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.

[Assessing the Impact of in-Hospital Formulary Policies on the Prescription Patterns of Direct Oral Anticoagulants (DOACs)].

Prescribing direct oral anticoagulants (DOACs) with off-label dosage and administration is discouraged due to concerns about their effectiveness and safety. Consequently, our hospital pharmacist established a formulary with physicians for oral anticoagulants. Our study aimed to assess the adherence to this formulary by investigating the rate of appropriate DOAC prescribing. We included patients who were newly prescribed or continued on DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) at our hospital. We calculated the percentage of patients prescribed the correct dosage and administration according to the package insert and compared this across three time periods: pre-intervention (period A; April-September 2019), post-intervention phase 1 (period B; August 2021-January 2022), and post-intervention phase 2 (period C; November 2022-April 2023). We also examined the number of inquiries and consultation requests made by hospital pharmacists regarding DOAC dosage and administration. A total of 782 patients were surveyed (191 in period A, 263 in period B, and 328 in period C). The appropriate prescribing rates for DOACs were 79.1% in period A, 84.4% in period B, and 86.6% in period C. The proportion of cases where hospital pharmacists questioned or consulted doctors about DOAC dosage and administration was 3.7% in period A, 6.1% in period B, and 10.1% in period C. These findings indicate that active intervention by hospital pharmacists using the formulary regarding oral anticoagulant formularies may promote appropriate DOAC use.

Short-term (24 weeks) treatment efficacy and safety of ruxolitinib cream in participants with vitiligo: a systematic review and meta-analysis.

IMPORTANCE: Vitiligo is a chronic skin disorder causing depigmentation. There is a lack of evidence-based medical evidence regarding ruxolitinib efficacy and safety for vitiligo. OBJECTIVE: To assess the efficacy and safety of ruxolitinib cream in the treatment of vitiligo. METHODS: The databases of PubMed, Embase, and Cochrane Library were searched. The literature screening was independently conducted by two reviewers. DATA EXTRACTION AND SYNTHESIS: For continuous variables, weighted mean difference (WMD) along with a 95% confidence interval (CI) was performed. For dichotomous outcomes, we calculated the odds ratios (ORs) or risk ratios (RRs), and their corresponding 95% CIs. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). MAIN OUTCOMES AND MEASURES: Symptoms, quality of life, and safety were evaluated using various measures, including the Facial Vitiligo Area Scoring Index (F-VASI), Total Vitiligo Area Scoring Index (T-VASI), Facial Body Surface Area (F-BAS), Total Body Surface Area (T-BAS) and Treatment-emergent Adverse Events (TEAEs). RESULTS: Three trials, involving a total of 830 participants from nine countries were included (female 388, 46.7%, male 442, 53.3%). The meta-analysis demonstrated a significant increase in the likelihood of participants achieving F-VASI75 (OR, 4.34 [95% CI 2.67-7.06]; high), F-VASI50 (OR 4.71 [95% CI 3.24-6.84]; high), T-VASI75 (OR 2.78 [95% CI 1.10-7.00]; moderate), and T-VASI50 (OR 4.47 [95% CI 2.52-7.92]; high) when compared ruxolitinib to vehicle. Ruxolitinib was associated with more lowered percentage change of F-VASI scores (MD - 32.79 [95% CI - 36.37 to - 29.21]; moderate), and T-VASI scores (MD - 20.22 [95% CI - 23.11 to - 17.33]; moderate) from baseline compared to vehicle. There may not be a significant difference in the occurrence of TEAEs between ruxolitinib and vehicle (RR 1.46 [95% CI 0.85-2.49]; high). CONCLUSIONS: The findings suggest that ruxolitinib cream holds promise as a treatment option for vitiligo. Further long-term studies are needed to assess its sustained efficacy and safety profile. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023431112.

GPR56 facilitates hepatocellular carcinoma metastasis by promoting the TGF-ß signaling pathway.

