Rapid kit-based (68)Ga-labelling and PET imaging with THP-Tyr(3)-octreotate:a preliminary comparison with DOTA-Tyr(3)-octreotate

BACKGROUND: Ge/(68)Ga generators provide an inexpensive source of a PET isotope to hospitals without cyclotron facilities. The development of new (68)Ga-based molecular imaging agents and subsequent clinical translation would be greatly facilitated by simplification of radiochemical syntheses. We report the properties of a tris(hydroxypyridinone) conjugate of the SSTR2-targeted peptide, Tyr(3)-octreotate (TATE), and compare the (68)Ga-labelling and biodistribution of [(68)Ga(THP-TATE)] with the clinical radiopharmaceutical [(68)Ga(DOTATATE)]. METHODS: A tris(hydroxypyridinone) with a pendant isothiocyanate group was conjugated to the primary amine terminus of H(2)N-PEG(2)-Lys(iv-Dde)(5)-TATE, and the resulting conjugate was deprotected to provide THP-TATE. THP-TATE was radiolabelled with (68)Ga(3+) from a (68)Ge/(68)Ga generator. In vitro uptake was assessed in SSTR2-positive 427-7 cells and SSTR2-negative 427 (parental) cells. Biodistribution of [(68)Ga(THP-TATE)] was compared with that of [(68)Ga(DOTATATE)] in Balb/c nude mice bearing SSTR2-positive AR42J tumours. PET scans were obtained 1 h post-injection, after which animals were euthanised and tissues/organs harvested and counted. RESULTS: [(68)Ga(THP-TATE)] was radiolabelled and formulated rapidly in <2 min, in ≥95 % radiochemical yield at pH 5–6.5 and specific activities of 60–80 MBq nmol(−1) at ambient temperature. [(68)Ga(THP-TATE)] was rapidly internalised into SSTR2-positive cells, but not SSTR2-negative cells, and receptor binding and internalisation were specific. Animals administered [(68)Ga(THP-TATE)] demonstrated comparable SSTR2-positive tumour activity (11.5 ± 0.6 %ID g(−1)) compared to animals administered [(68)Ga(DOTATATE)] (14.4 ± 0.8 %ID g(−1)). Co-administration of unconjugated Tyr(3)-octreotate effectively blocked tumour accumulation of [(68)Ga(THP-TATE)] (2.7 ± 0.6 %ID g(−1)). Blood clearance of [(68)Ga(THP-TATE)] was rapid and excretion was predominantly renal, although compared to [(68)Ga(DOTATATE)], [(68)Ga(THP-TATE)] exhibited comparatively longer kidney retention. CONCLUSIONS: Radiochemical synthesis of [(68)Ga(THP-TATE)] is significantly faster, proceeds under milder conditions, and requires less manipulation than that of [(68)Ga(DOTATATE)]. A (68)Ga-labelled tris(hydroxypyridinone) conjugate of Tyr(3)-octreotate demonstrates specificity and targeting affinity for SSTR2 receptors, with comparable in vivo targeting affinity to the clinical PET tracer, [(68)Ga(DOTATATE)]. Thus, peptide conjugates based on tris(hydroxypyridinones) are conducive to translation to kit-based preparation of PET tracers, enabling the expansion and adoption of (68)Ga PET in hospitals and imaging centres without the need for costly automated synthesis modules

Hierarchy of Lifshitz transitions in the surface electronic structure of Sr2RuO4 under uniaxial compression

Funding: We gratefully acknowledge support from the Engineering and Physical Sciences Research Council (Grant Nos. EP/T02108X/1 and EP/R031924/1), the European Research Council (through the QUESTDO project, 714193), and the Leverhulme Trust (Grant No. RL-2016-006). E.A.M., A.Z., and I.M. gratefully acknowledge studentship support from the International Max-Planck Research School for Chemistry and Physics of Quantum Materials. N.K. is supported by a KAKENHI Grants-in-Aids for Scientific Research (Grant Nos.18K04715, and 21H01033), and Core-to-Core Program (No. JPJSCCA20170002) from the Japan Society for the Promotion of Science (JSPS) and by a JST-Mirai Program (Grant No. JPMJMI18A3). APM and CWH acknowledge support from the Deutsche Forschungsgemeinschaft - TRR 435 288 - 422213477 (project A10). We thank Diamond Light Source for access to Beamline I05 (Proposals SI27471 and SI28412), which contributed to the results presented here.We report the evolution of the electronic structure at the surface of the layered perovskiteSr2RuO4 under large in-plane uniaxial compression, leading to anisotropic B1g strains of εxx − εyy = −0.9 ± 0.1%. From angle-resolved photoemission, we show how this drives a sequence of Lifshitz transitions, reshaping the low-energy electronic structure and the rich spectrum of van Hove singularities that the surface layer of Sr2RuO4 hosts. From comparison to tight-binding modelling, we find that the strain is accommodated predominantly by bond-length changes rather than modifications of octahedral tilt and rotation angles. Our study sheds new light on the nature of structural distortions at oxide surfaces, and how targeted control of these can be used to tune density of states singularities to the Fermi level, in turn paving the way to the possible realisation of rich collective states at the Sr2RuO4 surface.PostprintPeer reviewe

