Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. Methods: OncoFAP-23 was radiolabeled with the theranostic radionuclide ¹⁷⁷Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. ¹⁷⁷Lu-OncoFAP and ¹⁷⁷Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Results: ¹⁷⁷Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ~16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of ¹⁷⁷Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and ^natLu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. Conclusion: OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of ¹⁷⁷Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.

Single-domain antibodies (sdAbs) demonstrate favorable pharmacokinetic profiles for molecular imaging applications. However, their renal excretion and retention are obstacles for applications in targeted radionuclide therapy (TRT). Methods: Using a click-chemistry–based pretargeting approach, we aimed to reduce kidney retention of a fibroblast activation protein α (FAP)–targeted sdAb, 4AH29, for ¹⁷⁷Lu-TRT. Key pretargeting parameters (sdAb-injected mass and lag time) were optimized in healthy mice and U87MG (FAP⁺) xenografts. A TRT study in a pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (PDX) model was performed as a pilot study for sdAb-based pretargeting applications. Results: Modification of 4AH29 with trans-cyclooctene (TCO) moieties did not modify the sdAb pharmacokinetic profile. A 200-µg injected mass of 4AH29-TCO and an 8-h lag time for the injection of [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine resulted in the highest kidney therapeutic index (2.0 ± 0.4), which was 5-fold higher than that of [¹⁷⁷Lu]Lu-DOTA-4AH29 (0.4 ± 0.1). FAP expression in the tumor microenvironment was validated in a PDAC PDX model with both immunohistochemistry and PET/CT imaging. Mice treated with the pretargeting high-activity approach (4AH29-TCO + [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine; 3 x 88 MBq, 1 injection per week for 3 wk) demonstrated prolonged survival compared with the vehicle control and conventionally treated ([¹⁷⁷Lu]Lu-DOTA-4AH29; 3 x 37 MBq, 1 injection per week for 3 wk) mice. Mesangial expansion was reported in 7 of 10 mice in the conventional cohort, suggesting treatment-related kidney morphologic changes, but was not observed in the pretargeting cohort. Conclusion: This study validates pretargeting to mitigate sdAbs’ kidney retention with no observation of morphologic changes on therapy regimen at early time points. Clinical translation of click-chemistry–based pre-TRT is warranted on the basis of its ability to alleviate toxicities related to biovectors’ intrinsic pharmacokinetic profiles. The absence of representative animal models with extensive stroma and high FAP expression on cancer-associated fibroblasts led to a low mean tumor-absorbed dose even with high injected activity and consequently to modest survival benefit in this PDAC PDX.

Genetic-testing lab 23andMe plans to cut its workforce by 40% and end its therapeutics program in an effort to cut costs, the company announced Monday.

An American woman who was traveling in Hungary was killed in Budapest last week allegedly by a man she met on vacation.

Oct. 31, 2024 — Giga Computing, a subsidiary of GIGABYTE and a leader in generative AI servers and advanced cooling technologies, will participate in today’s AI Accelerator Skyscraper Congress, hosted […]

The post GIGABYTE Joins AI Accelerator Skyscraper Congress to Highlight Sustainable Supercomputing Advances appeared first on HPCwire.

A zoo on England's Isle of Wight announced the saga of its escaped raccoons came to a happy ending with the final animal safely recaptured.

HPC news headlines often highlight the latest hardware speeds and feeds. While advances on the hardware front are important, improving the ability to write software for advanced systems is equally […]

The post What’s New with Chapel? Nine Questions for the Development Team appeared first on HPCwire.

New cross-species research suggests a theory of mind is one thing that sets humans apart from apes

Genetic-testing lab 23andMe plans to cut its workforce by 40% and end its therapeutics program in an effort to cut costs, the company announced Monday.

Call for papers: SJDM, San Francisco, Nov 17-20, 2023. Submission deadline June 22, 2023

The student newspaper at duPont Manual High School in Louisville, Ky., first reported on the state's problematic police training material.

Eliminating gifted programs all together is the wrong solution to fixing racial and economic imbalances, argues James R. Delisle.

Steven F. Grieco
Nov 9, 2022; 42:8439-8449
Symposium and Mini-Symposium

Michele Deodato
Oct 2, 2024; 44:e2308232024-e2308232024
BehavioralSystemsCognitive

Krista L. Hyde
Mar 11, 2009; 29:3019-3025
Development Plasticity Repair

Recent visual experience heavily influences our visual perception, but how neuronal activity is reshaped to alter and improve perceptual discrimination remains unknown. We recorded from populations of neurons in visual cortical area V4 while two male rhesus macaque monkeys performed a natural image change detection task under different experience conditions. We found that maximizing the recent experience with a particular image led to an improvement in the ability to detect a change in that image. This improvement was associated with decreased neural responses to the image, consistent with neuronal changes previously seen in studies of adaptation and expectation. We found that the magnitude of behavioral improvement was correlated with the magnitude of response suppression. Furthermore, this suppression of activity led to an increase in signal separation, providing evidence that a reduction in activity can improve stimulus encoding. Within populations of neurons, greater recent experience was associated with decreased trial-to-trial shared variability, indicating that a reduction in variability is a key means by which experience influences perception. Taken together, the results of our study contribute to an understanding of how recent visual experience can shape our perception and behavior through modulating activity patterns in the mid-level visual cortex.

