Acceleration of radiative recombination for efficient perovskite LEDs.

The increasing demands for more efficient and brighter thin-film light-emitting diodes (LEDs) in flat-panel display and solid-state lighting applications have promoted research into three-dimensional (3D) perovskites. These materials exhibit high charge mobilities and low quantum efficiency droop1-6, making them promising candidates for achieving efficient LEDs with enhanced brightness. To improve the efficiency of LEDs, it is crucial to minimize nonradiative recombination while promoting radiative recombination. Various passivation strategies have been used to reduce defect densities in 3D perovskite films, approaching levels close to those of single crystals3. However, the slow radiative (bimolecular) recombination has limited the photoluminescence quantum efficiencies (PLQEs) of 3D perovskites to less than 80% (refs. 1,3), resulting in external quantum efficiencies (EQEs) of LED devices of less than 25%. Here we present a dual-additive crystallization method that enables the formation of highly efficient 3D perovskites, achieving an exceptional PLQE of 96%. This approach promotes the formation of tetragonal FAPbI3 perovskite, known for its high exciton binding energy, which effectively accelerates the radiative recombination. As a result, we achieve perovskite LEDs with a record peak EQE of 32.0%, with the efficiency remaining greater than 30.0% even at a high current density of 100 mA cm-2. These findings provide valuable insights for advancing the development of high-efficiency and high-brightness perovskite LEDs.

Phosphocholine-induced energy source shift alleviates mitochondrial dysfunction in lung cells caused by geospecific PM2.5 components.

Fine particulate matter (PM2.5) is globally recognized for its adverse implications on human health. Yet, remain limited the individual contribution of particular PM2.5 components to its toxicity, especially considering regional disparities. Moreover, prevention solutions for PM2.5-associated health effects are scarce. In the present study, we comprehensively characterized and compared the primary PM2.5 constituents and their altered metabolites from two locations: Taiyuan and Guangzhou. Analysis of year-long PM2.5 samples revealed 84 major components, encompassing organic carbon, elemental carbon, ions, metals, and organic chemicals. PM2.5 from Taiyuan exhibited higher contamination, associated health risks, dithiothreitol activity, and cytotoxicities than Guangzhou's counterpart. Applying metabolomics, BEAS-2B lung cells exposed to PM2.5 from both cities were screened for significant alterations. A correlation analysis revealed the metabolites altered by PM2.5 and the critical toxic PM2.5 components in both regions. Among the PM2.5-down-regulated metabolites, phosphocholine emerged as a promising intervention for PM2.5 cytotoxicities. Its supplementation effectively attenuated PM2.5-induced energy metabolism disorder and cell death via activating fatty acid oxidation and inhibiting Phospho1 expression. The highlighted toxic chemicals displayed combined toxicities, potentially counteracted by phosphocholine. Our study offered a promising functional metabolite to alleviate PM2.5-induced cellular disorder and provided insights into the geo-based variability in toxic PM2.5 components.

c-FLIP facilitates ZIKV infection by mediating caspase-8/3-dependent apoptosis.

c-FLIP functions as a dual regulator of apoptosis and inflammation, yet its implications in Zika virus (ZIKV) infection remain partially understood, especially in the context of ZIKV-induced congenital Zika syndrome (CZS) where both apoptosis and inflammation play pivotal roles. Our findings demonstrate that c-FLIP promotes ZIKV infection in placental cells and myeloid-derived macrophages, involving inflammation and caspase-8/3-mediated apoptosis. Moreover, our observations reveal that c-FLIP augments ZIKV infection in multiple tissues, including blood cell, spleen, uterus, testis, and the brain of mice. Notably, the partial deficiency of c-FLIP provides protection to embryos against ZIKV-induced CZS, accompanied by a reduction in caspase-3-mediated apoptosis. Additionally, we have found a distinctive parental effect of c-FLIP influencing ZIKV replication in fetal heads. In summary, our study reveals the critical role of c-FLIP as a positive regulator in caspase-8/3-mediated apoptosis during ZIKV infection, significantly contributing to the development of CZS.

