Aug 2021, Volume 15 Issue 4

Cover illustration

  • Schematic figure of the characteristics for CD34+CD117dim/CD34+CD117bri myeloblasts in t(8;21) AML. (Courtesy of Dr. Lu Jiang. See pages 608-620 by Xueping Li et al. for more information.)

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    William J. Liu, Haixia Xiao, Lianpan Dai, Di Liu, Jianjun Chen, Xiaopeng Qi, Yuhai Bi, Yi Shi, George F. Gao, Yingxia Liu

    The avian influenza A (H7N9) virus is a zoonotic virus that is closely associated with live poultry markets. It has caused infections in humans in China since 2013. Five waves of the H7N9 influenza epidemic occurred in China between March 2013 and September 2017. H7N9 with low-pathogenicity dominated in the first four waves, whereas highly pathogenic H7N9 influenza emerged in poultry and spread to humans during the fifth wave, causing wide concern. Specialists and officials from China and other countries responded quickly, controlled the epidemic well thus far, and characterized the virus by using new technologies and surveillance tools that were made possible by their preparedness efforts. Here, we review the characteristics of the H7N9 viruses that were identified while controlling the spread of the disease. It was summarized and discussed from the perspectives of molecular epidemiology, clinical features, virulence and pathogenesis, receptor binding, T-cell responses, monoclonal antibody development, vaccine development, and disease burden. These data provide tools for minimizing the future threat of H7N9 and other emerging and re-emerging viruses, such as SARS-CoV-2.

    Ziqi Chen, Xiaoqi Huang, Qiyong Gong, Bharat B. Biswal

    Major depressive disorder (MDD) causes great decrements in health and quality of life with increments in healthcare costs, but the causes and pathogenesis of depression remain largely unknown, which greatly prevent its early detection and effective treatment. With the advancement of neuroimaging approaches, numerous functional and structural alterations in the brain have been detected in MDD and more recently attempts have been made to apply these findings to clinical practice. In this review, we provide an updated summary of the progress in translational application of psychoradiological findings in MDD with a specified focus on potential clinical usage. The foreseeable clinical applications for different MRI modalities were introduced according to their role in disorder classification, subtyping, and prediction. While evidence of cerebral structural and functional changes associated with MDD classification and subtyping was heterogeneous and/or sparse, the ACC and hippocampus have been consistently suggested to be important biomarkers in predicting treatment selection and treatment response. These findings underlined the potential utility of brain biomarkers for clinical practice.

    Chen Wang, Hui Fang, Jiawei Zhang, Ying Gu

    Synthetic lethal screening, which exploits the combination of mutations that result in cell death, is a promising method for identifying novel drug targets. This method provides a new avenue for targeting “undruggable” proteins, such as c-Myc. Here, we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network, whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells. We further discuss strategies to identify these functional nodes in the context of synthetic lethality. We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently.

    Zhaoshi Bao, Yongzhi Wang, Qiangwei Wang, Shengyu Fang, Xia Shan, Jiguang Wang, Tao Jiang

    Glioma is the most common lethal tumor of the human brain. The median survival of patients with primary World Health Organization grade IV glioma is only 14.6 months. The World Health Organization classification of tumors of the central nervous system categorized gliomas into lower-grade gliomas and glioblastomas. Unlike primary glioblastoma that usually develop de novo in the elderly, secondary glioblastoma enriched with an isocitrate dehydrogenase mutant typically progresses from lower-grade glioma within 5–10 years from the time of diagnosis. Based on various evolutional trajectories brought on by clonal and subclonal alterations, the evolution patterns of glioma vary according to different theories. Some important features distinguish the normal brain from other tissues, e.g., the composition of the microenvironment around the tumor cells, the presence of the blood-brain barrier, and others. The underlying mechanism of glioma recurrence and evolution patterns of glioma are different from those of other types of cancer. Several studies correlated tumor recurrence with tumor heterogeneity and the immune microenvironment. However, the detailed reasons for the progression and recurrence of glioma remain controversial. In this review, we introduce the different mechanisms involved in glioma progression, including tumor heterogeneity, the tumor microenvironment and drug resistance, and their pre-clinical implements in clinical trials. This review aimed to provide new insights into further clinical strategies for the treatment of patients with recurrent and secondary glioma.

    Peng Wang, Zehao Zhao, Linghao Bu, Nijiati Kudulaiti, Qiao Shan, Yuyao Zhou, N. U. Farrukh Hameed, Yangming Zhu, Lei Jin, Jie Zhang, Junfeng Lu, Jinsong Wu

    The protection of language function is one of the major challenges of brain surgery. Over the past century, neurosurgeons have attempted to seek the optimal strategy for the preoperative and intraoperative identification of language-related brain regions. Neurosurgeons have investigated the neural mechanism of language, developed neurolinguistics theory, and provided unique evidence to further understand the neural basis of language functions by using intraoperative cortical and subcortical electrical stimulation. With the emergence of modern neuroscience techniques and dramatic advances in language models over the last 25 years, novel language mapping methods have been applied in the neurosurgical practice to help neurosurgeons protect the brain and reduce morbidity. The rapid advancements in brain--computer interface have provided the perfect platform for the combination of neurosurgery and neurolinguistics. In this review, the history of neurolinguistics models, advancements in modern technology, role of neurosurgery in language mapping, and modern language mapping methods (including noninvasive neuroimaging techniques and invasive cortical electroencephalogram) are presented.