The metastasis of hepatocellular carcinoma (HCC) poses a significant threat to the survival of patients. G protein-coupled receptor 56 (GPR56) has garnered extensive attention within malignant tumor research and plays a crucial role in cellular surface signal transmission. Nonetheless, its precise function in HCC remains ambiguous. Our investigation reveals a notable rise in GPR56 expression levels in human HCC cases, with heightened GPR56 levels correlating with unfavorable prognoses. GPR56 regulates TGF-ß pathway by interacting with TGFBR1, thereby promoting HCC metastasis. At the same time, GPR56 is subject to regulation by the canonical cascade of TGF-ß signaling, thereby establishing a positive feedback loop. Furthermore, the combination application of TGFBR1 inhibitor galunisertib (GAL) and GPR56 inhibitor Dihydromunduletone (DHM), significantly inhibits HCC metastasis. Interventions towards this signaling pathway could offer a promising therapeutic approach to effectively impede the metastasis of GPR56-mediated HCC.

A case of neoadjuvant targeted therapy with pralsetinib for locally advanced lung adenocarcinoma with RET fusion mutation.

This case report details the successful treatment of a 68-year-old male patient with locally advanced RET-rearranged lung adenocarcinoma using neoadjuvant pralsetinib. The patient initially presented with a suspicious right upper lobe nodule, which was later diagnosed as lung adenocarcinoma following genetic testing that revealed a RET exon 12 fusion. After 2 months of neoadjuvant treatment with pralsetinib, a significant radiological response was observed, with a reduction in tumor size and metabolic activity. Subsequently, the patient underwent video-assisted thoracoscopic right upper lobectomy and mediastinal lymph node dissection. Postoperative pathological analysis revealed a major pathological response, with only 5% residual tumor cells in the primary lesion and no viable tumor cells in the lymph nodes. Postoperative pathological staging of TNM was ypT1aN0M0, stage IA1(AJCC, 8th edition). The patient recovered well after surgery, demonstrating the potential efficacy of neoadjuvant pralsetinib in locally advanced RET-rearranged lung adenocarcinoma. However, further clinical validation is required to establish the role of neoadjuvant targeted therapy and postoperative adjuvant therapy in this patient population.

CCDC113 promotes colorectal cancer tumorigenesis and metastasis via TGF-ß signaling pathway.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Although CRC patients' survival is improved with surgical resection and immunotherapy, metastasis and recurrence remain major problems leading to poor prognosis. Therefore, exploring pathogenesis and identifying specific biomarkers are crucial for CRC early diagnosis and targeted therapy. CCDC113, a member of CCDC families, has been reported to play roles in ciliary assembly, ciliary activity, PSCI, asthma and early lung cancer diagnosis. However, the functions of CCDC113 in CRC still remain unclear. In this study, we find that CCDC113 is significantly highly expressed in CRC. High expression of CCDC113 is significantly correlated with CRC patients' poor prognosis. CCDC113 is required for CRC tumorigenesis and metastasis. RNA-seq and TCGA database analysis indicate that CCDC113 is positively correlated with TGF-ß signaling pathway. TGF-ß signaling pathway inhibitor galunisertib could reverse the increased proliferation and migration ability of CRC cells caused by CCDC113 overexpression in vitro and in vivo. These results indicate that CCDC113 promotes CRC tumorigenesis and metastasis via TGF-ß signaling pathway. In conclusion, it is the first time to explore the functions and mechanisms of CCDC113 in CRC tumorigenesis and metastasis. And CCDC113 may be a potential biomarker and therapeutic target for CRC intervention.

[Regulation of targeted blocking cannabinoid receptor 1 on spleen immune function and inflammatory response in mice under chronic intermittent hypoxia].

