Scientific Developments in Imaging and Dosimetry for Molecular Radiotherapy

Molecular radiotherapy is a rapidly developing field with new vector and isotope combinations continually added to market. As with any radiotherapy treatment, it is vital that the absorbed dose and toxicity profile are adequately characterised. Methodologies for absorbed dose calculations for radiopharmaceuticals were generally developed to characterise stochastic effects and not suited to calculations on a patient-specific basis. There has been substantial scientific and technological development within the field of molecular radiotherapy dosimetry to answer this challenge. The development of imaging systems and advanced processing techniques enable the acquisition of accurate measurements of radioactivity within the body. Activity assessment combined with dosimetric models and radiation transport algorithms make individualised absorbed dose calculations not only feasible, but commonplace in a variety of commercially available software packages. The development of dosimetric parameters beyond the absorbed dose has also allowed the possibility to characterise the effect of irradiation by including biological parameters that account for radiation absorbed dose rates, gradients and spatial and temporal energy distribution heterogeneities. Molecular radiotherapy is in an exciting time of its development and the application of dosimetry in this field can only have a positive influence on its continued progression.     

Dual nature of human ACE2 glycosylation in binding to SARS-CoV-2 spike

Binding of the spike protein of SARS-CoV-2 to the human angiotensin-converting enzyme 2 (ACE2) receptor triggers translocation of the virus into cells. Both the ACE2 receptor and the spike protein are heavily glycosylated, including at sites near their binding interface. We built fully glycosylated models of the ACE2 receptor bound to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Using atomistic molecular dynamics (MD) simulations, we found that the glycosylation of the human ACE2 receptor contributes substantially to the binding of the virus. Interestingly, the glycans at two glycosylation sites, N90 and N322, have opposite effects on spike protein binding. The glycan at the N90 site partly covers the binding interface of the spike RBD. Therefore, this glycan can interfere with the binding of the spike protein and protect against docking of the virus to the cell. By contrast, the glycan at the N322 site interacts tightly with the RBD of the ACE2-bound spike protein and strengthens the complex. Remarkably, the N322 glycan binds to a conserved region of the spike protein identified previously as a cryptic epitope for a neutralizing antibody. By mapping the glycan binding sites, our MD simulations aid in the targeted development of neutralizing antibodies and SARS-CoV-2 fusion inhibitors.

Angiotensin-converting enzyme 2 (ACE2) is an enzyme that catalyzes the hydrolysis of angiotensin II into angiotensin (1–7) to counterbalance the ACE receptor in blood pressure control (1). A single transmembrane helix anchors ACE2 into the plasma membrane of cells in the lungs, arteries, heart, kidney, and intestines (2). The vasodilatory effect of ACE2 has made it a promising target for drugs treating cardiovascular diseases (3).ACE2 also serves as the entry point for several coronaviruses into cells, including SARS-CoV and SARS-CoV-2 (4–6). The binding of the spike protein of SARS-CoV and SARS-CoV-2 to the peptidase domain (PD) of ACE2 triggers endocytosis and translocation of both the virus and the ACE2 receptor into endosomes within cells (4). The human transmembrane serine protease 2, TMPRSS2, primes spike for efficient cell entry by cleaving its backbone at the boundary between the S1 and S2 subunits or within the S2 subunit (4). The structure of the ACE2 receptor in complex with the SARS-CoV-2 spike receptor binding domain (RBD) (7–9) reveals the major RBD interaction regions as helix H1 (Q24–Q42), a loop in a beta sheet (K353–R357), and the end of helix H2 (L79–Y83). With a 4-Å heavy-atom distance cutoff, 20 residues of ACE2 interact with 17 residues of the RBD, forming a buried interface of ∼1,700 Ų (7).The structure of full-length ACE2 has been resolved in complex with B⁰AT1 (also known as SLC6A19) (9). B⁰AT1 is a sodium-dependent neutral amino acid transporter (10). ACE2 functions as chaperone for B⁰AT1 and is responsible for its trafficking to the plasma membrane of kidney and intestine epithelial cells (11). Although it was speculated that B⁰AT1 prevents ACE2 cleavage by TMPRSS2 and thus could suppress SARS-CoV-2 infection (9, 12), other studies showed that SARS-CoV-2 can infect human small intestinal enterocytes where ACE2 is expected to be in complex with B⁰AT1 (13).Both the ACE2 receptor and the spike protein are heavily glycosylated. Several glycosylation sites are near the binding interface (7, 9, 14, 15). Whereas the focus has largely been on amino acid interactions in the ACE2–spike binding interface (16, 17), the role of glycosylation in binding has been recognized (7, 18–20). The extracellular domain of the ACE2 receptor has seven N-glycosylation sites (N53, N90, N103, N322, N432, N546, and N690) and several O-glycosylation sites (e.g., T730) (9, 14). Among ACE2 glycosylation sites, the only well-characterized position regarding the effect on the spike binding and viral infectivity is N90. It is known from earlier SARS-CoV studies that glycosylation at the N90 position might interfere with virus binding and infectivity (21). Also, recent genetic and biochemical studies showed that mutations of N90, which remove the glycosylation site directly, or of T92, which remove the glycosylation site indirectly by eliminating the glycosylation motif (NXT), increase the susceptibility to SARS-CoV-2 infection (22, 23).We use extensive molecular dynamics (MD) simulations to gain a detailed molecular-level understanding of how ACE2 glycosylation impacts the host–virus interactions. Glycosylation sites N90 and N322 of human ACE2 emerge as major determinants of its binding to SARS-CoV-2 spike. Remarkably, glycans at these sites have opposite effects, interfering with spike binding in one case, and strengthening binding in the other. Our findings provide direct guidance for the design of targeted antibodies and therapeutic inhibitors of viral entry.     