    Hao Qu, Yu Zhao

    Spinal disease is an important cause of cervical discomfort, low back pain, radiating pain in the limbs, and neurogenic intermittent claudication, and its incidence is increasing annually. From the etiological viewpoint, these symptoms are directly caused by the compression of the spinal cord, nerve roots, and blood vessels and are most effectively treated with surgery. Spinal surgeries are primarily performed using two different techniques: spinal canal decompression and internal fixation. In the past, tactile sensation was the primary method used by surgeons to understand the state of the tissue within the operating area. However, this method has several disadvantages because of its subjectivity. Therefore, it has become the focus of spinal surgery research so as to strengthen the objectivity of tissue state recognition, improve the accuracy of safe area location, and avoid surgical injury to tissues. Aside from traditional imaging methods, surgical sensing techniques based on force, bioelectrical impedance, and other methods have been gradually developed and tested in the clinical setting. This article reviews the progress of different tissue state recognition methods in spinal surgery and summarizes their advantages and disadvantages.

    Yanhong Shou, Lu Yang, Yongsheng Yang, Xiaohua Zhu, Feng Li, Bo Yin, Yingyan Zheng, Jinhua Xu

    Stevens--Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe diseases. This study aimed to validate the predictive ability of risk models in patients with SJS/TEN and propose possible refinement in China. Patients in the Department of Dermatology of Huashan Hospital from January 2008 to January 2019 were included. Results showed that the severity-of-illness score for TEN (SCORTEN) had a good discrimination (area under the receiver operating characteristic curve (AUC), 0.78), and it was superior to auxiliary score (AS) and ABCD-10, which indicates age, bicarbonate level, cancer, dialysis, and 10% involved body surface area (AUC, 0.69 and 0.68, respectively). The calibration of SCORTEN (Hosmer–Lemeshow goodness-of-fit test, P = 0.69) was also better than that of AS (P = 0.25) and ABCD-10 (P = 0.55). SCORTEN and ABCD-10 were similar (Brier score (BS), 0.04 and 0.04) in terms of accuracy of predictions. In addition, the imaging appearance of pulmonary consolidation on computed tomography was associated with high mortality. Refined models were formed using the variables and this imaging appearance. The refined AS and ABCD-10 models were similar in discrimination compared with the original SCORTEN (0.74 vs. 0.78, P = 0.23; 0.74 vs. 0.78, P = 0.30, respectively). Therefore, SCORTEN showed good discrimination performance, calibration, and accuracy, and refined AS or ABCD-10 model may be an option when SCORTEN variables are not available.

    Nan Qin, Guang Xu, Yan Wang, Xiaoyan Zhan, Yuan Gao, Zhilei Wang, Shubin Fu, Wei Shi, Xiaorong Hou, Chunyu Wang, Ruisheng Li, Yan Liu, Jiabo Wang, Haiping Zhao, Xiaohe Xiao, Zhaofang Bai

    Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.

    Xueping Li, Yuting Dai, Bing Chen, Jinyan Huang, Saijuan Chen, Lu Jiang

    t(8;21)(q22;q22) acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy with a high relapse rate in China. Two leukemic myeloblast populations (CD34+CD117dim and CD34+CD117bri) were previously identified in t(8;21) AML, and CD34+CD117dim cell proportion was determined as an independent factor for this disease outcome. Here, we examined the impact of CD34+CD117dim/CD34+CD117bri myeloblast-associated gene expression on t(8;21) AML clinical prognosis. In this study, 85 patients with t(8;21) AML were enrolled. The mRNA expression levels of CD34+CD117dim-associated genes (LGALS1, EMP3, and CRIP1) and CD34+CD117bri-associated genes (TRH, PLAC8, and IGLL1) were measured using quantitative reverse transcription PCR. Associations between gene expression and clinical outcomes were determined using Cox regression models. Results showed that patients with high LGALS1, EMP3, or CRIP1 expression had significantly inferior overall survival (OS), whereas those with high TRH or PLAC8 expression showed relatively favorable prognosis. Univariate analysis revealed that CD19, CD34+CD117dim proportion, KIT mutation, minimal residual disease (MRD), and expression levels of LGALS1, EMP3, CRIP1, TRH and PLAC8 were associated with OS. Multivariate analysis indicated that KIT mutation, MRD and CRIP1 and TRH expression levels were independent prognostic variables for OS. Identifying the clinical relevance of CD34+CD117dim/CD34+CD117bri myeloblast-associated gene expression may provide new clinically prognostic markers for t(8;21) AML.

