Radiolabeled small-molecule DOTA-haptens can be combined with antitumor/anti-DOTA bispecific antibodies (BsAbs) for pretargeted radioimmunotherapy (PRIT). For optimized delivery of the theranostic - and β-emitting isotope ¹⁷⁷Lu with DOTA-based PRIT (DOTA-PRIT), bivalent Gemini (DOTA-Bn-thiourea-PEG4-thiourea-Bn-DOTA, aka (3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(DOTA-benzyl thiourea)) was developed. Methods: Gemini was synthesized by linking 2 S-2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [¹⁷⁷Lu]Lu-Gemini was prepared with no-carrier-added ¹⁷⁷LuCl₃ to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb-¹⁷⁷Lu-Gemini was verified in vitro. Subsequently, we evaluated biodistribution and whole-body clearance for [¹⁷⁷Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [¹⁷⁷Lu]Lu-S-2-(4-aminobenzyl)-DOTA ([¹⁷⁷Lu]Lu-DOTA-Bn) in naïve (tumor-free) athymic nude mice. For our proof-of-concept system, a 3-step pretargeting approach was performed with an established DOTA-PRIT regimen (anti-GPA33/anti-DOTA IgG-scFv BsAb, a clearing agent, and [¹⁷⁷Lu]Lu-Gemini) in mouse models. Results: Initial in vivo studies showed that [¹⁷⁷Lu]Lu-Gemini behaved similarly to [¹⁷⁷Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [¹⁷⁷Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [¹⁷⁷Lu]Lu-Gemini for blood, tumor, liver, spleen, and kidneys of 3.99, 455, 6.93, 5.36, and 14.0 cGy/MBq, respectively. Tumor–to–normal tissue absorbed-dose ratios (i.e., therapeutic indices [TIs]) for the blood and kidneys were 114 and 33, respectively. In addition, we demonstrate that the use of bivalent [¹⁷⁷Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [¹⁷⁷Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [¹⁷⁷Lu]Lu-DOTA-Bn. Finally, we established efficacy in SW1222 tumor-bearing mice, demonstrating that a single injection of anti-GPA33 DOTA-PRIT with 44 MBq (1.2 mCi) of [¹⁷⁷Lu]Lu-Gemini (estimated tumor-absorbed dose, 200 Gy) induced complete responses in 5 of 5 animals and a histologic cure in 2 of 5 (40%) animals. Moreover, a significant increase in survival compared with nontreated controls was noted (maximum tolerated dose not reached). Conclusion: We have developed a bivalent DOTA-radiohapten, [¹⁷⁷Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [¹⁷⁷Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [¹⁷⁷Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered ¹⁷⁷Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30).

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.

To date, the imaging and diagnosis of hepatocellular carcinoma (HCC) rely on CT/MRI, which have well-known limitations. Glypican-3 (GPC3) is a cell surface receptor highly expressed by HCC but not by normal or cirrhotic liver tissue. Here we report initial clinical results of GPC3-targeted PET imaging with [⁶⁸Ga]Ga-DOTA-RYZ-GPC3 (RAYZ-8009), a peptide-based GPC3 ligand in patients with known or suspected HCC. Methods: [⁶⁸Ga]Ga-RAYZ-8009 was obtained after labeling the peptide precursor with ⁶⁸Ga from a ⁶⁸Ge/⁶⁸Ga generator and heating at 90°C for 10 min followed by sterile filtration. After administration of [⁶⁸Ga]Ga-RAYZ-8009, a dynamic or static PET/CT scan was acquired between 45 min and 4 h after administration. Radiotracer uptake was measured by SUVs for the following tissues: suspected or actual HCC or hepatoblastoma lesions, non–tumor-bearing liver, renal cortex, blood pool in the left ventricle, and gastric fundus. Additionally, tumor–to–healthy-liver ratios (TLRs) were calculated. Results: Twenty-four patients (5 patients in the dynamic protocol; 19 patients in the static protocol) were scanned. No adverse events occurred. Two patients had no lesion detected and did not have HCC during follow-up. In total, 50 lesions were detected and analyzed. The mean SUV_max of these lesions was 19.6 (range, 2.7–95.3), and the mean SUV_mean was 10.1 (range, 1.0–49.2) at approximately 60 min after administration. Uptake in non–tumor-bearing liver and blood pool rapidly decreased over time and became negligible 45 min after administration (mean SUV_mean, <1.6), with a continuous decline to 4 h after administration (mean SUV_mean, 1.0). The opposite was observed for HCC lesions, for which SUVs and TLRs continuously increased for up to 4 h after administration. In individual lesion analysis, TLR was the highest between 60 and 120 min after administration. Uptake in the gastric fundus gradually increased for up to 45 min (to an SUV_max of 31.3) and decreased gradually afterward. Conclusion: [⁶⁸Ga]Ga-RAYZ-8009 is safe and allows for high-contrast imaging of GPC3-positive HCC, with rapid clearance from most normal organs. Thereby, [⁶⁸Ga]Ga-RAYZ-8009 is promising for HCC diagnosis and staging. Further research is warranted.

Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. ⁶⁸Ga-labeled fibroblast activation protein inhibitor ([⁶⁸Ga]Ga-FAPI-04) PET/MRI, [¹⁸F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter’s sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [⁶⁸Ga]Ga-FAPI-04 PET/MRI and [¹⁸F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [⁶⁸Ga]Ga-FAPI-04 change in SUL_peak percentage, where SUL_peak is SUV_peak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [⁶⁸Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SUL_peak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.

Understanding which patients with human epidermal growth factor receptor 2 (HER2)–negative or –low metastatic breast cancer (MBC) benefit from HER2-targeted strategies is urgently needed. We assessed the whole-body heterogeneity of HER2 expression on ⁸⁹Zr-trastuzumab PET (HER2 PET) and the diagnostic performance of HER2 PET in a large series of patients, including HER2-negative and -low MBC. Methods: In the IMPACT-MBC study, patients with newly diagnosed and nonrapidly progressive MBC of all subtypes were included. Metastasis HER2 status was determined by immunohistochemistry and in situ hybridization.⁸⁹Zr-trastuzumab uptake was quantified as SUV_max and SUV_mean. HER2 immunohistochemistry was related to the quantitative ⁸⁹Zr-trastuzumab uptake of all metastases and corresponding biopsied metastasis, uptake heterogeneity, and qualitative scan evaluation. A prediction algorithm for HER2 immunohistochemistry positivity based on uptake was developed. Results: In 200 patients, ⁸⁹Zr-trastuzumab uptake was quantified in 5,163 metastases, including 186 biopsied metastases. With increasing HER2 immunohistochemistry status, uptake was higher (geometric mean SUV_max of 7.0, 7.6, 7.3, and 17.4 for a HER2 immunohistochemistry score of 0, 1, 2, or 3+, respectively; P < 0.001). High uptake exceeding 14.6 (90th percentile) was observed in one third of patients with a HER2-negative or -low metastasis biopsy. The algorithm performed best when lesion site and size were incorporated (area under the curve, 0.86; 95% CI, 0.79–0.93). Conclusion: HER2 PET had good diagnostic performance in MBC, showing considerable whole-body HER2 heterogeneity and uptake above background in HER2-negative and -low MBC. This provides novel insights into HER2-negative and -low MBC compared with standard HER2 immunohistochemistry on a single biopsy.

SANTA CLARA, Calif., Oct. 25, 2024 — ServiceNow has announced that enterprise software industry veteran Amit Zavery will join the company as president, chief product officer (CPO), and chief operating officer […]

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PALO ALTO, Calif., Oct. 30, 2024 — D-Wave Quantum Inc. today announced the appointments of veteran technology industry leaders, John DiLullo and Rohit Ghai, to its board of directors. The new […]

The post D-Wave Expands Board with Industry Veterans John DiLullo and Rohit Ghai appeared first on HPCwire.

Australian Defense Minister Peter Dutton called for alliances to protect the nations and people of the Indo-Pacific region.

The USS Frank E. Petersen Jr. cleared another hurdle toward joining the Navy's fleet after it completed acceptance trials on Thursday.

Researchers once faced death threats for asking women what gives them pleasure. Now they’re helping individuals and couples figure it out themselves.

Health officials in Britain have detected the country's first confirmed human case of a new strain of mpox that has been spreading throughout Africa.

An additional case of a new strain of mpox has been detected in Britain, bringing the total number of infections in the country to four.

A boom in AI has created a problem for the organizers of the NeurIPS conference, which is considered an essential machine-learning research conference. The sheer number of registrations has overwhelmed […]

The post Lottery to Determine Major AI Conference Attendees Amid Registration Boom appeared first on HPCwire.

President Joe Biden on Monday addressed a Veterans Day crowd at the national cemetery in Virginia where he revealed newly-expanded veteran benefits and urged Americans to "come together" and "keep faith."

The U.S. Department of Veterans Affairs announced plans Monday to eliminate copayments for all VA telehealth services, while expanding online emergency care access for rural veterans.

Harriet Tubman was posthumously awarded the rank of brigadier general of the Maryland National Guard on Monday in recognition of her service.

President-elect Donald Trump on Tuesday night announced his nomination of Fox News host and Army veteran Pete Hegseth to head the Department of Defense.

The Taurid meteor will make its annual appearance in the midnight sky starting Tuesday through Nov. 12, with the "shooting star" appearing best after in the early morning hours.

