Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted ß- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

Chemokine Receptor 4-Targeted PET/CT With 68 Ga-Pentixather Detects More Lesions Than 68 Ga-Pentixafor PET/CT in Multiple Myeloma.

ABSTRACT: An 83-year-old woman with newly diagnosed multiple myeloma (MM) was enrolled in our 68 Ga-pentixather and 68 Ga-pentixafor PET/CT trial for evaluation of tumor burden. 68 Ga-pentixather PET/CT detected more focal bone lesions, and the uptake levels of focal bone lesions on 68 Ga-pentixather PET/CT were higher than those on 68 Ga-pentixafor PET/CT. This suggests that 68 Ga-pentixather PET/CT may be an alternative imaging modality and more sensitive in detecting MM lesions than 68 Ga-pentixafor PET/CT.

The effect of salt substitution on frequency and severity of headache: results from the SSaSS cluster-randomised controlled trial of 20,995 participants.

BACKGROUND: Headache is one of the most common neurological symptoms. Headache disorders are associated with a high global burden of disease. Prior studies indicate that short-to-medium term sodium reduction reduces headache symptom. This study evaluated the effects of long-term reduced-sodium, added-potassium salt on headache frequency and severity in rural China. METHODS: The Salt substitute and stroke study (SSaSS) was an open-label cluster-randomised trial in rural China designed to evaluate the effect of salt substitution on mortality and cardiovascular events. Participants included adults with a history of prior stroke and those aged ≥60 years with uncontrolled high blood pressure (BP). Villages were randomly assigned in a 1:1 ratio either to intervention with salt substitute (75% sodium chloride and 25% potassium chloride by mass) or to control with continued use of regular salt (100% sodium chloride). In this pre-specified analysis, between-group differences in headache frequency and severity were evaluated. The study was registered with ClinicalTrials.gov (identifier number: NCT02092090). RESULTS: A total of 20,995 participants were included in the trial (mean age 64.3 years, 51% female, mean follow-up 4.7 years). At final follow-up at the end of the study, headache outcome data including frequency and severity of headaches was available for 16,486 (98%) of 16,823 living participants. Overall, 4454/16,486 (27%) individuals reported having headache: 27.4% in the intervention group (2301/8386) vs 26.6% in the control group (2153/8100) (RR 1.04, 95% CI: 0.93, 1.16, p = 0.48). There was no difference in headache severity between intervention and control groups (p = 0.90). CONCLUSION: Long term salt substitution did not reduce the frequency or severity of headaches in this population.

High-resolution reconstruction of April-September precipitation and major extreme droughts in China over the past ∼530 years.

Extreme drought events have increased, causing serious losses and damage to the social economy under current warming conditions. However, short-term meteorological data limit our understanding and projection of these extremes. With the accumulation of proxy data, especially tree-ring data, large-scale precipitation field reconstruction has provided opportunities to explore underlying mechanisms further. Using point-by-point regression, we reconstructed the April-September precipitation field in China for the past ∼530 years on the basis of 590 proxy records, including 470 tree-ring width chronologies and 120 drought/flood indices. Our regression models explained average 50% of the variance in precipitation. In the statistical test on calibration and verification, our models passed the significance level that assured reconstruction quality. The reconstruction data performed well, showing consistency and better quality than previously reported reconstructions. The first three leading modes of variability in the reconstruction revealed the main distribution modes of precipitation over China. Wet/drought and extremely wet/drought years accounted for 12.81%/10.92% (68 years/58 years) and 1.69%/3.20% (9 years/17 years) of the past ∼530 years in China, respectively. Major extreme drought events can be identified explicitly in our reconstruction. The detailed features of the Chongzhen Great Drought (1637-1643), the Wanli Great Drought (1585-1590), and the Ding-Wu Great Famine (1874-1879), indicated the existence of potentially different underlying mechanisms that need further exploration. Although further improvements can be made for remote uninhabited areas and large deserts, our gridded reconstruction of April-September precipitation in China over the past ∼530 years can provide a solid database for studies on the attribution of climate change and the mechanism of extreme drought events.