Performance,Reaction Pathway and Kinetics of the Enhanced Dechlorination Degradation of 2,4-Dichlorophenol by Fe/Ni Nanoparticles Supported on Attapulgite Disaggregated by a Ball Milling–Freezing Process

Attapulgite (ATP) disaggregated by a ball milling–freezing process was used to support Fe/Ni bimetallic nanoparticles (nFe/Ni) to obtain a composite material of D-ATP-nFe/Ni for the dechlorination degradation of 2,4-dichlorophenol (2,4-DCP), thus improving the problem of agglomeration and oxidation passivation of nanoscale zero-valent iron (nFe) in the dechlorination degradation of chlorinated organic compounds. The results show that Fe/Ni nanoparticle clusters were dispersed into single spherical particles by the ball milling–freezing-disaggregated attapulgite, in which the average particle size decreased from 423.94 nm to 54.51 nm, and the specific surface area of D-ATP-nFe /Ni (97.10 m²/g) was 6.9 times greater than that of nFe/Ni (14.15 m²/g). Therefore, the degradation rate of 2,4-DCP increased from 81.9% during ATP-nFe/Ni application to 96.8% during D-ATP-nFe/Ni application within 120 min, and the yield of phenol increased from 57.2% to 86.1%. Meanwhile, the reaction rate K_obs of the degradation of 2,4-DCP by D-ATP-nFe/Ni was 0.0277 min⁻¹, which was higher than that of ATP-nFe/Ni (0.0135 min⁻¹). In the dechlorination process of 2,4-DCP by D-ATP-nFe/Ni, the reaction rate for the direct dechlorination of 2,4-DCP of phenol (k₅ = 0.0156 min⁻¹) was much higher than that of 4-chlorophenol (4-CP, k₂ = 0.0052 min⁻¹) and 2-chlorophenol (2-CP, k₁ = 0.0070 min⁻¹), which suggests that the main dechlorination degradation pathway for the removal of 2,4-DCP by D-ATP-nFe/Ni was directly reduced to phenol by the removal of two chlorine atoms. In the secondary pathway, the removal of one chlorine atom from 2,4-DCP to generate 2-CP or 4-CP as intermediate was the rate controlling step. The final dechlorination product (phenol) was obtained when the dechlorination rate accelerated with the progress of the reaction. This study contributes to the broad topic of organic pollutant treatment by the application of clay minerals.     

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update

BackgroundA previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments.MethodsThe guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided.ResultsWe found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts’ opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives.ConclusionMonoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01431-x.     

利拉鲁肽对糖尿病心肌病大鼠心功能及心肌代谢异常的改善作用

目的]研究利拉鲁肽对糖尿病心肌病(DCM)大鼠心肌代谢物及相关代谢通路的影响。 [方法]3周龄SPF级雄性SD大鼠60只,随机抽取10只作为正常对照组,其余均采用腹腔注射链脲佐菌素联合高糖高脂饮食法建立DCM大鼠模型。DCM造模成功大鼠36只,随机分为DCM模型组(DCM组)、低剂量利拉鲁肽治疗组(LL组)、高剂量利拉鲁肽治疗组(HL组),每组各12只。LL组(100 μg/kg)和HL组(200 μg/kg)分别给予利拉鲁肽腹腔注射,每日一次,干预12周后,经超声心动图检测心功能后麻醉处死大鼠,并取心脏组织进行代谢组学检测,筛选并富集与利拉鲁肽改善DCM大鼠心肌代谢可能有关的差异代谢物及相关通路。 [结果]超声结果显示,与正常对照组相比,DCM组左心室射血分数(LVEF)、左心室短轴缩短率(LVFS)显著降低,左心室舒张早期最大血流/二尖瓣心房收缩期最大血流比值(E/A)明显升高(P＜0.05)。与DCM组相比,LL组和HL组大鼠LVEF、LVFS明显升高,E/A比值显著降低(P＜0.05),提示LL组和HL组左心室收缩和舒张功能受损明显减轻。代谢组学检测共发现395种代谢物,其中DCM组与正常对照组、LL组与DCM组、HL组与DCM组各自富集出组间差异代谢物分别为239种、116种、187种,代谢通路分别为13条、6条、20条。以上三组共交集出关键差异代谢物29种,主要涉及3条代谢通路(P＜0.05),包括胆碱代谢通路、咖啡因代谢通路以及缬氨酸、亮氨酸和异亮氨酸生物合成通路,其中胆碱代谢通路差异最为显著。 [结论]利拉鲁肽可明显改善DCM大鼠心功能及心肌代谢异常,其中胆碱代谢通路可能在利拉鲁肽改善心肌代谢保护心脏功能过程中起到关键作用。     

