SPECT/CT imaging of EGFR-positive head and neck squamous cell carcinoma patient-derived xenografts with Pb-PSC-panitumumab in NRG mice.

Background: The objective of this research was the development and evaluation of Pb-labelled panitumumab (Pb-PSC-panitumumab) as an immuno-SPECT radioligand for the detection of EGFR + head and neck squamous cell carcinoma (HNSCC) in a patient-derived xenograft (PDX) mouse model. The 51.9 h physical half-life and favourable γ-emission (279 keV; 81%) of Pb offer an excellent opportunity for developing immuno-SPECT radioligands.

Aspects and prospects of preclinical theranostic radiopharmaceutical development.

This article provides an overview of preclinical theranostic radiopharmaceutical development, highlighting aspects of the preclinical development stages that can lead towards a clinical trial. The key stages of theranostic radiopharmaceutical development are outlined, including target selection, tracer development, radiopharmaceutical synthesis, automation and quality control, radiopharmaceutical analysis, selecting a suitable model, preclinical imaging and pharmacokinetic analysis, preclinical therapeutic analysis, dosimetry, toxicity, and preparing for clinical translation. Each stage is described and augmented with examples from the literature.

Bacterial cell surface characterization by phage display coupled to high-throughput sequencing.

The remarkable capacity of bacteria to adapt in response to selective pressures drives antimicrobial resistance. Pseudomonas aeruginosa illustrates this point, establishing chronic infections during which it evolves to survive antimicrobials and evade host defenses. Many adaptive changes occur on the P.

Cu production via the Zn(p,nα)Cu nuclear reaction: An untapped, cost-effective and high energy production route.

Introduction: Copper-64 (Cu, t = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of Cu produced via the Zn(p,nα)Cu nuclear reaction.

Theranostic Imaging Surrogates for Targeted Alpha Therapy: Progress in Production, Purification, and Applications.

This article highlights recent developments of SPECT and PET diagnostic imaging surrogates for targeted alpha particle therapy (TAT) radiopharmaceuticals. It outlines the rationale for using imaging surrogates to improve diagnostic-scan accuracy and facilitate research, and the properties an imaging-surrogate candidate should possess. It evaluates the strengths and limitations of each potential imaging surrogate.

A Theranostic Approach to Imaging and Treating Melanoma with Pb/Pb-Labeled Antibody Targeting Melanin.

Metastatic melanoma is a deadly disease that claims thousands of lives each year despite the introduction of several immunotherapeutic agents into the clinic over the past decade, inspiring the development of novel therapeutics and the exploration of combination therapies. Our investigations target melanin pigment with melanin-specific radiolabeled antibodies as a strategy to treat metastatic melanoma. In this study, a theranostic approach was applied by first labeling a chimeric antibody targeting melanin, c8C3, with the SPECT radionuclide Pb for microSPECT/CT imaging of C57Bl6 mice bearing B16-F10 melanoma tumors.

High-yield cyclotron production of Pb using a sealed Tl solid target.

Introduction: Pb (t = 51.9 h, 279 keV (81 %)) is a diagnostic SPECT imaging radionuclide ideally suited for theranostic applications in combination with Pb for targeted alpha particle therapy. Our objectives were to develop a high-yield solid target Pb cyclotron production route using isotopically enriched Tl target material and the Tl(p,3n)Pb reaction as an alternative to lower energy production via the Tl(p,n)Pb reaction.

Good practices for Ga radiopharmaceutical production.

Background: The radiometal gallium-68 (Ga) is increasingly used in diagnostic positron emission tomography (PET), with Ga-labeled radiopharmaceuticals developed as potential higher-resolution imaging alternatives to traditional Tc agents. In precision medicine, PET applications of Ga are widespread, with Ga radiolabeled to a variety of radiotracers that evaluate perfusion and organ function, and target specific biomarkers found on tumor lesions such as prostate-specific membrane antigen, somatostatin, fibroblast activation protein, bombesin, and melanocortin.

