The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

Class Ia phosphatidylinositol 3 kinase (PI3K) is required for oncogenic receptor-mediated transformation; however, the individual roles of the two commonly expressed class Ia PI3K isoforms in oncogenic receptor signaling have not been elucidated in vivo. Here, we show that genetic ablation of p110α blocks tumor formation in both polyoma middle T antigen (MT) and HER2/Neu transgenic models of breast cancer. Surprisingly, p110β ablation results in both increased ductal branching and tumorigenesis. Biochemical analyses suggest a competition model in which the less active p110β competes with the more active p110α for receptor binding sites, thereby modulating the level of PI3K activity associated with activated receptors. Our findings demonstrate a novel p110β-based regulatory role in receptor-mediated PI3K activity and identify p110α as an important target for treatment of HER2-positive disease.     

Maternally inherited partial monosomy 9p (pter → p24.1) and partial trisomy 20p (pter → p12.1) characterized by microarray comparative genomic hybridization

We report on a 17-year-old patient with midline defects, ocular hypertelorism, neuropsychomotor development delay, neonatal macrosomy, and dental anomalies. DNA copy number investigations using a Whole Genome TilePath array consisting, of 30K BAC/PAC clones showed a 6.36 Mb deletion in the 9p24.1-p24.3 region and a 14.83 Mb duplication in the 20p12.1-p13 region, which derived from a maternal balanced t(9;20)(p24.1;p12.1) as shown by FISH studies. Monosomy 9p is a well-delineated chromosomal syndrome with characteristic clinical features, while chromosome 20p duplication is a rare genetic condition. Only a handful of cases of monosomy 9/trisomy 20 have been previously described. In this report, we compare the phenotype of our patient with those already reported in the literature, and discuss the role of DMRT, DOCK8, FOXD4, VLDLR, RSPO4, AVP, RASSF2, PROKR2, BMP2, MKKS, and JAG1, all genes mapping to the deleted and duplicated regions.     

Could the new HIV combined p24 antigen and antibody assays replace p24 antigen specific assays?

The performance of twelve HIV combined p24 antigen and antibody assays available in Europe were compared. The assays were examined with a total of 1983 samples that included 1005 unselected HIV negative samples, 7 HIV-1 p24 Ag reference samples with HIV-1 Ag, 10 samples of a HIV antigen sensitivity commercial panel, 124 samples of 31 p24 antigen panels of different HIV-1 subtypes, 168 members of 24 HIV-1 seroconversion panels, 559 HIV-1 (groups M and O) antibody positive samples and 110 HIV-2 antibody positive samples. The specificity ranged from 99.4 to 100%. Ten of the 12 assays detected all anti-HIV positive samples irrespective of genotype while two assays missed one sample each (one subtype F and one subtype C). The combined assays could be classified into three groups. The first includes two assays (Enzygnost HIV Integral and Vironostika Ag/Ab) that have a clinical sensitivity similar to the two antibody only assays. The second includes the seven assays that detected infection after the p24 antigen only assay and show a delay from 3.3 to 5.17 days after HIV-1 RNA. The third group detected the infection before the p24 antigen assay and less than 3 days after nucleic acid testing (NAT). The improved ability to detect p24 Ag, at levels similar to specific HIV Ag assays, suggests that these new HIV combined Ag/Ab assays could replace p24 antigen only assays in situations for blood or organ screening when NAT is not feasible or not affordable.     

p40 (ΔNp63) expression in breast disease and its correlation with p63 immunohistochemistry

p63 protein is widely used to identify myoepithelial cells in breast disease. There have been no comparative studies of the p63 antibodies which detect different isoforms. In this study, we examine the expression profiles of p63 protein in benign proliferative diseases and malignant tumors of the breast using pan-p63 and p40 antibodies, and analyze their diagnostic utility and clinical implications. We selected 32 adenoses, 34 intraductal papillomas, 31 ductal carcinoma in situ (DCIS), 257 invasive ductal carcinoma (IDC), and 36 metaplastic carcinomas, and created tissue microarray blocks from them. Immunohistochemical assays for p63 protein were performed on these samples. We investigated the expression patterns of the pan-p63 (TP63, 4A4, Dako, 1:700), p40 antibody [5-17, CalBiochem/EMD Biosciences, 1:2000, p40 (CB)], and p40 antibody [polyclonal, Diagnostic BioSystems, 1:100, p40 (DB)] in various forms of breast disease. We determined that p63 and p40 (DB) expression in myoepithelial cells was broadly similar and showed cognate clinicopathologic features, unlike p40 (CB). p40 (CB) was more sensitive (99.0%) but less specific (85.8%), and p63 was less sensitive (93.8%) in adenosis, IP, and DCIS. In IDCs, p63 and p40 (DB) had similar expression in cancer cells; p40 (CB) expression, however, was statistically different. In metaplastic carcinomas, both p63 and p40 (DB) had distinct expression profiles, according to their histologic subtypes. We conclude that p40 antibodies as well as pan-p63 antibody are specific and sensitive myoepithelial cell markers. Interpretation of p40 positivity in cancer cells, however, should be considered carefully, due to their relatively lower specificity.     

