Adverse event profiles of PCSK9 inhibitors alirocumab and evolocumab: Data mining of the FDA adverse event reporting system.

BACKGROUND: Proprotein convertase subtilisin/kexin type (PCSK9) inhibitor is a new drug class approved for treating dyslipidemias. Herein, we aimed to investigate the safety profiles of PCSK9 inhibitors (alirocumab and evolocumab) using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We included adverse event (AE) reports regarding alirocumab and evolocumab submitted to the FAERs between 2015Q3 to 2021Q1. Disproportionality analyses, including reporting odds ratio (ROR), were performed to detect risk signals from the FAERs data to identify potential drug-AE associations. A signal was considered when the lower limit of the 95% confidence interval of ROR exceeded 1 and ≥3 AEs were reported. The definition relied on system organ class and preferred terms established by the Medical Dictionary for Regulatory Activities. RESULTS: The FAERS database documented 31 475 reports regarding PCSK9 inhibitors (alirocumab and evolocumab) from July 1, 2015, to March 31, 2021. Although some differences were detected, alirocumab and evolocumab shared considerably similar safety profiles. The most significant RORs and most common reports were injection-site reactions (eg, injection-site pain, bruising, haemorrhage, erythema), muscle-related AEs (eg, myalgia, back pain, arthralgia, muscle spasms), influenza-like illness, pain and headache. CONCLUSION: Data mining of the FAERs is useful for examining PCSK9 inhibitor-induced AEs. Herein, our findings were largely consistent with clinical experience and could help clinicians improve the safety of PCSK9 inhibitors in clinical practice.

Ligustilide inhibits the proliferation of non-small cell lung cancer via glycolytic metabolism.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide. The abnormal activation of glycolytic metabolism and PTEN/AKT signaling in NSCLC cells are highly correlated with their proliferation abilities and viability. Ligustilide is one of the major bioactive components of multiple Chinese traditional medicine including Angelica sinensis and Ligusticum. Ligustilide exposure inhibits the proliferation and viability of multiple cancer cell lines in vitro. However, the impact of ligustilide to the progression of NSCLC and its detailed pharmacological mechanisms remain unclear. In this research, CCK-8 and colony formation assay were performed to demonstrate ligustilide treatment inhibited the viability and proliferation ability of NSCLC cells in vitro. Caspase-3/-7 activity assay and nucleosome ELISA assay were utilized to show ligustilide promoted the apoptosis of NSCLC cells. Metabolic analysis and qRT-PCR assay were used to demonstrated that ligustilide dampened aerobic glycolysis of NSCLC cells. Nude mice were exposed to 5 mg/kg ligustilide and ligustilide inhibited orthotopic NSCLC growth in vivo. qRT-PCR and Western blot analysis were performed to substantiate the regulatory function of ligustilide to PTEN/AKT signaling in NSCLC cells. Overall, this study revealed that ligustilide regulated the proliferation, apoptosis and aerobic glycolysis of NSCLC cells through PTEN/AKT signaling pathway.

Integrated bioinformatics analysis reveals the bidirectional effects of TSPAN6 for cisplatin resistance in lung cancer.

Cisplatin-based chemotherapy is frequently employed as the primary therapeutic approach for advanced lung cancer. Nevertheless, a significant proportion of patients may develop resistance to cisplatin, leading to diminished efficacy of chemotherapy. Through analysis of Gene Expression Omnibus databases, TSPAN6 has been identified as a key factor in conferring resistance to cisplatin, attributed to its activation of the NF-κB signaling pathway. Knockdown of TSPAN6 using siRNA resulted in decreased expression levels of NF-κB in A549 cells. This indicates that TSPAN6 may have dual effects on lung cancer cisplatin resistance and could serve as a promising therapeutic target for individuals with cisplatin resistance.

An Innovative High-Strength Double-Network Hydrogel for Use as a Drilling Fluid Plugging Agent.