Objective: To observe the effects of targeting and blocking cannabinoid receptor 1 (CB1R) on mouse spleen immune function and inflammatory response under chronic intermittent hypoxia (CIH) conditions, and to explore its regulatory effort. Methods: Forty SPF male C57BL/6 mice aged 4 to 5 weeks,from May 2021 to August 2021 in Experimental Animal Center of the Second Hospital of Shanxi Medical University, were randomly divided into normal oxygen control group (NC), 6-week CIH group (6w CIH), 10-week CIH group (10w CIH), 6-week CIH+CB1R group (6w CIH+AM251) and 10-week CIH+CB1R group (10w CIH+AM251) according to the method of random number table. The advanced programmable intermittent low oxygen chamber was used to prepare the CIH mouse model. The morphological structure of spleen tissue of CIH mice was stained by hematoxylin-eosin (HE) staining. The expression levels of M1 and M2 macrophage surface markers CD86, CD206 were determined by immunofluorescence. The mRNA expression levels of CB1R, CD86, CD206 and the relative expression levels of RORγt and Foxp3,which are characteristic transcriptional regulators of T helper 17(Th17) and Treg cells were detected by quantitative reverse transcriptase PCR(qRT-PCR). The expression of inflammatory factors IL-6 and IL-10 was determined by ELISA. SPSS 26.0 and Graphpad prism 8.3 were used to analyze the data. Results: (1) Compared with NC group, spleen tissue structure was disordered, fibrous tissue hyperplasia, lymphocyte proliferation and disordered arrangement in periarteriole lymphatic sheath in CIH group. The expression of CB1R in CIH group was higher than that in NC group (P<0.05), and with the prolongation of CIH time, the expression of 10w CIH group was higher than that in 6w CIH group(P<0.05). The expression of CB1R in CIH+AM251 group was lower than that in the corresponding CIH group(all P<0.05). (2) Compared with NC group, the expression level of CD86 in macrophages in CIH group was higher than that in NC group(all P<0.05). The relative expression of RORγt in 6w and 10w CIH groups was 0.76±0.03 and 0.91±0.04, respectively, which was higher than that in NC group (0.65±0.06)(all P<0.05). The relative expression levels of inflammatory factor IL-6 were 10.80±1.73 and 14.86±0.01, respectively, which were higher than 6.69±0.23 in the NC group (all P<0.05). The expression level of CD206 in macrophages in the CIH+AM251 group was higher than that in the CIH group(all P<0.05). The relative expression levels of Foxp3 in 6w and 10w CIH+AM251 groups were 0.62±0.05 and 0.32±0.21, respectively, which were higher than those in 6w CIH group (0.28±0.02) and 10w CIH group (0.02±0.01)(P<0.05). The relative expression levels of anti-inflammatory factor IL-10 were 668.45±15.71 and 379.15±56.84, respectively, which were higher than those in CIH group (all P<0.05). Conclusion: Targeted sealing of CB1R may alleviate inflammatory response of mouse spleen under CIH conditions by regulating macrophage polarization and the expression of inflammatory factors, and may have some protective effect.

Heparin-Calibrated Anti-Factor Xa Assay for the Measurement of Direct Anticoagulants such as Apixaban, Rivaroxaban, and Edoxaban.

BACKGROUND: The first purpose of this study was to determine whether a measurement of the level of direct oral anticoagulants (DOACs) was possible with heparin-calibrated chromogenic anti-factor Xa activity (AXA). The second purpose of this study was to evaluate whether the antidote treatment decision level (30 or 50 ng/mL of DOAC) can be determined by unfractionated heparin (UHF)/low molecular weight heparin (LMWH)-calibrated AXA. METHODS: AXA was measured by using two reagents and dedicated analyzers (Sysmex CS-5100 analyzer and STA R Max3). Four types of calibrators were used: 1) Stago DOAC (rivaroxaban, edoxaban, and apixaban)-specific calibrator, 2) Stago LMWH calibrator, 3) Sysmex UHF calibrator, and 4) Sysmex LMWH calibrator. Regression analysis was used between assays. Receiver operating characteristic (ROC) curves were performed, and the concordance rate was calculated. RESULTS: The correlation coefficients were in the range of 0.75 - 0.91 for rivaroxaban and 0.81 - 0.94 for apixaban. The correlation coefficient between edoxaban-calibrated AXA and Sysmex LMWH/Sysmex UHF calibrator-calibrated AXA was low (r = 0.47). Overall correlation between DOAC-calibrated AXA and Stago LMWH-calibrated AXA was linear, at only low concentration in all three DOACs. The concordance rate (89.3 - 100%) is good for de-termining the antidote management level by UFH/LMWH-calibrated AXA, compared with those of DOAC-calibrated AXA in rivaroxaban and apixaban. The concordance rate ranged from 63% to 67% between Sysmex UFH/ LMWH-calibrated AXA and edoxaban-calibrated AXA. CONCLUSIONS: The findings of our study suggest limitations in calculating accurate concentrations, when using UFH/LMWH-calibrated AXA to measure DOAC. This study demonstrates that UFH/LMWH-calibrated AXA may be useful in determining the presence of DOACs at the cutoff level for the antidote treatment in rivarovaban and apixaban. However, in edoxaban, UFH/LMWH-calibrated AXA could not accurately measure the presence of DOACs at the cutoff for antidote treatment.