电喷雾离子阱质谱检测亮菌甲素琥珀酸单酯的负离子裂解途径

目的采用电喷雾离子阱（ESI-MS）质谱技术研究亮菌甲素琥珀酸单酯（ArAAE）的结构和裂解途径。方法采用蠕动注射泵直接进样,ESI-MS负离子模式检查,流速为0.3 mL/h,毛细管电压为4 500 V,雾化器压力、干燥器流速和干燥器温度分别为10 psi、5 L/min和350℃,质量扫描范围m/z 100～500。结果采用ESI-MS获得了m/z 333[M-H]-,采用ESI-MS2获得了m/z 233碎片离子,而采用ESI-MS3主要获得了m/z 215,203,189,177,171,163,147和135等碎片离子。ESI-MS和ESI-MS2主要有一种裂解途径,而ESI-MS3主要有3种裂解途径,主要是酯键的裂解,并对m/z 203,189和163特征碎片离子进行ESI-MS4质谱研究,归属了其主要特征碎片离子,分析和讨论了该化合物的结构和质谱特征。结论ESI-MS负离子模式下适用于检测亮菌甲素琥珀酸单酯各级碎片裂解,归属了主要的碎片裂解途径,其方法快速、简便,为进一步研究ArAAE的体内代谢过程与结构修饰提供试验依据。     

Osimertinib successfully combats EGFR-negative glioblastoma cells by inhibiting the MAPK pathway

Glioblastoma(GBM)patients have extremely poor prognoses,and currently no effective treatment available including surgery,radiation,and chemotherapy.MAPK-interacting kinases(MNK1/2)as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells.Research has shown that targeting MNKs may be an effective strategy to treat GBM.In this study we investigated the antitumor activity of osimertinib,an FDA-approved epidermal growth factor receptor(EGFR)inhibitor,against patient-derived primary GBM cells.Using high-throughput screening approach,we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients,found that osimertinib(3μM)suppressed the proliferation of a subset(10/22)of EGFR-negative GBM cells(>50%growth inhibition).We detected the gene expression difference between osimertinib-sensitive and-resistant cells,found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway.We further showed that osimertinib potently inhibited the MNK kinase activities with IC50 values of 324 nM and 48.6 nM,respectively,against MNK1 and MNK2 kinases;osimertinib(0.3–3μM)dose-dependently suppressed the phosphorylation of eukaryotic translation initiation factor 4E(eIF4E).In GBM patient-derived xenografts mice,oral administration of osimertinib(40 mg·kg^?1·d^?1,for 18 days)significantly suppressed the tumor growth(TGI=74.5%)and inhibited eIF4E phosphorylation in tumor cells.Given the fact that osimertinib could cross the blood–brain barrier and its toxicity was well tolerated in patients,our results suggest that osimertinib could be a new and effective drug candidate for the EGFR-negative GBM patients.     

Diagnosing pancreatic cancer in general practice: a cross-sectional study on associations between suspicion of cancer,urgent referral and time to diagnosis

ObjectiveThis study aimed to investigate the first point of contact in patients diagnosed with pancreatic cancer, and to study factors associated with the GP’s suspicion of cancer, Cancer Patient Pathway (CPP) referral and long diagnostic interval.DesignCross-sectional study combining register and survey data.PatientsPatients with incident pancreatic cancer recorded in the Danish National Patient Register (n = 303).Main outcome measuresThe patient’s first point of symptoms presentation, GP’s cancer suspicion, CPP referral and diagnostic interval.ResultsGeneral practice was the first point of contact for 85.5% of the population. At the first consultation, cancer was suspected in 32.7% and 22.9% were referred to a CPP. The GPs were more likely to suspect cancer or serious illness in patients aged >70 years (prevalence rate ratio (PRR) 1.34, 95% CI 1.09–1.66) and among patients with high comorbidity (PRR 1.23, 95% CI 1.04–1.47). A CPP referral was less likely among patients with low education. The median diagnostic interval was 39 days (interquartile range: 15–72). When the GP initially did not suspect cancer, the likelihood of longer diagnostic interval increased.ConclusionThe majority of patients with pancreatic cancer began their diagnostic route in general practice. Diagnosing pancreatic cancer swiftly in general practice was challenging; the GP did often not initially suspect cancer or refer to a CPP and several of the patient characteristics were associated with the GPs initial suspicion of cancer or CPP referral. Thus, there may be room for improvements in the diagnostics of pancreatic cancer in general practice.

