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Kenneth A Iczkowski

Publications and source records attributed to Kenneth A Iczkowski.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells.

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is overexpressed in prostate cancer, but the mechanism by which MIF exerts effects on tumor cells remains undetermined. MIF interacts with its identified membrane receptor, CD74, in association with CD44, resulting in ERK 1/2 activation. Therefore, we hypothesized that increased expression or surface localization of CD74 and MIF overexpression by prostate cancer cells regulated tumor cell viability. Prostate cancer cell lines (LNCaP and DU-145) had increased MIF gene expression and protein levels compared with normal human prostate or benign prostate epithelial cells (p < 0.01). Although MIF, CD74, and CD44 variant 9 expression were increased in both androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells, cell surface of CD74 was only detected in androgen-independent (DU-145) prostate cancer cells. Therefore, treatments aimed at blocking CD74 and/or MIF (e.g., inhibition of MIF or CD74 expression by RNA interference or treatment with anti-MIF- or anti-CD74- neutralizing Abs or MIF-specific inhibitor, ISO-1) were only effective in androgen-independent prostate cancer cells (DU-145), resulting in decreased cell proliferation, MIF protein secretion, and invasion. In DU-145 xenografts, ISO-1 significantly decreased tumor volume and tumor angiogenesis. Our results showed greater cell surface CD74 in DU-145 prostate cancer cells that bind to MIF and, thus, mediate MIF-activated signal transduction. DU-145 prostate cancer cell growth and invasion required MIF activated signal transduction pathways that were not necessary for growth or viability of androgen-dependent prostate cells. Thus, blocking MIF either at the ligand (MIF) or receptor (CD74) may provide new, targeted specific therapies for androgen-independent prostate cancer.

Animals↗
PubMed2006

Uncoupling of oxidative phosphorylation enables Candida albicans to resist killing by phagocytes and persist in tissue.

After five serial passages of Candida albicans SC5314 through murine spleens by intravenous inoculation, we recovered a respiratory mutant (strain P5) that exhibited reduced colony size, stunted growth in glucose-deficient media, increased oxygen consumption and defective carbohydrate assimilation. Strain P5 was indistinguishable from SC5314 by DNA typing methods, but had a greater concentration of mitochondria by SYTO18 staining. Treatment with various inhibitors demonstrated that strain P5's electron transport chain was intact and oxidative phosphorylation was uncoupled. During disseminated candidiasis, the mutant did not kill mice or cause extensive damage to kidneys. The burden of strain P5 within kidneys on the first 3 days of disseminated candidiasis was significantly reduced. By days 28 and 60, it was similar to that at the time of death among mice infected with SC5314, suggesting that the mutant persisted and proliferated without killing mice. Strain P5 was resistant to phagocytosis by neutrophils and macrophages. It was also significantly more resistant to paraquat, suggesting that it is able to neutralize reactive oxygen species. Our findings indicate that regulation of respiration influences the interaction between C. albicans and the host. Uncoupling of oxidative phosphorylation might be a mechanism by which the organism adapts to stressful host environments.

Animals↗
PubMed2006

Drug interactions and pharmacogenetic reactions are the basis for chloroquine and mefloquine-induced psychosis.

BACKGROUND: Chloroquine and mefloquine used for prophylaxis and treatment of malaria sometimes causes severe mental status changes, through mechanisms that are poorly understood. PRESENTATION OF THE HYPOTHESIS: Psychosis is caused by interactions with other drugs or by pharmacogenetic vulnerabilities that cause heightened responses to chloroquine or mefloquine alone, mediated through dopamine, acetylcholine, serotonin, P-glycoprotein, inhibited cortical activity, deranged calcium homeostasis, and impaired synaptogenesis. TESTING THE HYPOTHESIS: Retrospective studies can identify all other drugs taken coincident with chloroquine or mefloquine psychosis. Various genes from patients could be cloned and compared to those from individuals who tolerated chloroquine and mefloquine, culminating with transgenic animal studies. Identification of candidate genes may be aided by pharmacogenomic analysis of single nucleotide polymorphism maps. Finally, prospective studies with cerebrospinal fluid analysis and PET scanning could help verify the hypothesis. IMPLICATIONS OF THE HYPOTHESIS: If this hypothesis is correct, the incidence of chloroquine and mefloquine psychosis can be greatly reduced by avoiding interacting medications and by conducting genetic screening prior to initiating chloroquine and mefloquine. Validation of the hypothesis would also provide a paradigm to follow for avoiding neuropsychiatric side effects if antidepressants and neuroleptics are used to overcome chloroquine resistance, if new antimalarial drugs chemically related to chloroquine and mefloquine are developed and if chloroquine and mefloquine are used for non-malarial applications such as HIV and cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Macrophage migration inhibitory factor is increased in the urine of patients with urinary tract infection: macrophage migration inhibitory factor-protein complexes in human urine.

