• ISSN 1674-8301
  • CN 32-1810/R

2022 Vol. 36, No. 3

Review Article
Even though randomized controlled clinical trials (RCTs) have been accepted as the gold standard for official assessment of novel interventions, there is a substantial gap between the efficacy observed in RCTs and the impact on clinical practice and in terms of patient benefit. While real-world studies (RWS) are emerging to confer valuable complementing evidence in this regard and beyond, the evolving role of RWS is yet to be agreed. This article delineates an updated profile of RWS covering effectiveness verification, rare adverse effects discovery, indication repurposing, to name a few. RWS tends not only to improve the efficiency of clinical investigations for regulatory approval, but also optimizes the whole-life cycle evaluation of biomedical/pharmaceutical products.
Original Article
High-affinity antibodies are widely used in diagnostics and for the treatment of human diseases. However, most antibodies are isolated from semi-synthetic libraries by phage display and do not possess in vivo affinity maturation, which is triggered by antigen immunization. It is therefore necessary to engineer the affinity of these antibodies by way of in vitro assaying. In this study, we optimized the affinity of two human monoclonal antibodies which were isolated by phage display in a previous related study. For the 42A1 antibody, which targets the liver cancer antigen glypican-3, the variant T57H in the second complementarity-determining region of the heavy chain (CDR-H2) exhibited a 2.6-fold improvement in affinity, as well as enhanced cell-binding activity. For the I4A3 antibody to severe acute respiratory syndrome coronavirus 2, beneficial single mutations in CDR-H2 and CDR-H3 were randomly combined to select the best synergistic mutations. Among these, the mutation S53P-S98T improved binding affinity (about 3.7 fold) and the neutralizing activity (about 12 fold) compared to the parent antibody. Taken together, single mutations of key residues in antibody CDRs were enough to increase binding affinity with improved antibody functions. The mutagenic combination of key residues in different CDRs creates additive enhancements. Therefore, this study provides a safe and effective in vitro strategy for optimizing antibody affinity.
Tuberculosis (TB), is an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis), and presents with high morbidity and mortality. Alveolar macrophages play an important role in TB pathogenesis although there is heterogeneity and functional plasticity. This study aimed to show the characteristics of alveolar macrophages from bronchioalveolar lavage fluid (BALF) in active TB patients. Single-cell RNA sequencing (scRNA-seq) was performed on BALF cells from three patients with active TB and additional scRNA-seq data from three healthy adults were established as controls. Transcriptional profiles were analyzed and compared by differential geneexpression and functional enrichment analysis. We applied pseudo-temporal trajectory analysis to investigate correlations and heterogeneity within alveolar macrophage subclusters. Alveolar macrophages from active TB patients at the single-cell resolution are described. We found that TB patients have higher cellular percentages in five macrophage subclusters. Alveolar macrophage subclusters with increased percentages were involved in inflammatory signaling pathways as well as the basic macrophage functions. The TB-increased alveolar macrophage subclusters might be derived from M1-like polarization state, before switching to an M2-like polarization state with the development of M. tuberculosis infection. Cell-cell communications of alveolar macrophages also increased and enhanced in active TB patients. Overall, our study demonstrated the characteristics of alveolar macrophages from BALF in active TB patients by using scRNA-seq.
The present study aims to investigate the therapeutic effect and mechanism of glycyrrhizic acid (GA) in diabetic peripheral neuropathy (DPN). GA significantly mitigated nerve conduction velocity (NCV) deficit and morphological abnormality and reduced high-mobility group box-1 (HMGB1) expression in the sciatic nerves of diabetic rats independent of blood glucose and body weight. Notably, GA alleviated the increase of HMGB1 and the decrease of cell viability in high glucose-stimulated RSC96 cells. Furthermore, GA obviously reduced the concentration of inflammatory cytokines in the sciatic nerves of diabetic rats and supernatants of high glucose-exposed RSC96 cells, then restored the decreased expression levels of nerve growth factor (NGF) and neuritin-1, and the increased expression levels of cleaved caspase-3 and neuron-specific enolase. Additionally, GA markedly inhibited receptor for advanced glycation end products (RAGE) expression, p38MAPK phosphorylation, and the nuclear translocation of NF-κBp65 in diabetic rats and high glucose-exposed RSC96 cells. The promotional effect of high glucose in RSC96 cells was diminished following Hmgb1 siRNA treatment. Our findings indicate that GA may exert neuroprotection on DPN by suppressing HMGB1, which lead to extenuation of inflammation response, balance of NGF, neuritin-1 and caspase-3, as well as inactivation of RAGE/p38MAPK/NF-κBp65 signaling pathway.