The problem of wellbore leakage is a key challenge in the petroleum industry, limiting drilling progress and increasing drilling costs. Plugging agents play a role in repairing leaks and fractures; however, traditional plugging materials generally have low mechanical strength, poor adaptability to permeable strata, limited water absorption and expansion capabilities, and poor temperature and salt resistance. To address these limitations, a pioneering polyacrylic acid-polyacrylamide (PAA/PAM) double-network hydrogel was synthesized through aqueous solution polymerization in this study. Its strength, water absorption, expansion, temperature resistance, salt resistance, and plugging effectiveness were comprehensively evaluated. The results demonstrate that good mechanical performance is exhibited by the synthesized hydrogel, capable of withstanding a maximum stress of approximately 3.5 MPa at a 90% strain. Excellent water absorption and expansion are observed in the synthesized double-network hydrogel, with a maximum expansion of 6 times within 30 min and 8 times after 2 h. Test results show that the hydrogel had good temperature resistance and salt resistance, maintaining a strength grade E within the experimental range. The simulated evaluation of the plugging experiment indicates that, under conditions of 130 °C and 6 MPa, the leakage rate of the drilling fluid is maintained below 5 mL/min when the double-network hydrogel is utilized. From the above experimental results, it can be illustrated that excellent mechanical properties, impressive water absorption, and expansion capabilities are exhibited by the synthesized double-network hydrogel. Furthermore, the high-temperature resistance and salt resistance of the double-network hydrogel were also demonstrated. Therefore, In comparison to traditional plugging materials, significant promise is held by this newly synthesized double-network hydrogel material as a plugging agent in drilling fluids.

Adsorption of Welan Gum on Montmorillonite and Its Influencing Factors.

Welan gum is one of the most promising polymers used in polymer flooding for enhancing oil recovery, due to its excellent temperature resistance and salt-tolerance performance. However, welan gum, as a polymer with higher molecular weight, can be adsorbed and detained in the pore throat of the reservoir, which is characterized by a smaller size. Montmorillonite, a kind of clay mineral with high content in reservoir rocks, has strong adsorption capacity. Therefore, the adsorption behavior of welan gum on montmorillonite, as well as its influencing factors, are studied in this paper. The results show that the adsorption capacity is 2.07 mg/g. The adsorption capacity decreased with the increase in temperature. Both acidic and alkaline conditions reduced the adsorption capacity. The existence of inorganic salt affected the adsorption capacity. In addition, the higher the cation value, the lower the adsorption capacity. The characterization tests showed that the adsorption of welan gum on montmorillonite was characterized by physical adsorption and surface adsorption, indicating that there were no changes in the internal structure of montmorillonite. This study provides feasible methods to reduce the amount of welan gum adsorbed on montmorillonite, which is of great significance for reducing the permeability damage caused by welan gum adsorption and promoting the application of welan gum in polymer flooding for enhancing oil recovery.

Study on the Relationship between the Relative Molecular Mass of a Polymer Clay Stabilizer and the Permeability of a Tight Reservoir.

Water-sensitivity damage is inevitable during hydraulic fracturing for tight reservoir stimulation. A polymer clay stabilizer is the most effective and commonly used agent for reducing this kind of permeability damage. However, due to the small pore throat radii of tight reservoirs, polymers may be captured and detained, resulting in secondary permeability damage caused by polymer plugging. Therefore, it is necessary to clarify the matching relationship between the relative molecular mass of the clay stabilizer and the permeability of tight cores, which has not been reported yet. In response to this problem, the residual resistance factor and the permeability damage rate of PDMDAAC (poly dimethyl diallyl ammonium chloride, a kind of commonly used polymer clay stabilizer) to tight cores from Xinjiang Oilfield were investigated in cores with permeabilities of 0.10 × 10-3 µm2 (0.08-0.17 × 10-3 µm2), 0.05 × 10-3 µm2 (0.035-0.065 × 10-3 µm2), and 0.01 × 10-3 µm2 (0.007-0.020 × 10-3 µm2) through flow experiments. It was found that the relative molecular masses of PDMDAAC, which did not cause obvious core permeability damage, should be less than 10 000, 5000, and 2000, respectively. In addition, the bridging flocculation principle between the hydrodynamics radius of the clay stabilizer and the radius of the tight core pore throat can be used to explain the matching relationship between the relative molecular mass of the polymer clay stabilizer and the permeability of the tight reservoir. This study points out the direction for the optimization of the polymer clay stabilizer used in tight reservoir hydraulic fracturing and provides some references for the construction of hydraulic fracturing fluid systems for the efficient development of unconventional oil and gas resources.

Short-range transport of contaminants released from e-waste recycling site in South China.

