Facial synthesis of fluorine-engineered magnetic covalent organic framework for selective and ultrasensitive determination of fipronil, its metabolites and analogs in food samples.

To improve the adsorption affinity and selectivity of fipronils (FPNs), including fipronil, its metabolites and analogs, a magnetic covalent organic framework (Fe3O4@COF-F) with copious fluorine affinity sites was innovatively designed as an adsorbent of magnetic solid-phase extraction (MSPE). The enhanced surface area, pore size, crystallinity of Fe3O4@COF-F and its exponential adsorption capacities (187.3-231.5 mg g-1) towards fipronils were investigated. Combining MSPE with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), an analytical method was established for the selective determination of fipronils in milk and milk powder samples. This method achieved high sensitivity (LODs: 0.004-0.075 ng g-1), satisfactory repeatability and accuracy with spiked recoveries ranging from 89.9% to 100.3% (RSDs≤5.1%). Overall, the constructed Fe3O4@COF-F displayed great potential for the selective enrichment of fipronils, which could be ascribed to fluorine­fluorine interaction. This method proposed a feasible and promising strategy for the development of functionalized COF and broadened its application in fluorine containing hazards detection.

A rapid tick exposure test for monitoring acaricide resistance in Rhipicephalus sanguineus sensu lato ticks on dogs.

BACKGROUND: Brown dog ticks (Rhipicephalus sanguineus sensu lato) are vectors of pathogens adversely affecting the health of dogs in many regions of the world. The three-host life cycle of R. sanguineus s.l., with all stages feeding on dogs, can lead to an uncontrolled build-up of large tick populations if not controlled by acaricides. However, frequent tick control on dogs using acaricides has led to the emergence of resistance to permethrin and fipronil. Currently, the larval packet test (LPT) is the standard tick resistance test, which is laborious, requires laboratory facilities, and takes at least 6 weeks before larvae derived from engorged female ticks can be tested. Our novel approach is to expose semi-engorged adult ticks to acaricides immediately after removing them from dogs, obtaining results within 24 h. METHODS: Adult ticks from three laboratory colonies of R. sanguineus s.l. were tested in RaTexT®, a rapid tick exposure test in which ticks were confined to small compartments and exposed to an acaricide-impregnated, specially designed matrix. Resistance was confirmed by testing larvae derived from the same laboratory colonies using the LPT. RaTexT® was also used to determine the susceptibility of R. sanguineus acaricides in dog shelters. RESULTS: RaTexT® detected resistance to permethrin in adult R. sanguineus s.l. ticks from two Brazilian laboratory colonies compared to a susceptible laboratory strain originating in Greece. Resistance was confirmed by LPT testing of larvae from the same colonies with resistance factors between 2.2 and 3.1. All laboratory strains were susceptible to fipronil. A suspected case of fipronil resistance at a dog shelter in Caxias do Sul, Brazil, was resolved within 24 h by testing adult ticks in RaTexT® and could be attributed to improper treatment. CONCLUSIONS: RaTexT® is a valuable tool for monitoring the development of resistance to synthetic pyrethroids or phenylpyrazoles in tick-infested dogs.

Cu(II)-tyrosinase enzyme catalyst mediated synthesis of mosquito larvicidal active pyrazolidine-3,5-dione derivatives with molecular docking studies and their ichthyotoxicity analysis.

