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Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy

Min Zhang, Jingwen Yang, Wenjing Hua, Zhong Li, Zenghui Xu, Qijun Qian

《医学前沿（英文）》 2019年第13卷第1期页码 32-44 doi: 10.1007/s11684-018-0678-0

摘要：

Immunotherapy has become the fourth cancer therapy after surgery, chemotherapy, and radiotherapy. In particular, immune checkpoint inhibitors are proved to be unprecedentedly in increasing the overall survival rates of patients with refractory cancers, such as advanced melanoma, non-small cell lung cancer, and renal cell carcinoma. However, inhibitor therapies are only effective in a small proportion of patients with problems, such as side effects and high costs. Therefore, doctors urgently need reliable predictive biomarkers for checkpoint inhibitor therapies to choose the optimal therapies. Here, we review the biomarkers that can serve as potential predictors of the outcomes of immune checkpoint inhibitor treatment, including tumor-specific profiles and tumor microenvironment evaluation and other factors.

关键词： immune checkpoint companion diagnosis PD-L1 tumor mutation burden immune score

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662 A/G gene variation in human tumor necrosis factor receptor superfamily, member 9 (TNFRSF9)

QU Yanchun, YANG Ze, SUN Liang, JI Linong

《医学前沿（英文）》 2008年第2卷第3期页码 283-285 doi: 10.1007/s11684-008-0053-7

摘要： The aim of this paper is to report a new coding variance of the gene, a candidate for autoimmune diseases. We found the variation in two families with type 2 diabetes mellitus by D-HPLC mutation screening method and confirmed our results by direct sequencing and PCR-RFLP. Although without changing the amino acid coding, the variance may have an effect on codon usage and play a role in disease development, such as type 2 diabetes mellitus. However, we cannot define the role of this variance because the frequency of the minor allele is low in the Chinese population and no homozygote of the variance was found. More research in multiple populations will be necessary to define the role of this variance.

关键词： D-HPLC mutation development autoimmune PCR-RFLP candidate

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Curbing the burden of lung cancer

null

《医学前沿（英文）》 2016年第10卷第2期页码 228-232 doi: 10.1007/s11684-016-0447-x

摘要：

Lung cancer contributes substantially to the global burden of disease and healthcare costs. New screening modalities using low-dose computerized tomography are promising tools for early detection leading to curative surgery. However, the screening and follow-up diagnostic procedures of these techniques may be costly. Focusing on prevention is an important factor to reduce the burden of screening, treatment, and lung cancer deaths. The International Agency for Research on Cancer has identified several lung carcinogens, which we believe can be considered actionable when developing prevention strategies. To curb the societal burden of lung cancer, healthcare resources need to be focused on early detection and screening and on mitigating exposure(s) of a person to known lung carcinogens, such as active tobacco smoking, household air pollution (HAP), and outdoor air pollution. Evidence has also suggested that these known lung carcinogens may be associated with genetic predispositions, supporting the hypothesis that lung cancers attributed to differing exposures may have developed from unique underlying genetic mechanisms attributed to the exposure of interest. For instance, smoking-attributed lung cancer involves novel genetic markers of risk compared with HAP-attributed lung cancer. Therefore, genetic risk markers may be used in risk stratification to identify subpopulations that are at a higher risk for developing lung cancer attributed to a given exposure. Such targeted prevention strategies suggest that precision prevention strategies may be possible in the future; however, much work is needed to determine whether these strategies will be viable.

关键词： lung cancer screening risk factors environmental

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The epidemiology of norovirus gastroenteritis in China: disease burden and distribution of genotypes

Honglu Zhou, Songmei Wang, Lorenz von Seidlein, Xuanyi Wang

《医学前沿（英文）》 2020年第14卷第1期页码 1-7 doi: 10.1007/s11684-019-0733-5

摘要： With the improvements of sanitation and nationwide safe water supply the occurrence of bacterial diarrhea declined remarkably, while viruses became the leading causes of acute gastroenteritis (AGE). Of these viruses, noroviruses (NoVs) are responsible for a considerable burden of gastroenteritis, especially in children<2 years and elderly≥65 years. NoVs circulating in the Chinese population are antigenically highly diverse with the genotype GII.4 being the dominant strain followed by GII.3. Given the widespread contamination in environmental sources, and highly infectious nature of NoVs, vaccination would be the desirable strategy for the control of NoV infections. However, a better understanding of acquired immunity after infection, and a reliable immunological surrogate marker are urgently needed, since two vaccine candidates based on virus-like particles (VLPs) are currently moving into clinical evaluations in China.

