Targeting histone deacetylases for cancer therapy: Trends and challenges

Dysregulation of histone deacetylases (HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors (HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.

Helicobacter pylori promotes gastric cancer metastasis via up-regulating the expression of Bmi-1 / 细胞与分子免疫学杂志

Objective To clarify whether Helicobacter pylori (H. pylori) can promote metastasis of gastric cancer cells via the high-expression of induced B cell specific Moloney murine leukemia virus integration site 1 (Bmi-1). Methods The gastric cancer tissue specimens from 82 patients were collected for this study. The protein and gene expression level of Bmi-1 in gastric adenocarcinoma tissue were detected by immunohistochemistry and real time quantitative PCR, respectively. And meanwhile the correlation between Bmi-1 levels and pathological features, and prognosis of gastric cancer were analyzed retrospectively. Then, the GES-1 cells were transfected with pLPCX-Bmi-1 plasmid and infected with H. pylori respectively. After the Bmi-1 overexpression in GES-1 cells, the invasion ability of the GES-1 cells was detected by Transwell assay, and the cell cycle and apoptosis were detected by flow cytometry. Results The mRNA and protein of Bmi-1 expression in gastric cancer tissues were higher than tumor-adjacent tissue, and the high expression of Bmi-1 was positively correlated with tumor invasion, TNM stage, tumor differentiation, lymph node metastasis and H. pylori infection. When expression of Bmi-1 was up-regulated as a result of H.pylori infection or pLPCX-Bmi-1 transfection, the GES-1 cells had higher invasiveness and lower apoptosis rate with the above treatment respectively. Conclusion H. pylori infection can inhibit the apoptosis of gastric cancer cells and promote their invasion via up-regulating expression of Bmi-1.

Effects of broad-spectrum antibiotics on the efficacy of 5-fluorouracil treatment of CT26 tumor-bearing mice / 中华微生物学和免疫学杂志

Objective:To study the effects of broad-spectrum antibiotics and induced antibiotic-resistant bacteria on the efficacy of 5-fluorouracil (5-FU) chemotherapy for mice with colon cancer and to investigate the underlying mechanisms associated with anti-tumor immune responses.Methods:BALB/c mice were subcutaneously injected with CT26 colon cancer cells and randomized into four groups: tumor-bearing control group, antibiotic group treated with ampicillin, streptomycin and colistin, 5-FU group and anitibiotic+ 5-FU group. Tumor volumes and body weights were measured and recorded. Seven days after the last 5-FU treatment, the percentages of splenic immune cell subpopulations and proliferated CD8 + T cells after co-culturing with CT26 were analyzed by flow cytometry. Gut microbiota composition was detected by 16S rRNA sequencing and the bacteria in mesenteric lymph nodes (mLN) were isolated and cultured. Bone marrow-derive macrophages were stimulated with identified bacteria and the expression of M1 and M2 polarization markers were assessed by quantitative PCR. The proliferation of CD8 + T cells co-cultured with bacteria-treated macrophages was analyzed by flow cytometry. In addition, tumor-bearing mice were treated with 5-FU and oral gavage of bacteria isolated from antibiotic+ 5-FU group or PBS. Tumor volumes, gut microbiota composition and the percentages of proliferated CD8 + T cells co-cultured with CT26 were assessed. Results:Tumor volumes were larger and body weights were lower in the antibiotic+ 5-FU group than in the 5-FU group. The percentages of CD4 + T cells, CD8 + T cells and neutrophils did not varied significantly after using antibiotics, however, the percentage of monocytes was increased in the antibiotic group. The percentage of proliferated tumor-specific CD8 + T cells in the antibiotic+ 5-FU group was decreased compared with that in the 5-FU group. Compared with the control group and 5-FU group, antibiotic usage was associated with the changes in gut microbiota composition with decreased α diversity indexes. Escherichia coli, Klebsiella pneumonia, and Proteus mirabilis were isolated from mLNs of the antibiotic group, 5-FU group and antibiotic+ 5-FU group, respectively. Bone marrow-derived macrophages stimulated with Proteus mirabilis expressed arginase at a high level, which was a M2 polarization marker of macrophage, and associated with the decreased percentage of proliferated CD8 + T cells after co-culturing. Bacteria of the genus Proteus were enriched in the gut microbiota of 5-FU-treated tumor-bearing mice with the oral gavage of Proteus mirabilis. Although no significant inhibitory effect on tumor growth was observed, the oral gavage of Proteus mirabilis was associated with the decreased percentage of proliferated tumor-specific CD8 + T cells in vitro. Conclusions:Broad-spectrum antibiotics inhibited the efficacy of chemotherapy and the proliferation of tumor-specific CD8 + T cells, in which antibiotic-resistant bacteria might be involved.