PURPOSE: MIF is a proinflammatory cytokine present in preformed stores in human urothelium. In animal models of bladder inflammation, including bacterial cystitis, MIF is up-regulated in the bladder and released from the bladder as a high molecular weight complex. We compared urine MIF amounts in patients with UTI to that in patients without UTI, and we examined and identified MIF-protein complexes in urine. MATERIALS AND METHODS: Using enzyme-linked immunosorbent assay we compared MIF levels in the urine of 14 patients with UTI to levels in 16 controls with no UTI. Western blotting under native, denaturing and reducing conditions was done to examine MIF complexes found in urine. Mass spectrometry identified MIF associated proteins in urine, while co-immunoprecipitation confirmed the associations. RESULTS: Mean urine MIF amounts +/- SEM determined by enzyme-linked immunosorbent assay were significantly greater in 14 patients with UTI compared to that in 16 controls (1.96 +/- 0.40 vs 0.59 +/- 0.09 ng/mg creatinine, p <0.01). Western blotting under denaturing conditions showed several high molecular weight complexes (100 to 165 kDa) that increased in UTI urine as well as typical, monomeric MIF (12 kDa). Mass spectrometry identified associated MIF proteins, including ceruloplasmin, albumin and uromodulin. Co-immunoprecipitation confirmed mass spectrometry findings and also identified MIF interaction with alpha-2-macroglobulin. CONCLUSIONS: Increased urine MIF amounts in patients with bacterial cystitis support our experimental evidence showing a role for MIF in pelvic visceral inflammation. The novel finding of an association of MIF with other urine proteins suggest that the physiologically relevant form of MIF may be an MIF-protein complex.

Bacterial Infections↗
PubMed2006

Coordinated peak expression of MMP-26 and TIMP-4 in preinvasive human prostate tumor.

The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detection and treatment are critical for the medical management of patients. Disruption in the continuity of both the basal cell layer and basement membrane is essential for the progression of high-grade prostatic intraepithelial neoplasia (HGPIN) to invasive adenocarcinoma in human prostate. The molecules involved in the conversion to an invasive phenotype are the subject of intense scrutiny. We have previously reported that matrix metalloproteinase-26 (MMP-26) promotes the invasion of human prostate cancer cells via the cleavage of basement membrane proteins and by activating the zymogen form of MMP-9. Furthermore, we have found that tissue inhibitor of metalloproteinases-4 (TIMP-4) is the most potent endogenous inhibitor of MMP-26. Here we demonstrate higher (p<0.0001) MMP-26 and TIMP-4 expression in HGPIN and cancer, compared to non-neoplastic acini. Their expression levels are highest in HGPIN, but decline in invasive cancer (p<0.001 for each) in the same tissues. Immunohistochemical staining of serial prostate cancer tissue sections suggests colocalization of MMP-26 and TIMP-4. The present study indicates that MMP-26 and TIMP-4 may play an integral role during the conversion of HGPIN to invasive cancer and may also serve as markers for early prostate cancer diagnosis.

Animals↗
PubMed2006

A working group classification of focal prostate atrophy lesions.

Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability. This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy. In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of "training" images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct "test" images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of "standard" diagnoses and the kappa statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median kappa) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median kappa for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation. Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was excellent. Three of 4 pathologists with low agreement with the standard diagnosis for simple atrophy improved their scores after repeating the analysis after re-examination of the "training set" of images. In conclusion, these criteria for variants of focal prostate atrophy may facilitate studies to examine the relation between various patterns of prostate atrophy and prostate cancer.

Atrophy↗
PubMed2006

Current prostate biopsy interpretation: criteria for cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and use of immunostains.

