68Ga-FAP-2286 PET of Solid Tumors: Biodistribution, Dosimetry, and Comparison with 18F-FDG.

Fibroblast activation protein (FAP), expressed in the tumor microenvironment of a variety of cancers, has become a target of novel PET tracers. The purpose of this report is to evaluate the imaging characteristics of 68Ga-FAP-2286, present the first-to our knowledge-dosimetry analysis to date, and compare the agent with 18F-FDG and FAPI compounds. Methods: Patients were administered 219 ± 43 MBq of 68Ga-FAP-2286 and scanned after 60 min. Uptake was measured in up to 5 lesions per patient and within the kidneys, spleen, liver, and mediastinum (blood pool). Absorbed doses were evaluated using MIM Encore and OLINDA/EXM version 1.1 using the International Commission on Radiological Protection publication 103 tissue weighting factor. Results: Forty-six patients were imaged with 68Ga-FAP-2286 PET. The highest average uptake was seen in sarcoma, cholangiocarcinoma, and colon cancer. The lowest uptake was found in lung cancer and testicular cancer. The average SUVmax was significantly higher on 68Ga-FAP-2286 PET than on 18F-FDG PET in cholangiocarcinoma (18.2 ± 6.4 vs. 9.1 ± 5.0, P = 0.007), breast cancer (11.1 ± 6.8 vs. 4.1 ± 2.2, P < 0.001), colon cancer (13.8 ± 2.2 vs. 7.6 ± 1.7, P = 0.001), hepatocellular carcinoma (9.3 ± 3.5 vs. 4.7 ± 1.3, P = 0.01), head and neck cancer (11.3 ± 3.5 vs. 7.6 ± 5.5, P = 0.04), and pancreatic adenocarcinoma (7.4 ± 1.8 vs. 3.7 ± 1.0, P = 0.01). The total-body effective dose was estimated at 1.16E-02 mSv/MBq, with the greatest absorbed organ dose in the urinary bladder wall (9.98E-02 mGy/MBq). Conclusion: 68Ga-FAP-2286 biodistribution, dosimetry, and tumor uptake were similar to those of previously reported FAPI compounds. Additionally,68Ga-FAP-2286 PET had consistently higher uptake than 18F-FDG PET. These results are especially promising in the setting of small-volume disease and differentiating tumor from inflammatory uptake.

Assessing Response to PSMA Radiopharmaceutical Therapies with Single SPECT Imaging at 24 Hours After Injection.

Understanding the relationship between lesion-absorbed dose and tumor response in 177Lu-PSMA-617 radiopharmaceutical therapies (RPTs) remains complex. We aimed to investigate whether baseline lesion-absorbed dose can predict lesion-based responses and to explore the connection between lesion-absorbed dose and prostate-specific antigen (PSA) response. Methods: In this retrospective study, we evaluated 50 patients with 335 index lesions undergoing 177Lu-PSMA-617 RPT, who had dosimetry analysis performed on SPECT/CT at 24 h after cycles 1 and 2. First, we identified the index lesions for each patient and measured the lesion-based absorbed doses. Lesion-based response was calculated after cycle 2. Additionally, PSA50 response (a decline of 50% from baseline PSA) after cycle 2 was also calculated. The respective responses for mean and maximum absorbed doses and prostate-specific membrane antigen (PSMA) volumetric intensity product (VIP-PSMA) at cycles 1 and 2 were termed SPECTmean, SPECTmaximum, and SPECTVIP-PSMA, respectively. Results: Of the 50 patients reviewed, 46% achieved a PSA50 response after cycle 2. Of the 335 index lesions, 58% were osseous, 32% were lymph nodes, and 10% were soft-tissue metastatic lesions. The SPECT lesion-based responses were higher in PSA responders than in nonresponders (SPECTmean response of 46.8% ± 26.1% vs. 26.2% ± 24.5%, P = 0.007; SPECTmaximum response of 45% ± 25.1% vs. 19% ± 27.0%, P = 0.001; SPECTVIP-PSMA response of 49.2% ± 30.3% vs. 14% ± 34.7%, P = 0.0005). An association was observed between PSA response and SPECTVIP-PSMA response (R 2 = 0.40 and P < 0.0001). A limited relationship was found between baseline absorbed dose measured with a 24-h single time point and SPECT lesion-based response (R 2 = 0.05, P = 0.001, and R 2 = 0.03, P = 0.007, for mean and maximum absorbed doses, respectively). Conclusion: In this retrospective study, quantitative lesion-based response correlated with patient-level PSA response. We observed a limited relationship between baseline absorbed dose and lesion-based responses. Most of the variance in response remains unexplained solely by baseline absorbed dose. Establishment of a dose-response relationship in RPT with a single time point at 24 h presented some limitations.

