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Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors

《医学前沿（英文）》 2022年 第16卷 第5期   页码 701-713 doi: 10.1007/s11684-022-0951-0

摘要： A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, which have shown remarkable success in the treatment of advanced NSCLC with EGFR activating mutations, in order to achieve maximal response duration or treatment remission. Apoptosis is a major type of programmed cell death tightly associated with cancer development and treatment. Evasion of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer therapy. It has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFR-TKIs, particularly osimertinib, to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired resistance. Hence, restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFR-TKIs.

关键词： acquired resistance     EGFR inhibitor     apoptosis     lung cancer    

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lung microbiota and important taxa predicting clinical prognosis in patients with severe community-acquired

《医学前沿（英文）》 2022年 第16卷 第3期   页码 389-402 doi: 10.1007/s11684-021-0856-3

摘要： Few studies have described the key features and prognostic roles of lung microbiota in patients with severe community-acquired pneumonia (SCAP). We prospectively enrolled consecutive SCAP patients admitted to ICU. Bronchoscopy was performed at bedside within 48 h of ICU admission, and 16S rRNA gene sequencing was applied to the collected bronchoalveolar lavage fluid. The primary outcome was clinical improvements defined as a decrease of 2 categories and above on a 7-category ordinal scale within 14 days following bronchoscopy. Sixty-seven patients were included. Multivariable permutational multivariate analysis of variance found that positive bacteria lab test results had the strongest independent association with lung microbiota (R2=0.033; P=0.018), followed by acute kidney injury (AKI; R2=0.032; P=0.011) and plasma MIP-1β level (R2=0.027; P=0.044). Random forest identified that the families Prevotellaceae, Moraxellaceae, and Staphylococcaceae were the biomarkers related to the positive bacteria lab test results. Multivariable Cox regression showed that the increase in α-diversity and the abundance of the families Prevotellaceae and Actinomycetaceae were associated with clinical improvements. The positive bacteria lab test results, AKI, and plasma MIP-1β level were associated with patients’ lung microbiota composition on ICU admission. The families Prevotellaceae and Actinomycetaceae on admission predicted clinical improvements.

关键词： severe community-acquired pneumonia     lung microbiota     clinical improvements     7-category ordinal scale     Prevotellaceae    

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bone marrow transplantation in patients with severe aplastic anemia-II that progressed from non-severe acquired

《医学前沿（英文）》 2021年 第15卷 第5期   页码 718-727 doi: 10.1007/s11684-020-0807-4

摘要： Severe aplastic anemia II (SAA-II) progresses from non-severe aplastic anemia (NSAA). The unavailability of efficacious treatment has prompted the need for haploidentical bone marrow transplantation (haplo-BMT) in patients lacking a human leukocyte antigen (HLA)-matched donor. This study aimed to investigate the efficacy of haplo-BMT for patients with SAA-II. Twenty-two patients were included and followed up, and FLU/BU/CY/ATG was used as conditioning regimen. Among these patients, 21 were successfully engrafted, 19 of whom survived after haplo-BMT. Four patients experienced grade II–IV aGvHD, including two with grade III–IV aGvHD. Six patients experienced chronic GvHD, among whom four were mild and two were moderate. Twelve patients experienced infections during BMT. One was diagnosed with post-transplant lymphoproliferative disorder and one with probable EBV disease, and both recovered after rituximab infusion. Haplo-BMT achieved 3-year overall survival and disease-free survival rate of 86.4%±0.73% after a median follow-up of 42 months, indicating its effectiveness as a salvage therapy. These promising outcomes may support haplo-BMT as an alternative treatment strategy for patients with SAA-II lacking HLA-matched donors.

关键词： severe aplastic anemia     non-severe acquired aplastic anemia     haploidentical bone marrow transplantation     outcomes    

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Analysis of antibiotic usage for viral community-acquired pneumonia in adults