CONTEXT: The past decade has brought major changes in prostate biopsy sampling, interpretation, and reporting. OBJECTIVE: To summarize current information on diagnostic decision making, Gleason grading, "atypical" diagnoses, and use of immunostaining. DATA SOURCES: Pertinent literature from 1985 to 2005 is reviewed, emphasizing recent findings. CONCLUSIONS: Diagnosis begins by evaluating a focus of atypical single-cell layer lined acini according to the 3 minimal diagnostic criteria for cancer: an infiltrative pattern, nuclear enlargement and hyperchromasia, and prominent nucleoli. The Gleason score and linear extent or percent of each core containing cancer should be reported. Atypical small acinar proliferation suspicious for malignancy designates foci that have either qualitative or quantitative limitations in atypia precluding a definite cancer diagnosis. It has about a 3% incidence as an isolated finding. Contemporary studies indicate a 39% predictive value for cancer on repeat biopsy. Isolated high-grade prostatic intraepithelial neoplasia has a 3% to 14% incidence and predicts cancer on repeat biopsy in 23% of cases. Immunostaining for a marker of benign prostate (cytoplasmic keratin 34betaE12 or nuclear p63) and a marker of cancer (alpha-methylacyl coA racemase, clone P504S) may or may not resolve atypical small acinar proliferation diagnoses. Performance of 34betaE12 and P504S immunostains resolved 76% of atypical small acinar proliferation diagnoses per consensus of 3 urologic pathologists studied; a technical limitation is preservation of the focus in question on the levels used for immunostaining.

Biomarkers, Tumor↗
PubMed2006

New immunohistochemical markers in testicular tumors.

The annual incidence of testicular neoplasms has doubled in the last 40 years, with an estimated 7,500 new cases of germ cell tumor each year. The role of immunostaining has increased with the introduction of several novel markers in the last decade. The role of the following markers in differential diagnosis is featured: alpha-fetoprotein, c-kit, CD30, cytokeratin AE1/3, glypican-3, human chorionic gonadotropin, OCT3/4, NANOG, p63, placental-like alkaline phosphatase, topoisomerase II, and VASA.

Biomarkers, Tumor↗
PubMed2005

Calcitonin increases invasiveness of prostate cancer cells: role for cyclic AMP-dependent protein kinase A in calcitonin action.

Calcitonin (CT) is synthesized and secreted in prostate epithelium, and its secretion from malignant prostates is several-fold higher than from benign prostates. CT receptor (CTR) is expressed in malignant prostate epithelium, and its activation stimulates growth of prostate cancer (PC) cells via activation of adenylyl cyclase and calcium/phospholipid pathways. To identify the role of "CT System" in prostate cancer, we tested the expression of CT and CTR mRNAs in invading tumor cells of prostate cancer specimens. The effect of CT on in vitro invasion of PC cell lines and on activation of gelatinases was also examined. The cells of primary tumors and those invading stroma co-expressed CT/CTR mRNAs. Exogenously added CT increased in vitro invasion of PC cell lines and caused a rapid, several-fold but transient increase in protein kinase A activity. In contrast, anti-CT serum caused a dose-dependent inhibition of in vitro invasion of PC-3M cells. CT also increased the concentration and activities of MMP-2 and MMP-9. Rp.cAMP, a competitive inhibitor of cAMP-dependent protein kinase A, myristoylated protein kinase A inhibitory peptide (PKI) as well as the expression of dominant negative form of PKA all attenuated basal in vitro invasion of PC-3M cells, and CT could not increase in vitro invasiveness in their presence. These results suggest that overexpression of "CT System" in invasive PC tumors significantly contributes to increased invasiveness of prostate cancer cells. The action of CT may be mediated by protein kinase A signaling, which subsequently leads to increased cell invasion and secretion of gelatinases.