Livestream, group movement program for people living with cognitive impairment and care partners: A randomized clinical trial.

INTRODUCTION: There are few widely-available, evidence-based options to support quality of life (QOL) for people living with Alzheimer's disease and related dementias. METHODS: We performed a randomized, controlled trial with a Waitlist control group to determine whether an online, livestream, mind-body, group movement program (Moving Together, 1 hour, 2 days/week, 12 weeks) improves QOL in people with cognitive impairment (PWCI) or care partners (CPs) and explore mechanisms of action. The primary outcome for both participants was self-reported QOL. Secondary outcomes and potential mediators included mobility, isolation, well-being, cognitive function, and sleep in PWCI and burden, positive emotions, caregiver self-efficacy, stress management, and sleep in CPs. Blinded assessors collected outcome data at baseline, 12, and 24 weeks. We assessed adverse events including falls through monthly check-in surveys and collected qualitative data through evaluation surveys. Intention-to-treat analyses used linear mixed models to compare mean change over time between groups and calculated standardized effect sizes (ESs). RESULTS: Ninety-seven dyads enrolled (PWCI: age 76 ± 11 years, 43% female, 80% non-Hispanic White; CPs: age 66 ± 12 years, 78% female, 71% non-Hispanic White); 15% withdrew before 12 weeks and 22% before 24 weeks. PWCI self-reported significantly better QOL from baseline to 12 weeks in the Moving Together group compared to the Waitlist group (ES = 0.474, p = 0.048) and CPs self-reported improved ability to manage stress (ES = 0.484, p = 0.021). Improvements in participant self-reported QOL were mediated by improvements in their self-reported well-being and CP-reported ability to manage stress. Results were similar when the Waitlist group participated in the program (QOL ES = 0.663, p = 0.006; stress management ES = 0.742, p = 0.002) and were supported by qualitative data. Exploratory analyses suggested possible fall reduction in PWCI. There were no study-related serious adverse events. DISCUSSION: Online programs such as Moving Together offer a scalable strategy for supporting high QOL for PWCI and helping CPs manage stress. TRIAL REGISTRATION: ClinicalTrials.gov NCT04621448. Highlights: The approval of new medications that slow cognitive decline in people living with Alzheimer's disease and related disorders (ADRD) has raised hope and excitement. However, these medications do not appear to impact quality of life, which is often considered by patients and care partners to be the most important outcome.In this randomized clinical trial, we found that an evidence-based, online, livestream, mind-body, group movement program significantly and meaningfully improves self-rated quality of life in people with ADRD and helps care partners manage stress. Mediation analyses revealed that the key drivers of improvements in participants' quality of life were improvements in their feelings of well-being and care partners' ability to manage stress. Exploratory analyses also suggested a 30% reduction in falls.These results are important because they suggest that an online program, which is available now and can be performed by people from the comfort of home or other location of choice, could be recommended as a complement or alternative to new therapies to help maximize quality of life for people living with ADRD and their care partners.

China's Fossil Fuel CO2 Emissions Estimated Using Surface Observations of Coemitted NO2.

Accurate estimates of fossil fuel CO2 (FFCO2) emissions are of great importance for climate prediction and mitigation regulations but remain a significant challenge for accounting methods relying on economic statistics and emission factors. In this study, we employed a regional data assimilation framework to assimilate in situ NO2 observations, allowing us to combine observation-constrained NOx emissions coemitted with FFCO2 and grid-specific CO2-to-NOx emission ratios to infer the daily FFCO2 emissions over China. The estimated national total for 2016 was 11.4 PgCO2·yr-1, with an uncertainty (1σ) of 1.5 PgCO2·yr-1 that accounted for errors associated with atmospheric transport, inversion framework parameters, and CO2-to-NOx emission ratios. Our findings indicated that widely used "bottom-up" emission inventories generally ignore numerous activity level statistics of FFCO2 related to energy industries and power plants in western China, whereas the inventories are significantly overestimated in developed regions and key urban areas owing to exaggerated emission factors and inexact spatial disaggregation. The optimized FFCO2 estimate exhibited more distinct seasonality with a significant increase in emissions in winter. These findings advance our understanding of the spatiotemporal regime of FFCO2 emissions in China.