基于超分子“气析”理论构建中药制剂靶向性评价方法及实验验证

目的 构建基于超分子“气析”理论的中药制剂的靶向性评价方法，并对柴胡影响片仔癀的肝靶向性进行研究。方法 采用分子连接性指数分析主要归肝经的药材、片仔癀中的各成分“印迹模板”特征及肝靶向趋势；利用中药多成分“印迹模板”自主作用特征，结合靶区动力学和总量统计矩原理建立中药制剂的靶向性评价方法，并对片仔癀组、柴胡组、片仔癀+柴胡组、空白组4组作用的肝癌大鼠进行实验验证。结果 扣除主要归肝经药材分子连接性指数平均值后，片仔癀组与柴胡组的分子连接性指数相似度0.376 8，片仔癀+柴胡组与柴胡组的分子连接性指数相似度0.988 2，预测柴胡可增强片仔癀的肝靶向性。建立中药复方靶向性的评价体系，包括相对总量摄取率（RUE_T），相对总量浓度（RC_T），相对“印迹”趋势（RIT_T）及相对“印迹”方差（RIV_T）；各组织中肝脏的RUE_T和RC_T均为最大（RUE_T=1.88>1，RC_T=2.30>1），其他组织这2个参数则均<1，说明片仔癀结合柴胡后能增加其在肝脏的分布，肝靶向性增强；除血浆外，其他组织的RIT_T及RIV_T均在1.0附近波动，说明靶向修饰不改变片仔癀的“印迹”作用趋势，对成分种类也无明显影响。结论 在超分子“气析”理论指导下，可建立以分子连接性指数和总量统计矩参数表征中药制剂多成分“印迹”作用的靶向性评价参数体系，实现对中药制剂靶向性的评价，柴胡的加入可增加片仔癀的肝靶向性。     

Addition of platelet‐rich plasma supports immune modulation and improved mechanical integrity in Alloderm mesh for ventral hernia repair in a rat model

The recurrence of ventral hernias continues to be a problem faced by surgeons, in spite of efforts toward implementing novel repair techniques and utilizing different materials to promote healing. Cadaveric acellular dermal matrices (Alloderm) have shown some promise in numerous surgical subspecialties, but these meshes still suffer from subsequent failure and necessitation of re‐intervention. Here, it is demonstrated that the addition of platelet rich plasma to Alloderm meshes temporally modulates both the innate and cytotoxic inflammatory responses to the implanted material. This results in decreased inflammatory cytokine production at early time points, decreased matrix metalloproteinase expression, and decreased CD8+ T cell infiltration. Collectively, these immune effects result in a healing phenotype that is free from mesh thinning and characterized by increased material stiffness.     

Neurólise do tronco celíaco com o uso de agulha única versus agulha dupla no manejo da dor abdominal maligna: estudo randômico controlado

BackgroundComputerized tomography‐guided celiac plexus neurolysis has become almost a safe technique to alleviate abdominal malignancy pain. We compared the single needle technique with changing patients’ position and the double needle technique using posterior anterocrural approach.MethodsIn Double Needles Celiac Neurolysis Group (n = 17), we used two needles posterior anterocrural technique injecting 12.5 mL phenol 10% on each side in prone position. In Single Needle Celiac Neurolysis Group (n = 17), we used single needle posterior anterocrural approach. 25 mL of phenol 10% was injected from left side while patients were in left lateral position then turned to right side. The monitoring parameters were failure block rate and duration of patient positioning, technique time, Visual Analog Scale, complications (hypotension, diarrhea, vomiting, hemorrhage, neurological damage and infection) and rescue analgesia.ResultsThe failure block rate and duration of patient positioning significantly increased in double needles celiac neurolysis vs. single needle celiac neurolysis (30.8% vs. 0.13.8±1.2 vs. 8.9 ± 1; p = 0.046, p ≤ 0.001 respectively). Also, the technique time increased significantly in double needles celiac neurolysis than single needle celiac neurolysis (24.5 ± 5.1 vs. 15.4 ± 1.8; p ≤ 0.001). No significant differences existed as regards visual analogue scale: double needles celiac neurolysis = 2 (0‐5), 2 (0‐4), 3 (0‐6), 3 (2‐6) and single needle celiac neurolysis = 3 (0‐5), 2 (0‐5), 2 (0‐4), 4 (2‐6) after 1 day, 1 week, 1 and 3 months respectively. However, visual analogue scale in each group reduced significantly compared with basal values (p ≤ 0.001). There were no statistically significant differences as regards rescue analgesia and complications (p > 0.05).ConclusionSingle needle celiac neurolysis with changing patients’ position has less failure block rate, less procedure time, shorter duration of patient positioning than double needles celiac neurolysis in abdominal malignancy.