The PKA-CREB1 axis regulates coronavirus proliferation by viral helicase nsp13 association.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a worldwide threat in the past 3 years. Although it has been widely and intensively investigated, the mechanism underlying the coronavirus-host interaction requires further elucidation, which may contribute to the development of new antiviral strategies. Here, we demonstrated that the host cAMP-responsive element-binding protein (CREB1) interacts with the non-structural protein 13 (nsp13) of SARS-CoV-2, a conserved helicase for coronavirus replication, both in cells and in lung tissues subjected to SARS-CoV-2 infection. The ATPase and helicase activity of viral nsp13 were shown to be potentiated by CREB1 association, as well as by Protein kinase A (PKA)-mediated CREB1 activation. SARS-CoV-2 replication is significantly suppressed by PKA Cα, cAMP-activated protein kinase catalytic subunit alpha (PRKACA), and CREB1 knockdown or inhibition. Consistently, the CREB1 inhibitor 666-15 has shown significant antiviral effects against both the WIV04 strain and the Omicron strain of the SARS-CoV-2. Our findings indicate that the PKA-CREB1 signaling axis may serve as a novel therapeutic target against coronavirus infection. IMPORTANCE: In this study, we provide solid evidence that host transcription factor cAMP-responsive element-binding protein (CREB1) interacts directly with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) helicase non-structural protein 13 (nsp13) and potentiate its ATPase and helicase activity. And by live SARS-CoV-2 virus infection, the inhibition of CREB1 dramatically impairs SARS-CoV-2 replication in vivo. Notably, the IC50 of CREB1 inhibitor 666-15 is comparable to that of remdesivir. These results may extend to all highly pathogenic coronaviruses due to the conserved nsp13 sequences in the virus.

OsmiR319-OsPCF5 modulate resistance to brown planthopper in rice through association with MYB proteins.

BACKGROUND: The brown planthopper (BPH) is a kind of piercing-sucking insect specific to rice, with the damage tops the list of pathogens and insects in recent years. microRNAs (miRNAs) are pivotal regulators of plant-environment interactions, while the mechanism underlying their function against insects is largely unknown. RESULTS: Here, we confirmed that OsmiR319, an ancient and conserved miRNA, negatively regulated resistance to BPHs, with overexpression of OsmiR319 susceptible to BPH, while suppression of OsmiR319 resistant to BPH in comparison with wild type. Meanwhile, we identified several targets of OsmiR319 that may mediate BPH resistance. Among them, OsPCF5 was the most obviously induced by BPH feeding, and over expression of OsPCF5 was resistance to BPH. In addition, various biochemical assays verified that OsPCF5 interacted with several MYB proteins, such as OsMYB22, OsMYB30, and OsMYB30C.Genetically, we revealed that both OsMYB22 and OsMYB30C positively regulated BPH resistance. Genetic interaction analyses confirmed that OsMYB22 and OsMYB30C both function in the same genetic pathway with OsmiR319b to mediate BPH resistance. CONCLUSIONS: Altogether, we revealed that OsPCF5 regulates BPH resistance via association with several MYB proteins downstream of OsmiR319, these MYB proteins might function as regulators of BPH resistance through regulating the phenylpropane synthesis.

Tenofovir Alafenamide versus Tenofovir Disoproxil Fumarate for Preventing Vertical Transmission in Chronic Hepatitis B Mothers: A Systematic Review and Meta-Analysis.

OBJECTIVE: International guidelines recommend maternal tenofovir disoproxil fumarate (TDF) therapy accompanied by infant immunoprophylaxis to prevent HBV mother-to-child transmission (MTCT) in highly viremic mothers. However, pooled analyses for tenofovir alafenamide (TAF) effects and comparisons between the two regimens are lacking. DESIGN: In this meta-analysis, pairs of independent reviewers performed multiple database searches from inception to March 31, 2024, and extracted data from cohort studies and RCTs in highly viremic mothers. The outcomes of interest were the reduction of MTCT and safety in the TDF-treated, TAF-treated, and control groups. RESULTS: We included 31 studies with 2,588 highly viremic mothers receiving TDF, 280 receiving TAF, and 1,600 receiving no treatment. Compared to the control, TDF therapy reduced the MTCT rate in infants aged 6-12 months (risk ratio: 0.10, 95% confidence interval 0.07-0.16). Pairwise meta-analysis between TAF and TDF revealed similar effects on reducing MTCT (risk ratio: 1.09, 95% confidence interval 0.16-7.61). Network meta-analysis showed the equal efficacy of the two regimens in reducing MTCT (risk ratio: 1.09, 95% confidence interval 0.15-7.65). The surface under the cumulative ranking curve revealed TDF as the best regimen compared with TAF (probability ranking: 0.77 vs. 0.72), while receiving a placebo during pregnancy had the lowest efficacy (probability ranking 0.01). There were no safety concerns for mothers and infants in all regimens. CONCLUSION: Compared to placebo or no treatment, maternal TDF and TAF prophylaxis are equally effective and without safety concerns in reducing MTCT in highly viremic mothers.

