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Fanconi anemia (FA) is an inheritable disorder that presents with bone marrow failure, developmental anomalies, and an increased susceptibility to cancer. The etiology of this condition stems from a genetic mutation that disrupts the proper repair of interstrand DNA cross-links (ICLs). The resultant dysregulation of the DNA damage response mechanism can induce genomic instability, thereby elevating the mutation rates and the likelihood of developing cancer. The FA pathway assumes a pivotal role in safeguarding genome stability through its involvement in the repair of DNA cross-links and the maintenance of overall genomic integrity. A mutation in the germ line of any of the genes responsible for encoding the FA protein results in the development of FA. The prevalence of aberrant FA gene expression in somatic cancer, coupled with the identification of a connection between FA pathway activation and resistance to chemotherapy, has solidified the correlation between the FA pathway and cancer. Consequently, targeted therapies that exploit FA pathway gene abnormalities are being progressively developed and implemented. This review critically examines the involvement of the FA protein in the repair of ICLs, the regulation of the FA signaling network, and its implications in cancer pathogenesis and prognosis. Additionally, it explores the potential utility of small-molecule inhibitors that target the FA pathway.
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Objective To evaluate the diagnostic value of T cells spot test of tuberculosis infection (T-SPOT .TB) on blood and cerebrospinal fluid for tuberculous meningitis (TBM ).Methods One hundred and fifteen adult patients with suspected tuberculous meningitis were retrospectively enrolled from March 2013 to March 2017 in Huashan Hospital affiliated to Fudan University .Among them ,30 were diagnosed with TBM (7 definite ,19 highly probable and 4 possible) ,37 with other infectious meningitis and 29 with non-infectious meningitis .The diagnostic sensitivity ,specificity ,positive predictive values (PPV) and negative predictive values (NPV) of T-SPOT .TB on peripheral mononuclear cells (PBMC) and cerebrospinal fluid mononuclear cells (CSF-MC ) were analyzed using Fisher exact test , and the diagnostic performance was evaluated by using receiver operating characteristic (ROC ) curve and area under the curve (AUC).Results When including the 30 TBM cases and 66 non-TBM cases into analysis , the sensitivities and specificities , PPV and NPV of PBMC and CSF-MC for diagnosing TBM were as follows :93 .1% and 66 .7%,77% and 87 .7%,65 .9% and 71 .4%,95 .9% and 85 .1%,respectively . When including the 30 TBM and 37 other infectious meningitis into analysis , the sensitivities and specificities ,PPV and NPV of the PBMC and CSF-MC for diagnosing TBM were as follows :93 .1% and 66.7%,68 .6% and 86 .5%,71.1% and 80 .0%,92 .3% and 76 .2%,respectively .By ROC curve analysis ,the AUC of blood and CSF were 0 .882 (95% CI :0 .795－0 .969) and 0 .814 (95% CI :0 .704－0 .925) ,respectively .Using a cut-off value of 32 spot forming cells (SFC) per million CSF-MC for T-SPOT .TB on CSF-MC showed a sensitivity of 66 .7%,a specificity of 91 .9%,PPV of 87 .0% and NPV of 77 .3% .The positive likelihood ratio and negative likelihood ratio were 8 .22 and 0 .363 respectively . Conclusions T-SPOT .TB on CSF-MC has a role in diagnosing TBM .And 32 SFC per million CSF-MC might be the optimal cut-off value to differentiate TBM and non-TBM .