Seven guest collaborators bring new eyes to a Smithsonian museum founder’s collection of American art

The work of Diné artist DY Begay, now on view at the National Museum of the American Indian, blends tradition and modernity

FAO is pleased to announce the release of the Global Plan of Action for the Conservation, Sustainable Use and Development of Aquatic Genetic Resources for Food [...]

Zookeepers at the National Zoo keep orangutans mentally stimulated with an innovative use of iPads

From Smithsonian.com's story on Dave Shealy, Florida's self-proclaimed skunk ape expert: www.smithsonianmag.com/science-nature/trail-floridas-bigfoot-skunk-ape-180949981/

If the structures look familiar, it's probably because nature has been using them for a long time in places like nautilus shells, zebra stripes and onions

On this day in 1690, "Publick Occurrences Both Forreign and Domestick" attracted colonial officials' ire by repeating a scandalous rumor and condemning a British alliance with the Mohawk

Authorities have not yet identified the cause of death for the 12.5-foot-long shark, which was named Koala

A special committee has until January 15 to finalize the design, location and funding for a monument that will be erected on the lawn of the South Carolina State House

This story and others have come to light during a project to translate and digitize a series of texts about archbishops in York, England

Volunteers will be cutting hair at a salon based inside a Cape Breton food bank. The goal is to provide clients with the same salon experience paying customers would receive.

A Port Hawkesbury woman has long imagined a Remembrance Day with her great-uncle's war medals. It will happen this year for the first time thanks to some sleuthing and the kindness of her great-uncle's foster family.

The British explorer named dozens of geographical features and sites in the region, ignoring the traditions of the Indigenous peoples who’d lived there for millennia

After nearly six complete seasons, the Canadian Premier League finds itself at an inflection point. Ahead of Saturday’s championship match, it appears there’s some stability — and, consequently, an opportunity to further establish the league’s place within the rapidly growing soccer landscape.

Several firearms, body armour, diamonds and fentanyl shaped like dog treats were among the items seized in a recent bust, say Metro Vancouver Transit Police.

New rebuilding regulations in Jasper have been approved, but roadblocks — including the sheer number of people that are needed for construction — are popping up.

Longtime SOLIDWORKS and COSMOS customer reduces costs and time to market

Effie Award Recognizes Marketing Company Small Army and DS SolidWorks for ‘3 Dudes Gone 3D’ Campaign

Using SOLIDWORKS Software, Norwegian Company Seabed Rig Designs Breakthrough System Operating on Ocean Floor

Saudi Arabia has been burning through its currency reserves amid the fall in oil prices. Is the economy heading toward peril or will reforms save the day?

High costs could hamper diversification of supply lines in a post-pandemic era.

In a major update to the camera system, analyst Ming-Chi Kuo says the iPhone 18 Pro's wide angle lens will be upgraded to have a variable aperture.

Three Ga. high school seniors have been charged with aggravated sexual battery and consumption of alcohol by a minor stemming from an alleged sexual assault during a post-prom party.

Scholars have identified several reasons why cities want to host the Games, and there's little evidence to support some of the claims. But that doesn't mean it's not worth doing, says Johan Fourie.

Spanish and accounting student Jessica Krieger completed an internship with KPMG as one of 28 Liberal Arts students in the Chapel Executive Internship Program this summer.

Sabrina Knox completed an internship with Westinghouse Nuclear as one of 28 Liberal Arts students in the Chapel Executive Internship Program this summer.

Western Cape MEC for local government, environmental affairs and development Anton Bredell has filed an application for leave to appeal a high court order suspending construction of a R4.5 billion project that will house Amazon’s Africa headquarters.

About 80% of trophy home sales in Cape Town were along the Atlantic Seaboard, especially in Camps Bay, Clifton, Bantry Bay, Fresnaye and at the Waterfront.

Underprivileged kids learn about Jesus through a weekly football programme.

The mock test papers series-I will commence from November 18, 2024 while that for series-II will begin from December 9, 2024.

The Delaware Public Archives is pleased to announce the digital release of “The Abram H. Draper Collection.” This unique collection consists of 34 pieces of correspondence including letters and poetry from Sergeant Abram H. Draper to his wife Anna M. Wiley Draper during the American Civil War. The content ranges from detailed descriptions of Draper’s […]

Potential victims encouraged to contact (302) 577-5293 or ReportAbuse@delaware.gov   Tyrone Clark, 64, has been sentenced to a total of 125 years for the rape and abuse of a 12-year-old child in his care.  “No crime is more offensive, more heinous, and more dangerous than the sexual abuse of a child,” said Attorney General Jennings. “I’m grateful to […]

Attorney General Kathy Jennings and her colleagues have announced that a proposed settlement has been reached in the 2020 lawsuit against the Environmental Protection Agency (EPA) for its failure to require Pennsylvania to develop and implement a plan to meet its commitments to reduce pollution under the Chesapeake Clean Water Blueprint. One-third of Delaware is […]

TOWNSEND, Del. (September 7, 2022) – Volunteers are needed to plant 2,000 hardwood seedlings along the Cypress Branch at Blackbird State Forest on Saturday, September 17 to provide scenic beauty, enhance wildlife habitat, fight invasive species, and improve water quality in the critical Chesapeake Bay Watershed. State Forester Michael Valenti said, “Planting trees is a […]