Clinical analysis of methylmalonic acidemia and hyperhomocysteinemia with diffuse lung disease as an initial or main presentation / 中华儿科杂志

Objective@#To improve the awareness of methylmalonic acidemia and hyperhomocysteinemia with diffuse lung disease as an initial or main presentation.@*Methods@#A retrospective analysis of the clinical manifestations, radiological features, laboratory tests, genetic variations, treatments and prognoses was conducted in six children presented with diffuse lung disease and finally diagnosed with methylmalonic acidemia and hyperhomocysteinemia in Ward 2 of Department of Respiratory Diseases, Beijing Children′s Hospital, from August 2017 to November 2018.@*Results@#Six children were included in this study. Two children were male and four were female. The average age of onset was 28 months. The mean age at diagnosis was 34 months. The average interval from onset to diagnosis was 6 months. Four children who underwent genetic tests were found to have variants of gene MMACHC and diagnosed with CblC type. All children had respiratory symptoms and signs as initial or main presentation, which were tachypnea (5 cases), exercise intolerance (5 cases), cough (4 cases), cyanosis (4 cases), clubbing (4 cases), dyspnea (3 cases) and retractions (3 cases). Pulmonary arterial hypertension was found in all six children. Pericardial effusion (4 cases), kidney involvement (3 cases), nervous system involvement (3 cases), gastrointestinal system involvement (3 cases) and anemia (2 cases) also coexisted. The high resolution computed tomography (HRCT) features included dilated pulmonary artery (6 cases), ground-glass opacities (4 cases), diffuse poorly defined ground-glass centrilobular nodules (3 cases), pleural effusion (3 cases), thickening of interlobular septum (2 cases), etc. All children had an elevated concentration of methylmalonic acid in urine and homocysteine in plasma. Genetic tests were performed in four patients, and MMACHC genetic mutations were found in all of them. Clinical manifestations, HRCT features and pulmonary arterial hypertension turned better in five children after treatment. One patient who was not regularly followed-up died.@*Conclusions@#Pulmonary involvement including diffuse lung disease and pulmonary arterial hypertension could coexist with methylmalonic acidemia and hyperhomocysteinemia, which may have respiratory symptoms and signs as the initial or main presentation. Characteristic HRCT features were found in some patients. Plasma homocysteine test is a quick method for screening the disease in children with diffuse lung disease and (or) pulmonary arterial hypertension. Both diffuse lung disease and pulmonary arterial hypertension may turn better after treatment.

Clinical features of pediatric tuberculous pleurisy / 中华实用儿科临床杂志

Objective To sum up the clinical manifestations and laboratory features for the diagnosis of pediatric tuberculous pleurisy,and to improve the recognition of this disease in early stage.Methods A retrospective study of 113 children diagnosed as tuberculous pleurisy from August 2006 to September 2014 in the Second Department of Respiratory Medicine,Beijing Children's Hospital Affiliated to Capital Medical University was conducted.Meanwhile,another 113 cases of children with mycoplasma pneumoniae pneumonia complicated with pleurisy were selected as control group.The general information,clinical symptoms,pleural effusion and imaging features between 2 groups were analyzed and compared by using SPSS 16.0 statistical software.Results The proportion of patients with cough in tuberculous pleurisy group and control group was 47.79％ (54/113 cases) and 99.12％ (112/113 cases) (x2 =76.33,P ＜ 0.01) respectively,and the proportion with severe cough was 3.70％ (2/54 cases) and 97.32％ (109/112 cases) (x2 =144.10,P ＜0.01),while the disease duration was 15.00 (10.00,30.00) days and 10.00 (8.00,14.50) days (W =8 668.00,P ＜ 0.01),respectively,and all the differences between 2 groups were significant.The proportion of patients with low fever,moderate fever,high fever and hyper fever was 8.65％ (9/104 cases),47.12％ (49/104 cases),44.23 ％ (46/104 cases) and 0,respectively in tuberculous pleurisy group,while the proportion was 0.90％ (1/111 cases),18.92％ (21/111 cases),79.28％ (88/111 cases) and0.90％ (1/111 cases) respectively in control group,and the difference between 2 groups was significant(W =9 064.00,P ＜ 0.01).The unilateral effusion ratio in tuberculous pleurisy group and the control group was 94.69％ (107/113 cases) and 71.68％ (81/113 cases),respectively (x2 =21.39,P ＜ 0.01).The monocyte ratio was higher in tuberculous pleurisy group [0.89 (0.76,0.93)] than that in the controlgroup [0.60 (0.30,0.78)] (W =888.50,P ＜ 0.01) and the level of protein in 2 groups was [51.00 (47.35,54.20) g/L] and [42.10 (37.85,46.15) g/L],respectively (W =842.50,P ＜ 0.01).The level of lactate dehydrogenase (LDH) in tuberculous pleurisy group[553.50 (358.00,749.25) U/L] was lower than that in the control group[1 189.10 (670.95,1 820.00) U/L] (W =2 186.00,P ＜ 0.01),and the differences were significant between 2 groups.In addition to pleural effusion,the high density was the main feature of imaging examination in 2 groups.The proportion of patients with atelectasis was 77.88％ (88/113 cases) and 4.42％ (5/113 cases) (x2 =125.90,P ＜ 0.01),while the proportion of patients with consolidation was 4.42％ (5/113 cases) and 72.57 ％ (82/113 cases),respectively (x2=110.80,P ＜ 0.01).All the differences between 2 groups were significant.The sputum culture-positive rate of mycobacterium tuberculosis was only 1.77％ (2/113 cases) and the other pathogen examinations were negative in tuberculous pleurisy group.Conclusions For patients with unilateral pleural effusion,when the onset only has fever (moderate-high fever),and respiratory symptoms are not clear or symptoms are not proportional to radiographic severity,or when high monocytes proportion (＞ 0.70) in pleural effusion and radiographic evidence of compression atelectasis are observed,tuberculous pleurisy should be considered and further questioning of the predisposing factors,purified protein derivative test should be taken so as to diagnose the tuberculous pleurisy at early stage.

