Evaluation of Liver and Renal Toxicity in Peptide Receptor Radionuclide Therapy for Somatostatin Receptor Expressing Tumors: A 2-Year Follow-Up

BackgroundPeptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin receptor (SSR) analogs is now an established systemic treatment for neuroendocrine tumors (NET). However, more short- and long-term data about renal and hepatotoxicity is needed. Here we present our experience in this clinical scenario.MethodsEighty-six patients with progressive SSR-expressing malignancies underwent PRRT with Lu-177 Dotatate and were followed up for up to 2 years. Laboratory tests were done 1 week before each cycle and every 2 months at follow-up. Hepatic and renal toxicity was determined based on NCI CTCAE V5.0.Results55/86 (64%) patients completed all 4 cycles of PRRT; 18/86 (20.9%) are currently being treated; 13/86 (15.1%) had to discontinue PRRT: 4/13 (31%) due to hematologic toxicity, 9/13 (69%) due to non-PRRT-related comorbidities. Out of the patients who finished treatment, only transient grade 2 toxicities were observed during PRRT: hypoalbuminemia in 5.5% (3/55), and renal toxicity (serum creatinine and estimated glomerular filtration rate) in 1.8% (1/55). No grade 3 or 4 liver and renal toxicity occurred. Patients presenting with impaired liver or renal function prior to PRRT, either improved or had stable findings. No deterioration was observed.ConclusionPeptide receptor radionuclide therapy does not have a negative impact on liver and renal function, even in patients with pre-existing impaired parameters. No grade 3 or 4 hepatic or renal toxicity was identified. Only transient grade 2 hypoalbuminemia in 5.5% and nephrotoxicity in 1.8% of patients were seen during PRRT.     

尿白蛋白排泄率与糖尿病中医症状关系的临床研究

目的:研究尿白蛋白排泄率与糖尿病患者中医症状的关系,为中医糖尿病的诊断治疗提供一种可量化的方法。方法:测取入选患者的尿白蛋白排泄率和中医证候得分并进行统计分析。结果:糖尿病中医症状表现越严重,尿白蛋白排泄率越高。结论:尿白蛋白排泄率与糖尿病中医证候之间存在固有的联系,可以为中医糖尿病的诊断治疗提供一种可量化的方法,传统的中医证候的科学性可以被现代医学证实。     

兔骨髓诱导的内皮细胞和纤维蛋白凝胶体外共培养

目的将兔骨髓诱导的内皮细胞接种于纤维蛋白凝胶内并观察其生长增值情况。方法梯度离心分离兔骨髓单个核细胞（MNCs）,直接向内皮细胞诱导培养,传代培养至第2代细胞,倒置显微镜观察细胞形态及生长特点,免疫组化鉴定;以10^5密度接种于纤维蛋白凝胶中培养并定期观察细胞生长情况,单纯细胞及胶原内的细胞分别用MTT法检测其生长并绘制生长曲线,胶原切片并作苏木精．伊红染色观察细胞在胶原内的生长。结果诱导的内皮细胞为铺路石样。呈单层生长,第2代细胞CD31、八因子相关抗原免疫组化均为阳性,摄取低密度脂蛋白和结合凝集素实验均阳性;细胞在纤维蛋白凝胶内成立体生长,细胞在纤维蛋白凝胶内3d后成梭形铺开,6d后自发形成管腔样结构;细胞在纤维蛋白凝胶内生长曲线成“s”形。结论骨髓诱导的内皮细胞在纤维蛋白凝胶内生长增值良好,纤维蛋白凝胶可以作为接种骨髓诱导的内皮细胞的基质材料。     

