German Pihan

P504S: a new molecular marker for the detection of prostate carcinoma.

* ون ي ،لوئسم هدنس نسح ناديم ،نارهت ،انيس ناتسراميب ،دابآ يژولوتاپ شخب نفلت : 9 66701041 email: ahmadise@tums.ac.ir فده و هنيمز : رب ديكات دوز فشك طرس ماگنه ب تاتسورپ نا ه كمك ارت يفارگونوسارتلوا سن لاـتكر ،ينزوـس يسـپويب و تسيژولوتاپ ار اه ناطرس صيخشت لضعم اب تـسا هدومن هجاوم كچوك ياه . ارـيخا ̋ زا ركراـم P504S صيخشـت تـهج يسپويب رد ناطرس يعطق تسا هدش هدافتسا كچوك ياه . يسررب شور : گنر ركرام يزيمآ P504S يارب 70 سپويب هنومن ي و تاتسورپ ينزوس شش زر هنومن ك هك ارجم قيرط زا نويس يگمه نوناك يواح ياه كوكشم ) پيتآ ـ ي ك ( و دـندوب زـين 40 هنومن تاتسورپ يعطق ناطرس ، لماش تشه لولس ياراد هنومن فك ياه دولآ (foamy) ب ه دمآ لمع . هتفاي اـه : 36 زا هـنومن 40 ،يعطق ناطرس يسپويب زا يتاجرد گنر يارب يريذپ P504S دـنداد ناشن ) تيساسـح 90 (% ؛ ود و كـچوك ناطرـس ود لولس اب ناطرس فك ياه گنر دقاف دولآ دندوب يريذپ . عومجم زا 76 ،كوكشم دروم 18 ـ ب دروم ه لـخاد يزلاپوـئن ناوـنع يپا لااب هجرد يلايلت (HGPIN) دش هتخانش دن هك 16 دروم اهنآ گنر دنداد ناشن رشتنم طسوتم يريذپ . زا 58 دروم يقاب هدـنام ياراد يلورپ نويسارف كچوك ددغ آ يت كيپ 14 ًايوق دروم ب ه ن ف دوب ناطرس ع هك راهچ گـنر دـقاف اـهنآ دروـم يريذـپ P504S دندوب . رد نيب 44 پيتآ دروم ي ك ب ه عفن شوخ ميخ ي ، 14 پيتآ يموندآ يزلاپرپيه دروم ي ك اب ود گنر دروم فيعـض يريذـپ يعضوم و ود ب يپيتآ دروم ه ب يباتوترپ لابند ا كي گنر دروم و دش هدهاشم يعضوم يريذپ 28 رـگيد هـنومن P504S يـفنم دندوب . هجيتن يريگ : تيساسح P504S يم روصت ًلابق هچنآ زا تاتسورپ ناطرس فشك يارب نيياپ دش تـسا رت . يـفنم يـّقلت ندش ناطرس نكمم كچوك ياه ا ب تس ه گـنر ينوگمهاـن ليلد دـشاب يريذـپ . نويـسارفيلورپ رد كـچوك ددـغ تآ پي ـ ي ،ك گنر رشتنم و تبثم يريذپ P504S گنر مدع يلو تسا ناطرس صيخشت يايوگ ًايوق يـمن در ارنآ يريذپ دـنك . تيساسـحThe ability to diagnose prostate carcinoma would be improved by the detection of a tumor-associated antigen. P504S, a cytoplasmic protein, was recently identified by cDNA library subtraction in conjunction with high throughput microarray screening from prostate carcinoma. The aim of this study was to establish the pattern of expression of P504S in prostate carcinoma and benign prostatic tissue. A total of 207 cases, including 137 cases of prostate carcinoma and 70 cases of benign prostate, from prostatectomies (n = 77), prostate needle biopsies (n = 112), and transurethral prostate resections (n = 18) were examined by immunocytochemistry for P504S. P504S showed strong cytoplasmic granular staining in 100% of prostate carcinomas regardless of Gleason scores and diffuse (>75% of tumor) staining in 92% of cases. In contrast, 171 of 194 (88%) of benign prostates, including 56 of 67 (84%) benign prostate cases and 115 of 127 (91%) cases of benign glands adjacent to cancers were negative for P504S. The remainders of benign prostates were focally and weakly positive for P504S. The staining pattern of these normal glands was different and easily distinguishable from that observed in prostate carcinoma. Expression of P504S was not found in basal cell hyperplasia, urothelial cells/metaplasia and small atrophic glands that may mimic prostate carcinoma. Our findings indicate that P504S is a highly sensitive and specific positive marker for prostate carcinoma.

Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue

Wnt5a is a member of the Wnt family of secreted glycoproteins that play essential organizing roles in development. Similar to other Wnt members, Wnt5a can upregulate cell proliferation and has been proposed to have oncogenic function. Here we report that Wnt5a signals through the noncanonical Wnt/Ca++ pathway to suppress cyclin D1 expression and negatively regulate B cell proliferation in a cell-autonomous manner. Wnt5a hemizygous mice develop myeloid leukemias and B cell lymphomas that are clonal in origin and display loss of Wnt5a function in tumor tissues. Furthermore, analysis of human primary leukemias reveals deletion of the WNT5A gene and/or loss of WNT5A expression in a majority of the patient samples. These results demonstrate that Wnt5a suppresses hematopoietic malignancies.

Free radicals and lipid peroxidation in ethanol- or aspirin-induced gastric mucosal injury

In this study the role of free radicals and lipid peroxidation as mediators of chemically induced mucosal damage was investigated. Two enzymatic antioxidants, superoxide dismutase or catalase injected intravenously, reduced mucosal damage either by ethanol or aspirin. Of six nonenzymatic antioxidants, given in a wide dose range subcutaneously 30 min before intragastric administration of absolute ethanol, only propyl gallate decreased mucosal damage, while four of the antioxidants tested against aspirin were protective. These nonenzymatic antioxidants were antisecretory in the pylorus-ligated rat. The concentration of conjugated dienes and malondialdehyde measured in the gastric mucosa shortly after ethanol or aspirin administration remained unchanged or slightly decreased. These results indicate that free radicals may be involved in the pathogenesis of acute gastric mucosal injury caused by chemicals, but their mechanisms of action probably does not involve lipid peroxidation.

Survival signaling mediated by c-Jun NH 2 -terminal kinase in transformed B lymphoblasts

The c-Jun NH2-terminal kinase (JNK) is implicated in the apoptotic response of cells exposed to stress, but the JNK signal transduction pathway may not act exclusively in apoptosis. In some studies of tumor cells, JNK has been implicated in signaling cell survival. The possibility that JNK might mediate a survival signal in tumor cells is consistent with the observation that it is activated in response to some oncogenes, such as the leukemogenic oncogene BCR–ABL, which is created by a reciprocal translocation between human chromosomes 9 and 22 (ref. 2). The BCR-ABL protein activates the JNK signaling pathway in hematopoietic cells and increases transcriptional activity mediated by the transcription factor AP1 (ref. 3). Also, inhibition of c-Jun or JNK prevents BCR–ABL-induced cell transformation in vitro. Although this implicates the JNK signaling pathway in transformation by BCR–ABL, the possible role of JNK in this process is unclear. We find that disruption of the JNK ortholog Mapk8 (also known as Jnk1) in mice causes defective transformation of pre-B cells by BCR–ABL in vitro and in vivo. The Jnk1 protein is required for the survival of the transformed cells in the absence of stromal support. Failure to survive is associated with decreased expression of Bcl2, and the effect of Jnk1 deficiency can be rescued by transgenic expression of Bcl2. Our results show that Jnk1 signals cell survival in transformed B lymphoblasts and suggest that it may contribute to the pathogenesis of some proliferative diseases.

Early microcirculatory stasis in acute gastric mucosal injury in the rat and prevention by 16,16-dimethyl prostaglandin E2 or sodium thiosulfate

We used in vivo microscopy and laser-Doppler velocimetry to examine the effects on the gastric mucosal microcirculation and in gastric mucosal blood flow of agents that induce acute gastric mucosal damage. In vivo microscopic observation of superficial mucosal capillaries revealed vascular stasis within a mean of 54, 81, or 61 s after 100% ethanol, 0.6 N HCl, or 0.2 N NaOH, with the subsequent development of hemorrhagic mucosal lesions. Mucosal blood flow estimated by laser-Doppler velocimetry decreased by 30% at 5 min after luminal application of 100% ethanol, and decreased further to about 40% of basal levels by 15 min. The decreased mucosal blood flow 15 min after application of 50% ethanol correlated with the extent of hemorrhagic mucosal lesions. Examination of the submucosal vessels that supply and drain the mucosa showed moderate dilation of small arterioles 1, 3, and 6 min after exposure to 100% ethanol but there were no consistent changes in venules. Mild vasoconstriction of small- and medium-sized venules could be detected 6, 10, and 15 min after NaOH but not after exposure to HCl. Pretreatment with 16,16-dimethyl prostaglandin E2 or sodium thiosulfate before exposure of the mucosa to ethanol prevented capillary stasis, maintained mucosal blood flow, and prevented the development of hemorrhagic gastric mucosal lesions. Topical mucosal application of 16,16-dimethyl prostaglandin E2 decreased, whereas topical exposure to sodium thiosulfate increased gastric mucosal blood flow, indicating that change in blood flow per se is an unlikely mediator of protection.