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Objective To analyze the expressions of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) in the peripheral blood of patients with active tuberculosis (ATB ) or latent tuberculosis infection (LTBI) ,and to evaluate its diagnostic value in differentiation of ATB and LTBI .Methods Forty-eight patients including 18 ATB cases and 30 LTBI cases were continuously enrolled from Wuxi No . 5 People′s Hospital and Huashan Hospital affiliated to Fudan University from January 2011 to March 2013 .Flow cytometry was applied to detect the CTLA-4 expression in CD4+CD25+ FoxP3+ T cells in the peripheral blood of the 48 subjects .CTLA-4 levels were compared using non-parametric Mann-Whitney U test .Results The median percentage of CTLA-4+ Treg in CD4+ CD25+ Foxp3+ Treg cells of ATB patients was 18 .95％ (quantile range :13 .86％ ,27 .73％ ) ,and that in LTBI patients was 6 .67％(quantile range :5 .74％ ,9 .59％ ) ,which was statistically significant (U=18 .0 , P< 0 .01) .Receiver operating curve (ROC) based on the CTLA-4 expression indicated that the area under the curve was 0 .96 , with the optimum cut-off value of 13 .25％ .Thus ,the sensitivity and specificity for the diagnosis of ATB were 86 .7％ and 94 .4％ ,respectively .Conclusion CTLA-4 has highly sensitivity and specificity for the differential diagnosis of ATB and LTBI whose interferon-gamma releasing assays are all positive ,which may also provide meaningful clue for the study of pathogenesis of ATB .
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Objective To explore the role of basic leucine zipper ATF-like transcription factor (BATF) in active tuberculosis, and to provide clues for diagnosis and therapy of tuberculosis.Methods Sixteen patients with active tuberculosis (ATB), ten cases of latent tuberculosis infection (LTBI) and fourteen healthy controls (HC) were included in this study.Flow cytometry was applied to detect the expressions of BATF and programmed death-1 (PD-1) in T lymphocytes, and the changes of BATF by blockade of PD-1/PD-L pathway using specific blocking antibody antiPD-1, antiPD-L1 and antiPD-L2.The expressions of BATF were compared using Mann-Whitney U test.And the relation of BATF and PD-1 was analyzed using Pearson correlation analysis.Results The CD4+ T lymphocytes expressing BATF accounted for 5.16% (2.96%,8.71%) of CD4+ T lymphocytes in ATB group, which was higher than 1.05% (0.40%,1.27%) in LTBI group and 0.71%(0.43%,1.21%) in HC group, and the difference were statistically significant (U value were 6.5 and 9.0, respectively, both P<0.01).The CD8+ T lymphocytes expressing BATF accounted for 4.10% (2.27%,8.17%) of CD8+ T lymphocytes in ATB group, which was higher than 0.55% (0.34%,1.18%) in LTBI group and 0.84% (0.41%,1.29%) in HC group, and the difference were statistically significant (U value were 5.0 and 8.0, respectively, both P<0.01).Furthermore, the percentage of BATF+ PD-1+ CD4+ T lymphocytes in the peripheral blood of ATB was significantly higher than those in the peripheral blood of LTBI and HC, the difference were statistically significant (Uvalue were 16.0 and 14.5, respectively, both P<0.01), and the percentage of BATF+ PD-1+ CD8+ T lymphocytes in the peripheral blood of ATB was significantly higher than those in the peripheral blood of LTBI and HC, the difference were statistically significant (Uvalue were 10.0 and 16.5, respectively, both P<0.01).In addition, there was a positive correlation between the percentage of BATF+ T cells and PD-1+ T cells, both in CD4+ T cells (r=0.676,P=0.016) and CD8+ T cells (r=0.610,P=0.035).The expressions of BATF both in CD4+ T cells and CD8+ T cells were decreased followed by blockade of PD-1/PD-L pathway (P<0.05).Conclusions BATF may be involved in the regulation of immune pathogenesis of tuberculosis.In order to provide a theory for anti-tuberculosis immunotherapy fargeting BATF, further research need to be proceeded.