Discovery, synthesis and SAR of 2-acyl-1-biarylmethyl pyrazolidines, dual orexin receptor antagonists designed as fast and short-acting sleeping drugs.

Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (<4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and in vivo experiments to identify DORAs eliciting this specific hypnotic profile. A high-throughput screening campaign revealed hits based on a rarely precedented tricyclic pyrazolidine scaffold. After unsuccessful structure-activity-relationship (SAR) studies on this hit series, a scaffold hopping exercise, aimed at reducing the molecular complexity of the tricyclic scaffold, resulted in the discovery of the 2-acyl-1-biarylmethylpyrazolidine series. SAR studies on this achiral series gave rise to the lead compound DORA 42. In vitro and in vivo parameters of DORA 42, and its PK-PD simulation for human use are detailed.

[The efficacy and safety of ibrutinib in the treatment of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia].

Objective: To explore the efficacy and safety of ibrutinib for the treatment of newly treated and relapsed refractory (R/R) lymphoplasmacytic lymphoma (LPL) /Waldenström macroglobulinemia (WM) . Methods: Retrospectively collected clinical data of 98 cases of newly treated and R/R LPL/WM patients who received ibrutinib treatment at the Hematology & Blood Diseases Hospital of the Chinese Academy of Medical Sciences from March 2016 to June 2023, and analyzed their efficacy and safety. Results: A total of 98 LPL/WM patients were included, which consisted of 45 newly treated patients and 53 R/R patients. Of these, 74 were males (75.5%) and the cohort had a median age of 64 (42-87) years. Eighty-eight patients were eligible for efficacy evaluation with a median treatment time of 20.8 (2.1-55.0) months, a major remission rate (MRR) of 78.4%, and an overall response rate (ORR) of 85.2%. The MRR and ORR of the newly treated patients were 78.4% and 86.5%, respectively, whereas the MRR and ORR of the R/R patients were 78.4% and 84.3%, respectively. There were no statistically significant differences in MRR and ORR between the initial treatment and R/R patients (all P values >0.05) . The median follow-up period was 29.1 (2.9-50.3) months and the median overall survival time for newly treated and R/R patients was not reached. The median progression-free survival time was 23.5 (95% CI 10.5-36.5) months and 45.0 (95% CI 34.0-56.0) months, respectively, with no statistically significant differences (all P values >0.05) . There were 25 deceased patients and no deaths were related to ibrutinib treatment. The main adverse reactions of ibrutinib were thrombocytopenia (5.1%) , pneumonia (8.1%) , and hyperuricemia (21.4%) . The incidence of atrial fibrillation was 2.0%. Conclusion: Ibrutinib exhibits good efficacy and safety for newly treated and R/R LPL/WM patients.

Ibrutinib-Related Uveitis in Non-Hodgkin Lymphoma Patients: A Case Report and Literature Review.

PURPOSE: To report two cases of ibrutinib-related uveitis and review the literature to date. METHODS: We report two cases of ibrutinib-related uveitis using CARE guidelines and review the cases reported in the literature. RESULTS: Case 1) A 55-year-old female with recurrent primary central nervous system lymphoma presented with bilateral decreased visual acuity, photophobia, and floaters that started one month after initiating oral treatment with ibrutinib. Chronic non-granulomatous bilateral anterior-intermediate uveitis with macular edema was identified. Secondary causes were ruled out, and a presumptive diagnosis of ibrutinib-related uveitis was made. Case 2) A 57-year-old female with Waldenström macroglobulinemia who was treated with ibrutinib for two years presented with bilateral blurred vision, photophobia, red eyes, and floaters. A diagnosis of non-granulomatous, noninfectious panuveitis with bilateral cystoid macular edema was made. Secondary causes were ruled out, and ibrutinib toxicity was the most likely cause. CONCLUSION: Ibrutinib-related uveitis is a novel and under-diagnosed clinical entity. The most frequent clinical presentation in the literature is bilateral, non-granulomatous, anterior, and intermediate uveitis. Macular edema is a frequent complication. Uveitis usually requires topical treatment and the suspension of ibrutinib. Switching to second-generation Bruton tyrosine kinase inhibitors is proposed as a potential therapeutic alternative.

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 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.