Ocular A-to-I RNA editing signatures associated with SARS-CoV-2 infection.

Ophthalmic manifestations have recently been observed in acute and post-acute complications of COVID-19 caused by SARS-CoV-2 infection. Our precious study has shown that host RNA editing is linked to RNA viral infection, yet ocular adenosine to inosine (A-to-I) RNA editing during SARS-CoV-2 infection remains uninvestigated in COVID-19. Herein we used an epitranscriptomic pipeline to analyze 37 samples and investigate A-to-I editing associated with SARS-CoV-2 infection, in five ocular tissue types including the conjunctiva, limbus, cornea, sclera, and retinal organoids. Our results revealed dramatically altered A-to-I RNA editing across the five ocular tissues. Notably, the transcriptome-wide average level of RNA editing was increased in the cornea but generally decreased in the other four ocular tissues. Functional enrichment analysis showed that differential RNA editing (DRE) was mainly in genes related to ubiquitin-dependent protein catabolic process, transcriptional regulation, and RNA splicing. In addition to tissue-specific RNA editing found in each tissue, common RNA editing was observed across different tissues, especially in the innate antiviral immune gene MAVS and the E3 ubiquitin-protein ligase MDM2. Analysis in retinal organoids further revealed highly dynamic RNA editing alterations over time during SARS-CoV-2 infection. Our study thus suggested the potential role played by RNA editing in ophthalmic manifestations of COVID-19, and highlighted its potential transcriptome impact, especially on innate immunity.

Could ceftriaxone be a viable alternative to penicillin for the treatment of ocular syphilis?

This study was conducted to compare the effectiveness of ceftriaxone with that of aqueous crystalline penicillin G in treating ocular syphilis. We conducted a retrospective study from 2010 to 2021. Syphilis patients were administered either ceftriaxone (2 g intravenously daily for 14 days) or aqueous crystalline penicillin G [4 million units (MU) intravenously every 4 h for 14 days] as therapeutic interventions. Subsequently, we utilized these two groups to assess the serological results, cerebrospinal fluid analysis, and visual acuity at time intervals spanning 3 to 6 months post-treatment. A total of 205 patients were included, with 34 assigned to the ceftriaxone group and 171 to the penicillin group. The median age of patients was 56 years, with an interquartile range of 49-62 years, and 137 of them (66.8%) were male. Between 3 and 6 months after treatment, 13 patients (38.2%) in the ceftriaxone group and 82 patients (48.0%) in the penicillin group demonstrated effective treatment based on the clinical and laboratory parameters. The crude odds ratio (OR) was 0.672 (95% confidence interval [CI]: 0.316-1.428, P = 0.301), indicating no significant difference in effectiveness between the two groups. Thirty patients (17.5%) in the penicillin group and six patients (17.6%) in the ceftriaxone group did not experience successful outcomes. Notably, no serious adverse effects were reported in both the groups. There was no significant difference in the effectiveness of ceftriaxone and aqueous crystalline penicillin G in treating ocular syphilis. The administration of ceftriaxone without requiring hospitalization presents a convenient and safe alternative treatment option for ocular syphilis.

A PCR-independent approach for mtDNA enrichment and next-generation sequencing: comprehensive evaluation and clinical application.