Rongmeng Jiang, Bing Han, Chang Dou, Fei Zhou, Bin Cao, Xingwang Li

《医学前沿（英文）》 2021年 第15卷 第1期   页码 139-143 doi: 10.1007/s11684-019-0736-2

摘要： The rationale for the antibiotic treatment of viral community-acquired pneumonia (CAP) in adults was analyzed to develop a clinical reference standard for this condition. Clinical data from 166 patients diagnosed with viral pneumonia across 14 hospitals in Beijing from November 2010 to December 2017 were collected. The indications for medications were evaluated, and the rationale for the use of antibiotics was analyzed. A total of 163 (98.3%) patients with viral pneumonia were treated with antibiotics. A combination of C-reactive protein (CRP) and procalcitonin (PCT) was used as markers to analyze the possible indications for antibiotic use. With threshold levels set at 0.25 µg/L for PCT and 20 mg/L for CRP, the rate of unreasonable use of antibiotics was 55.2%. By contrast, at a CRP level threshold of 60 mg/L, the rate of antibiotic misuse was 77.3%. A total of 39 of the 163 (23.9%) patients did not meet the guidelines for drug selection for viral CAP in adults. The unreasonable use of antibacterial drugs for the treatment of viral CAP in adults is a serious concern. Clinicians must reduce the unnecessary use of antibiotics.

关键词： adult     antibiotic     viral pneumonia    

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Diagnosis and management of acquired thrombotic thrombocytopenic purpura in southeast China: a single

null

《医学前沿（英文）》 2016年 第10卷 第4期   页码 430-436 doi: 10.1007/s11684-016-0492-5

摘要：

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening thrombotic microangiopathy. This study aimed to provide a profile of the diagnosis and management of patients with acquired TTP collected in 10 years in a single center in southeast China. A total of 60 patients diagnosed with acute acquired TTP from March 2005 to August 2015 were enrolled. Among the 60 patients, 52 patients presented with their first episodes, and eight patients had two or more episodes. The median age at presentation was 49 (range, 17 to 78) years with a female predominance (male:female ratio, 1:1.60). ADAMTS 13 activity were analyzed in 43 patients, among whom 33 (76.7%) patients had a baseline level of<5%. Mortality was 30%. Plasma exchange (PEX) was performed in 62 of 69 (89.9%) episodes. Corticosteroids were administered in 54 of 69 (78.3%) episodes. Other immunosuppressants (e.g., vincristine, cyclosporine, and cyclosporin) were used in 7 of 69 (10.1%) episodes. Rituximab was documented in 4 patients with refractory/relapsed TTP for 5 episodes, showing encouraging results. In conclusion, the diagnosis of TTP depended on a comprehensive analysis of clinical data. Plasma ADAMTS13 activity assay helped confirm a diagnosis. PEX was the mainstay of the therapy, and rituximab can be used in relapsed/refractory disease.

关键词： thrombotic thrombocytopenic purpura     ADAMTS 13     plasma exchange    

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Prevalence of antifolate drug resistance markers in in China

《医学前沿（英文）》 2022年 第16卷 第1期   页码 83-92 doi: 10.1007/s11684-021-0894-x

摘要： The dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes of Plasmodium vivax and antifolate resistance-associated genes were used for drug resistance surveillance. A total of 375 P. vivax isolates collected from different geographical locations in China in 2009–2019 were used to sequence Pvdhfr and Pvdhps. The majority of the isolates harbored a mutant type allele for Pvdhfr (94.5%) and Pvdhps (68.2%). The most predominant point mutations were S117T/N (77.7%) in Pvdhfr and A383G (66.8%) in Pvdhps. Amino acid changes were identified at nine residues in Pvdhfr. A quadruple-mutant haplotype at 57, 58, 61, and 117 was the most frequent (57.4%) among 16 distinct Pvdhfr haplotypes. Mutations in Pvdhps were detected at six codons, and the double-mutant A383G/A553G was the most prevalent (39.3%). Pvdhfr exhibited a higher mutation prevalence and greater diversity than Pvdhps in China. Most isolates from Yunnan carried multiple mutant haplotypes, while the majority of samples from temperate regions and Hainan Island harbored the wild type or single mutant type. This study indicated that the antifolate resistance levels of P. vivax parasites were different across China and molecular markers could be used to rapidly monitor drug resistance. Results provided evidence for updating national drug policy and treatment guidelines.

关键词： drug resistance     antifolates     molecular markers     Plasmodium vivax     China    

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Metagenomic analysis on resistance genes in water and microplastics from a mariculture system

《环境科学与工程前沿（英文）》 2022年 第16卷 第1期   页码 4-4 doi: 10.1007/s11783-021-1438-y

摘要：

Microplastics existing widely in different matrices have been regarded as a reservoir for emerging contaminants. Mariculture systems have been observed to host microplastics and antibiotic resistance genes (ARGs). However, more information on proliferation of ARGs and metal resistance genes (MRGs) in mariculture system at the presence of microplastics is needed.

