity. In vitro, DOTATOC labeled with cobalt has shown greater affinity for SSTR2 than DOTATOC labeled with gallium and yttrium. Similarly, [58mCo]Co-DOTATATE has shown improved cell-killing capabilities as compared to DOTATATE labeled with either indium-111 or lutetium-177. Finally, PET imaging with an isotope such as cobalt-55 allows for image acquisition at much later timepoints than gallium, allowing for an increased degree of biological clearance of non-bound radiotracer. We discuss the accelerator targetry and radiochemistry used to produce cobalt-55,58m, emphasizing the implications of these techniques to downstream radiotracers being developed for imaging and therapy.

To compare renal functional outcomes in patients with and without chronic kidney disease (CKD) to identify predictors of change in renal function after percutaneous nephrolithotomy (PCNL). We reviewed patients who underwent PCNL by a single surgeon over 3.5 years. Patients’ pre- and post-operative Glomerular Filtration Rate (GFR) was calculated. Baseline GFR < 60 ml/min/1.73 m2 (stage ≥ 3 CKD) defined our CKD cohort. Patients’ baseline renal function, comorbidities, stone parameters, and intra-operative variables were analyzed to determine the relationship with post-operative renal function after PCNL by multivariate analysis. 202 patients were analyzed. Mean follow-up time was 16 months. At baseline, 163 (80.7%) patients were free of CKD and 39 (19.3%) had CKD. Patients without CKD had an overall decrease in GFR from 105.6 to 103.3 ml/min/1.73 m2 (p = 0.494). 14/163 (8.6%) non-CKD patients experienced a significant decline in renal function after PCNL; 7/163 (4.3%) developed de novo CKD and 7 had a ≥ 30% decline in GFR. Patients with CKD had an overall increase in mean GFR post-operatively, from 47.3 to 54.0 ml/min/m2 (p = 0.067). Two in this cohort (5.1%) experienced a > 30% decline in renal function post-operatively. Age, gender, African American race, presence of comorbidities and pre-operative CKD were not significant predictors of renal function post-operatively on multivariate analysis. PCNL in this cohort appears GFR neutral in the setting of baseline CKD. CKD was not predictive of renal functional decline after PCNL. Given that stone disease carries a high recurrence rate and that CKD is associated with stone formers, further investigation into predictors of renal function change after PCNL is warranted.

Background Beyond the use of conventional short-lived PET radionuclides, there is a growing interest in tracking larger biomolecules and exploring radiotheranostic applications. One promising option for imaging medium-sized molecules and peptides is ⁵⁵Co (T₁/₂ = 17.5 h, β⁺ = 76%), which enables imaging of new and already established tracers with blood circulation of several hours. Additionally, ⁵⁵Co can be paired with the Auger-Meitner emitter 58m Co (T₁/₂ = 9 h, 100% IC) for radiotheranostic applications. Here we report on 55 Co production via the 58 Ni(p,α) 55 Co reaction channel using pressed 58 Ni and Mg matrix targets. Results This set up is capable to produce and isolate 240 ± 20 MBq [ 55 Co]Co + 2 (80% RCY) with 4 ml 0.25 M HEPES at 35 min post End Of Bombardment for 3 h, 25 µA protons irradiation. The RNP of the eluate is 99.98 ± 0.014% as measured 2 h & 17 h post EOB. AMA was determined to 1.5 ± 0.5 GBq/µmol [ 55 Co]Co-DOTA at EOB. Mg dissolves rapidly in the acid mixture, leaving behind a porous, sponge-like Ni matrix increasing the surface area of the Ni and therefore accelerating the dissolution. Conclusion We present a novel, simple, and rapid method to produce ⁵⁵Co with pressed ⁵⁸Ni/Mg matrix targets enabling faster target fabrication and dissolution. By using a simple hydraulic press, mechanically stable target coins useful for solid target irradiation are fabricated within 5 min and can be dissolved in 10 min at room temperature. The foils remain intact after irradiation and can endure irradiation conditions providing sufficient activity (> 200 MBq) for clinical doses. The method presented here using Mg as a support metal for fixation of the actual target material into target coins is applicable for other target combinations as well. Using Mg as a support metal is suitable due to its thermal conductivity, low activation, minimal impact on purification chemistry, softness, ductility, and rapid dissolution in acid.

People use two types of scheduling styles to schedule their daily activities, namely clock-time or event-time. When people use clock time, they organize tasks based on a clock. When they use event-time, they organize tasks based on their order of completion. This research shows that adopting different scheduling styles influence consumers' assortment size preferences. We demonstrate, through two studies, that consumers using event-time scheduling style prefer a larger assortment size whereas consumers using clock-time scheduling style prefer a smaller assortment size. We also show that this effect is mediated by desirability-feasibility consideration. Specifically, event-time scheduling style leads consumers to focus on the desirability considerations, which leads them to prefer larger assortment size while shopping. On the other hand, clock-time scheduling style leads consumers to focus on the feasibility considerations, which leads them to prefer smaller assortment size while shopping. We also discuss the theoretical and managerial implications of our research.

Purpose This study aims to understand the underlying mechanism and boundary conditions of the IKEA effect in self-expressive mass customization (MC). It examines the effect of the extent of choice in MC toolkits in terms of perceived value of self-designed products, as well as how self-expression mediates this effect and what kind of consumers are more inclined to experience such effect. Design/methodology/approach Two experiments were conducted, using online MC toolkits. In total, 393 consumers participated in the experiments. Data collected were analyzed using t-tests, analyses of variance, path analyses, bootstrap analyses and spotlight tests. Findings The results show that offering a greater extent of choice in MC toolkits to consumers provides a greater opportunity for self-expression, resulting in higher product valuation. Further, consumers who have high romanticism in aesthetic preference and high self-esteem are more inclined to influences associated with this effect. Originality/value This research adds to the literature on the IKEA effect in self-expressive MC by identifying a key antecedent (extent of choice), its underlying mechanism (self-expression), and two boundary conditions (aesthetic preference and self-esteem). The results of this study provide firms with a better understanding of how they can improve their self-expressive MC strategies.