How do you reach people trapped in a reality shaped by propaganda? Exploring the dark psychology of disinformation, author and academic Peter Pomerantsev draws on lessons from a forgotten World War II operation to suggest strategies for cutting through misinformation and rebuilding trust in facts today.

The U.S. Department of Education's office for civil rights says that Connecticut's interscholastic sports governing body violates Title IX with its transgender participation policy.

The Trump administration argues that the U.S. Supreme Court's decision that federal law protects transgender employees does not apply to transgender athletes in school.

South Carolina's public universities only produce enough teachers each year to fill half of the state's vacant teacher positions.

Georgia and Miami misery translates into joy for the Texas Longhorns. Thanks to losses by the 'Canes and Bulldogs on Saturday, the Horns move up two spots in the college football playoff ranki

The second release of College Football Playoff rankings changes the projected bracket. Here's what it looks like if the season ended today.

Caroline Fenton & Jason Fitz react to the second edition of the 2024 College Football Playoff Rankings, discuss Heisman pretenders vs. contenders and preview the biggest matchups of Week 12.

Different people listening to the same story may converge upon a largely shared interpretation while still developing idiosyncratic experiences atop that shared foundation. What linguistic properties support this individualized experience of natural language? Here, we investigate how the "concrete–abstract" axis—the extent to which a word is grounded in sensory experience—relates to within- and across-subject variability in the neural representations of language. Leveraging a dataset of human participants of both sexes who each listened to four auditory stories while undergoing functional magnetic resonance imaging, we demonstrate that neural representations of "concreteness" are both reliable across stories and relatively unique to individuals, while neural representations of "abstractness" are variable both within individuals and across the population. Using natural language processing tools, we show that concrete words exhibit similar neural representations despite spanning larger distances within a high-dimensional semantic space, which potentially reflects an underlying representational signature of sensory experience—namely, imageability—shared by concrete words but absent from abstract words. Our findings situate the concrete–abstract axis as a core dimension that supports both shared and individualized representations of natural language.

A new book from the Smithsonian’s National Museum of African American History and Culture shows the images and impacts of athletes on and off the playing field

The early polygraph machine was considered the most scientific way to detect deception—but that was a myth

In his address to the Joint Meeting of the Finance and Programme Committees this morning, the Director-General assured Members of the determination and commitment to delivery of the current Programme [...]

In March 1895, Boston and New York City began an epic and highly competitive race to become the first American city with a working subway system.

In 1905, New York City hosted a grand procession for the last living soldier of a war that ended 90 years earlier

While President Kennedy may be one of the best known gravesites in Arlington, there are many other notable Americans buried in these sacred grounds (Ryan Reed and Molly Roberts). Read more at http://smithsonian.com/arlington

Have you ever wondered whether lie detectors actually...work? Join us as we delve into the history and science behind these devices - from how they measure "deception" to the controversies surrounding their use. This video is the first episode of the National Treasure series, where we share behind-the-scenes stories of objects in the Smithsonian Collections. --------- To learn more about the exhibition "Forensic Science on Trial" at Smithsonian's National Museum of American History, read below: What a 100-Year-Old Lie Detector and 150-Year-Old Arsenic Tests Tell Us About Forensic Science Today https://www.smithsonianmag.com/smithsonian-institution/what-a-100-year-old-lie-detector-and-150-year-old-arsenic-tests-tell-us-about-forensic-science-today-180984623/ Forensic Science on Trial https://americanhistory.si.edu/explore/exhibitions/forensic-science-trial Digital Editorial Director: Brian Wolly Supervising Producer & Scriptwriter: Michelle Mehrtens Producer: Nicki Marko Producer & Editor: Sierra Theobald Motion Designer: Ricardo Jaimes Original Footage: Cade Martin

ARTICLE: https://www.smithsonianmag.com/history/civil-war-veterans-come-alive-in-audio-and-video-recordings-97841665/ In this exclusive clip from the 1930s, Confederate veterans step up to the mic and let out their version of the fearsome rallying cry.

(Footage: Erin Trieb. Video Editing: Nicole Boliaux)

Recently digitized footage shows the 5th Div. cemetery dedication on Iwo Jima with band, gun salute and officers speaking. In the final scene, tow Marines kneel over the temporary resting place of 3/13 PFC Ernest T. Langbeen. (U.S. Marine Corps History Division and Moving Image Research Collections, University of South Carolina)

Atlantic staff writer Frank Foer interviews Damion Thomas about athletes moving from a position of apathy to engagement

The 12,000 year old skeleton of a teenage girl was found in Hoyo Negro, an underwater cave system on the Yucatan Peninsula.

Researchers studying the ancient site of Fregellae reveal the consequences of challenging the Roman army

The brain diagram, called a connectome, could revolutionize researchers' understanding of the human brain, which has many parallels with a fruit fly's

Experts say that the trove of silver currency is official treasure and includes coins from England and Ireland