The objective of this study was to develop pyrazolidine-3,5-dione derivatives with potential as environmentally friendly pesticides for pest control, specifically focusing on their efficacy as larvicidal agents. A novel one-pot synthesis of multicomponent pyrazolidine-3,5-dione derivatives (1a-m) was accomplished via the grindstone method using Cu(II)tyrosinase enzyme as a catalyst under mild reaction conditions, yielding 84%-96%. The synthesised derivatives (1a-m) were characterized using various spectroscopic methods (mass spectrometry, elemental analysis, FT-IR, and 1H and 13C NMR). NMR characterisation using DMSO-d6 as a solvent. The larvicidal and antifeedant activities of the synthesised compounds were screened and in silico computational studies were performed. The larvicidal activity against Culex quinquefasciatus and antifeedant activity against Oreochromis mossambicus were evaluated. Among the synthesised compounds, compound 1c demonstrated superior efficacy (LD50: 9.7 µg/mL) against C. quinquefasciatus compared to permethrin (LD50: 17.1 µg/mL). Regarding antifeedant activity, compounds 1a, 1e, 1f, 1j, and 1k exhibited 100% mortality at 100 µg/mL. Molecular docking analysis was performed to assess the binding capacity of a mosquito odorant-binding protein (3OGN) from Culex quinquefasciatus to compound 1c. The results revealed that compound 1c had a docking score of -10.4 kcal/mol, surpassing that of standard permethrin (-9.5 kcal/mol). Furthermore, DFT calculations were conducted to acquire theoretical data aligned with the experimental FT-IR results. According to experimental research, compound 1c demonstrates promising larvicidal activity against mosquito larvae of C. quinquefasciatus.

Phase IB part of LOC-R01, a LOC network non-comparative randomized phase IB/II study testing R-MPV in combination with escalating doses of lenalidomide or ibrutinib for newly diagnosed primary central nervous system lymphoma (PCNSL) patients.

BACKGROUND: Results of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy. METHODS: Patients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. RESULTS: Twenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively. CONCLUSION: Targeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing. TRIAL REGISTRATION: NCT04446962.

The Fat Body-Specific GST Gene SlGSTe11 Enhances the Tolerance of Spodoptera litura to Cyantraniliprole and Nicotine.

Spodoptera litura is a significant agricultural pest, and its glutathione S-transferase (GST) plays a crucial role in insecticide resistance. This study aimed to investigate the relationship between the SlGSTe11 gene of S. litura and resistance to cyantraniliprole and nicotine. Transcriptome analysis revealed that SlGSTe11 is highly expressed mainly in fat bodies, with a significant increase in SlGSTe11 gene expression under induction by cyantraniliprole and nicotine. The ectopic expression of the SlGSTe11 gene in transgenic fruit flies resulted in a 5.22-fold increase in the tolerance to cyantraniliprole. Moreover, compared to the UAS-SlGSTe11 line, the Act5C-UAS>SlGSTe11 line laid more eggs and had a lower mortality after nicotine exposure. RNAi-mediated inhibition of SlGSTe11 gene expression led to a significant increase in the mortality of S. litura under cyantraniliprole exposure. In vitro metabolism experiments demonstrated that the recombinant SlGSTe11 protein efficiently metabolizes cyantraniliprole. Molecular docking results indicated that SlGSTe11 has a strong affinity for both cyantraniliprole and nicotine. These findings suggest that SlGSTe11 is involved in the development of resistance to cyantraniliprole and nicotine in S. litura.

Direct Oral Anticoagulants in Antiphospholipid Syndrome-Associated Venous Thromboembolism: Real World Evidence.

BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs) versus warfarin in patients with antiphospholipid syndrome-associated venous thromboembolism (APS-VTE) remain uncertain. We aimed to evaluate efficacy and safety of DOACs in patients with APS-VTE. METHODS: Using the Korean Health Insurance Review and Assessment Service database, we retrospectively identified all APS-VTE cases. We examined the VTE recurrence, arterial thrombosis, death and bleeding in patients who received DOACs compared with warfarin for therapeutic anticoagulation. RESULTS: Of all the VTE cases (n = 84,916) detected between 2014 and 2018, patients with APS-VTE (n = 410) accounted for 0.48%. Most patients with APS-VTE (73%) were aged < 60 years. The recurrent VTE occurred in 8 of 209 patients (3.8%) who received DOACs and in 7 of 201 (3.5%) who received warfarin (relative risk [RR], 1.099; 95% confidence interval [CI], 0.41-2.98; P = 1.000). The arterial thrombosis (ATE) occurred in 8 of 209 patients (3.8%) who received DOAC and in 20 of 201 (10%) who received warfarin (RR, 0.385; 95% CI, 0.17-0.85; P = 0.024). The composite outcomes of VTE recurrence, ATE, or mortality were significantly lower in patients (9.1%) on DOAC than in those (16.3%) on warfarin (RR, 0.537; 95% CI, 0.32-0.91; P = 0.028). The bleeding outcome occurred in 7 of 209 (3.4%) patients in the DOACs group and 7 of 201 (3.5%) patients in the warfarin group (RR, 0.96; 95% CI, 0.34-2.69; P = 0.840). CONCLUSION: In patients with APS-VTE, DOACs group showed comparable rates of recurrent VTE, bleeding, and deaths, but a significantly lower incidence of ATE and composite outcomes compared with the warfarin group in Korea.