Closed reduction and intramedullary nails for acute completely displaced femoral diaphysis fracture in children aged 2-6.

Background: The management of femoral fractures in children aged two to six years is still controversial. The purpose of this study was to assess the results of closed reduction and elastic stable intramedullary nail (ESIN) fixation in completely displaced fractures of the femoral diaphysis in children in this age group. Methods: A retrospective review of all children with acute completely displaced fractures of the femoral diaphysis in children aged 2-6 years treated from 2013 to 2020 was performed. A total of 34 patients were treated who met the inclusion criteria: Group 1: 21 fractures (transverse and short oblique); Group 2: 13 fractures (long oblique and spiral) that underwent closed reduction and elastic stable intramedullary nail (ESIN) fixation. No differences existed between the 2 groups with respect to age, extremity, sex, time to treatment, mechanism of injury, or fracture displacement. Demographic characteristics and radiographs were reviewed, and the following parameters were documented: surgery time, time to union, return to activities, range of motion of knee joints, and complications. Major complications were defined as those with presumptive long-term side effects or those requiring a reoperation. No major complications were observed in the two groups. All included fractures were treated by a single senior paediatric surgeon. The mean follow-up period was 28.4 months (range 24-45 months). The level of significance was set at p < 0.05. Results: Thirty-four children with acute completely displaced fractures of the femoral diaphysis were included: Group 1: 21 fractures; Group 2: 13 fractures. The patients included 15 girls (44.1%) and 19 boys (55.9%), with an average age of 4.4 years (range 2.8 to 6.5 years). The mean follow-up period was 28.4 months (range 24.2-45.0 months). The demographic characteristics did not differ between the two groups of patients. Overall, successful closed reduction and elastic stable intramedullary nail (ESIN) fixation could be achieved in all 34 patients. The mean surgical time was 40.4 and 43.0 min in Group 1 and Group 2, respectively (p = 0.857). Fluoroscopy time was not significantly different between the two groups (37.0 vs. 36.1 s, respectively; p = 0.247). Cosmetic results were described as good and satisfactory by all patients. There were no refractures and no incidences of nonunion or growth arrest in the proximal epiphysis. Only two patients suffered from a superficial infection, which was resolved after the pins were shortened and oral antibiotics were administered. Conclusion: Closed reduction and elastic stable intramedullary nail (ESIN) fixation can be successfully used to treat completely displaced fractures of the femoral diaphysis in children aged two to six years. This technique is efficient and minimally invasive, and the results are satisfactory.

Supramolecularly modulated carbon-centered radicals: toward selective oxidation from benzyl alcohol to aldehyde.

The reactivity of ketyl radicals and benzoyl radicals, two key intermediates of photo-induced oxidation of benzyl alcohol, can be stabilized by the host-guest interaction of the radicals with cucurbit[7]uril. As a result, the selectivity of photo-induced oxidation from benzyl alcohol to aldehyde is significantly improved by diminishing side reactions and inhibiting the generation of carboxylic acid products. This work presents a new route to modulate the reactivity of radical intermediates, enriching the chemistry of supramolecular intermediates and the toolbox of supramolecular catalysis.

Intercalated PtCo Electrocatalyst of Vanadium Metal Oxide Increases Charge Density to Facilitate Hydrogen Evolution.

Efforts to develop high-performance electrocatalysts for the hydrogen evolution reaction (HER) are of utmost importance in ensuring sustainable hydrogen production. The controllable fabrication of inexpensive, durable, and high-efficient HER catalysts still remains a great challenge. Herein, we introduce a universal strategy aiming to achieve rapid synthesis of highly active hydrogen evolution catalysts using a controllable hydrogen insertion method and solvothermal process. Hydrogen vanadium bronze HxV2O5 was obtained through controlling the ethanol reaction rate in the oxidization process of hydrogen peroxide. Subsequently, the intermetallic PtCoVO supported on two-dimensional graphitic carbon nitride (g-C3N4) nanosheets was prepared by a solvothermal method at the oil/water interface. In terms of HER performance, PtCoVO/g-C3N4 demonstrates superior characteristics compared to PtCo/g-C3N4 and PtCoV/g-C3N4. This superiority can be attributed to the notable influence of oxygen vacancies in HxV2O5 on the electrical properties of the catalyst. By adjusting the relative proportions of metal atoms in the PtCoVO/g-C3N4 nanomaterials, the PtCoVO/g-C3N4 nanocomposites show significant HER overpotential of η10 = 92 mV, a Tafel slope of 65.21 mV dec-1, and outstanding stability (a continuous test lasting 48 h). The nanoarchitecture of a g-C3N4-supported PtCoVO nanoalloy catalyst exhibits exceptional resistance to nanoparticle migration and corrosion, owing to the strong interaction between the metal nanoparticles and the g-C3N4 support. Pt, Co, and V simultaneous doping has been shown by Density Functional Theory (DFT) calculations to enhance the density of states (DOS) at the Fermi level. This augmentation leads to a higher charge density and a reduction in the adsorption energy of intermediates.