Phenotypic overlapping of trisomy 12p and Pallister–Killian syndrome

Trisomy of 12p is a rare chromosomal abnormality, which sometimes coexists with other chromosomal anomalies. We report on a patient with a supernumerary chromosome involving chromosomes 12 and 14, which was confirmed by array-comparative genomic hybridization (aCGH). He had developmental delay and dysmorphic features overlapped with those of Pallister–Killian syndrome, which is derived from an isodicentric chromosome 12. The microblepharon identified in our patient is a characteristic feature of 12p trisomy. Further patients are needed to establish the phenotypic difference between trisomy 12p and Pallister–Killian syndrome.     

Lack of prognostic significance of p16 and p27 after radical prostatectomy in hormone-naïve prostate cancer

Background  

Loss of normal cell cycle control is an early event in the evolution of cancer. The expression of cyclin-dependent kinase (CDK) inhibitors p16 and p27 has been previously associated with progression of prostate cancer (PC). 70 patients diagnosed with early stage PCwere treated with radical prostatectomy (RP) at our institution and their tumor specimens were immunohistochemically evaluated for expression of p16 and p27. Available clinical data of time to PSA recurrence were correlated with the examined parameters and combined with pre-operative PSA level, Gleason score and pathological TNM (pT) stage assessment.     

Interleukin-12p40 overexpression promotes interleukin-12p70 and interleukin-23 formation but does not affect bacille Calmette-Guérin and Mycobacterium tuberculosis clearance

Interleukin (IL)-12p40, a subunit of IL-12p70 and IL-23, has previously been shown to inhibit IL-12p70 activity and interferon-gamma (IFN-gamma) production. However, recent evidence has suggested that the role of IL-12p40 is more complex. To study the contribution of IL-12p40 to immune responses against mycobacterial infections, we have used transgenic (tg) mice overexpressing IL-12p40 under the control of a major histocompatibility complex-II promoter. The IL-12p40 transgene was expressed during steady state at concentrations of 129 +/- 25 ng/ml of serum and 75 +/- 13 ng per spleen, while endogenous IL-12p40 was hardly detectable in control littermates. Bacille Calmette-Guérin (BCG) infection strongly induced the expression of IL-12p40 transgene in infected organs, and IL-12p40 monomeric and dimeric forms were identified in spleen of IL-12p40 tg mice. Excessive production of IL-12p40 resulted in a 14-fold increase in IL-12p70 serum levels in tg mice versus non-transgenic mice. IL-23 was also strongly elevated in the serum and spleens of IL-12p40 tg mice through BCG infection. While IFN-gamma and tumour necrosis factor protein levels were similar in IL-12p40 tg and non-transgenic mice, Th2 type immune responses were reduced in IL-12p40 tg mice. The number of BCG granulomas and macrophage expressing inducible nitric oxide synthase were similar in IL-12p40 tg and non-transgenic mice. IL-12p40 tg mice were as resistant as non-transgenic mice to BCG and Mycobacterium tuberculosis infections as they could efficiently control bacillary growth. These data show that high amounts of IL-12p40 promotes IL-12p70 and IL-23 formation, but that does not affect T helper 1 type immune responses and granuloma function, thus leading to normal mycobacterial clearance in infected organs.     

Do soluble p55 and p75 TNF-α receptor concentrations play a role in women with primary sterility?

Introduction

In modern medicine the cause of infertility is believed to be immune mechanism disorders as well as immune over-reactivity. The objective of this thesis is to evaluate the diagnostic usefulness of measuring the concentration of soluble TNF-α receptors p55 and p75 in women with primary infertility.