Enhancement of oral bioavailability of ibrutinib using a liposil nanohybrid delivery system.

Liposils, synthesized via the liposome templating method, offer a promising strategy for enhancing liposome stability by employing a silica coating. This study focuses on the development of nanocarriers utilizing silica-coated nanoliposomes for encapsulating the poorly water-soluble drug, ibrutinib. Ibrutinib-loaded nanoliposomes were meticulously formulated using the reverse-phase evaporation technique, serving as templates for silica coating, resulting in spherical liposils with an average size of approximately 240 nanometers. Comprehensive characterization of the liposil's physical and chemical properties was conducted using various analytical methods, including dynamic light scattering, transmission electron microscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction analysis. Liposils demonstrated superior performance compared to ibrutinib-loaded nanoliposomes, showing sustained drug release profiles in simulated intestinal fluids and resistance to simulated gastric fluid, as confirmed by dissolution studies. Moreover, ibrutinib liposils exhibited a significant increase in half-life (4.08-fold) and notable improvement in bioavailability (3.12-fold) compared to ibrutinib suspensions, as determined by pharmacokinetic studies in rats. These findings underscore the potential of liposils as nanocarriers for orally delivering poorly water-soluble drugs, offering enhanced stability and controlled release profiles, thereby improving bioavailability prospects and therapeutic efficacy. This approach holds promise for addressing challenges associated with the oral administration of drugs with limited solubility, thereby advancing drug delivery technologies and clinical outcomes in pharmaceutical research and development.

Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain.

Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [18F]WL1-3. Among these, [18F]WL1 showed specific binding to RIPK1 in mouse brain sections in vitro through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain2 min = 4.89% ID/g) and rapid washout (brain60 min = 0.21% ID/g). PET studies in rat brains revealed that [18F]WL1 could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled WL1 and GSK'547. Notably, [18F]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.

Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: A retrospective German claims data analysis.

BACKGROUND: Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials. METHODS: Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding. RESULTS: Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p < 0.001) but not for dabigatran (p = 0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p < 0.001) and 13.0% for dabigatran versus 12.8% for VKA (p = 0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine-Gray regression models on the basis of the entire cohort. CONCLUSIONS: In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs.

Effects of GBT1118, a voxelotor analog, on bone disease in sickle cell disease mice.

We assessed the effect of GBT1118, a sickle hemoglobin polymerization inhibitor on bone loss in humanized sickle cell disease (SCD) mice. Healthy control (Ctrl) 4-months-old female and male mice were fed Vehicle-chow for 2-months, while SCD mice were fed Vehicle-chow or GBT1118-chow. By micro-CT, GBT1118 significantly increased femur metaphyseal trabecular thickness (Tb.Th) and tissue mineral density (TMD), and significantly decreased trabecular spacing in female SCD mice. In SCD male mice, there was significant reduction in epiphyseal trabecular bone volume fraction (BV/TV), Tb.Th and TMD and GBT1118 significantly increased BV/TV and TMD but not Tb.Th. A significant decrease in cortical area fraction in SCD female mice was rescued by GBT1118 but not SCD males. Markedly decreased mineralized femur trabeculae in SCD females and males was partially rescued by GBT1118. Bone histomorphometry of femurs demonstrated significantly decreased bone formation parameters and increased bone resorption parameters in SCD mice of both sex that were rescued by GBT1118. Significant alteration in bone and hypoxia related genes of SCD mice of both sexes were differentially modulated by GBT1118. We conclude that "a sickle hemoglobin polymerization inhibitor" might be efficacious in improving some parameters of SCD bone loss.

