Heterogeneous nuclear ribonucleoproteins (hnRNPs) play an important role as the autoantigens in certain autoimmune disorders including neurological diseases such as HTLV‐1–associated ...myelopathy/tropical spastic paraparesis and paraneoplastic neurological syndromes. To clarify their implication in multiple sclerosis (MS), we assayed antibodies (Abs) against hnRNP A and B proteins in sera and cerebrospinal fluid (CSF) of MS patients and compared the results with 25 patients with other neurological diseases (ONDs). Using recombinant hnRNP A1, A2, and B1 proteins and Western blotting for the assay, we found Abs against hnRNP B1 in CSF from 32 of 35 MS patients (91.4%) but not in any sera or CSF of the 25 OND patients. Most notably, no Abs against hnRNP B1 were found in sera of all 22 MS patients examined. Although Abs against hnRNP A1 and A2 were concomitantly found in CSF reacting with B1, their incidence and immunoreactivity were lower or weaker than those of anti–hnRNP B1 Abs. There was no correlation between the reactivity of CSF with hnRNP B1 and CSF parameters—such as the number of the cells and the IgG level—or clinical parameters—such as duration of illness and disease activity. The selective generation of Abs against hnRNP B1 in CSF was shown to be highly specific for MS, which makes them a disease marker. Ann Neurol 2004
A case‐control study was carried out to investigate the impact of factors including virus infection, aflatoxin B1, microcystins, smoking/drinking and dietary habits as well as genetic polymorphisms ...of aldehyde dehydrogenase 2 (ALDH2) and cytochrome P4502E1 (CYP2E1), on susceptibility to hepatocellular carcinoma (HCC) in Haimen, China. A total of 248 patients with HCC and 248 sex‐, age‐ and residence‐matched population‐based controls were recruited into the study. Virus infection, and ALDH2 and CYP2E1 gene polymorphisms were assessed in 134 paired cases and controls. By univariate analysis, hepatitis B virus (HBV) infection (odds ratio OR=9.75; 95% confidence interval CI =4.71–20.2), history of intravenous injection (OR=1.50; 95%CI=1.02–2.22), average income (OR=0.63; 95% CI=0.43–0.92), frequent intake of foods rich in protein, e.g., egg (OR=0.6; 95% CI=0.42–0.87), chicken (OR=0.53; 95% CI=0.35–0.79), pork (OR=0.67; 95% CI=0.46–0.98) and fresh fish (OR=0.58; 95% CI=0.39–0.87) significantly differed between cases and controls. However, peanut intake (OR=0.66; 95% CI=0.43–1.01), source of drinking water, including tap (OR=1.33; 95% CI=0.81–2.20), deep well (OR=0.94; 95% CI=0.56–1.55), shallow well (OR=0.85; 95% CI=0.55‐–1.30), river (OR=0.95; 95% CI=0.65–1.38), ditch (OR=1.09; 95% CI=0.76–1.55) and pond water (OR=1.0; 95% CI=0.14–7.10) were not significantly associated with risk. Univariate analysis also indicated that the 1–1 genotype of ALDH2 (OR=1.38; 95% CI=0.86–2.23) as well as the Pst1‐ and Rsa1‐digested c1/c1 genotype of CYP2E1 (OR=1.36; 95% CI=0.81–2.28), was slightly more frequent in the case group. On multivariate analysis, HBV infection (OR=13.9; 95% CI=5.78–33.6) and history of intravenous injection (OR=2.72; 95% CI=1.24–6.00) were still associated with significantly increased risk of HCC, while frequent intake of fresh fish (OR=0.32; 95% CI=0.12–0.86) decreased this risk. These findings suggest that whereas peanut intake, water sources as well as genetic polymorphisms in ALDH2 and CYP2E1 do not significantly correlate with the risk of HCC, HBV infection is a main risk factor, and dietary items rich in protein, especially fresh fish, might protect against the risk of HCC in Haimen, China.