BACKGROUND: Sequencing the mitochondrial genome has been increasingly important for the investigation of primary mitochondrial diseases (PMD) and mitochondrial genetics. To overcome the limitations originating from PCR-based mtDNA enrichment, we set out to develop and evaluate a PCR-independent approach in this study, named Pime-Seq (PCR-independent mtDNA enrichment and next generation Sequencing). RESULTS: By using the optimized mtDNA enrichment procedure, the mtDNA reads ratio reached 88.0 ± 7.9% in the sequencing library when applied on human PBMC samples. We found the variants called by Pime-Seq were highly consistent among technical repeats. To evaluate the accuracy and reliability of this method, we compared Pime-Seq with lrPCR based NGS by performing both methods simultaneously on 45 samples, yielding 1677 concordant variants, as well as 146 discordant variants with low-level heteroplasmic fraction, in which Pime-Seq showed higher reliability. Furthermore, we applied Pime-Seq on 4 samples of PMD patients retrospectively, and successfully detected all the pathogenic mtDNA variants. In addition, we performed a prospective study on 192 apparently healthy pregnant women during prenatal screening, in which Pime-Seq identified pathogenic mtDNA variants in 4 samples, providing extra information for better health monitoring in these cases. CONCLUSIONS: Pime-Seq can obtain highly enriched mtDNA in a PCR-independent manner for high quality and reliable mtDNA deep-sequencing, which provides us an effective and promising tool for detecting mtDNA variants for both clinical and research purposes.

pH-Responsive Amphiphilic Triblock Fluoropolymers as Assemble Oxygen Nanoshuttles for Enhancing PDT against Hypoxic Tumor.

Photodynamic therapy (PDT) is a cancer treatment strategy that utilizes photosensitizers to convert oxygen within tumors into reactive singlet oxygen (1O2) to lyse tumor cells. Nevertheless, pre-existing tumor hypoxia and oxygen consumption during PDT can lead to an insufficient oxygen supply, potentially reducing the photodynamic efficacy. In response to this issue, we have devised a pH-responsive amphiphilic triblock fluorinated polymer (PDP) using copper-mediated RDRP. This polymer, composed of poly(ethylene glycol) methyl ether acrylate, 2-(diethylamino)ethyl methacrylate, and (perfluorooctyl)ethyl acrylate, self-assembles in an aqueous environment. Oxygen, chlorine e6 (Ce6), and doxorubicin (DOX) can be codelivered efficiently by PDP. The incorporation of perfluorocarbon into the formulation enhances the oxygen-carrying capacity of PDP, consequently extending the lifetime of 1O2. This increased lifetime, in turn, amplifies the PDT effect and escalates the cellular cytotoxicity. Compared with PDT alone, PDP@Ce6-DOX-O2 NPs demonstrated significant inhibition of tumor growth. This study proposes a novel strategy for enhancing the efficacy of PDT.

Systematic pole-zero sorting method for neuro-TF modeling of electromagnetic response.

Neuro-transfer functions (neuro-TF) modeling method has been developed as one of the popular methods for parametric modeling of electromagnetic (EM) filter responses. The discontinuity issue of zero and pole data caused by extraction using vector fitting w.r.t. geometrical parameters change affects the neuro-TF training process and limits its modeling accuracy. This issue is addressed by this paper which proposes a novel systematic pole-zero sorting method for neuro-TF parametric modeling. The proposed method can obtain continuous pole-zero data which change much more smooth w.r.t. geometrical parameters change than the existing neuro-TF method, especially solves the difficulty of disorder of positive and negative values due to small values. The proposed systematic sorting method can substantially improve the modeling accuracy during the establishment and training of neuro-TF model over the existing neuro-TF method without systematic sorting.

Pharmacokinetic/Pharmacodynamic Assessment of the Structural Refinement of Clopidogrel Focusing on the Balance between Bioactivation and Deactivation.