A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613

Background: HER2 (ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibodybased (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio \u3e 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (\u3e5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 - 7.6) months in TP group and 3.7 (95%CI: 1.6 - 6.7) months in CETIRI group (p = 0.35). Grade≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of31%.Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy

City of El Campo Downtown Revitalization Plan

The Revitalization Plan for Downtown El Campo is a planning document that provides guidance for the development of Downtown El Campo. This planning document includes an overview and analysis of the existing conditions in the City of El Campo and the El Campo Downtown Revitalization Area, a design proposal with vision, goals, and objectives for enhancing Downtown El Campo and a detailed implementation chapter for successful execution of the plan.This planning document presents the revitalization plan for downtown El Campo, Texas. This document was developed by Texas Target Communities (TTC) in partnership with the City of El Campo. The City of El Campo collaborated with Texas Target Communities in fall 2016 through the summer of 2017 to create a plan for revitalization of downtown El Campo. The purpose of the collaboration was to assess current community conditions, develop goals, objectives, and implementation strategies related to future development & growth strategies, through a public participatory process, in order to help guide the future growth of the City

City of El Campo Downtown Revitalization Plan

The Revitalization Plan for Downtown El Campo is a planning document that provides guidance for the development of Downtown El Campo. This planning document includes an overview and analysis of the existing conditions in the City of El Campo and the El Campo Downtown Revitalization Area, a design proposal with vision, goals, and objectives for enhancing Downtown El Campo and a detailed implementation chapter for successful execution of the plan.This planning document presents the revitalization plan for downtown El Campo, Texas. This document was developed by Texas Target Communities (TTC) in partnership with the City of El Campo. The City of El Campo collaborated with Texas Target Communities in fall 2016 through the summer of 2017 to create a plan for revitalization of downtown El Campo. The purpose of the collaboration was to assess current community conditions, develop goals, objectives, and implementation strategies related to future development & growth strategies, through a public participatory process, in order to help guide the future growth of the City

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Communications Biophysics

Contains research objectives, summary of research and reports on four research projects.National Institutes of Health (Grant 5 P01 GM14940-05)National Institutes of Health (Grant 5 TOl GM01555-05)National Aeronautics and Space Administration (Grant NGL 22-009-304)B-D ElectrodyneBoston City Hospital Purchase Order 1065

A Comparative Neuroanatomical Study of the Red Nucleus of the Cat, Macaque and Human

BACKGROUND:The human red nucleus (Nr) is comparatively less well-studied than that of cats or monkeys. Given the functional importance of reticular and midbrain structures in control of movement and locomotion as well as from an evolutionary perspective, we investigated the nature and extent of any differences in Nr projections to the olivary complex in quadrupedal and bipedal species. Using neuroanatomical tract-tracing techniques we developed a "neural sheet" hypothesis allowing us to propose how rubro-olivary relations differ among the three species. METHODS AND FINDINGS:Wheat germ agglutinin-horseradish peroxidase staining supports findings that the cat's nucleus accessories medialis of Bechtrew (NB) projects mainly to the lateral bend of the principal olive. We clarified boundaries among nucleus of Darkschewitsch (ND), NB and parvicellular red nucleus (pNr) of the cat's neural sheet. The macaque's ND-medial accessory olivary projection is rostro-caudally organized and the dorsomedial and ventrolateral parts of the macaque's pNr may project to the principal olive's rostral and caudal dorsal lamella; in cat it projects as well to pNr. Myelin- and Nissl-stained sections show that a well-developed dorsomedial part of the human Nr consists of densely packed cells, deriving small myelinated fibers that continue into the medial central tegmental tract. CONCLUSIONS:Based on these findings we suggest there are distinct bipedal-quadrupedal differences for Nr projections to the olivary complex. We propose the Nr of cats and monkeys comprise the ND, NB and pNr in a zonal sheet-like structure, retaining clear nuclear boundaries and an isolated, well-developed mNr. The human NB may be distinguished from its more specialised ND (ND lies alongside a well-developed pNr) in the human central gray. Phylogenetically, the NB may have been translocated into a roll-shaped Nr in the reticular formation, the dorsomedial portion of which might correspond to the cat's and monkey's NB