Dromedary camel nanobodies broadly neutralize SARS-CoV-2 variants

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is a trimer of S1/S2 heterodimers with three receptor-binding domains (RBDs) at the S1 subunit for human angiotensin-converting enzyme 2 (hACE2). Due to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. To isolate high-affinity nanobodies, large libraries with great diversity are highly desirable. Dromedary camels (Camelus dromedarius) are natural reservoirs of coronaviruses like Middle East respiratory syndrome CoV (MERS-CoV) that are transmitted to humans. Here, we built large dromedary camel V_HH phage libraries to isolate nanobodies that broadly neutralize SARS-CoV-2 variants. We isolated two V_HH nanobodies, NCI-CoV-7A3 (7A3) and NCI-CoV-8A2 (8A2), which have a high affinity for the RBD via targeting nonoverlapping epitopes and show broad neutralization activity against SARS-CoV-2 and its emerging variants of concern. Cryoelectron microscopy (cryo-EM) complex structures revealed that 8A2 binds the RBD in its up mode with a long CDR3 loop directly involved in the ACE2 binding residues and that 7A3 targets a deeply buried region that uniquely extends from the S1 subunit to the apex of the S2 subunit regardless of the conformational state of the RBD. At a dose of ≥5 mg/kg, 7A3 efficiently protected transgenic mice expressing hACE2 from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting its therapeutic use against COVID-19 variants. The dromedary camel V_HH phage libraries could be helpful as a unique platform ready for quickly isolating potent nanobodies against future emerging viruses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of COVID-19 (1, 2) that enters human cells by binding its envelope anchored type I fusion protein (spike) to angiotensin-converting enzyme 2 (ACE2) (3, 4). The SARS-CoV-2 spike is a trimer of S1/S2 heterodimers with three ACE2 receptor-binding domains (RBDs) attached to the distal end of the spike via a hinge region that allows conformational flexibility (4). In the all-down conformation, the RBDs are packed with their long axes contained in a plane perpendicular to the axis of symmetry of the trimer. Transition to the roughly perpendicular up conformation exposes the receptor-binding motif (RBM), located at the distal end of the RBD, which is sterically occluded in the down state. Numerous neutralizing antibodies targeting the spike, particularly its RBD, have been developed to treat COVID-19 using common strategies such as single B cell cloning, animal immunization, and phage display (5–9). Most vaccines, including those that are messenger RNA based, are designed to induce immunity against the spike or RBD (10–12). However, emerging SARS-CoV-2 variants such as D614G, B.1.1.7 (Alpha, United Kingdom), B.1.351 (Beta, South Africa), and P.1 (Gamma, Brazil) have exhibited increased resistance to neutralization by monoclonal antibodies or postvaccination sera elicited by the COVID-19 vaccines (13, 14). Monoclonal antibodies with Emergency Use Authorization for COVID-19 treatment partially (Casirivimab) or completely (Bamlanivimab) failed to inhibit the B.1.351 and P.1 variants. Similarly, these variants were less effectively inhibited by convalescent plasma and sera from individuals vaccinated with a COVID-19 vaccine (BNT162b2) (13). The B.1.617.2 (Delta, India) variant became the prevailing strain in many countries (15). Highly effective and broadly neutralizing antibody therapy is urgently demanded for COVID-19 patients.Due to their small size and unique conformations, camelid V_HH single-domain antibodies (also known as nanobodies) can recognize protein cavities that are not accessible to conventional antibodies (16). To isolate high-affinity nanobodies without a need for further affinity maturation, it is highly desirable to construct large nanobody libraries with great diversity. Dromedary camels have been found as potential natural reservoirs of Middle East respiratory syndrome CoV (MERS-CoV) (17). We speculated that dromedary camels would be an ideal source of neutralizing nanobodies against coronaviruses. In the present study, we built large camel V_HH single-domain antibody phage libraries with a diversity of over 10¹¹ from six dromedary camels (Camelus dromedarius), three males and three females, with ages ranging from 3 mo to 20 y. We used both the SARS-CoV-2 RBD and the stabilized spike ectodomain trimer protein as baits to conduct phage panning for nanobody screening. Among all the binders, we found NCI-CoV-7A3 (7A3), NCI-CoV-1B5 (1B5), NCI-CoV-8A2 (8A2), and NCI-CoV-2F7 (2F7) to be potent ACE2 blockers. In addition, these dromedary camel nanobodies displayed potent neutralization activity against the B.1.351 and B.1.1.7 variants and the original strain (Wuhan-Hu-1). The cryoelectron microscopy (cryo-EM) structure of the spike trimer protein complex with these V_HH nanobodies revealed two distinct nonoverlapping epitopes for neutralizing SARS-CoV-2. In particular, 7A3 recognizes a unique and deeply buried region that extends to the apex of the S2 subunit of the spike. Combined treatment with 7A3 and 8A2 shows more potent protection against various variants in culture and mice infected with the B.1.351 variant. Interestingly, 7A3 alone retains its neutralization activity against the lethal challenge of the B.1.617.2 variant in mice.     

Acoustic Metamaterials for Low-Frequency Noise Reduction Based on Parallel Connection of Multiple Spiral Chambers

Acoustic metamaterials based on Helmholtz resonance have perfect sound absorption characteristics with the subwavelength size, but the absorption bandwidth is narrow, which limits the practical applications for noise control with broadband. On the basis of the Fabry–Perot resonance principle, a novel sound absorber of the acoustic metamaterial by parallel connection of the multiple spiral chambers (abbreviated as MSC-AM) is proposed and investigated in this research. Through the theoretical modeling, finite element simulation, sample preparation and experimental validation, the effectiveness and practicability of the MSC-AM are verified. Actual sound absorption coefficients of the MSC-AM in the frequency range of 360–680 Hz (with the bandwidth Δf₁ = 320 Hz) are larger than 0.8, which exhibit the extraordinarily low-frequency sound absorption performance. Moreover, actual sound absorption coefficients are above 0.5 in the 350–1600 Hz range (with a bandwidth Δf₂ = 1250 Hz), which achieve broadband sound absorption in the low–middle frequency range. According to various actual demands, the structural parameters can be adjusted flexibly to realize the customization of sound absorption bandwidth, which provides a novel way to design and improve acoustic metamaterials to reduce the noise with various frequency bands and has promising prospects of application in low-frequency sound absorption.     