关键词： Antibiotic resistance genes     Metal resistance genes     Metagenomic analysis     Microplastics     Mariculture    

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Sudden death due to arrhythmogenic right ventricular cardiomyopathy: Two case reports

CHEN Xinshan, ZHANG Yigu, RAO Guangxun, HUANG Guangzhao

《医学前沿（英文）》 2007年 第1卷 第3期   页码 338-342 doi: 10.1007/s11684-007-0065-8

摘要： Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a kind of primary myocardial disease characterized by the regional or global replacement of right ventricular myocardium by fatty and fibrolipomatous tissues. The ARVC, usually presenting with different clinical manifestations and pathological changes, were mainly seen in young men and is one of the main causes of sudden death in the young. Here two autopsied cases of Chinese men aged 30 and 23 years old who appeared healthy but died suddenly while at work are reported respectively. One of the victims had extensive and severe pathological changes in his heart involving the left ventricular wall as well as the ventricular septum and the right atrium. Not only was there a global fatty and fibrolipomatous tissue replacement of the right ventricular myocardia, but also mild sarcoplasmic coagulation in the myocardium and focal lymphocytic infiltration in the myocardial interstitium of the right ventricular wall. In addition, slight atherosclerosis of the coronary artery and intimal thickening of the sino-atrial node were observed. It is believed that there are no marked differences in the pathological changes of ARVC between Chinese patients and patients from western countries. The etiology and pathogenesis of ARVC could not be explained by a single cause or factor and they are probably related to various congenital and acquired causes or factors.

关键词： sarcoplasmic coagulation     acquired     ventricular myocardium     sino-atrial     autopsied    

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Taking advantage of drug resistance, a new approach in the war on cancer

null

《医学前沿（英文）》 2018年 第12卷 第4期   页码 490-495 doi: 10.1007/s11684-018-0647-7

摘要：

Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit. We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy.

关键词： cancer     drug resistance     genetic screens     senescence     targeted therapy    

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Transmission of antibiotic resistance genes in agroecosystems: an overview

Jizheng HE, Zhenzhen YAN, Qinglin CHEN

《农业科学与工程前沿（英文）》 2020年 第7卷 第3期   页码 329-332 doi: 10.15302/J-FASE-2020333

摘要：

The use of antibiotics in human medicine and animal husbandry has resulted in the continuous release of antibiotics into the environment, which imposes high selection pressure on bacteria to develop antibiotic resistance. The spread and aggregation of antibiotic resistance genes (ARGs) in multidrug-resistant pathogens is one of the most intractable clinical challenges. Numerous studies have been conducted to profile the patterns of ARGs in agricultural ecosystems, as this is closely related to human health and wellbeing. This paper provides an overview of the transmission of ARGs in agricultural ecosystems resulting from the application of animal manures and other organic amendments. The future need to control and mitigate the spread of antibiotic resistance in agricultural ecosystems is also discussed, particularly from a holistic perspective, and requires multiple sector efforts to translate fundamental knowledge into effective strategies.

关键词： agroecosystem     antibiotic resistance     public health     soil-plant system    

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swine manure with sulfamethoxazole and norfloxacin: Dynamics of microbial communities and evolution of resistance

《环境科学与工程前沿（英文）》 2021年 第15卷 第5期 doi: 10.1007/s11783-020-1342-x

摘要：

• SMX addition had negative effect on acetoclastic methanogens in mesophilic AD.

关键词： Pig manure     Antibiotics     Anaerobic digestion     Resistance genes     Microbial community    

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Degradation of extracellular genomic, plasmid DNA and specific antibiotic resistance genes by chlorination

Menglu Zhang, Sheng Chen, Xin Yu, Peter Vikesland, Amy Pruden

《环境科学与工程前沿（英文）》 2019年 第13卷 第3期 doi: 10.1007/s11783-019-1124-5

摘要：

Extracellular DNA structure damaged by chlorination was characterized.

Integrity of extracellular ARG genetic information after chlorination was determined.

Typical chlorine doses will likely effectively diminish extracellular DNA and ARGs.