Co-exposure to lead and high-fat diet aggravates systemic inflammation in mice by altering gut microbiota and the LPS/TLR4 Pathway.

This study reports the toxicity of Pb exposure on systemic inflammation in high-fat diet (HFD) mice and the potential mechanisms. Results indicated that Pb exacerbated intestinal barrier damage and increased serum levels of lipopolysaccharide (LPS) and diamine oxidase in HFD mice. Elevated LPS activates the colonic and ileal LPS-TLR4 inflammatory signaling pathway and further induces hepatic and adipose inflammatory expression. The 16S rRNA gene sequencing results showed that Pb promoted the abundance of potentially harmful and LPS-producing bacteria such as Coriobacteriaceae_UCG-002, Alloprevotella and Oscillibacter in the intestines of HFD mice, and their abundance was positively correlated with LPS levels. Additionally, Pb inhibited the abundance of the beneficial bacteria Akkermansia, resulting in lower levels of the metabolite SCFAs. Meanwhile, Pb inhibited adenosine 5'-monophosphate-activated protein kinase signaling-mediated lipid metabolism pathways promoting hepatic lipid accumulation. The above results suggest that Pb exacerbates systemic inflammation and lipid disorders in HFD mice by altering the gut microbiota, intestinal barrier and the mediation of metabolites LPS and SCFAs. Our study provides potential novel mechanisms of human health related to Pb-induced metabolic damage and offers new evidence for a comprehensive assessment of Pb risk.

Maternal PFOS exposure in mice induces hepatic lipid accumulation and inflammation in adult female offspring: Involvement of microbiome-gut-liver axis and autophagy.

Perfluorooctane sulfonates (PFOS) are the persistent organic pollutants. In the present study, 0, 0.3, or 3-mg/kg PFOS were administered to pregnant mice from GD 11 to GD 18. The histopathology of liver and intestine, serum and hepatic lipid levels, lipid metabolism related genes, and gut microbiota were examined in adult female offspring. The results suggested that maternal PFOS exposure increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and induced F4/80+ macrophage infiltration in adult female offspring, in addition to the elevation of TNF-α and IL-1ß mRNA levels in low-dose and high-dose groups, respectively. Furthermore, maternal exposure to PFOS increased serum triglyceride (TG) and hepatic total cholesterol (TC) levels, which was associated with the alteration of the process of fatty acid transport and ß-oxidation, TG synthesis and transport, cholesterol synthesis and excretion in the liver. The AMPK/mTOR/autophagy signaling was also inhibited in the liver of adult female offspring. Moreover, changes in gut microbiota were also related to lipid metabolism, especially for the Desulfovibrio, Ligilactobacillus, Enterorhabdus, HT002 and Peptococcaceae_unclassified. Additionally, maternal exposure to PFOS decreased mRNA expressions of the tight junction protein and AB+ goblet cells in the colon, while increasing the overproduction of lipopolysaccharides (LPS) and F4/80+ macrophage infiltration. Collectively, maternal PFOS exposure induced liver lipid accumulation and inflammation, which strongly correlated with the disruption of the gut-liver axis and autophagy in adult female offspring, highlighting the persistent adverse effects in offspring exposed to PFOS.

Isotope engineering achieved by local coordination design in Ti-Pd co-doped ZrCo-based alloys.