Main Body: These Ga radiopharmaceuticals include agents such as [Ga]Ga-macroaggregated albumin for myocardial perfusion evaluation, [Ga]Ga-PLED for assessing renal function, [Ga]Ga-t-butyl-HBED for assessing liver function, and [Ga]Ga-PSMA for tumor imaging.

Radiolanthanum: Promising theranostic radionuclides for PET, alpha, and Auger-Meitner therapy.

Lanthanum radiometals are well positioned to serve as theranostic PET radiometals for targeted radionuclide therapy. The positron emitters La and La show promise to serve as unique PET imaging agents for Ac targeted alpha-particle therapy, the Ce/La pair has PET imaging potential with both Ac and Th, and La has potential in targeted Auger-Meitner electron therapy. With easily accessible cyclotron production routes, effective and efficient chemical separations, and robust chelation chemistry, these radionuclides are well poised for additional preclinical and clinical PET and targeted radionuclide therapy studies.

Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617.

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical.

Symptomatic diabetic autonomic neuropathy in type 1 diabetes (T1D): Findings from the T1D exchange.

Aims: We aimed to evaluate the contemporary prevalence of and risk factors for symptomatic diabetic autonomic neuropathy (DAN) in participants with type 1 diabetes (T1D) enrolled in the T1D Exchange Clinic Registry.

Methods: DAN symptoms and severity were assessed with the Survey of Autonomic Symptoms (SAS) in adults with ≥5 years of T1D participating in the T1D Exchange from years 2010-2017. Associations of demographic, clinical, and laboratory factors with symptomatic DAN were assessed.

Endothelial Unc5B controls blood-brain barrier integrity.

Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we show that the endothelial Unc5B receptor controls BBB integrity by maintaining Wnt/β-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice leads to BBB leak from brain capillaries that convert to a barrier-incompetent state with reduced Claudin-5 and increased PLVAP expression.

Inhibition of renalase drives tumour rejection by promoting T cell activation.

Background: Although programmed cell death protein 1 (PD-1) inhibitors have revolutionised treatment for advanced melanoma, not all patients respond. We previously showed that inhibition of the flavoprotein renalase (RNLS) in preclinical melanoma models decreases tumour growth. We hypothesised that RNLS inhibition promotes tumour rejection by effects on the tumour microenvironment (TME).

Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617.

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical.

First In Vivo and Phantom Imaging of Cyclotron-Produced La as a Theranostic Radionuclide for Ac and La.

Theranostic isotope pairs have gained recent clinical interest because they can be labeled to the same tracer and applied for diagnostic and therapeutic purposes. The goals of this study were to investigate cyclotron production of clinically relevant La activities using natural and isotopically enriched barium target material, compare fundamental PET phantom imaging characteristics of La with those of common PET radionuclides, and demonstrate in vivo preclinical PET tumor imaging using La-PSMA-I&T. La was produced on a 24-MeV cyclotron using an aluminum-indium sealed target with 150-200 mg of isotopically enriched BaCO, BaCO, and Ba metal.

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications.

This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short and highly ionizing path of α-particle emissions; the ability of TAT to complement and provide superior efficacy over existing forms of radiotherapy; the physical decay properties and radiochemistry of common α-emitters, including Ac, Bi, Ra, Pb, Th, Ra, At, and Tb; the production techniques and proper handling of α-emitters in a radiopharmacy; recent preclinical developments; ongoing and completed clinical trials; and an outlook on the future of TAT.

High yield cyclotron production of a novel La theranostic pair for nuclear medicine.

This study reports the high-yield production of a novel La theranostic pair at a 22 MeV proton beam energy as an attractive alternative to the recently introduced La pair, demonstrating over an order of magnitude production increase of La (231 ± 8 MBq La and 166 ± 5 MBq La at End of Bombardment (EOB)) compared to 11.9 MeV production of La (0.82 ± 0.

