[Clinical characteristics of human recombination activating gene 1 mutations in 8 immunodeficiency patients with diverse phenotypes].

Objective: To investigate the clinical characteristics of 8 immunodeficiency cases caused by human recombination activating gene 1 (RAG1) mutations, and to explore the relationship among genotypes, clinical manifestations and immunophenotypes. Methods: Clinical data were collected and analyzed from patients with RAG1 mutations who visited the Department of Clinical Immunology, Children's Hospital of Fudan University between October 2013 and June 2017. The data included clinical manifestations, immunophenotypes and genotypes. Results: A total of 8 patients were diagnosed with RAG1 deficiency (6 boys and 2 girls). The minimum age of onset was 2 months, and the maximum age was 4 months. The minimum age of diagnosis was 2 months, and the maximum age was 13 years. Four patients had a family history of infant death due to severe infections. Two cases were born to the same consanguineous parents. All cases had recurrent infections, including involvement of respiratory tract (8 cases), digestive tract (6 cases), urinary tract (1 case), and central nervous system (1 case). The pathogens of infection included bacteria, viruses and fungi. Rotavirus was found in 3 cases, cytomegalovirus (CMV) in 5 cases, bacillus Calmette-Guérin adverse reaction in 2 cases (1 of whom had a positive acid-fast smear from lymph node puncture fluid), fungal infection in 3 cases. One case had multiple nodular space-occupying lesions in lungs and abdominal cavity complicated with multiple bone destruction. The peripheral blood lymphocyte counts of all patients ranged between 0.1 ×10(9)/L and 3.3×10(9)/L (median, 0.65×10(9)/L). Eosinophilia was found in 3 cases (range, (0.48-1.69) ×10(9)/L). The patients were classified according to immunophenotype as severe combined immunodeficiency phenotype (4 cases), leaky severe combined immunodeficiency (2 cases), Omenn syndrome (1 case) and combined immunodeficiency (1 case) . Decreased serum IgG levels were found in 3 cases, increased serum IgM levels in 3 cases, increased serum IgE levels in 5 cases. RAG1 homozygous mutations were detected in 5 cases and RAG1 compound heterozygous mutations in 3 cases. Two novel mutations and six previously reported mutations were identified. Three cases were successfully treated with hematopoietic stem cell transplantation. Four cases died due to infections, and the 13 year-old patient was still under follow-up in the outpatient clinic. Conclusions: Different RAG1 gene mutations can lead to diverse clinical presentations and immune phenotypes. Clinicians should pay attention to the family history of infant death with severe infection. In that situation, immunological evaluation and gene detection should be performed as early as possible.

[Analyses of clinicopathologic factors affecting neck control after postoperative radiation as adjuvant treatment for lymph node metastasis in head and neck squamous cell carcinoma].

OBJECTIVE: To investigate the clinicopathologic factors associated with neck control and distant metastasis in patients with neck metastases in head and neck squamous cell carcinoma (HNSCC) after postoperative radiation as adjuvant treatment. METHODS: Clinicopathologic data of 208 pathologic N+ (pN+ ) patients with HNSCC initially treated with neck dissection and postoperative radiation in Bethune International Peace Hospital of China from January 2004 to December 2009 were reviewed. The clinicopathologic factors, includeding age, sex, primary tumor site, pathologic T and N stage, tumor growth pattern, histological grade, tumor resection margin, size and number of positive lymph node, number of levels with positive lymph node, and extracapsular nodal spread (ECS), were evaluated for their association with neck control and distant metastasis in patients with HNSCC after postoperative radiation. Univariate χ(2) test and multiple stepwise logistic regression model were used for the analysis. RESULTS: Overall 5-year neck control rate after postoperative radiotherapy was 72.6% (151/208), with 84.0% (63/75) for SND, 72.9% (78/107) for MRND, and 38.5% (10/26) for RND, respectively. Univariate analysis showed that neck control after postoperative radiation was related with following factors: primary tumor site, pathologic N stage, size of positive node, number of levels with positive node, number of positive node, and ECS. Pathologic N stage and number of levels with positive lymph node were associated with distant metastasis. Multivariate analysis indicated that ECS was the most significant risk factor for neck metastasis after surgery and postoperative radiotherapy and the number of levels with positive node was the most significant risk factor for distant metastasis. CONCLUSIONS: ECS is the most important pathologic factor in planning postoperative adjuvant treatment for pN+ patients with HNSCC, therefore ECS should be evaluated routinely after neck dissection. The value of postoperative radiotherapy in controlling the ECS-related recurrence after surgery is limited. Postoperative concurrent chemoradiotherapy and targeted therapy can be considered in HNSCC patients with ECS.

Synthesis and DNA cleavage activity of a novel bleomycin A(5) glycoconjugate.

[structure in text] To explore the possibility of modifying bleomycin in a fashion that could alter its physiological distribution in a therapeutic setting, a new analogue of bleomycin has been prepared. This analogue is intended to target the asialoglycoprotein receptor on liver cells. Critically, despite the large C-substituent, the bleomycin conjugate was found to degrade DNA in the same fashion as bleomycin A(5) itself, and with only modestly decreased efficiency.

Imidazole-imidazole pair as a minor groove recognition motif for T:G mismatched base pairs.