关键词： molecular epidemiology norovirus disease burden genotype China

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Novel mutation c.1210-3C>G in with a poly-T tract of 5T affects mRNA splicing in a Chinese patient

《医学前沿（英文）》 2022年第16卷第1期页码 150-155 doi: 10.1007/s11684-021-0846-5

摘要： Cystic fibrosis (CF) is a rare autosomal recessive disease with only one pathogenic gene cystic fibrosis transmembrane conductance regulator (CFTR). To identify the potential pathogenic mutations in a Chinese patient with CF, we conducted Sanger sequencing on the genomic DNA of the patient and his parents and detected all 27 coding exons of CFTR and their flanking intronic regions. The patient is a compound heterozygote of c.2909G>A, p.Gly970Asp in exon 18 and c.1210-3C>G in cis with a poly-T of 5T (T5) sequence, 3 bp upstream in intron 9. The splicing effect of c.1210-3C>G was verified via minigene assay in vitro, indicating that wild-type plasmid containing c.1210-3C together with T7 sequence produced a normal transcript and partial exon 10-skipping-transcript, whereas mutant plasmid containing c.1210-3G in cis with T5 sequence caused almost all mRNA to skip exon 10. Overall, c.1210-3C>G, the newly identified pathogenic mutation in our patient, in combination with T5 sequence in cis, affects the CFTR gene splicing and produces nearly no normal transcript in vitro. Moreover, this patient carries a p.Gly970Asp mutation, thus confirming the high-frequency of this mutation in Chinese patients with CF.

关键词： cystic fibrosis CFTR splicing mutation minigene

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Nanomaterials for environmental burden reduction, waste treatment, and nonpoint source pollution control

Guobin SHAN , Rajeshwar D. TYAGI , Rao Y. SURAMPALLI , Tian C. ZHANG

《环境科学与工程前沿（英文）》 2009年第3卷第3期页码 249-264 doi: 10.1007/s11783-009-0029-0

摘要： Nanomaterials are applicable in the areas of reduction of environmental burden, reduction/treatment of industrial and agricultural wastes, and nonpoint source (NPS) pollution control. First, environmental burden reduction involves green process and engineering, emissions control, desulfurization/denitrification of nonrenewable energy sources, and improvement of agriculture and food systems. Second, reduction/treatment of industrial and agricultural wastes involves converting wastes into products, groundwater remediation, adsorption, delaying photocatalysis, and nanomembranes. Third, NPS pollution control involves controlling water pollution. Nanomaterials alter physical properties on a nanoscale due to their high specific surface area to volume ratio. They are used as catalysts, adsorbents, membranes, and additives to increase activity and capability due to their high specific surface areas and nano-sized effects. Thus, nanomaterials are more effective at treating environmental wastes because they reduce the amount of material needed.

关键词： nanomaterials industrial agricultural nonpoint source pollution environmental burden reduction

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Mutation profiling of 16 candidate genes in

Yang Zhang, Fang Wang, Xue Chen, Wenjing Liu, Jiancheng Fang, Mingyu Wang, Wen Teng, Panxiang Cao, Hongxing Liu

《医学前沿（英文）》 2019年第13卷第2期页码 229-237 doi: 10.1007/s11684-018-0616-1

摘要： This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing. We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. was the most common mutated gene (16.2%, 42/259), followed by (15.1%, 39/259), (14.7%, 38/259), and (13.5%, 35/259). Concurrence was observed in 97.1% of the mutated cases and in 29.6% of the double mutated cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the gene: mutations were associated with and/or mutations, whereas mutations co-occurred with mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.

关键词： leukemia myeloid acute gene mutation

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Heterogeneity of the tumor immune microenvironment and clinical interventions

《医学前沿（英文）》 2023年第17卷第4期页码 617-648 doi: 10.1007/s11684-023-1015-9

摘要： Heterogeneity of the tumor immune microenvironment and clinical interventions

关键词： Heterogeneity tumor immune

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Proteins moonlighting in tumor metabolism and epigenetics

Lei Lv, Qunying Lei

《医学前沿（英文）》 2021年第15卷第3期页码 383-403 doi: 10.1007/s11684-020-0818-1

摘要： Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

关键词： moonlighting function tumor metabolism epigenetics

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Complex interplay between tumor microenvironment and cancer therapy

null

《医学前沿（英文）》 2018年第12卷第4期页码 426-439 doi: 10.1007/s11684-018-0663-7

摘要：

Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

关键词： tumor microenvironment therapy response treatment resistance

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Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma

