Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02029443","term_id":"NCT02029443"}}NCT02029443, {"type":"clinical-trial","attrs":{"text":"NCT02475681","term_id":"NCT02475681"}}NCT02475681, {"type":"clinical-trial","attrs":{"text":"NCT02970318","term_id":"NCT02970318"}}NCT02970318 and {"type":"clinical-trial","attrs":{"text":"NCT02337829","term_id":"NCT02337829"}}NCT02337829). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with high-risk CLL (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02477696","term_id":"NCT02477696"}}NCT02477696) prospectively assess differences in CV toxicity between the two agents.     

The attenuation effect of potassium 2‐(1‐hydroxypentyl)‐benzoate in a mouse model of diabetes‐associated cognitive decline: The protein expression in the brain

Aims dl‐PHPB (potassium 2‐(1‐hydroxypentyl)‐benzoate) has been shown to have neuroprotective effects against acute cerebral ischemia, vascular dementia, and Alzheimer''s disease. The aim of this study was to investigate the effects of dl‐PHPB on memory deficits and preliminarily explore the underlying molecular mechanism.MethodsBlood glucose and behavioral performance were evaluated in the KK‐A^y diabetic mouse model before and after dl‐PHPB administration. Two‐dimensional difference gel electrophoresis (2D‐DIGE)‐based proteomics was used to identify differentially expressed proteins in brain tissue. Western blotting was used to study the molecular mechanism of the related signaling pathways.ResultsThree‐month‐old KK‐A^y mice were given 150 mg/kg dl‐PHPB by oral gavage for 2 months, which produced no effect on the level of serum glucose. In the Morris water maze test, KK‐A^y mice treated with dl‐PHPB showed significant improvements in spatial learning and memory deficits compared with vehicle‐treated KK‐A^y mice. Additionally, we performed 2D‐DIGE to compare brain proteomes of 5‐month KK‐A^y mice treated with and without dl‐PHPB. We found 14 altered proteins in the cortex and 11 in the hippocampus; two of the 25 altered proteins and another four proteins that were identified in a previous study on KK‐A^y mice were then validated by western blot to further confirm whether dl‐PHPB can reverse the expression levels of these proteins. The phosphoinositide 3‐kinase/protein kinase B/glycogen synthase kinase‐3β (PI3K/Akt/GSK‐3β) signaling pathway was also changed in KK‐A^y mice and dl‐PHPB treatment could reverse it.ConclusionsThese results indicate that dl‐PHPB may play a potential role in diabetes‐associated cognitive impairment through PI3K/Akt/GSK‐3β signaling pathway and the differentially expressed proteins may become putative therapeutic targets.     

食管癌淋巴管的形态学观察

目的:观察食管癌淋巴管的形态分布规律、超微结构特征,为探讨食管癌淋巴转移机理提供形态学依据.方法:采用半薄切片光镜观察、超薄切片电镜观察人食管癌组织中央区、周边区和正常区内淋巴管的形态学变化.结果:食管癌中央区未见淋巴管,周边区淋巴管数量较正常区明显增多,管腔扩大;毛细淋巴管管壁破坏,细胞器发生明显改变.正常区毛细淋巴管的形态和超微结构未见明显改变.结论:毛细淋巴管壁的破坏和内皮细胞的开放连接可能是食管癌淋巴道转移的主要途径.     

Human Milk Metabolomics Are Related to Maternal Adiposity,Infant Growth Rate and Allergies: The Chinese Human Milk Project

The metabolomic profiles of Chinese human milk have been poorly documented. The objective of the study was to explore associations between human milk metabotypes, maternal adiposity, infant growth patterns, and risk of allergies. Two hundred mother–infant dyads from seven cities were randomly selected from the Chinese Human Milk Project (CHMP). Untargeted human milk metabolomic profiles were determined using HPLC-MS/MS. Two human milk metabotypes were identified using principal component analysis. Principal component (PC) 1 was characterized by high linoleic acid metabolites with low purine nucleosides and metabolites of glutamate and glutathione metabolism. PC 2 was characterized by high glycerophospholipids and sphingomyelins content. Higher PC1 scores were associated with slower infant growth rate and higher ambient temperature (p < 0.05). Higher PC 2 scores were related to higher maternal BMI and increased risk of infant allergies (p < 0.05). Future work is needed to understand the biologic mechanisms of these human milk metabotypes.     