The delicate balance between ischemic and bleeding risks is a critical factor in antiplatelet therapy administration. Clopidogrel and prasugrel, belonging to the thienopyridine class of antiplatelet drugs, are known for their variability in individual responsiveness and high incidence of bleeding events, respectively. The present study is centered on the development and assessment of a range of deuterated thienopyridine derivatives, leveraging insights from structure-pharmacokinetic relationships of clopidogrel and prasugrel. Our approaches were grounded in the molecular framework of clopidogrel and incorporated the C2-pharmacophore design from prasugrel. The selection of ester or carbamate substituents at the C2-position facilitated the generation of the 2-oxointermediate through hydrolysis, akin to prasugrel, thereby bypassing the issue of CYP2C19 dependency. The bulky C2-pharmacophore in our approach distinguishes itself from prasugrel's acetyloxy substituent by exhibiting a moderated hydrolysis rate, resulting in a more gradual formation of the active metabolite. Excessive and rapid release of the active metabolite, believed to be linked with an elevated risk of bleeding, is thus mitigated. Our proposed structural modification retains the hydrolysis-sensitive methyl ester of clopidogrel but substitutes it with a deuterated methyl group, shown to effectively reduce metabolic deactivation. Three promising compounds demonstrated a pharmacokinetic profile similar to that of clopidogrel at four times the dose, while also augmenting its antiplatelet activity. SIGNIFICANCE STATEMENT: Inspired by the structure-pharmacokinetic relationship of clopidogrel and prasugrel, a range of clopidogrel derivatives were designed, synthesized, and assessed. Among them, three promising compounds have been identified, striking a delicate balance between efficacy and safety for antiplatelet therapy. Additionally, the ozagrel prodrug conjugate was discovered to exert a synergistic therapeutic effect alongside clopidogrel.

Effect of SGLT-2 inhibitors on arrhythmia events: insight from an updated secondary analysis of > 80,000 patients (the SGLT2i-Arrhythmias and Sudden Cardiac Death).

OBJECTIVE: We aimed to assess the effect of SGLT2i on arrhythmias by conducting a meta-analysis using data from randomized controlled trials(RCTs). BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have shown cardioprotective effects via multiple mechanisms that may also contribute to decrease arrhythmias risk. METHODS: We searched in databases (PubMed, Embase, Cochrane Library, and clinicaltrials.gov) up to April 2023. RCTs comparing SGLT2i with placebo were included. The effects of SGLT2i on atrial fibrillation(AF), atrial flutter(AFL), composite AF/AFL, ventricular fibrillation(VF), ventricular tachycardia(VT), ventricular extrasystoles(VES), sudden cardiac death(SCD) and composite VF/VT/SCD were evaluated. RESULTS: 33 placebo-controlled RCTs were included, comprising 88,098 patients (48,585 in SGLT2i vs. 39,513 in placebo). The mean age was 64.9 ± 9.4 years, 63.0% were male. The mean follow-up was 1.4 ± 1.1 years. The pooled-results showed that SGLT2i was associated with a significantly lower risk of AF [risk ratio(RR): 0.88, 95% confidence interval(CI) 0.78-1.00, P = 0.04] and composite AF/AFL (RR: 0.86, 95%CI 0.77-0.96, P = 0.01). This favorable effect appeared to be substantially pronounced in patients with HFrEF, male gender, dapagliflozin, and > 1 year follow-up. For SCD, only in heart failure patients, SGLT2i were found to be associated with a borderline lower risk of SCD (RR: 0.67, P = 0.05). No significant effects of SGLT2i on other ventricular arrhythmic outcomes were found. CONCLUSIONS: SGLT2i lowers the risks of AF and AF/AFL, and this favorable effect appeared to be particularly pronounced in patients with HFrEF, male gender, dapagliflozin, and longer follow-up (> 1 year). SGLT2i lowers the risk of SCD only in heart failure patients.

In vivo evaluation of efficacy and safety of Coagulansin-A in treating arthritis.

The current study aimed to determine the safety and efficacy of Coag-A through in vivo analysis in CFA induced mice model. Treatment of CFA induced arthritis in mice with Coagulansin-A (10 mg/kg i.p. daily for 28 days), a withanolide obtained from Withania coagulans, as well as standard drug treatment with Dexamethasone (5 mg/kg i.p) was provided. The effect of Coag-A on body weight, relative organ weight, hematology, serum biochemistry, survival rate, oxidative stress markers, and antioxidant enzymes was evaluated. The liver and kidney histopathology were also assessed to ascertain its safety profile. Treatment of arthritic mice with Coag-A considerably improved body weight, relative organ weight of liver, kidney, and spleen, ameliorated hematology and serum biochemistry, and increased survival and antioxidant potential. Coag-A was found to be safer with fewer adverse effects showing hepato-protective, nephroprotective, and anti-inflammatory effect. It also significantly (p < 0.001) improved histopathology of CFA-induced mice when compared with Dexa. In conclusion, compared to dexamethasone, Coag-A has demonstrated a greater therapeutic benefit and fewer side effects in the treatment of arthritis against the CFA-induced model.