临床带教老师要注重培养护生的“慎独”修养

本文从“慎独”修养的含义、“慎独”在护理工作中的重要性出发，就如何培养和锻炼实习 护生阐述了自己的观点，临床带教老师应通过言传身教，使实习护生提高认识，刻意追求，努力达到 “慎独”。     

Does losing money truly hurt? The shared neural bases of monetary loss and pain

Both monetary loss and pain have been studied for decades, but evidence supporting the relationship between them is still lacking. We conducted a meta‐analysis to explore the overlapping brain regions between monetary loss and pain, including physical pain and social pain. Regardless of the type of pain experienced, activation of the anterior insula was a shared neural representation of monetary loss and pain. The network representation pattern of monetary loss was more similar to that of social pain than that of physical pain. In conclusion, our research provided evidence of the common neural correlates of monetary loss and pain.     

Anti-Corrosion Performance of Migratory Corrosion Inhibitors on Reinforced Concrete Exposed to Varying Degrees of Chloride Erosion

This study investigated the anti-corrosion performance of commercial amino alcohol migratory corrosion inhibitors (MCIs) on concrete that underwent varying degrees of chloride erosion. Electrochemical impedance spectroscopy (EIS), potentiodynamic polarization (PD), scanning electron microscopy, and energy dispersive spectroscopy (SEM-EDS) analyses were performed to study the anti-corrosion performance and mechanism of the MCIs on the steel bars. The results indicated that the corrosion resistance of the steel bars in concrete was significantly improved by coating with the MCIs, and the earlier the specimens were coated with the MCIs, the higher the anti-corrosion efficiency. The anti-corrosion efficiency was 55.35% when the MCIs coating was applied before chloride erosion; however, the anti-corrosion efficiency decreased to 3.40% when the MCIs coating was applied after the ninth drying–wetting cycle. The improvement in corrosion resistance of the steel bar in concrete coated with MCIs was due to the protective MCIs-molecule film that formed on the steel bar surfaces, and the oxidative dissolution of iron at the anode was effectively inhibited by the MCIs coating.     

Shugan granule contributes to the improvement of depression‐like behaviors in chronic restraint stress‐stimulated rats by altering gut microbiota

AimThe investigation aims to evaluate the potential effect of Shugan Granule (SGKL) on the gut, brain, and behaviors in rats exposed to chronic restraint stress (CRS).MethodsThe fecal microbiota and metabolite changes were studied in rats exposed to CRS and treated with SGKL (0.1 mg/kg/day). Depressive behaviors of these rats were determined through an open‐field experiment, forced swimming test, sucrose preference, and weighing. Moreover, LPS‐stimulated microglia and CRS‐stimulated rats were treated with SGKL to investigate the regulation between SGKL and the PI3K/Akt/pathway, which is inhibited by LY294002, a PI3K inhibitor.Results(i) SGKL improved the altered behaviors in CRS‐stimulated rats; (ii) SGKL ameliorated the CRS‐induced neuronal degeneration and tangled nerve fiber and also contributed to the recovery of intestinal barrier injury in these rats; (iii) SGKL inhibited the hippocampus elevations of TNF‐α, IL‐1β, and IL‐6 in response to CRS modeling; (iv) based on the principal coordinates analysis (PCoA), SGKL altered α‐diversity indices and shifted β‐diversity in CRS‐stimulated rats; (v) at the genus level, SGKL decreased the CRS‐enhanced abundance of Bacteroides; (vi) Butyricimonas and Candidatus Arthromitus were enriched in SGKL‐treated rats; (vii) altered gut microbiota and metabolites were correlated with behaviors, inflammation, and PI3K/Akt/mTOR pathway; (viii) SGKL increased the LPS‐decreased phosphorylation of the PI3K/Akt/mTOR pathway in microglia and inhibited the LPS‐induced microglial activation; (ix) PI3K/Akt/mTOR pathway inactivation reversed the SGKL effects in CRS rats.ConclusionSGKL targets the PI3K/Akt/mTOR pathway by altering gut microbiota and metabolites, which ameliorates altered behavior and inflammation in the hippocampus.     

High Expression of Insulin-like Growth Factor H (IGF-Ⅱ) Using Bac-to-Bac Expression System

Objective In order to obtain mature insulin-like growth factor- Ⅱ ( IGF- Ⅱ ), we used Bac-to-Bac baculovirus expression system. Methods Firstly the IGF- Ⅱ cDNA was cloned into a donor plasmid pFastBac1 and the recombinant pFastBac1 was then introduced into competent cells DH 10Bac. Recombinant bacmids were constructed by transposing a mini-Tn7 element from a donor plasmid pFastBac1 to the mini-attTn7 attachment site on the bacmid where the Tn7 transposition functions were provided in trans by a helper plasmid, and then used to transfect Sf9 insect cells to get recombinant baculovirus. The recombinant baculovirus was used to infect insect cells. Results Agarose gel analysis showed that recombinant donor plasmid pFastBac1 was constructed successfully; Agarose gel analysis of PCR products confirmed recombinant bacmid ; SDS-PAGE and Western Blotting showed that a 7KD protein band appeared. Conclusion The mature IGF- Ⅱ with immunogenecity has been expressed and produced by using Bac-to-Bac expression system.