Development and Characterizations of Pullulan and Maltodextrin-Based Oral Fast-Dissolving Films Employing a Box–Behnken Experimental Design

Migraine is a neurological disorder characterized by severe headaches, visual aversions, auditory, and olfactory disorders, accompanied by nausea and vomiting. Zolmitriptan (ZMT^®) is a potent 5HT1B/1D serotonin receptor agonist frequently used for the treatment of migraine. It has erratic absorption from the gastrointestinal tract (GIT), but its oral bioavailability is low (40–45%) due to the hepatic metabolism. This makes it an ideal candidate for oral fast dissolving formulations. Hence, the current study was undertaken to design and develop oral fast-dissolving films (OFDFs) containing ZMT for migraine treatment. The OFDFs were formulated by the solvent casting method (SCM) using Pullulan (PU) and maltodextrin (MDX) as film-forming agents and propylene glycol (PG) as a plasticizer. The strategy was designed using Box–Behnken experimental design considering the proportion of PU:MDX and percentage of PG as independent variables. The effectiveness of the OFDF’s was measured based on the following responses: drug release at five min, disintegration time (D-time), and tensile strength (TS). The influence of formulation factors, including percent elongation (%E), thickness, water content, moisture absorption, and folding endurance on ZMT-OFDFs, were also studied. The results showed a successful fabrication of stable ZMT-OFDFs, with surface uniformity and amorphous shape of ZMT in fabricated films. The optimized formulation showed a remarkable rapid dissolution, over 90% within the first 5 min, a fast D-time of 18 s, and excellent mechanical characteristics. Improved maximum plasma concentration (C max) and area under the curve (AUC 0–t) in animals (rats) treated with ZMT-OFDFs compared to those treated with an intra-gastric (i-g) suspension of ZMT were also observed. Copolymer OFDFs with ZMT is an exciting proposition with great potential for the treatment of migraine headache. This study offers a promising strategy for developing ZMT-OFDFs using SCM. ZMT-OFDFs showed remarkable rapid dissolution and fast D-time, which might endeavor ZMT-OFDFs as an auspicious alternative approach to improve patient compliance and shorten the onset time of ZMT in migraine treatment.     

Advances in Bovine Coronavirus Epidemiology

Bovine coronavirus (BCoV) is a causative agent of enteric and respiratory disease in cattle. BCoV has also been reported to cause a variety of animal diseases and is closely related to human coronaviruses, which has attracted extensive attention from both cattle farmers and researchers. However, there are few comprehensive epidemiological reviews, and key information regarding the effect of S-gene differences on tissue tendency and potential cross-species transmission remain unclear. In this review, we summarize BCoV epidemiology, including the transmission, infection-associated factors, co-infection, pathogenicity, genetic evolution, and potential cross-species transmission. Furthermore, the potential two-receptor binding motif system for BCoV entry and the association between BCoV and SARS-CoV-2 are also discussed in this review. Our aim is to provide valuable information for the prevention and treatment of BCoV infection throughout the world.     

Vitamin D Status Presents Different Relationships with Severity in Metabolic-Associated Fatty Liver Disease Patients with or without Hepatitis B Infection

Whether the associations between serum vitamin D (VitD) and metabolic-associated fatty liver disease (MAFLD) vary with chronic hepatitis B (CHB) infection has not been well established. This study aims to investigate the relationships between serum VitD and metabolism, liver fat content (LFC) and fibrosis among MAFLD patients with and without CHB. Consecutive subjects (healthy controls: 360, CHB: 684, MAFLD: 521, CHB with MAFLD: 206) were prospectively enrolled between January 2015 and December 2021. Anthropometric, laboratory, imaging, and histological evaluations were conducted, with LFC measured via magnetic resonance imaging-based proton density fat fraction (MRI-PDFF). Serum VitD levels were lower in MAFLD patients than in healthy controls and patients with CHB alone or overlapping with MAFLD (24.4 ± 8.1 vs. 29.0 ± 9.5 vs. 27.4 ± 9.6 vs. 26.8 ± 8.4 ng/mL respectively; p < 0.001 in one-way ANOVA test). After adjusting for confounding factors, including season, hypersensitive C-reactive protein, insulin resistance, liver stiffness measurements, sun exposure, exercise and dietary intake, multivariate linear regression analysis revealed that VitD remained significantly negatively correlated with LFC in MAFLD patients (β = −0.38, p < 0.001), but not in CHB with MAFLD patients. Moreover, quantile regression models also demonstrated that lower VitD tertiles were inversely associated with the risk of insulin resistance and moderate–severe steatosis in the MAFLD group (p for trend <0.05) but not in the MAFLD with CHB group. VitD deficiency was associated with the severity of metabolic abnormalities and steatosis independent of lifestyle factors in MAFLD-alone subjects but not in MAFLD with CHB subjects.     

Simulations and Experiments on the Micro-Milling Process of a Thin-Walled Structure of Al6061-T6

Aluminum alloy (Al6061-T6) is an alloy with strong corrosion resistance, excellent disassembly, and moderate strength, which is widely used in the fields of construction, automobile, shipping, and aerospace manufacturing. Researching on the influence of machining precision and surface quality on the micro-milling process of thin-walled structures of Al6061 is highly significant. Combined with the two simulations (DEFORM-3D simulation and interactive finite element numerical simulation (FEM)) and milling experimental verification, the deformations, errors, and surface quality of milling thin-walled Al6061 were analyzed. The simulations and experimental results show that the deformation of milling a micro thin-walled structure was caused by the vertical stiffness of the thin-walled structure and the cutting force. Surface micromorphology further characterized and showed a poorer quality area, top burr, and concave defects, which directly affect machining quality. It is necessary to improve the surface quality, reduce the surface defects, and increase the stiffness at the top of thin-walled structures in future work.