Calcitonin↗
PubMed2005

Further evidence for increased macrophage migration inhibitory factor expression in prostate cancer.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine associated with prostate cancer, based on histologic evidence and circulating (serum) levels. Recent studies from another laboratory failed to document these results. This study's aims were to extend and confirm our previous data, as well as to define possible mechanisms for the discrepant results. Additional aims were to examine MIF expression, as well as the location of MIF's receptor, CD74, in human prostatic adenocarcinoma compared to matched benign prostate. METHODS: MIF amounts were determined in random serum samples remaining following routine PSA screening by ELISA. Native, denaturing and reducing polyacrylamide gels and Western blot analyses determined the MIF form in serum. Prostate tissue arrays were processed for MIF in situ hybridization and immunohistochemistry for MIF and CD74. MIF released into culture medium from normal epithelial, LNCaP and PC-3 cells was detected by Western blot analysis. RESULTS: Median serum MIF amounts were significantly elevated in prostate cancer patients (5.87 +/- 3.91 ng/ml; +/- interquartile range; n = 115) compared with patients with no documented diagnosis of prostate cancer (2.19 +/- 2.65 ng/ml; n = 158). ELISA diluent reagents that included bovine serum albumin (BSA) significantly reduced MIF serum detection (p < 0.01). MIF mRNA was localized to prostatic epithelium in all samples, but cancer showed statistically greater MIF expression. MIF and its receptor (CD74) were localized to prostatic epithelium. Increased secreted MIF was detected in culture medium from prostate cancer cell lines (LNCaP and PC-3). CONCLUSION: Increased serum MIF was associated with prostate cancer. Diluent reagents that included BSA resulted in MIF serum immunoassay interference. In addition, significant amounts of complexed MIF (180 kDa under denaturing conditions by Western blot) found in the serum do not bind to the MIF capture antibody. Increased MIF mRNA expression was observed in prostatic adenocarcinoma compared to benign tissue from matched samples, supporting our earlier finding of increased MIF gene expression in prostate cancer.

Adenocarcinoma↗
PubMed2005

The dual 5-alpha-reductase inhibitor dutasteride induces atrophic changes and decreases relative cancer volume in human prostate.

OBJECTIVES: To perform the first evaluation of the effects of the 5-alpha-reductase inhibitor class of drugs on cancer histopathologic features at radical prostatectomy in a placebo-controlled multicenter trial. METHODS: We analyzed prostatectomy slides in a blinded manner from 17 men treated with dutasteride, an inhibitor of types 1 and 2 isoenzymes of 5-alpha-reductase, and 18 men treated with placebo for 5 to 11 weeks before radical prostatectomy. The histopathologic features of benign epithelium, high-grade prostatic intraepithelial neoplasia, and cancer were recorded, and the treatment effect was scored. Digital imaging analysis was used to measure the stroma/epithelium ratio and epithelial height, as well as the nuclear area in cancer. RESULTS: In benign epithelium, treatment caused distinctive cytoarchitectural changes of atrophy and a decrease in the epithelial height (P = 0.053). The peripheral zone showed the most marked response to treatment. In cancer tissue, the tumor volume was significantly lower in the dutasteride-treated men than in the placebo-treated men (mean 15% versus 24%, respectively, P = 0.025), the percentage of atrophic epithelium was increased (P = 0.041), and the stroma/gland ratio was doubled (P = 0.046). The treatment alteration effect score was doubled (P = 0.055) and did not correlate with any Gleason score changes. CONCLUSIONS: After short-term dutasteride treatment, benign epithelium showed involution and epithelial shrinkage, and prostate cancer tissue demonstrated a decrease in epithelium relative to stroma. These findings indicate that dutasteride induces significant phenotypic alterations in both the benign and the neoplastic prostate, supportive of a chemopreventive or chemoactive role.

5-alpha Reductase Inhibitors↗
PubMed2005

Macrophage migration inhibitory factor is released as a complex with alpha1-inhibitor-3 in the intraluminal fluid during bladder inflammation in the rat.

PURPOSE: Macrophage migration inhibitory factor (MIF) is released into intraluminal fluid (ILF) during bladder inflammation in the rat. We investigated the forms of MIF that are released. We examined MIF release after subcutaneous substance P (SP) or intravesical capsaicin and studied proteins associated with excreted MIF in ILF. MATERIALS AND METHODS: Anesthetized male rats with the bladder isolated from the kidneys were injected with SP subcutaneously (saline vehicle) or with intravesical capsaicin (vehicle, 0.1 mM and 1 mM). After 1 hour the ILF was removed and MIF levels were determined using enzyme-linked immunosorbent assay or Western blotting procedures under native, nonreducing and reducing conditions. Mass spectrometry was used to identify proteins associated with MIF in ILF and results were verified by immunoprecipitation. RESULTS: SP and intravesical capsaicin increased the total amount of MIF in ILF. MIF was found in high molecular weight complexes that resolved into 2 bands under nonreducing conditions. SP and capsaicin differentially increased the MIF bands. Mass spectrometry determined that MIF was complexed with acute phase proteins. MIF immunoprecipitation followed by Western blotting confirmed that MIF was complexed to alpha1-inhibitor-3. CONCLUSIONS: MIF is complexed with alpha1-inhibitor-3, a member of the alpha-2-macroglobulin proteinase inhibitor family, in the rat. Although SP and capsaicin increased the total amount of MIF detected by enzyme-linked immunosorbent assay in ILF, the patterns of MIF complexes elicited by these 2 treatments were different. These findings suggest that in association with other proteins MIF forms part of a complex elicited by bladder inflammation.