Granulocyte colony‐stimulating factor (G‐CSF)‐supported, post‐remission chemotherapy (Cx) for adult acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) was evaluated. One hundred and ...forty‐three eligible patients (median age, 41 years) including 126 ALL and 17 LBL receiving induction Cx (vincristine, cyclophosphamide, prednisolone PSL, doxorubicin, L‐asparaginase, intrathecal‐methotrexate IT‐MTX) were analyzed. For patients achieving complete response (CR), two courses of post‐remission Cx (course A of daunorubicin, cytosine arabinoside, vindesine, PSL plus IT‐MTX; course B of mitoxantrone, etoposide, vincristine, PSL plus IT‐MTX) with the use of G‐CSF were repeated alternately; thereafter, maintenance Cx including MTX and 6‐mercaptopurine was given for 2 years. One hundred and nineteen (83%) patients achieved CR, while 14 (10%) died during induction. Among the 119 patients achieving CR, five died in remission, 76 relapsed, and the remaining 38 were alive without disease. The median survival time of the 143 eligible patients was 26 months (95% confidence interval, 19–34). At a median follow‐up time of 9 years, the 5‐year survival rate was 32% and the 5‐year progression‐free survival (PFS) rate was 26%. The 5‐year survival rate of 36 patients who underwent autologous (n = 20) or allogeneic stem cell transplantation (SCT; n = 16) in the first CR group was 58%. Compared with the authors’ previous trials, survival and PFS were markedly improved. In conclusion, G‐CSF‐supported, intensive post‐remission Cx and subsequent SCT are worthy of further investigation for the treatment of adult ALL and LBL. (Cancer Sci 2007; 98: 1350–1357)
Tob is a member of the Tob/BTG family, a novel class of anti-proliferative proteins. To investigate the involvement of
tob as a tumor suppressor gene in human lung cancer, we analyzed the expression ...of
tob mRNA and protein in lung cancer tissue and adjacent normal lung tissue. Immunohistochemical analysis using anti-Tob antibody showed decreased expression of Tob in 72% (31/43) of lung cancer tissues. Furthermore, 95% (19/20) of squamous cell carcinoma patients showed an apparent decrease in Tob in cancer tissues, associated with smoking status. The phosphorylated form of Tob, an inactive form of Tob, was detected in 76% (16/21) of cancer tissues of adenocarcinoma patients, but not in normal alveolar epithelial cells. Either a decrease in Tob expression or an accumulation of phosphorylated Tob was observed from early clinical stages, even in bronchial dysplasia, a premalignant lesion of squamous cell carcinoma. The above findings suggest that the disruption of anti-proliferative Tob plays a distinct part in the early stage of lung carcinogenesis.
Heterogeneous nuclear ribonucleoprotein B1, an RNA‐binding protein required for mRNA maturation, reportedly is overexpressed in early lung cancer and in several other tumors, including precancerous ...lesions. Expression of the protein was assessed immunohistochemically in 39 specimens of malignant mesothelioma and five of non‐neoplastic pleura, and by flow cytometry in a human epithelioid mesothelioma cell line. No tumor showed overexpression, but 29 of 39 cases showed modest expression. Patients whose tumors showed expression had significantly better survival rates than others. Epithelioid tumors and reactive mesothelial cells were more likely to express the protein than sarcomatoid tumors and resting mesothelial cells. Flow cytometric analysis of an epithelioid mesothelioma cell line demonstrated stronger expression in exponentially growing than growth‐restricted cells. Heterogeneous nuclear ribonucleoprotein B1 is expressed widely in malignant mesotheliomas and in reactive mesothelial cells, but is not overexpressed. This protein may regulate proliferation linked with differentiation toward epithelioid morphology in mesothelial cells. Expression of the protein may be a prognostic indicator for patents with malignant mesothelioma. (Cancer Sci 2006; 97: 1175–1181)
EGFR mutations in lung cancer increase sensitivity to an EGFR tyrosine kinase inhibitor, gefitinib. Mutation analysis of EGFR is essential for prediction of gefitinib response and avoidance of the ...coincidental severe side effects for the unresponsive population. The purpose of the present study is to apply DHPLC as a screening system of detection of EGFR mutations for large scaled population.
