Bone bridge fixation has superior biomechanics on posterior knees to bone plug fixation after lateral meniscal allograft transplantation – A biomechanical study simulating partial weight-bearing conditions

BackgroundIt remains unknown how biomechanics change in posterior lateral knee using different fixation techniques in lateral meniscal allograft transplantation (MAT) during simulated toe-touch partial weight-bearing. This study aimed to compare the biomechanical effects on posterior knee between bridge and bone plug fixation in lateral MAT.MethodsIntact knee, bone bridge fixation, and bone plug fixation were tested with 500 N of axial load during knee flexion at 0°, 30°, and 60°, which simulated toe-touch partial weight-bearing. Contact area and peak pressure were assessed on posterior knee and the shift of peak pressure position were measured.ResultsOn the posterior lateral compartment, the contact mechanics of bone bridge fixation were similar to those of the intact knee (all P-values > 0.05), but its peak pressure was higher than that of intact knee at 60° (P = 0.002). For bone plug fixation, the contact area of the posterior lateral knee was significantly lower than those of intact knee and bone bridge fixation at 30° and 60° (all P-values < 0.05). The peak pressure of the posterior lateral knee was higher than that of the intact knee at all flexions and higher than that of bone bridge fixation at 30° and 60° (all P-values < 0.05). The peak pressure position of bone plug fixation shifted more laterally and posteriorly compared with intact knee and bone bridge fixation during knee flexion.ConclusionBone bridges could maintain posterior knee biomechanics better than bone plug fixation during knee bending during partial weight-bearing.     

营养教育咨询降低质子重离子治疗期间显著体重下降率

目的探讨以指南为依据的肿瘤放疗患者营养教育咨询方案，在降低质子重离子治疗期间显著体重下降发生率方面 的有效性。方法以质子重离子治疗期间的肿瘤放疗患者为研究对象，采用历史对照研究设计，方案实施前以2016年1月至12月 收治的患者为对照组，方案实施后以2018年1月至8月收治的患者为试验组。对照组在方案实施前仍实行原有的常规护理，试验 组给予以指南为依据的营养教育咨询方案。结果本研究共纳入713例肿瘤患者，其中对照组374例，试验组339例，两组平均年 龄为54岁和53岁，45%和49%为头颈部肿瘤患者。放疗期间对照组平均体重下降0.51 kg，平均体重丢失0.75%，显著体重下降 发生率为11.2%（42例）；试验组体重下降0.66 kg，平均体重丢失0.90%，显著体重下降发生率为9.4%（32例）。在控制放疗总剂量、 射线类型、肿瘤部位、同期化疗和性别的混杂因素影响后，试验组显著体重下降的风险下降了34%（OR=0.66，95%CI=0.48~0.91）。 结论以指南为依据的肿瘤放疗患者营养教咨询方案能够帮助改善质子重离子治疗期间的患者营养状态，有效降低显著体重下 降的风险。     

基于分子影像的非小细胞肺癌分子靶向治疗及免疫治疗进展

我国癌症发病率与死亡率中肺癌均高居第一位，其中非小细胞肺癌（NSCLC）占肺癌85%以上， NSCLC传统治疗方式包括手术、化疗、放疗等。近十几年来，NSCLC相关临床治疗取得巨大突破，代表性治疗新方案即为分子靶向治疗和免疫治疗，然而，上述治疗方式成功发挥治疗作用前提和关键则是精准选择NSCLC患者治疗优势人群。分子影像可以在活体状态下，应用影像学方法对人或动物体内细胞和分子水平生物学过程进行成像、定性和定量研究，着眼于生物过程基础变化而不是生物变化最终结果，进而实现精准选择治疗优势人群、分子水平精准监测治疗效果、及时进行预后评估等目的，对分子靶向治疗以及免疫治疗意义重大。该文综述分子影像在NSCLC分子靶向治疗以及免疫治疗中开展的相关研究。     

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.