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OBJECTIVE:To investigate clinical efficacy and safety of trastuzumab combined with neoadjuvant chemotherapy on breast cancer,and discuss its effects on the expression of HER2 protein,B7 homolog 1(B7-H1)and IL-2. METHODS:62 patients with breast cancer confirmed by pathological biopsy,whose test results of immunohistochemistry combined with fluorescence in situ hybridization(FISH)was overexpression of HER2,were selected as the research object. They were randomly divided into observa-tion group and control group with 31 cases in each group. Control group was given carboplatin combined with docetaxel neoadjuvant chemotherapy before surgery. Observation group was additionally given Trastuzumab for injection intravenously 4 mg/kg in the first week,2 mg/kg in second-eighteenth week,once a week,for consecutive 18 weeks. Modified radical mastectomy was conducted 2 weeks after chemotherapy. Clinical efficacy and the occurrence of ADR were observed in 2 groups. The expression of HER2 protein, B7-H1 and IL-2 in tumor tissues were compared between 2 groups before and after treatment. With 1-year follow-up,tumor recur-rence rates,metastasis rates and survival rates were recorded in 2 groups. RESULTS:After treatment,total effective rate of observa-tion group was 83.87%,which was significantly higher than that of control group (58.06%),with statistical significance (P0.05). During 1-year follow-up period,except that there was no statistically significant difference in survival rate be-tween 2 groups(P>0.05),the recurrence rate and metastasis rate of observation group were significantly lower than those of control group,with statistical significance(P<0.05). CONCLUSIONS:The application of trastuzumab combined with neoadjuvant chemo-therapy before breast cancer modified radical mastectomy can effectively improve the expression levels of HER2 protein,B7-H1 and IL-2 in lesion tissue of patients with breast cancer,promote clinical efficacy with good safety and low risk of tumor recurrence and metastasis after operation.
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Objective To analyze the expression of interleukin (IL)-31 in tuberculous pleural effusion,and to evaluate its diagnostic value of tuberculous effusion.Methods Seventy-one patients with pleural effusion were enrolled,including 40 cases of tuberculous pleural effusion and 31 cases of malignant pleural effusion.Luminex method was applied to detect the IL-31 expression in pleural effusion.IL-31 levels were compared using non-parametric Mann-WhitneyU test,and the receiver operator characteristic (ROC)curve was used to elvaluate the diagnostic value of IL-31 .Results IL-31 expression in tuberculous pleural effusion was significantly higher than that in malignant pleural effusion with statistical significance (529.4 ng/L vs 13.8 ng/L,U =62,P <0.01 ).Based on the level of IL-31 expression,area under the ROC curve was 0.95 with the optimum cut-off value of 67.5 ng/L.Thus,the sensitivity and specificity of IL-31 ≥67.5 ng/L for diagnosis of tuberculous pleurisy were 82.5 % (95 %CI :73.3% - 94.2%)and 100.0% (95 %CI :91 .4%-100.0%),respectively.Conclusion IL-31 is highly sensitive and specific for the diagnosis of tuberculous pleural effusion, which favors the differentiation of tuberculosis from malignance.
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Objective To investigate the incidence,bacterial pathogen and risk factors of bacterial meningitis after major craniotomy.Methods Clinical data of patients who underwent at least one craniotomy in Huashan Hospital Affiliated to Fudan University in 2008 were collected.All subjects were ≥ 18 years old,and survived at least 7 days after surgery.Patients with only cerebrospinal fluid drainage,burr holes,cranioplasty,vascular interventional surgery,transsphenoidal or spinal surgery were excluded.Risk factors for bacterial meningitis after major craniotomy were analyzed by Logistic regression.Results A total of 691 patients were enrolled,in 60 of whom (8.68％) bacterial meningitis was identified.Among 44 samples,5 were positive in culture with 2 of Acinetobacter baumannii,1 of Enterococcus faecalis,1 of Streptococcus intermedius and 1 of Klebsiella pneumonia.Diabetes (OR =5.79,95％ CI:1.40-23.93,P =0.02),Glasgow Coma Scale score ＜ 12 (OR =6.56,95％ CI:1.17-36.80,P =0.03),external ventricular drainage (OR =4.31,95％ CI:1.57-11.82,P =0.01),and continuous lumbar cistern drainage (OR =22.82,95％ CI:10.31-50.52,P =0.00) were independent risk factors for bacterial meningitis after major craniotomy.Patients with external ventricular drainage ＞ 7 d were 11.82 times more likely to develop bacterial meningitis,and those with continuous lumbar cistern drainage ＞ 10 d were 25.50 times more likely to develop bacterial meningitis.Conclusions Bacterial meningitis remains a common complication after major craniotomy,and most are induced by Gram-negative bacilli.Diabetes,Glasgow Coma Scale score,external ventricular drainage and continuous lumbar cistern drainage may increase its incidence.