Plasmid DNA/ARGs were less readily broken down than genomic DNA.

The Bioanalyzer methodology effectively documented damage incurred to DNA.

关键词： Antibiotic resistance     Antibiotic resistance genes (ARGs)     Extracellular DNA/ARGs     Chlorination    

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Insulin resistance and the metabolism of branched-chain amino acids

null

《医学前沿（英文）》 2013年 第7卷 第1期   页码 53-59 doi: 10.1007/s11684-013-0255-5

摘要：

Insulin resistance (IR) is a key pathological feature of metabolic syndrome and subsequently causes serious health problems with an increased risk of several common metabolic disorders. IR related metabolic disturbance is not restricted to carbohydrates but impacts global metabolic network. Branched-chain amino acids (BCAAs), namely valine, leucine and isoleucine, are among the nine essential amino acids, accounting for 35% of the essential amino acids in muscle proteins and 40% of the preformed amino acids required by mammals. The BCAAs are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in insulin resistant conditions and/or insulin deficiency. Although increased circulating BCAA concentration in insulin resistant conditions has been noted for many years and BCAAs have been reported to be involved in the regulation of glucose homeostasis and body weight, it is only recently that BCAAs are found to be closely associated with IR. This review will focus on the recent findings on BCAAs from both epidemic and mechanistic studies.

关键词： branched-chain amino acids     leucine     isoleucine     valine     insulin resistance    

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Immunometabolism: a new dimension in immunotherapy resistance

《医学前沿（英文）》 2023年 第17卷 第4期   页码 585-616 doi: 10.1007/s11684-023-1012-z

摘要： Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.

关键词： immune cell     immunometabolism     metabolic reprogramming     immunotherapy     resistance     tumor microenvironment     immune checkpoint inhibitor    

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Characteristics of two transferable aminoglycoside resistance plasmids in

Chengjun Pu, Xiaoyan Gong, Ying Sun

《环境科学与工程前沿（英文）》 2019年 第13卷 第3期 doi: 10.1007/s11783-019-1119-2

摘要：

pRKZ3 is a non-conjugative IncQ plasmid, while pKANJ7 is a conjugative IncX plasmid.

The optimal mating time of pKANJ7 varied under different conditions.

Both of the two transferable ARPs had little impact on the growth of their hosts.

A relatively high level of fitness cost was observed for pKANJ7.

The fitness cost of ARPs depended on their hosts.

关键词： Escherichia coli     Characteristics     Aminoglycoside resistance plasmids     Transfer     Persistence    

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标题 作者 时间 类型 操作

Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors

期刊论文

lung microbiota and important taxa predicting clinical prognosis in patients with severe community-acquired

期刊论文

bone marrow transplantation in patients with severe aplastic anemia-II that progressed from non-severe acquired

期刊论文

Analysis of antibiotic usage for viral community-acquired pneumonia in adults

Rongmeng Jiang, Bing Han, Chang Dou, Fei Zhou, Bin Cao, Xingwang Li

期刊论文

Diagnosis and management of acquired thrombotic thrombocytopenic purpura in southeast China: a single

null

期刊论文

Prevalence of antifolate drug resistance markers in in China

期刊论文

Metagenomic analysis on resistance genes in water and microplastics from a mariculture system

期刊论文

Sudden death due to arrhythmogenic right ventricular cardiomyopathy: Two case reports

CHEN Xinshan, ZHANG Yigu, RAO Guangxun, HUANG Guangzhao

期刊论文

Taking advantage of drug resistance, a new approach in the war on cancer

null

期刊论文

Transmission of antibiotic resistance genes in agroecosystems: an overview

Jizheng HE, Zhenzhen YAN, Qinglin CHEN

期刊论文

swine manure with sulfamethoxazole and norfloxacin: Dynamics of microbial communities and evolution of resistance

期刊论文

Degradation of extracellular genomic, plasmid DNA and specific antibiotic resistance genes by chlorination

Menglu Zhang, Sheng Chen, Xin Yu, Peter Vikesland, Amy Pruden

期刊论文

Insulin resistance and the metabolism of branched-chain amino acids

null

期刊论文

Immunometabolism: a new dimension in immunotherapy resistance

期刊论文

Characteristics of two transferable aminoglycoside resistance plasmids in

Chengjun Pu, Xiaoyan Gong, Ying Sun

期刊论文