The T:G mismatched base pair is associated with many genetic mutations. Understanding its biological consequences may be aided by studying the structural perturbation of DNA caused by a T:G base pair and by specific probing of the mismatch using small molecular ligands. We have shown previously that AR-1-144, a tri-imidazole (Im-Im-Im) minor groove binder, recognizes the sequence CCGG. NMR structural analysis of the symmetric 2:1 complex of AR-1-144 and GAACCGGTTC revealed that each AR-1-144 binds to four base pairs with the guanine N2 amino group forming a bifurcated hydrogen bond to a side-by-side Im/Im pair. We predicted that the free G-N2 amino group in a T:G wobble base pair can form two individual hydrogen bonds to a side-by-side Im/Im pair. Thus an Im/Im pair may be a good recognition motif for a T:G base pair in DNA. Cooperative and tight binding of an AR-1-144 homodimer to GAACTGGTTC permits a detailed structural analysis by 2D NOE NMR refinement and the refined structure confirms our prediction. Surprisingly, AR-1-144 does not bind to GAATCGGTTC. We further show that both the Im-Im-Im/Im-Py-Im heterodimer and the Im-Im-Im/Im-Im-Im homodimer bind strongly to the CACGGGTC + GACTCGTG duplex. These results together suggest that an Im/Im pair can specifically recognize a single T:G mismatch. Our results may be useful in future design of molecules (e.g. linked dimers) that can recognize a single T:G mismatch with specificity.

Sequence-specific alkylation of DNA by duocarmycin A and its novel derivatives bearing PY/IM polyamides.

A new class of sequence-specific DNA alkylating agents were developed based on the reactivity of duocarmycin A and the DNA-reading ability of pyrrole-imidazole polyamide. The DNA alkylation sequence specificity by duocarmycin A can be modulated by a variety of pyrrole-imidazole triamides in a predictable manner. Novel hybrids of the segment A of duocarmycin A and pyrrole-imidazole polyamides efficiently and highly selectively alkylated the target base possessing match sequences of Dervan's binding code.

Synthesis of pyrrole-imidazole-duocarmycin polyamide and its sequence selective DNA alkylation.

The new solid phase synthesis of sequence-specific DNA alkylating polyamides containing segment A of Du86 (Duo), N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids is described. New monomer building block N-carboxylmethyl Py (Pyc) was synthesized from 2-methylpyrrolecarboxylate by eight steps. After normal coupling of FMOC-protected-Im and -Py monomer, the deprotection of silyl group generates free carboxylic acid. Introduction of various types of functional groups on solid support will be presented.

[Epidemiological survey in a high background radiation area in Yangjiang, China].

The results of the health survey in a high background radiation area (HBRA) from 1972 to 1990, in Yangjiang, China, are presented in this paper. Radiological measurements of the environmental and human bodies with different methods revealed that 330 mR/a in HBRA and 114 mR/a in the control area (CA) were the doses that annually an individual exposure to the external environmental gamma radiation and effective doses to whole body are 6.4 mSv in HBRA and 2.4 mSv in CA annually. The carcinogenic and mutagenic factors were surveyed. The Results showed that these factors in the two areas were similar. Up till now, no harmful impact induced by natural radiation, based on the data as: cancer mortality from 1,008,769 person-years in HBRA and 995,070 person-years in CA; hereditary diseases and congenial malformations from 13,425 subjects in HBRA and 13,087 subjects in CA; human chromosome aberrations, and immune function of the inhabitants, was found. In addition, in this paper the authors discussed the results of cancer mortality, of chromosome aberrations and of immune function, and analyzed the possible relationship among them. The carcinogenic risk induced by low dose radiation was also estimated and discussed.

Thyroid nodularity and chromosome aberrations among women in areas of high background radiation in China.

Thyroid nodularity following continuous low-dose radiation exposure in China was determined in 1,001 women aged 50-65 years who resided in areas of high background radiation (330 mR/yr) their entire lives, and in 1,005 comparison subjects exposed to normal levels of radiation (114 mR/yr). Cumulative doses to the thyroid were estimated to be of the order of 14 cGy and 5 cGy, respectively. Personal interviews and physical examinations were conducted, and measurements were made of serum thyroid hormone levels, urinary iodine concentrations, and chromosome aberrations in circulating lymphocytes. For all nodular disease, the prevalences in the high background and control areas were 9.5% and 9.3%, respectively. For single nodules, the prevalences were 7.4% in the high background area and 6.6% in the control area (prevalence ratio = 1.13; 95% confidence interval = 0.82-1.55). There were no differences found in serum levels of thyroid hormones. Women in the high background region, however, had significantly lower concentrations of urinary iodine and significantly higher frequencies of stable and unstable chromosome aberrations. Increased intake of allium vegetables such as garlic and onions was associated with a decreased risk of nodular disease, which seems consistent with experimental studies suggesting that allium compounds can inhibit tumor growth and proliferation. The prevalence of mild diffuse goiter was higher in the high background radiation region, perhaps related to a low dietary intake of iodine. These data suggest that continuous exposure to low-level radiation throughout life is unlikely to appreciably increase the risk of thyroid cancer. However, such exposure may cause chromosomal damage.