Acute-Phase Proteins↗
PubMed2005

High-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: predictive value for cancer in current practice.

In earlier studies, prostate cancer (PCa) has been reported to appear in 21% to 48% of subsequent biopsies for isolated high-grade prostatic intraepithelial neoplasia (PIN) and in 34% to 60% for isolated atypical small acinar proliferation suspicious for, but not diagnostic of, malignancy (ASAP). We report results of follow-up biopsies in a recent cohort of community practice patients who underwent biopsy for PSA abnormalities. The study group consisted of 336 men with initial diagnoses of PIN (n = 204), ASAP (n = 78), or both lesions (n = 54) who underwent at least one repeat biopsy. Mean follow-up intervals in months were 6.0 for PIN, 3.8 for ASAP, and 4.9 for PIN/ASAP. Follow-up PCa detection rates were 23%, 37%, and 33%, respectively. The predictive value of ASAP was significantly higher than that for PIN (P = 0.0188). In 23 PIN studies with chronologic midpoints in the early 1990s, follow-up PCa was detected in a mean of 36% of cases, whereas this value was 21% after the year 2000. In 13 ASAP studies, mean PCa detection on follow-up was 45% until 1996 and 39% from 1997 to present. PIN/ASAP predicted PCa in 33% of cases in our study, similar to ASAP alone (P = 0.65) and had a mean predictive value of 44% in the literature. Factors that may account for the decline in PIN predictive values include: 1) extended biopsy techniques that yield higher rates of initial cancer detection, 2) lower detection rate for the remaining small cancers that may accompany PIN, and 3) remaining PIN cases may lack concomitant cancer.

Aged↗
PubMed2005

Small lymphocytic lymphoma involving an enlarging complex renal cyst.

A 47-year-old white man presented for evaluation of a complex right renal mass. He had a history of human immunodeficiency virus. Cervical lymph node biopsy had revealed small lymphocytic lymphoma. Computed tomographic scan disclosed diffuse mesenteric and retroperitoneal adenopathy consistent with chronic lymphocytic leukemia, as well as a 4.5-cm complex cystic right renal mass, which 17 months later enlarged to 6.2 cm. The mass resembled multiloculated cystic nephroma. Partial nephrectomy revealed infiltration of the cyst wall by small lymphocytic lymphoma. To our knowledge, this is the first reported case of lymphoma arising in or colonizing a renal cyst.

Humans↗
PubMed2004

Androgen ablation therapy for prostate carcinoma suppresses the immunoreactive telomerase subunit hTERT.

BACKGROUND: Telomerase is a ribonucleoprotein complex that protects the ends of chromosomes from degradation. Its catalytic subunit, hTERT, controls its activity. Prior data in prostate carcinoma cases indicated that immunohistochemical hTERT reactivity increases with tumor grade and may be absent in lower grade cases. The effect of complete androgen ablation (CAA) on tumor hTERT expression was uncertain. METHODS: hTERT immunostaining was performed on the cancerous pretreatment biopsy tissue of 30 men who consecutively underwent CAA with bicalutamide and goserelin acetate for 30 days prior to undergoing radical prostatectomy, and on their tumor tissue from radical prostatectomy. As controls, biopsy and prostatectomy samples from 30 untreated men were studied. Nuclear staining was evaluated by two observers, and the change in staining between biopsy and prostatectomy samples was evaluated using the Student t test in both groups. RESULTS: The percent of reactive tumor nuclei in treated men declined from 36.7% to 13.2% (P = 0.0001), and declined from 19.8% to 16.1% in untreated men (P = 0.4). The greater mean hTERT reactivity in the treated men's biopsy specimens was attributed to an increased proportion of higher (Gleason score > or = 7) grade tumors. The decline in hTERT immunostaining remained significant after normalizing it to that of the untreated group (P = 0.002). The original Gleason scores, corresponding declines in the percentage of reactive tumor nuclei, and significance were: Gleason score < or = 6: 11% (P = 0.03); Gleason score of 7: 23% (P < 0.006); and Gleason score > or = 8: 46% (P < 0.005) (from a mean 63% to 17%). CONCLUSIONS: CAA for prostate carcinoma can be considered an antitelomerase therapy. The steepest reduction in telomerase activity was noted in the highest grade tumors.