Clinical spectrum of late symptomatic neurosyphilis in China: an 11-year retrospective study.

OBJECTIVES: This study aimed to describe the clinical features of neurosyphilis in Chinese patients in an attempt to find clinical features that are helpful for the early identification of neurosyphilis. METHODS: This retrospective study included people with syphilis who visited Shanghai Skin Disease Hospital between January 2010 and December 2020. Lumbar puncture was performed on those who met the inclusion and exclusion criteria. The diagnosis of neurosyphilis was based on clinical and laboratory findings. The parameters were analysed statistically. RESULTS: Of the 3524 patients with neurosyphilis, 2111 (59.9%) and 1413 (40.1%) were asymptomatic and symptomatic neurosyphilis, respectively. General paresis was the most common type of symptomatic neurosyphilis (46.8%). The clinical manifestations of symptomatic neurosyphilis include psychiatric and neurotic symptoms, among which general paresis predominantly presented as psychiatric symptoms such as affective (66.7%) and memory disorder (72.9%). Tabes dorsalis is often presented as neurotic symptoms. One hundred fifty patients (10.6%) with symptomatic neurosyphilis presented candy signs, a rare and specific neurosyphilis symptom that is common in general paresis. Girdle sensation was presented in 13 patients, mainly with tabes dorsalis, which had not been reported in previous studies. CONCLUSIONS: Notably, the candy sign is identified as a specific symptom of general paresis, while girdle sensations are highlighted as a particular symptom of tabes dorsalis. This is the largest study describing the clinical spectrum of neurosyphilis since the onset of the penicillin era and could help doctors learn more about the disease. A comprehensive description of the possible clinical manifestations of late symptomatic neurosyphilis, particularly highlighting rare symptoms, can identify suspicious patients and prevent diagnostic delays.

Development of a nomogram based on the clinicopathological and CT features to predict the survival of primary pulmonary lymphoepithelial carcinoma patients.

BACKGROUND: The aim of this study was to develop a nomogram by combining chest computed tomography (CT) images and clinicopathological predictors to assess the survival outcomes of patients with primary pulmonary lymphoepithelial carcinoma (PLEC). METHODS: 113 patients with stage I-IV primary PLEC who underwent treatment were retrospectively reviewed. The Cox regression analysis was performed to determine the independent prognostic factors associated with patient's disease-free survival (DFS) and cancer-specific survival (CSS). Based on results from multivariate Cox regression analysis, the nomograms were constructed with pre-treatment CT features and clinicopathological information, which were then assessed with respect to calibration, discrimination and clinical usefulness. RESULTS: Multivariate Cox regression analysis revealed the independent prognostic factors for DFS were surgery resection and hilar and/or mediastinal lymphadenopathy, and that for CSS were age, smoking status, surgery resection, tumor site in lobe and necrosis. The concordance index (C­index) of nomogram for DFS and CSS were 0.777 (95% CI: 0.703-0.851) and 0.904 (95% CI: 0.847-0.961), respectively. The results of the time­dependent C­index were internally validated using a bootstrap resampling method for DFS and CSS also showed that the nomograms had a better discriminative ability. CONCLUSIONS: We developed nomograms based on clinicopathological and CT factors showing a good performance in predicting individual DFS and CSS probability among primary PLEC patients. This prognostic tool may be valuable for clinicians to more accurately drive treatment decisions and individualized survival assessment.

[18F]-D3FSP ß-amyloid PET imaging in older adults and alzheimer's disease.