Orexin signaling has been associated with energy expenditure and brown adipose tissue (BAT) function. However, conflicting data exist in the field about how orexin signaling regulates BAT thermogenesis. In this study, we show that a specific orexin receptor type 2 (OX2R) agonist [Ala11, D-Leu15]-OxB (OB-Ala) inhibited intrascapular brown adipose tissue (iBAT) thermogenesis by reducing sympathetic output to iBAT. This effect is mediated by OX2Rs located on afferent nerve endings innervating iBAT instead of brown adipocyte itself. Microinjection of OB-Ala into iBAT inhibited iBAT thermogenesis in mice upon cold exposure and neuronal activity in the paraventricular nucleus. Findings suggest that OB-Ala could inhibit iBAT thermogenesis by attenuating sensory input thereby inhibiting the sympathetic-sensory iBAT feedback loop. Our study uncovers a novel primary action site of orexin in the regulation of energy balance.
Osteoporotic vertebral compression fracture (OVCF) has become a major public health issue that becomes more pressing with increasing global aging. Percutaneous kyphoplasty (PKP) is an effective treatment for OVCF. Robot-assisted PKP has been utilized in recent years to improve accuracy and reduce complications. However, the effectiveness of robot-assisted PKP in the treatment of multi-segmental OVCF has yet to be proved. This study was designed to compare the efficacy of robot-assisted and conventional fluoroscopy-assisted multi-segmental PKP. A total of 30 cases with multi-segmental OVCF between April 2019 and April 2021 were included in this study. Fifteen cases were assigned to the robot-assisted PKP group (robot group) and 15 cases to the conventional fluoroscopy-assisted PKP group (conventional fluoroscopy group). The number of fluoroscopic exposures, fluoroscopic dose, operation time, cement leakage rate, visual analog scale (VAS) score, vertebral kyphosis angle (VKA), and height of fractured vertebral body (HFV) were compared between the 2 groups. The number of fluoroscopic exposures, fluoroscopic doses, and cement leakage rates in the robot group were lower than in the conventional fluoroscopy group (P<0.05) while the operative time in the robot group was longer than in the conventional fluoroscopy group (P<0.05). VAS score and VKA were decreased and HFV was increased after surgery in both groups (P<0.05). Therefore, robot-assisted PKP for the treatment of multi-segmental OVCF can reduce the number of fluoroscopic exposures, fluoroscopic doses, and cement leakage compared to conventional treatment. As such, robot-assisted PKP has good application prospects and is potentially more effective in the treatment of multi-segmental OVCF.
Case Report
Sterculia gum, the dry exudate of Sterculia versicolor and other members of the same genus, is used as a thickener and emulsifier in foods. It is generally considered safe as a food or drug, and its adverse reactions, such as Sterculia-induced liver injury, have never been reported. A 46-year-old woman was admitted to hospital with fatigue, nausea, abdominal distension, jaundice and a >16-fold increase in transaminase and bilirubin level. The patient had used Sterculia gum prior to the onset of her symptoms. Her symptoms and clinical indicators improved after treatment. The possibility of acute viral hepatitis, autoimmune hepatitis, and metabolic liver disease was excluded. After discharge from hospital, the patient had a severe liver injury again when re-exposed to Sterculia gum. And the Roussel Uclaf Causality Assessment Method score was updated from 5 to 7, which was consistent with probable drug-induced liver injury. This is the first report of Sterculia-induced liver injury. Clinicians need to be aware of the potential hepatotoxicity of Sterculia.