Aged↗
PubMed2004

Prostate cancer invasion is influenced more by expression of a CD44 isoform including variant 9 than by Muc18.

The standard form of cell adhesion glycoprotein CD44 is a metastasis suppressor in prostate cancer. However, we previously showed by RT-PCR and Western blotting that cancer overexpresses unique CD44 variant v7-v10 isoforms. Muc18 is another cell adhesion marker reportedly overexpressed by prostate cancer. Matched frozen section-confirmed tumor and benign tissues were harvested from 10 prostatectomy specimens and tumor was microdissected from two lymph node metastases. Tissues were homogenized for RNA preparations, and RT-PCR was performed for the CD44v7-v10 sequence. In cultured prostate cancer cells, we caused RNA interference against CD44v9 and/or Muc18. We used PC3M cells and a derivative cell line called G(s)alpha, that constitutively expresses this G-protein and is more invasive. Lipofection was performed for a green fluorescent protein plasmid and for two 22-mer DNA fragments, cloned into a plasmid expression vector to generate hairpin, interfering dsRNA. Assays for invasion into Matrigel, a basement membrane matrix, were performed in 4-5 experiments. RT-PCR demonstrated expression of a 608 bp band representing CD44v7-v10 or a 638 bp band of CD44v6-v10 in prostate cancer tissues and metastases but not benign tissue. Cultured G(s)alpha cells overexpressed CD44v9 by comparison with PC3M cells. At 90 h after 6-hour lipofection, protein silencing was evident by Western blots. Silencing the CD44v9 expression reduced invasiveness into Matrigel to 21.6+/-7.0% in PC3M cells (P<0.001) and 31.2+/-18.3% in G(s)alpha cells (P=0.001), compared to cells exposed to transfection vehicle alone. Silencing Muc18 expression reduced invasiveness to 76.9+/-13.5% of the control value in PC3M cells (P<0.05) and 84.8+/-29.9% in G(s)alpha cells (P=0.18). Prostate cancer invasion is facilitated more by its overexpression of CD44 variant 9 than by Muc18. Its relative overexpression by G(s)alpha cells is a novel finding, suggesting a link between signal transduction and cell adhesion marker expression.

Antigens, CD↗
PubMed2004

P504S immunostaining boosts diagnostic resolution of "suspicious" foci in prostatic needle biopsy specimens.

From 1.5% to 9.0% of prostatic needle biopsy specimens disclose atypical small acinar proliferations (ASAPs) suggestive of malignancy, carrying an approximate 45% predictive value for cancer. We applied keratin 34 beta E12 and P504S monoclonal immunostains to 93 cases that were judged as ASAP after H&E staining alone. Forty-one ASAP foci survived recutting for both immunostains. Three urologic pathologists independently assigned post-keratin 34 beta E12 diagnoses of cancer, ASAP, high-grade prostatic intraepithelial neoplasia, or benign and then reviewed P504S slides and assigned final diagnoses. Eight foci (20%) were resolved unanimously after keratin 34 beta E12 staining; 18 (44%) were resolved by 1 or 2 evaluators and 29 (71%) by at least 1. According to whether post-keratin 34 beta E12 ASAP designation was given by 3, 2, or 1 evaluator(s), P504S immunostaining unanimously resolved an additional 5 (12%), 10 (24%), or 23 (56%) of 41 ASAP foci and cumulatively, 31 foci (76%). Among 35 men (excluding 6 with cancer in other cores of the original biopsy), these immunostains could have permitted cancer diagnosis in 11 (31%), without repeated biopsy. Thus, the consensus diagnosis rate improved from poor to good after supplementing 34 beta E12 immunostaining with P504S.

Adenocarcinoma↗