Diagnostic value of transbronchial lung biopsy in pediatric interstitial lung diseases / 中华实用儿科临床杂志

Objective To evaluate the diagnostic value of transbronchial lung biopsy (TBLB) in pediatric interstitial lung diseases.Methods Retrospective data evaluation the efficacy and application of 10 undiagnosed pediatric interstitial lung diseases patients by No-X-ray guided TBLB between December 2013 and December 2014 were investigated.Results Specimens from all cases were successfully obtained,6 patients were confirmed by pathological diagnoses,and4 patients were confirmed by pathology and clinical manifestations.Among 10 patients,3 of them had allergic alveolitis,2 cases had bronchiolitis obliterans organizing pneumonia (BOOP),1 had pulmonary vasculitis,2 cases had nonspecific interstitial pneumonia,and the other 2 had bronchiolitis obliterans.The complications include 2 pneumothorax,1 case was cured with thoracic cavity closed drainage,and the other case case did not receive special treatment and alleviated himself.No bleeding and other complications occurred.Conclusion The results suggest that TBLB is a safe and effective minimally invasive modality for the diagnosis of pediatric diffuse lung disease.

Clinical characteristics of children with Langerhans cell histiocytosis with pulmonary involvement / 中华儿科杂志

<p><b>OBJECTIVE</b>To improve the recognition of the clinical presentation and radiologic manifestation of children with Langerhans cell histiocytosis (LCH) with pulmonary involvement.</p><p><b>METHOD</b>A retrospective analysis was conducted on children who presented with respiratory symptoms or abnormal lung radiologic findings, and finally diagnosed with LCH in Ward 2 of Divison of Respiratory Diseases, Beijing Children's Hospital during the last 4 years.</p><p><b>RESULT</b>Fourteen children (10 boys and 4 girls) were included in this study. Male to female ratio was 2.5: 1. The median age was 1.3 years. Pulmonary involvements were coexisted with other involved organs in all the patients, such as skin (10 cases, 71%), liver (8 cases, 57%), and bone involvement (7 cases, 50%). The most common symptoms were cough and fever (7 cases, 50%). Respiratory symptoms were nonspecific, and 3 children had no respiratory symptom but abnormal findings on lung high-resolution CT (HRCT). The most common HRCT finding was the coexistence of nodules and cysts (6 cases, 43%). Other findings include cysts only (5 cases, 36%), nodules only (1 case), and with neither nodule nor cyst (2 cases, 14%). Pneumothorax was found in 7% of children.</p><p><b>CONCLUSION</b>Pulmonary involvement in children with LCH is easily misdiagnosed, and often coexisted with other involved tissues/organs such as skin and liver. Rash, which is easily missed in physical examination is very important for the diagnosis of LCH. The characteristic findings of lung HRCT (nodules and/or cysts) are helpful for diagnosis.</p>

Influence of Heat Shock Treatment upon the Expression of Membrane HSP70 and Its mRNA of H22 Cell / 中国肿瘤生物治疗杂志

To identify the best inducing condition, we studied the expression of membrane protein HSP70 and mRNA of H22 cell at various temperature. Using MTT,RT-PCR, immunofluorescence and FCM techniques, we observed H22 cell survival rate, the expression of HSP70 mRNA and membrane HSP70. No effects of H22 cell survival rate under 42 ~ 43℃ was observed, but cell survival rate declined with increasing stress time at 44 ~ 45 ℃; the level of HSP70 mRNA decreased initially (0.5~4.0) hours but gradually resumed and increased from 8 to 12 hours at 42℃. Membrane HSP70 expressing cells were significently higher in heat shock treatment group than in a control group ( P