The transport behaviors of a suite of contaminants released from electronic waste (e-waste) recycling operations, including polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and heavy metals, were evaluated by analyzing the contaminant residues in surface soils sampled in the surrounding area of an e-waste recycling site in South China. Concentrations of PBDEs and PCBs in the soil samples ranged from 0.565 to 2908 ng g(-1) dw and from 0.267 to 1891 ng g(-1) dw, respectively, while soil residues were 0.082-2.56, 3.22-287, and 16.3-162 µg g(-1) dw for Cd, Cu, and Pb, respectively. Concentrations of PBDEs and PCBs in soil decreased with increasing distance from the source of pollution, indicating possible PBDE and PCB contamination in the surrounding areas due to the short-range transport of these compounds from the e-waste recycling site. Although no significant difference in the short-range transport potential among PBDE and PCB congeners was observed, reductions in concentrations of the highly-brominated-BDEs and highly-chlorinated-CBs were slightly quicker than those of their less-halogen-substituted counterparts. Conversely, heavy metals showed the lowest transport potential due to their low vapor pressure, and results showed metals would remain near the pollution source instead of diffusing into the surrounding areas. Finally, mass inventories in areas near the e-waste site were 0.920, 0.134, 0.860, 4.68, 757, and 673 tons for BDE209, PBDEs (excluding BDE209), PCBs, Cd, Cu, and Pb, respectively.

Study on a Nonionic Surfactant/Nanoparticle Composite Flooding System for Enhanced Oil Recovery.

The composite flooding system composed of a surfactant and nanoparticles has shown great application potential in enhancing oil recovery. However, at present, these research studies are mainly focused on anionic surfactants. Relatively speaking, alkanolamide (CDEA), a nonionic surfactant, has the characteristics of a small adsorption amount on the rock surface, no cloud point, good temperature resistance, and good salt resistance. However, to the best of our best knowledge, there is no research report on the composite flooding system composed of CDEA and nanoparticles. Therefore, the surfactant/nanoparticle (S/NP) flooding system based on CDEA and nano-SiO2 was studied in this paper. The S/NP flooding system (0.1% CDEA + 0.05% SiO2) was constructed based on the performance in reducing the oil-water interfacial tension (IFT) and the stability of the composite system. The IFT between the S/NP flooding system and the crude oil can reach ultra-low values (3 × 10-3 mN/m), and there is no obvious sedimentation within 72 h. The sandpack flood tests show that the oil recovery rate is increased by 16.8% compared with water flooding and finally reaches 58.2%. Based on micromodel flooding tests, the mechanisms of the S/NP flooding system are studied as follows: the synergistic effect of nanoparticles and surfactants can re-enforce its oil-water interface performance and improve the oil displacement efficiency and the Jamin effect of emulsified oil droplets, combined with the thickening property and retention plugging of nanoparticles, improves the sweep efficiency. As the surfactant and nanoparticle used in this study are commercially available industrial products, the research results have important guiding significance for promoting the industrial application of surfactant/nanoparticle composite flooding technology.

A retrospective analysis from a single center for 60 COVID-19 patients with asymptomatic, mild to moderate, and severe conditions in Wuxi, China.

ABSTRACT: The aim of this study was to retrospectively analyze the clinical data of COVID-19 patients with different severity during February 2020 in Wuxi, China.The present retrospective study included a total of 60 cases who were diagnosed as COVID-19 patients and hospitalized in the Wuxi Fifth People's Hospital during February 2020 to March 2020. Among all patients 14 cases were asymptomatic, 25 cases were with mild stage, 13 cases were with moderate stage, and 8 cases were with severe stage. Basic clinical data as well as clinical characteristics, including temperature, respiratory rate, heart rate, blood gas analysis data, whole blood test data, and the prognosis condition, were collected and analyzed. Statistical analysis was conducted in different severity stage patients.Among the patients, the median temperature gradually increased from the asymptomatic to the severe patients and the median age increased from the mild to the severe patients with statistical difference. The hospitalization duration was the highest in severe patients. Higher heart rate, as well as lower oxygen partial pressure and oxygenation index were observed in severe patients than the other groups. Besides, higher CRP and globulin levels after admission were found in severe patients, and were gradually increased from the asymptomatic patients to the severe patients. On the contrary, the lymphocyte ratio and count was significant lower in severe patients. We also observed higher D-Dimer levels in the severe patients and the difference was statistical. Among all patients, 2 cases (3.33%) died and other patients were all cured after treatment.Statistical difference was mainly found mainly in age, hospitalization duration, temperature, CRP levels, O2 partial pressure and oxygenation index, globulin, lymphocyte ratio, and D-Dimer in patients with different severity. The higher CRP levels, lower O2 partial pressure and oxygenation index, higher globulin, lower lymphocyte ratio, and higher D-Dimer might be associated with the patients' severity.