Material and methods

Examination subjects: 41 female patients with primary sterility in the period January-September 2005. The control group consisted of 13 female patients. For identification of soluble receptors’ p55 and p75 TNF-α concentration was used commercial ELISA kits. Quantitative in vitro method of hormone identification in blood serum of plasma (ECLIA) has been used to estimate hormone concentration. Results have been analyzed with Student''s t-test, Wilcoxon''s test, Fisher''s exact test and Spearman''s test. P value<0.05 was considered significant.

Results

There is no significant statistical relation between concentration of soluble p55 and p75 TNF-α receptors and age, BMI index, or length of periods. In the case of soluble p75 TNF-α receptor a statistical correlation with length of period was found (p = 0.004). From the statistical point of view, the most advantageous relation was found in the case of p75 TNF-α soluble receptor and thickness of endometrium (p = 0.007) as well as the correlation of p55/p75 soluble receptors (p = 0.05). The statistical analysis of correlations between TNFR1 and TNFR2 receptors and concentration of hormones FSH, LH, PRL, E2 and testosterone showed no dependence of TNFR1 and TNFR2 receptor concentrations and concentrations of examined hormones. Statistical analysis of relations of TNFR1/TNFR2 receptor concentrations revealed a significant correlation between these receptors and concentration of LH (p = 0.05).

Conclusions

The correlation between endometrium thickness, size of dominating vesicle and concentration of LH compared to concentrations of soluble TNF-α?receptors p55 and p75 and their ratio might condition the time of survival of the vesicle or lead to excessive expression of its atresion-leading conditions.     

Three-year-old girl with partial trisomy 4p and partial monosomy 8p with resemblance to Brachmann-de Lange syndrome--another locus for Brachmann-de Lange syndrome on 4p?

We describe a 3-year-old girl with partial trisomy 4p and partial monosomy 8p who had prenatal and postnatal growth retardation, mental retardation, no speech development, mild synophrys, hirsutism, apparently low-set ears, dysphonic hoarse voice, hyperactivity, and small hands with proximal placement of the thumbs. She had recurrent lung infections, due to earlier aspiration and immune deficiency (chronic granulomatous disease). Cytogenetic findings in this and other cases with suggestive phenotype may point to an additional locus for Brachmann-de Lange phenotype.     

p53家族新成员:p51

p5 3是一种广谱的肿瘤抑制基因 ,其新家族成员 p5 1具有同 p5 3相似的 DNA结合特性和相似的功能 ,同样可以转录激活 p5 3基因的内源性靶分子 ,如细胞周期抑制基因 p2 1、导致细胞凋亡和生长受抑。本文阐述了它的研究进展     

p73：p53的类似物

ｐ７３是近来发现的与ｐ５３在结构与功能上非常相似的一个基因,位于１ｐ３６。ｐ７３具有类似于ｐ５３的抑制细胞生长、促进凋亡的功能,还具有与ｐ５３不同的单基因表达方式,不与病毒癌蛋白相互作用。ｐ７３与肿瘤的关系密切,但到底是通过抑癌基因,癌基因,还是表基因机制在肿瘤的发生中起作用则尚未明确。     

p73:p53的类似物

p73是近来发现的与p5 3在结构与功能上非常相似的一个基因 ,位于 1p36。p73具有类似于p5 3的抑制细胞生长、促进凋亡的功能 ,还具有与p5 3不同的单基因表达方式 ,不与病毒癌蛋白相互作用。p73与肿瘤的关系密切 ,但到底是通过抑癌基因、癌基因 ,还是表基因机制在肿瘤的发生中起作用则尚未明确。     

Myocardial ischemia and reperfusion-induced cell death depends on JNK activation and leads to phosphorylation of mitochondrial p46

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p170,p53,p16和p21蛋白在膀胱癌中表达的意义

ｐ１７０、ｐ５３、ｐ１６和ｐ２１蛋白在膀胱癌中表达的意义杨毅郭雪西高伟陈丽张辉朱振庆一、材料和方法５０例膀胱癌标本取自我院病理科１９８６～１９９４年手术切除标本，膀胱移行细胞癌４６例，其中Ⅰ级６例，Ⅱ级１４例，Ⅲ级２６例，鳞癌４例。另取６例正常膀胱粘...