Key points

• Patients with pancreatic cancer have a poor prognosis, as pancreatic cancer is often diagnosed in late stage.
• The majority of patients with pancreatic cancer began their diagnostic process in general practice.
• General practitioners (GPs) suspected cancer at the first consultation in one out of three patients with pancreatic cancer; more often in older and comorbid patients.
• The GPs suspicion of cancer was associated with urgent referral and shorter time to diagnosis.

     

噻唑烷二酮类药物对糖尿病肾病的直接作用及其机制

近年的研究显示 ,噻唑烷二酮类药物 (TZD)具有不依赖于胰岛素增敏作用的肾直接保护作用 ,在未降低糖尿病大鼠高血糖水平的情况下 ,TZD可减少清蛋白尿 ,抑制肾小球系膜肥大及细胞外基质 (ECM)增生。其可能的作用机制是 :在高血糖状态下 ,TZD通过激活肾小球中二酰基甘油激酶 (DGK) ,抑制二酰基甘油 (DAG) 蛋白激酶C(PKC) 细胞信号调节激酶 (ERK)通路活性而改善肾小球高滤过状态、抑制ECM蛋白的过度产生。也有研究认为 ,TZD与改善硫酸乙酰肝素原多糖 (HSPG)合成及硫酸化、从而抑制肾小球基膜 (GBM)外疏松层的阴离子位点有关。此外 ,TZD可能通过调节肾小球系膜细胞的表型转化达到肾保护作用。     

Serrated polyps: new classifications highlight clinical importance

Aim Many lesions previously classified as hyperplastic polyps and therefore thought to be innocuous have been reclassified as sessile serrated adenomas/polyps (SSA/Ps), establishing their place in the serrated pathway and underscoring their malignant potential. The clinical relevance of this new nomenclature is incompletely defined. This study examines the incidence and characteristics of colorectal SSA/Ps and describes other associated colorectal neoplasia. Method A single institution pathology database was searched for the diagnosis of SSA/Ps between January 2004 and October 2007. SSA/Ps found by colonoscopy were included. Patient demographics, SSA/P characteristics and associated colonoscopic findings were retrospectively recorded. Results A total of 585 SSA/Ps were removed during 519 colonoscopies in 483 patients performed by 64 different endoscopists. This represented an overall incidence of SSA/Ps per colonoscopy of 2.1% in the 28 054 colonoscopies performed during the study period. The median SSA/P size was 0.8 cm (range 0.2–4.5) and 188 (69%) were ≥ 1.0 cm. Of the 585 SSA/Ps, 366 (63%) were right‐sided, 129 (22%) were in the left colon and 90 (15%) were in the rectum. Also, 439 synchronous polyps of other histology (mainly adenomas and hyperplastic polyps) were found during the same 519 colonoscopies. Conclusion SSA/Ps are rare lesions found during colonoscopy that may coexist with small hyperplastic polyps. Because SSA/Ps are part of the serrated oncogenic pathway, all, even those appearing to be hyperplastic, should be removed or biopsied for diagnosis. Careful review of historical lesions with application of new definitions may redefine risk for malignancy.     

The Administration of Panax Ginseng Berry Extract Attenuates High-Fat-Diet-Induced Sarcopenic Obesity in C57BL/6 Mice

Sarcopenia and obesity are serious health problems that are highly related to several metabolic diseases. Sarcopenic obesity, a combined state of sarcopenia and obesity, results in higher risks of metabolic diseases and even mortality than sarcopenia or obesity alone. Therefore, the development of therapeutic agents for sarcopenic obesity is crucial. C57BL/6 mice were fed with a high-fat diet (HFD) for 9 weeks. Then, mice were administered with Panax ginseng berry extract (GBE) for an additional 4 weeks, with continuous HFD intake. GBE significantly decreased the food efficiency ratio, serum lipid and insulin levels, adipose tissue weights, and adipocyte size. It significantly increased the grip strength, muscle masses, and myofiber cross-sectional area. It deactivated the protein kinase C (PKC) theta and zeta, resulting in activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, which is known to regulate muscle synthesis and degradation. Furthermore, it inhibited the production of inflammatory cytokines in the muscle tissue. GBE attenuated both obesity and sarcopenia. Thus, GBE is a potential agent to prevent or treat sarcopenic obesity.