Lactobacillus rhamnosus GG strain mitigated the development of obstructive sleep apnea-induced hypertension in a high salt diet via regulating TMAO level and CD4+ T cell induced-type I inflammation.

Obstructive sleep apnea (OSA) and high salt content in modern diet has been particularly implicated in systemic hypertension, leading to increased morbidity and mortality. Gut dysbiosis, associated with increased risk of systemic immunological imbalance, plays a causal role in the development of cardiovascular diseases. Here, we investigated the effect of Lactobacillus rhamnosus GG strain (LGG) on the development of hypertension induced by OSA and high salt diet. In this study, hypertension was modeled in rats by feeding a high salt diet (HSD) for 6 wk and exposuring to chronic intermittent hypoxia (CIH) during the sleep cycle. We found that OSA combined with HSD increased the severity of hypertension through increasing level of blood Trimethylamine-Oxide (TMAO), release of Th1-related cytokine (IFN-γ) and inhibition of anti-inflammatory cytokine (TGF-ß1), and affected the gut microbiome in rats, particularly by depleting Lactobacillus. In addition, expression of PERK1/2, PAkt and PmTOR increased in the aorta from rats with a CIH exposure and HSD. Consequently, treatment of model rats with LGG prevented aggravation of hypertension by reducing blood TMAO levels, modulating Th1/Th2 cytokine imbalance and suppressing phosphorylation levels of ERK1/2, Akt and mTOR. In line with these findings, our results connect high salt diet to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract the development of OSA-induced hypertension basing on a high salt diet.

Amphiphilic diblock copolymer of hydrophilic-functionalized lactone and lactide via switchable organocatalytic polymerization.

Main-chain degradable amphiphilic diblock copolymers composed of a hydrophilic-functionalized polyester and PLA were facilely prepared by one-pot ring-opening polymerization (ROP) via actively manipulating the catalytic states of an acid-base catalytic system. The resultant block copolymers showed low critical micelle concentration (CMC) in water and were capable of forming stable micelles with optimal hydrodynamic particle size (average diameter 83 nm) and narrow particle distribution.

[A case of huge malignant maxillofacial tumor].

Patients found two years left of the new biology, surface erosion,exudates long. Postoperative pathology examination: inflammatory fibrous background visible uniform small cells arranged in cords, pseudorosette formation region is considered not except basal cell carcinoma , neuroendodrne carcinoma. Diagnosis of immunohistochemical support of basal cell carcinonma.

Assessing heavy metal pollution in the surface soils of a region that had undergone three decades of intense industrialization and urbanization.

Heavy metals in the surface soils from lands of six different use types in one of the world's most densely populated regions, which is also a major global manufacturing base, were analyzed to assess the impact of urbanization and industrialization on soil pollution. A total of 227 surface soil samples were collected and analyzed for major heavy metals (As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, and Zn) by using microwave-assisted acid digestion and inductively coupled plasma-mass spectrometry (ICP-MS). Multivariate analysis combined with enrichment factors showed that surface soils from the region (>7.2 × 10(4) km(2)) had mean Cd, Cu, Zn, and As concentrations that were over two times higher than the background values, with Cd, Cu, and Zn clearly contributed by anthropogenic sources. Soil pollution by Pb was more widespread than the other heavy metals, which was contributed mostly by anthropogenic sources. The results also indicate that Mn, Co, Fe, Cr, and Ni in the surface soils were primarily derived from lithogenic sources, while Hg and As contents in the surface soils were controlled by both natural and anthropogenic sources. The pollution level and potential ecological risk of the surface soils both decreased in the order of: urban areas > waste disposal/treatment sites ∼ industrial areas > agricultural lands ∼ forest lands > water source protection areas. These results indicate the significant need for the development of pollution prevention and reduction strategies to reduce heavy metal pollution for regions undergoing fast industrialization and urbanization.