Identification of potent and orally efficacious phosphodiesterase inhibitors in Cryptosporidium parvum-infected immunocompromised male mice.

Cryptosporidium parvum and C. hominis are parasites that cause life-threatening diarrhea in children and immunocompromised people. There is only one approved treatment that is modestly effective for children and ineffective for AIDS patients. Here, screening 278 compounds from the Merck KGaA, Darmstadt, Germany collection and accelerated follow-up enabled by prior investigation of the compounds identifies a series of pyrazolopyrimidine human phosphodiesterase (PDE)-V (hPDE-V) inhibitors with potent anticryptosporidial activity and efficacy following oral administration in C. parvum-infected male mice. The lead compounds affect parasite host cell egress, inhibit both C. parvum and C. hominis, work rapidly, and have minimal off-target effects in a safety screening panel. Interestingly, the hPDE-V inhibitors sildenafil and the 4-aminoquinoline compound 7a do not affect Cryptosporidium. C. parvum expresses one PDE (CpPDE1) continuously during asexual growth, the inhibited life stage. According to homology modeling and docking, the lead compounds interact with CpPDE1. Bulkier amino acids (Val900 and His884) in the CpPDE1 active site replace alanines in hPDE-V and block sildenafil binding. Supporting this, sildenafil kills a CRISPR-engineered Cryptosporidium CpPDE1 V900A mutant. The CpPDE1 mutation also alters parasite susceptibility to pyrazolopyrimidines. CpPDE1 is therefore a validated pyrazolopyrimidine molecular target to exploit for target-based optimization for improved anticryptosporidial development.

Comparison of nitrification inhibitors for mitigating cadmium accumulation in pakchoi and their associated microbial mechanisms. / å‡æŽ§å°é’èœé•‰æ±¡æŸ“çš„é«˜æ•ˆç¡åŒ–æŠ‘åˆ¶å‰‚ç­›é€‰åŠå ¶å¾®ç”Ÿç‰©å­¦æœºåˆ¶ç ”ç©¶.

The use of nitrification inhibitors has been suggested as a strategy to decrease cadmium (Cd) accumulation in crops. However, the most efficient nitrification inhibitor for mitigating crop Cd accumulation remains to be elucidated, and whether and how changes in soil microbial structure are involved in this process also remains unclear. To address these questions, this study applied three commercial nitrification inhibitors, namely, dicyandiamide (DCD), 3,4-dimethylpyrazole phosphate (DMPP), and nitrapyrin (NP), to pakchoi. The results showed that both DCD and DMPP (but not NP) could efficiently decrease Cd concentrations in pakchoi in urea- and ammonium-fertilized soils. In addition, among the three tested nitrification inhibitors, DMPP was the most efficient in decreasing the Cd concentration in pakchoi. The nitrification inhibitors decreased pakchoi Cd concentrations by suppressing acidification-induced Cd availability and reshaping the soil microbial structure; the most effective nitrification inhibitor was DMPP. Ammonia oxidation generates the most protons during nitrification and is inhibited by nitrification inhibitors. Changes in environmental factors and predatory bacterial abundance caused by the nitrification inhibitors changed the soil microbial structure and increased the potential participants in plant Cd accumulation. In summary, our study identified DMPP as the most efficient nitrification inhibitor for mitigating crop Cd contamination and observed that the soil microbial structural changes caused by the nitrification inhibitors contributed to decreasing Cd concentration in pakchoi.

Unusual renal displacement due to massive splenomegaly: a rare case report and review of literature.

Here, the case of a female patient in her late 60s, who presented to hospital for a scheduled health check relating to a history of myelofibrosis for the previous 9 years, is described. She recently experienced weight loss and abdominal distention. Physical examination revealed no abnormality or tenderness. Laboratory examination showed decreased blood cells, platelets and haemoglobin, and normal renal function. Ultrasound and computed tomography scans revealed a massively enlarged spleen and displaced and compressed left kidney with abnormal features, but normal right kidney. The patient declined surgery and her myelofibrosis was treated with ruxolitinib, with a recommendation of annual follow-up observation. Despite many recorded cases of left renal displacement caused by splenomegaly, it is very rare for the left kidney to be pushed across the midline to the right side by an enlarged spleen. This article explores the causes and management of this uncommon condition and provides a review of previous literature reports with the aim of enhancing the understanding of unusual renal displacement due to massive splenomegaly, and its potential treatment options.