Deuterium/Tritium (D/T) handling in defined proportions are pivotal to maintain steady-state operation for fusion reactors. However, the hydrogen isotope effect in metal-hydrogen systems always disturbs precise D/T ratio control. Here, we reveal the dominance of kinetic isotope effect during desorption. To reconcile the thermodynamic stability and isotope effect, we demonstrate a quantitative indicator of Tgap and further a local coordination design strategy that comprises thermodynamic destabilization with vibration enhancement of interstitial isotopes for isotope engineering. Based on theoretical screening analysis, an optimized Ti-Pd co-doped Zr0.8Ti0.2Co0.8Pd0.2 alloy is designed and prepared. Compared to ZrCo alloy, the optimal alloy enables consistent isotope delivery together with a three-fold lower Tgap, a five-fold lower energy barrier difference, a one-third lower isotopic composition deviation during desorption and an over two-fold higher cycling capacity. This work provides insights into the interaction between alloy and hydrogen isotopes, thus opening up feasible approaches to support high-performance fusion reactors.

Finite element study on post-screw removal stress in toy poodle radius with different plate designs and screw arrangements.

Background: The study employs finite element analysis to investigate stress distribution in the radius of toy poodles after screw removal. The examination focuses on the biomechanical implications of varied screw hole configurations using 1.5 and 2.0-mm locking compression plates (LCPs) with notched head T-Plates. Aim: To provide a noninvasive approach to analyzing the immediate consequences of screw removal from the radius bone in toy poodles. Specifically, it explores the impact of varied plate designs and screw arrangements on stress distribution within the forelimb bones. Methods: The study constructs a three-dimensional bone model of the toy poodle's forelimb based on computed tomography (CT) images. Simulations were designed to replicate jumping and landing from a 40 cm height, comparing stress distribution in the radius post-screw removal. Results: The analysis reveals significant variations in stress distribution patterns between the two LCPs. The radius implanted with the 2.0-mm LCP displays a uniform stress distribution, contrasting with the 1.5-mm plates. Localized stress concentration is observed around the screw holes, while trabecular bone regions near the screw holes exhibit lower stress levels. Conclusion: The study highlights the plate designs and screw configurations that affect bone stress in toy poodle forelimbs post-screw removal. The findings provide valuable insights for veterinarians, aiding informed decisions in veterinary orthopedic practices.

Conductive Hyaluronic Acid/Deep Eutectic Solvent Composite Hydrogel as a Wound Dressing for Promoting Skin Burn Healing Under Electrical Stimulation.

Burns can cause severe damage to the skin due to bacterial infection and severe inflammation. Although conductive hydrogels as electroactive burn-wound dressings achieve remarkable effects on accelerating wound healing, issues such as imbalance between their high conductivity and mechanical properties, easy dehydration, and low transparency must be addressed. Herein, a double-network conductive eutectogel is fabricated by integrating polymerizable deep eutectic solvents (PDESs)including acrylamide/choline chloride/glycerol (acrylamide-polymerization crosslink) and thiolated hyaluronic acid (disulfide-bonding crosslink). The introduction of PDESs provides the eutectogel with a conductivity (up to 0.25 S·m-1) and mechanical strength (tensile strain of 59-77%) simulating those of natural human skin, as well as satisfactory tissue adhesiveness, self-healing ability, and antibacterial properties. When combined with exogenous electrical stimulation, the conductive eutectogel exhibits the ability to reduce inflammation, stimulate cell proliferation and migration, promote collagen deposition and angiogenesis, and facilitate skin tissue remodeling. This conductive eutectogel shows great potential as a dressing for healing major burn wounds.

1D Cu(I)-based chiral organic-inorganic hybrid material with second harmonic generation and circular polarized luminescence.

In recent years, organic-inorganic hybrid materials have demonstrated exceptional performance in nonlinear optics, attracting widespread attention. However, there are relatively few examples of coordination compounds synthesized with Cu as the metal center that exhibit excellent nonlinear optical properties. In this study, we successfully synthesized a pair of enantiomers named R/S-Cu2I2 by reacting chiral ligands with CuI. The crystal structure reveals a one-dimensional copper-iodide chain structure built by Cu2I2 clusters, and its ordered arrangement in space provides not only a strong second harmonic generation (SHG) signal (1.24 × KDP) but also a large birefringence (0.15@1064 nm). Under excitation at 395 nm, the crystals exhibit red fluorescence peaked at 675 nm. The CD spectra of R/S-Cu2I2 show a distinct mirror-symmetric Cotton effect, and their CPL signals are corresponding and opposite in the emission range, with a maximum glum of approximately ±2.5 × 10-3. Theoretical calculations using density functional theory were also carried out to enhance our understanding of the correlation between their structures and optical properties.