    Jiayi Wu, Weiqi Gao, Xiaosong Chen, Chunxiao Fei, Lin Lin, Weiguo Chen, Ou Huang, Siji Zhu, Jianrong He, Yafen Li, Li Zhu, Kunwei Shen

    Multi-gene assays have emerged as crucial tools for risk stratification in early-stage breast cancer. This study aimed to evaluate the prognostic significance of the 21-gene recurrence score (RS) in Chinese patients with pN0-1, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2) breast cancer. Among 800 patients recruited between 2009 and 2016, the median RS was 24 (0–69), with 27.4%, 46.8%, and 25.9% patients classified into low-, intermediate-, and high-risk groups. Cox regression analysis demonstrated that the high-risk category was associated with significantly higher odds of invasive disease-free survival (IDFS) and distant disease-free survival (DDFS) events compared with the low-risk category (IDFS: HR= 2.450, 95% CI 1.017–5.902, P= 0.046; DDFS: HR= 2.829, 95% CI 1.013–7.901, P= 0.047). No significant association between RS category and overall survival (OS) was found (intermediate vs. low: HR= 1.244, 95% CI 0.292–5.297, P= 0.768; high vs. low: HR= 2.933, 95% CI 0.759–11.327, P= 0.119). RS, as a continuous variable, was a highly significant predictor for IDFS (HR= 1.028, 95% CI 1.010–1.047, P= 0.002), DDFS (HR= 1.030, 95% CI 1.010–1.051, P= 0.003), and OS (HR= 1.034, 95% CI 1.007–1.063, P= 0.014). Our findings suggested that RS may predict IDFS in Chinese patients with ER+/HER2 breast cancer with N0 or N1 disease.

    Yu Wang, Lan Li, Yuanjiang Pan, Yu He, Zuhua Chen, Yunhao Xun, Yuhan Xu, Yilei Guo, Jiehong Yang, Jianchun Guo, Haitong Wan

    Cardio-cerebrovascular disease (CCVD) is a major comorbidity of coronavirus disease 2019 (COVID-19). However, the clinical characteristics and outcomes remain unclear. In this study, 102 cases of COVID-19 from January 22, 2020 to March 26, 2020 in Xixi Hospital of Hangzhou were included. Twenty cases had pre-existing CCVD. Results showed that compared with non-CCVD patients, those with CCVD are more likely to develop severe disease (15% versus 1%), and the proportion of pneumonia severity index grade IV was significantly higher (25% versus 3.6%). Computed tomography images demonstrated that the proportion of multiple lobe lesion involvement was significantly higher in the CCVD group than in the non-CCVD group (90% versus 63.4%). Compared with non-CCVD group, the levels of C-reactive protein, fibrinogen, D-dimer, and serum amyloid-A were higher, whereas the total protein and arterial partial PaO2 were lower in the CCVD group. Although no statistical difference was observed in the outcomes between groups, CCVD patients received more intensive comprehensive treatment to improve COVID-19 symptoms compared with non-CCVD patients. Integrated Chinese and Western medicine treatments have certain advantages in controlling the severe conversion rate and mortality of COVID-19. In addition, given that COVID-19 patients are usually related to coagulation disorders and thrombosis risk, the application of Chinese medicine in promoting blood circulation and removing stasis should be strengthened.

    Weijian Hang, Chen Chen, Xin A. Zhang, Dao Wen Wang

    The COVID-19 pandemic has caused numerous deaths around the world. A growing body of evidence points to the important role of overwhelming inflammatory responses in the pathogenesis of COVID-19 and the effectiveness of anti-inflammation therapy against COVID-19 is emerging. In addition to affecting the lungs, COVID-19 can be a severe systemic inflammatory disease that is related to endothelial dysfunction. We are calling for closer attention to endothelial dysfunction in COVID-19 not only for fully revealing the pathogenic mechanism of COVID-19 but also for properly adjusting the strategy of clinical intervention.

    Rongtao Lai, Tianhui Zhou, Xiaogang Xiang, Jie Lu, Haiguang Xin, Qing Xie

    The coronavirus disease 2019 (COVID-19) has caused global public health and economic crises. Thus, new therapeutic strategies and effective vaccines are urgently needed to cope with this severe pandemic. The development of a broadly neutralizing antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the attractive treatment strategies for COVID-19. Currently, the receptor-binding domain (RBD) of the spike (S) protein is the main target of neutralizing antibodies when SARS-CoV-2 enters human cells through an interaction between the S protein and the angiotensin-converting enzyme 2 expressed on various human cells. A single monoclonal antibody (mAb) treatment is prone to selective pressure due to increased possibility of targeted epitope mutation, leading to viral escape. In addition, the antibody-dependent enhancement effect is a potential risk of enhancing the viral infection. These risks can be reduced using multiple mAbs that target nonoverlapping epitopes. Thus, a cocktail therapy combining two or more antibodies that recognize different regions of the viral surface may be the most effective therapeutic strategy.