[The efficacy and safety of avapritinib in the treatment of molecular biologically positive core binding factor-acute myeloid leukemia with KIT mutation after allogeneic hematopoietic stem cell transplantation].

Objective: To investigate the efficacy and safety of avapritinib in the treatment of molecular biologically positive core binding factor-acute myeloid leukemia (CBF-AML) with KIT mutation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: We retrospectively analyzed the clinical data of six patients with molecular biologically positive CBF-AML with KIT mutation after allo-HSCT, who were treated with avapritinib at Henan Cancer Hospital from December 2021 to March 2023, and evaluated the efficacy and safety of avapritinib. Results: After 1 month of treatment with avapritinib, the transcription level of the fusion gene decreased in six patients, and the transcription level decreased by ≥1 log in five patients. In four patients who received avapritinib for ≥3 months, the fusion gene turned negative, and the median time to turn negative was 2.0 (range: 1.0-3.0) months. Up to the end of follow-up, four patients had no recurrence. The most common adverse reaction of avapritinib was myelosuppression, including neutropenia in two cases, thrombocytopenia in two cases, and anemia in one case. The non-hematological adverse reactions were nausea in two cases, edema in one case, and memory loss in one case, all of which were grades 1-2. Conclusion: Avapritinib was effective for molecular biologically positive CBF-AML patients with KIT mutation after allo-HSCT. The main adverse reaction was myelosuppression, which could generally be tolerated.

Equine metabolic investigation of the phosphodiesterase-4 inhibitor ibudilast as a potential performance enhancer.

RATIONALE: Phosphodiesterase 4 (PDE4) inhibitors are a newer class of drugs that induce bronchodilation and have anti-inflammatory effects, making them susceptible to misuse as performance enhancers in competitive sports. METHODS: This study explores the metabolic conversion of PDE4 inhibitor ibudilast in thoroughbred horses after oral administration and in vitro using equine liver microsomes and Cunninghamella elegans. A liquid chromatography-high resolution mass spectrometry method was used to postulate the plausible structures of the detected metabolites. RESULTS: A total of 20 in vivo metabolites were identified under experimental conditions, including 12 Phase I and 8 Phase II conjugated metabolites. Phase I metabolites were predominantly formed through hydroxylation (mono-, di-, and tri-hydroxylation). Demethylated metabolites were also identified during this investigation. Additionally, the research detected Phase II metabolites conjugated with glucuronic and sulfonic acids. CONCLUSIONS: The data presented here can assist in detecting the PDE4 inhibitor ibudilast and uncover its illicit use in competitive sports.

Darolutamide-mediated phospholipid remodeling induces ferroptosis through the SREBP1-FASN axis in prostate cancer.

Darolutamide, an androgen receptor inhibitor, has been approved by the Food and Drug Administration (FDA) for the treatment of prostate cancer (PCa), especially for patients with androgen receptor mutations. Owing to the unique lipidomic profile of PCa and the effect of darolutamide, the relationship between darolutamide and ferroptosis remains unclear. The present study showed that darolutamide significantly induces ferroptosis in AR+ PCa cells. Mechanistically, darolutamide promotes ferroptosis by downregulating SREBP1, which then inhibits the transcription of FASN. FASN knockdown modulates phospholipid remodeling by disrupting the balance between polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs), which induces ferroptosis. Clinically, SREBP1 and FASN are significantly overexpressed in PCa tissues and are related to poor prognosis. Moreover, the synergistic antitumor effect of combination therapy with darolutamide and ferroptosis inducers (FINs) was confirmed in PCa organoids and a mouse xenografts model. Overall, these findings revealed a novel mechanism of darolutamide mediated ferroptosis in PCa, laying the foundation for the combination of darolutamide and FINs as a new therapeutic strategy for PCa patients.