EGFR mutations were detected by both DHPLC procedure and direct sequencing using lung cancer tissue samples obtained from 97 patients (81 surgical specimens and 16 pleural effusions of non-resectable lung cancer patients).
DHPLC analysis detected EGFR mutations in 5 h as opposed to 18 h by direct sequencing for ten samples, and it costs eightfold more expensive by direct sequencing than DHPLC. In addition, DHPLC analysis was sixfold more sensitive than sequencing analysis for detection of the point mutation of exon 21, L858R. Using this system, EGFR mutations in exons 18, 19 and 21 were found in 34 of 97 patients (36%). Thirteen of the 15 patients with exon 21 mutations (87%) were female non-smokers, who were diagnosed with adenocarcinomas with the feature of BAC. Eight of the 18 patients with exon 19 mutations (44%) were 7 male and 1 female current or former smokers, and BAC feature was observed in 61% (8/18).
DHPLC analysis for screening followed by sequencing analysis appears to be more sensitive and accurate, as well as easier and faster. In addition, these results suggest different mutagenesis and carcinogenesis pathways for mutations.
A 67-year-old Japanese woman who presented with erythema on the abdomen and pancytopenia was found to have acute promyelocytic leukemia (APL). A skin biopsy revealed invasion of APL cells. She was ...started on induction treatment with all-trans retinoic acid (ATRA) at 45 mg/m
2
. On day 4, the leukemic cell number had increased to over 1.0 × 10
9
/L. Consequently, chemotherapy with idarubicin and cytarabine was initiated. On day 10, dryness of the lips appeared. The lower lip swelled and developed painful black eschars. A high fever was also present. Despite discontinuing ATRA on day 20 and administering antibiotics, an anti-fungal agent and valaciclovir, these signs did not improve. Histopathologically, the biopsied lip revealed infiltration of neutrophils and vasculitis. The patient was given ATRA on days 29 and 30 due to an increase in APL cell numbers, after which the gangrenous cheilitis extended over the whole lip. On day 49, the patient was started on re-induction treatment with arsenic trioxide. She achieved complete remission and the gangrenous cheilitis slowly healed over the following 8 weeks. Since the clinical features of the gangrenous cheilitis in this case were similar to those of ATRA-associated scrotal ulcers, it appears that activated neutrophils derived from differentiated APL cells may have caused the gangrenous cheilitis. Physicians should be alert to the development of gangrenous cheilitis during treatment with ATRA.
Human T cell leukemia virus type 1 (HTLV-1) mainly infects CD4+ T cells and induces chronic, persistent infection in infected individuals, with some developing adult T cell leukemia/lymphoma (ATL). ...HTLV-1 alters cellular differentiation, activation, and survival; however, it is unknown whether and how these changes contribute to the malignant transformation of infected cells. In this study, we used single-cell RNA-sequencing and T cell receptor-sequencing to investigate the differentiation and HTLV-1-mediated transformation of T cells. We analyzed 87,742 PBMCs from 12 infected and 3 uninfected individuals. Using multiple independent bioinformatics methods, we demonstrated the seamless transition of naive T cells into activated T cells, whereby HTLV-1-infected cells in an activated state further transformed into ATL cells, which are characterized as clonally expanded, highly activated T cells. Notably, the greater the activation state of ATL cells, the more they acquire Treg signatures. Intriguingly, the expression of HLA class II genes in HTLV-1-infected cells was uniquely induced by the viral protein Tax and further upregulated in ATL cells. Functional assays revealed that HTLV-1-infected cells upregulated HLA class II molecules and acted as tolerogenic antigen-presenting cells to induce anergy of antigen-specific T cells. In conclusion, our study revealed the in vivo mechanisms of HTLV-1-mediated transformation and immune escape at the single-cell level.
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