《医学前沿（英文）》 2023年第17卷第4期页码 699-713 doi: 10.1007/s11684-022-0972-8

摘要： Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%–50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

关键词： anti-CD19 chimeric antigen receptor T immunotherapy diffuse large B cell lymphoma tumor microenvironment tumor-associated macrophage metabolism

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先进设备减轻糖尿病患者的葡萄糖监测负担

Chris Palmer

《工程（英文）》 2021年第7卷第5期页码 547-549 doi: 10.1016/j.eng.2021.03.008

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Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives

null

《医学前沿（英文）》 2012年第6卷第1期页码 67-78 doi: 10.1007/s11684-012-0176-8

摘要：

Antitumor angiogenic therapy has been shown promising in the treatment of several advanced cancers since the approval of the first antiangiogenic drug Avastin in 2004. Although the current antiangiogenic drugs reduce the density of tumor blood vessels and result in tumor shrinkage at the early stage of treatment, recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy, resulting in tumor recurrence in patients after several months of treatment. Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues, which fosters tumor cells to become more aggressive and metastatic. In 2001, Jain proposed tumor vascular normalization as an alternative approach to treating cancers based on the pioneering work on tumor blood vessels by several other researchers. At present, normalizing the disorganized tumor vasculature, rather than disrupting or blocking them, has emerged as a new option for anticancer therapy. Preclinical and clinical data have shown that tumor vascular normalization using monoclonal antibodies, proteins, peptides, small molecules, and pericytes resulted in decreased tumor size and reduced metastasis. However, current tumor vascular normalizing drugs display moderate anticancer efficacy. Accumulated data have shown that a variety of vasculogenic/angiogenic tumor cells and genes play important roles in tumor neovascularization, growth, and metastasis. Therefore, multiple-targeting of vasculogenic tumor cells and genes may improve the efficacy of tumor vascular normalization. To this end, the combination of antiangiogenic drugs with tumor vascular normalizing therapeutics, as well as the integration of Western medicine with traditional Chinese medicine, may provide a good opportunity for discovering novel tumor vascular normalizing drugs for an effective anticancer therapy.

关键词： angiogenesis vasculogenesis neovascularization tumor vasculature normalization traditional Chinese medicine

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Natural killer cell lines in tumor immunotherapy

null

《医学前沿（英文）》 2012年第6卷第1期页码 56-66 doi: 10.1007/s11684-012-0177-7

摘要：

Natural killer (NK) cells are considered to be critical players in anticancer immunity. However, cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells. Current NK cell-based cancer immunotherapy is aimed at overcoming NK cell paralysis through several potential approaches, including activating autologous NK cells, expanding allogeneic NK cells, usage of stable allogeneic NK cell lines and genetically modifying fresh NK cells or NK cell lines. The stable allogeneic NK cell line approach is more practical for quality-control and large-scale production. Additionally, genetically modifying NK cell lines by increasing their expression of cytokines and engineering chimeric tumor antigen receptors could improve their specificity and cytotoxicity. In this review, NK cells in tumor immunotherapy are discussed, and a list of therapeutic NK cell lines currently undergoing preclinical and clinical trials of several kinds of tumors are reviewed.

关键词： natural killer cell natural killer cell line tumor immunotherapy genetic modification

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Nanovaccines for remodeling the suppressive tumor microenvironment: New horizons in cancer immunotherapy

Kai Shi, Matthew Haynes, Leaf Huang

《化学科学与工程前沿（英文）》 2017年第11卷第4期页码 676-684 doi: 10.1007/s11705-017-1640-4

摘要： Despite limited successes in clinical development, therapeutic cancer vaccines have experienced resurgence in recent years due to an enhanced emphasis upon co-mitigating factors underlying immune response. Specifically, reversing the immune-suppressive effects of the tumor microenvironment, mediated by a variety of cellular and molecular signaling mechanisms, has become fundamental toward enhancing therapeutic efficacy. Therein, our lab has implemented various nano-vaccines based on the lipid-coated calcium phosphate platform for combined immunotherapy, in which antigenic, epitope-associated peptides as well as immune-suppression inhibitors can be co-delivered, often functioning through the same formulation. In probing the mechanism of action of such systems and , an improved effect synergy can be elucidated, inspiring future preclinical efforts and hope for clinical success.

关键词： vaccine nanoparticle tumor immunotherapy microenvironment