Mutations and aneuploidy: Co-conspirators in cancer?

The role of intragenic point mutations in human cancer is well established. However, the contribution of massive genomic changes collectively known as aneuploidy is less certain. Recent experimental work suggests that aneuploidy is required for sporadic carcinogenesis in mice and that it may collaborate with intragenic mutations during tumorigenesis. The genomic plasticity afforded by aneuploidy could facilitate emergence of protumorigenic gene dosage changes and accelerate accumulation of oncogenes and loss of tumor suppressor genes. These new findings force us to rethink the pathogenesis of carcinoma in ways that have significant implications for diagnosis and therapy.

VASCULAR INJURY IN ACUTE GASTRIC MUCOSAL DAMAGE. MEDIATORY ROLE OF LEUKOTRIENES

Recent investigations indicate that microvascular injury, leading to increased vascular permeability and capillary stasis, precede the development of chemically induced hemorrhagic mucosal lesions in the stomach. The vascular damage is more amenable to protection by prostaglandins and sulfhydryls than the diffuse surface mucosal cell injury. The vascular and mucosal lesions may be the result of direct toxicity of damaging agents (eg, ethanol, HCl, NaOH) and the release of vasoactive amines and leukotrienes. We review here our recent studies performed in rats indicating that intraarterial infusion of LTC4 or LTD4 in the stomach caused vascular injury as revealed by monastral blue. Infusion of leukotrienes alone caused no hemorrhagic mucosal lesions but aggravated the damage caused by 25, 50, or 100% ethanol and 0.2 N HCl given intragastrically. The ethanol-induced mucosal lesions were slightly diminished by the lipoxygenase inhibitor L-651,392 and markedly decreased by eicosapentaenoic acid, which competes with arachiconic acid as a substrate for 5-lipoxygenase. These results are discussed and correlated with biochemical results from other laboratories demonstrating increased levels of leukotrienes in the gastric mucosa after administration of ethanol and decreased release following pretreatment with prostaglandins or sulfhydryl-related agents. New data thus support a mediatory role for leukotrienes in the pathogenesis of vascular injury and mucosal lesions in the stomach.

Centrosome Dysfunction Contributes to Chromosome Instability, Chromoanagenesis, and Genome Reprograming in Cancer

The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker’s precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegregated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies.

Facile, comprehensive, high-throughput genotyping of human genital papillomaviruses using spectrally addressable liquid bead microarrays.

Human papillomavirus (HPV) is the worldwide cause of carcinoma of the uterine cervix, a cancer that is the second most common neoplasm in women, resulting in nearly 250,000 deaths a year. The magnitude of the risk of cancer after HPV infection, however, is virus type-specific. Over 40 HPV types can infect the genital tract. Comprehensive, high-throughput typing assays for HPV, however, are not currently available. Blending multiplex PCR and multiplex hybridization using spectrally addressable liquid bead microarrays we have developed a high-throughput, fast, single-tube-typing assay capable of simultaneously typing 45 HPV. The overall incidence of HPV in 429 women tested using this new assay was 72.2% for those with squamous intraepithelial lesions, 51.5% for those with atypical squamous cells of undetermined significance and 15.4% for women with normal cytology, respectively. This compared well with the incidence of HPV detected by a parallel non-typing generic high-risk assay. The new assay detected a wide spectrum of HPV types and a high incidence of mixed infections. We believe our assay may find widespread applications in areas requiring virus type-specific information, such as in epidemiological studies, cancer screening programs, monitoring therapeutic interventions, and evaluating the efficacy of HPV vaccine trials.

Alterations in blood vessels during gastric injury and protection.

Recent investigations suggest that the mucosal vascular endothelium is not a passive bystander, and that alterations within the blood vessel wall actively participate in the pathogenesis of gastric mucosal injury. We review here our data on rapidly developing vascular injury as detected by monastral blue deposition and increased vascular permeability measured by Evans blue extravasation in dose- and time-dependent experiments with ethanol, HCl, and NaOH in the rat. In addition, using in vivo microscopy and laser-Doppler velocimetry, we demonstrate circulatory stasis in the superficial capillaries within about 1 min after topical application of damaging agents, and a gradual decrease in blood flow that correlates with the extent of hemorrhagic erosions. Prostaglandins or sulfhydryl agents prevented the circulatory standstill and the development of hemorrhagic mucosal lesions. We conclude that microvascular damage, increased vascular permeability, and capillary stasis precede the development of hemorrhagic mucosal lesions.