Structural Design of Single-Atom Catalysts for Enhancing Petrochemical Catalytic Reaction Process.

Petroleum, as the "lifeblood" of industrial development, is the important energy source and raw material. The selective transformation of petroleum into high-end chemicals is of great significance, but still exists enormous challenges. Single-atom catalysts (SACs) with 100% atom utilization and homogeneous active sites, promise a broad application in petrochemical processes. Herein, the research systematically summarizes the recent research progress of SACs in petrochemical catalytic reaction, proposes the role of structural design of SACs in enhancing catalytic performance, elucidates the catalytic reaction mechanisms of SACs in the conversion of petrochemical processes, and reveals the high activity origins of SACs at the atomic scale. Finally, the key challenges are summarized and an outlook on the design, identification of active sites, and the appropriate application of artificial intelligence technology is provided for achieving scale-up application of SACs in petrochemical process.

Genomic analysis of lumpy skin disease virus asian variants and evaluation of its cellular tropism.

Lumpy skin disease virus (LSDV) is a poxvirus that mainly affects cattle and can lead to symptoms such as severe reduction in milk production as well as infertility and mortality, which has resulted in dramatic economic loss in affected countries in Africa, Europe, and Asia. In this study, we successfully isolated two strains of LSDV from different geographical regions in China. Comparative genomic analyses were performed by incorporating additional LSDV whole genome sequences reported in other areas of Asia. Our analyses revealed that LSDV exhibited an 'open' pan-genome. Phylogenetic analysis unveiled distinct branches of LSDV evolution, signifying the prevalence of multiple lineages of LSDV across various regions in Asia. In addition, a reporter LSDV expressing eGFP directed by a synthetic poxvirus promoter was generated and used to evaluate the cell tropism of LSDV in various mammalian and avian cell lines. Our results demonstrated that LSDV replicated efficiently in several mammalian cell lines, including human A549 cells. In conclusion, our results underscore the necessity for strengthening LSD outbreak control measures and continuous epidemiological surveillance.

Elucidation of the radius and ulna fracture mechanisms in toy poodle dogs using finite element analysis.

Fractures occurring in the distal radius and ulna of toy breed dogs pose distinctive challenges for veterinary practitioners, requiring specialized treatment approaches primarily based on anatomical features. Finite Element Analysis (FEA) was applied to conduct numerical experiments to determine stress distribution across the bone. This methodology offers an alternative substitute for directly investigating these phenomena in living dog experiments, which could present ethical obstacles. A three-dimensional bone model of the metacarpal, carpal, radius, ulna, and humerus was reconstructed from Computed Tomography (CT) images of the toy poodle and dachshund forelimb. The model was designed to simulate the jumping and landing conditions from a vertical distance of 40 cm to the ground within a limited timeframe. The investigation revealed considerable variations in stress distribution patterns between the radius and ulna of toy poodles and dachshunds, indicating notably elevated stress levels in toy poodles compared to dachshunds. In static and dynamic stress analysis, toy poodles exhibit peak stress levels at the distal radius and ulna. The Von Mises stresses for toy poodles reach 90.07 MPa (static) and 1,090.75 MPa (dynamic) at the radius and 1,677.97 MPa (static) and 1,047.98 MPa (dynamic) at the ulna. Conversely, dachshunds demonstrate lower stress levels for 5.39 MPa (static) and 231.79 MPa (dynamic) at the radius and 390.56 MPa (static) and 513.28 MPa (dynamic) at the ulna. The findings offer valuable insights for modified treatment approaches in managing fractures in toy breed dogs, optimizing care and outcomes.

Exploring the enigmatic association between PNLIP variants and risk of chronic pancreatitis in a large Chinese cohort.