PURPOSE: [18F]-D3FSP is a new ß-amyloid (Aß) PET imaging tracer designed to decrease nonspecific signals in the brain by reducing the formation of the N-demethylated product. However, its optimal reference region for calculating the standardized uptake value ratio (SUVR) and its relation to the well-established biomarkers of Alzheimer's disease (AD) are still unclear. METHODS: We recruited 203 participants from the Greater Bay Area Healthy Aging Brain Study (GHABS) to undergo [18F]-D3FSP Aß PET imaging. We analyzed plasma Aß42/Aß40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. We compared the standardized uptake value (SUV) of five reference regions (cerebellum, cerebellum cortex, brainstem/PONs, white matter, composite of the four regions above) and AD typical cortical region (COMPOSITE) SUVR among different clinical groups. The association of D3FSP SUVR with plasma biomarkers, imaging biomarkers, and cognition was also investigated. RESULTS: Brainstem/PONs SUV showed the lowest fluctuation across diagnostic groups, and COMPOSITE D3FSP SUVR had an enormous effect distinguishing cognitively impaired (CI) individuals from cognitively unimpaired (CU) individuals. COMPOSITE SUVR (Referred to brainstem/PONs) was positively correlated with p-Tau181 (p < 0.001), GFAP (p < 0.001), NfL (p = 0.014) in plasma and temporal-metaROI tau deposition (p < 0.001), and negatively related to plasma Aß42/Aß40 (p < 0.001), temporal-metaROI cortical thickness (p < 0.01), residual hippocampal volume (p < 0.001) and cognition (p < 0.001). The voxel-wise analysis replicated these findings. CONCLUSION: This study suggests brainstem/PONs as an optimal reference region for calculating D3FSP SUVR to quantify cortical Aß plaques in the brain. [18F]-D3FSP could distinguish CI from CU and strongly correlates with well-established plasma biomarkers, tau PET, neurodegeneration, and cognitive decline. However, future head-to-head comparisons of [18F]-D3FSP PET images with other validated Aß PET tracers or postmortem results are crucial.

First-in-human study of PSMA-targeting agent, [18F]AlF-P16-093: dosimetry and initial evaluation in prostate cancer patients.

PURPOSE: This is a first-in-human study to evaluate the radiation dosimetry of a new prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, [18F]AlF-P16-093, and also initial investigation of its ability to detect PSMA-positive tumors using PET scans in a cohort of prostate cancer (PCa) patients. METHODS: The [18F]AlF-P16-093 was automatically synthesized with a GE TRACERlab. A total of 23 patients with histopathologically proven PCa were prospectively enrolled. Dosimetry and biodistribution study investigations were carried out on a subset of six (6) PCa patients, involving multiple time-point scanning. The mean absorbed doses were estimated with PMOD and OLINDA software. RESULTS: [18F]AlF-P16-093 was successfully synthesized, and radiochemical purity was > 95%, and average labeling yield was 36.5 ± 8.3% (decay correction, n = 12). The highest tracer uptake was observed in the kidneys, spleen, and liver, contributing to an effective dose of 16.8 ± 1.3 µSv/MBq, which was ~ 30% lower than that of [68Ga]Ga-P16-093. All subjects tolerated the PET examination well, and no reportable side-effects were observed. The PSMA-positive tumors displayed rapid uptake, and they were all detectable within 10 min, and no additional lesions were observed in the following multi-time points scanning. Each patient had at least one detectable tumor lesion, and a total of 356 tumor lesions were observed, including intraprostatic, lymph node metastases, bone metastases, and other soft tissue metastases. CONCLUSIONS: We report herein a streamlined method for high yield synthesis of [18F]AlF-P16-093. Preliminary study in PCa patients has demonstrated its safety and acceptable radiation dosimetry. The initial diagnostic study indicated that [18F]AlF-P16-093 PET/CT is efficacious and potentially useful for a widespread application in the diagnosis of PCa patients.

Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [177Lu]Lu-P17-087, and its albumin binder modified derivative, [177Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3). METHODS: Patients with PSMA-positive tumors were enrolled after [68Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [177Lu]Lu-P17-087 and four other patients received [177Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168 h after injection and one SPECT/CT imaging was performed at 24 h post-injection for each patient. Dosimetry evaluation was compared in both patient groups. RESULTS: Patients showed no major clinical side-effects under this low dose treatment. As expected [177Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [177Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [177Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [177Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively. CONCLUSION: [177Lu]Lu-P17-088 and [177Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy. TRIAL REGISTRATION: 177Lu-P17-087/177Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022). URL OF REGISTRY: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05603559 .