Taking cyclotron Ga production to the next level: Expeditious solid target production of Ga for preparation of radiotracers.

Introduction: Gallium-68 is an important radionuclide for positron emission tomography (PET) with steadily increasing applications of Ga-based radiopharmaceuticals for clinical use. Current Ga sources are primarily Ge/Ga-generators, along with successful attempts of Ga production using a cyclotron. This study evaluated cyclotron Ga production and automated separation using expeditiously manufactured solid targets, demonstrates an order of magnitude improvement in yield compared to Ge/Ga generators, and presents a convenient alternative to existing cyclotron production processes.

Transforming Performance of Clinical Trials in Pediatric Type 2 Diabetes: A Consortium Model.

Completing phase 3 trials of new drugs for youth with type 2 diabetes is challenging. The Pediatric Diabetes Consortium (PDC) of U.S.

Identification and Validation of a Novel Biologics Target in Triple Negative Breast Cancer.

The goal of this study was to identify a novel target for antibody-drug conjugate (ADC) development in triple negative breast cancer (TNBC), which has limited treatment options, using gene expression datasets and in vitro siRNA/CRISPR and in vivo functional assays. We analyzed 4467 breast cancers and identified GABRP as top expressed gene in TNBC with low expression in most normal tissues. GABRP protein was localized to cell membrane with broad range of receptors/cell (815-53,714) and expressed by nearly half of breast cancers tissues.

Improving Diabetes Control Through Remote Glucose Monitoring in a Diabetes Self-Management Program for Employees of a Health System.

This study investigates the combination of diabetes education, telehealth, a wireless enabled meter, and medication algorithms to improve care for a targeted population of employees with type 1 or type 2 diabetes. After more than 2 years of follow-up, mean A1C was reduced by 1.8%, and a reduction was observed in cost of care, along with an increase in visits with the managing physician provider.

Structure-Guided Combinatorial Engineering Facilitates Affinity and Specificity Optimization of Anti-CD81 Antibodies.

Hepatitis C viral infection is the major cause of chronic hepatitis that affects as many as 71 million people worldwide. Rather than target the rapidly shifting viruses and their numerous serotypes, four independent antibodies were made to target the host antigen CD81 and were shown to block hepatitis C viral entry. The single-chain variable fragment of each antibody was crystallized in complex with the CD81 large extracellular loop in order to guide affinity maturation of two distinct antibodies by phage display.

Sleep in children with type 1 diabetes and their parents in the T1D Exchange.

Objectives: Sleep has physiological and behavioral impacts on diabetes outcomes, yet little is known about the impact of sleep disturbances in children with type 1 diabetes. The current study sought to characterize sleep in children with type 1 diabetes and in their parents and to examine the associations between child sleep, glycemic control and adherence, parent sleep and well-being, parental fear of hypoglycemia, and nocturnal caregiving behavior.

Methods: Surveys were emailed to parents of 2- to 12-year-old participants in the Type 1 Diabetes (T1D) Exchange clinic registry.

Invadolysin acts genetically via the SAGA complex to modulate chromosome structure.

Identification of components essential to chromosome structure and behaviour remains a vibrant area of study. We have previously shown that invadolysin is essential in Drosophila, with roles in cell division and cell migration. Mitotic chromosomes are hypercondensed in length, but display an aberrant fuzzy appearance.

Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region.

Somatic oncogenic mutations in the receptor tyrosine kinase KIT function as major drivers of gastrointestinal stromal tumors and a subset of acute myeloid leukemia, melanoma, and other cancers. Although treatment of these cancers with tyrosine kinase inhibitors shows dramatic responses and durable disease control, drug resistance followed by clinical progression of disease eventually occurs in virtually all patients. In this report, we describe inhibitory KIT antibodies that bind to the membrane-proximal Ig-like D4 of KIT with significant overlap with an epitope in D4 that mediates homotypic interactions essential for KIT activation.