BACKGROUND & AIMS: Protease-sensitive PNLIP variants were recently associated with chronic pancreatitis (CP) in European populations. The pathological mechanism yet remains elusive. Herein, we performed a comprehensive genetic and functional analysis of PNLIP variants found in a large Chinese cohort, aiming to further unravel the enigmatic association of PNLIP variants with CP. METHODS: All coding and flanking intronic regions of the PNLIP gene were analyzed for rare variants by targeted next-generation sequencing in 1082 Chinese CP patients and 1196 controls. All novel missense variants were subject to analysis of secretion, lipase activity, and proteolytic degradation. One variant was further analyzed for its potential to misfold and induce endoplasmic reticulum (ER) stress. p.F300L, the most common PNLIP variant associated with CP, was used as a control. RESULTS: We identified 12 rare heterozygous PNLIP variants, with 10 being novel. The variant carrier frequency did not differ between the groups. Of them, only the variant p.A433T found in a single patient was considered pathologically relevant. p.A433T exhibited increased susceptibility to proteolytic degradation, which was much milder than p.F300L. Interestingly, both variants exhibited an increased tendency to misfold, leading to intracellular retention as insoluble aggregates, reduced secretion, and elevated ER stress. CONCLUSIONS: Our genetic and functional analysis of PNLIP variants identified in a Chinese CP cohort suggests that the p.A433T variant and the previously identified p.F300L variant are not only protease-sensitive but also may be potentially proteotoxic. Mouse studies of the PNLIP p.F300L and p.A433T variants are needed to clarify their role in CP.

CPD-002, a novel VEGFR2 inhibitor, relieves rheumatoid arthritis by reducing angiogenesis through the suppression of the VEGFR2/PI3K/AKT signaling pathway.

Synovial angiogenesis is a key player in the development of rheumatoid arthritis (RA), and anti-angiogenic therapy is considered a promising approach for treating RA. CPD-002 has demonstrated efficacy in suppressing tumor angiogenesis as a VEGFR2 inhibitor, but its specific impacts on RA synovial angiogenesis and possible anti-RA effects need further study. We examined the influences of CPD-002 on the migration and invasion of human umbilical vein endothelial cells (HUVECs) and its impacts on HUVECs' tube formation and vessel sprouting ex vivo. The therapeutic potential of CPD-002 in adjuvant-induced arthritis (AIA) rats and its suppression of synovial angiogenesis were examined. The involvement of the VEGFR2/PI3K/AKT pathway was assessed both in HUVECs and AIA rat synovium. Here, CPD-002 inhibited the migration and invasion of VEGF-stimulated HUVECs, decreased their chemotactic response to RA fibroblast-like synoviocyte-released chemoattractants, and exhibited anti-angiogenic effects in vitro and ex vivo. CPD-002's targeting of VEGFR2 was confirmed with molecular docking and cellular thermal shift assays, supported by the abolishment of CPD-002's effects upon using VEGFR2 siRNA. CPD-002 relieved paw swelling, arthritis index, joint damage, and synovial angiogenesis, indicating its anti-arthritic and anti-angiogenic effects in AIA rats. Moreover, the anti-inflammatory effects in vivo and in vitro of CPD-002 contributed to its anti-angiogenic effects. Mechanistically, CPD-002 hindered the activation of VEGFR2/PI3K/AKT pathway in VEGF-induced HUVECs and AIA rat synovium, as evidenced by reduced p-VEGFR2, p-PI3K, and p-AKT protein levels alongside elevated PTEN protein levels. Totally, CPD-002 showed anti-rheumatoid effects via attenuating angiogenesis through the inhibition of the VEGFR2/PI3K/AKT pathway.

Real-World Experience with 177Lu-PSMA-617 Radioligand Therapy After Food and Drug Administration Approval.

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy.

Study on the mechanism of 20-hydroxyeicosatetraenoic acid in retinal ischemia-reperfusion injury.

PURPOSE: To explore the effect of 20-hydroxyeicosatetraenoic acid (20-HETE) on retinal ischemia-reperfusion injury (RIRI) and the protective effect of N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine (HET0016) on RIRI. METHODS: Male Sprague-Dawley rats were randomly divided into the normal control group, experimental model group (RIRI group), experimental solvent group (RIRI + solvent group), and experimental treatment group (RIRI + HET0016 group). RESULTS: The levels of 20-HETE, tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) in the retina of rats at 24 h after reperfusion were measured by enzyme-linked immunosorbent assay. Hematoxylin-eosin staining was used to observe the retinal morphological and thickness changes at 24 h, 48 h, and 7 days after reperfusion. The number and localized expression of matrix metalloproteinase-9-positive cells in the retina of the rats at 24 h after reperfusion and the activation and localized expression of retinal microglia at 48 h after reperfusion were measured using an immunohistochemical method. The nuclear metastasis of nuclear factor kappa-B (NF-κB, p65) cells at 24 h after reperfusion was observed using an immunofluorescence method. CONCLUSION: Overall, 20-HETE might activate microglia to aggravate RIRI by the NF-κB pathway, but HET0016 has significant protective effects for the retina.