bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype
Authors: Balliet Renee M. , Chen Gang , Gallagher Carla J. , Dellinger Ryan W. , Sun Dongxiao , Lazarus Philip
Published: March 2009

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor used in the treatment of cutaneous T-cell lymphoma and in clinical trials for treatment of multiple other cancers. A major mode of SAHA metabolism is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To characterize the UGTs active against SAHA, homogenates from HEK293 cell lines overexpressing UGT wild-type or variant UGT were used. The hepatic UGTs 2B17 and 1A9 and the extrahepatic UGTs 1A8 and 1A10 exhibited the highest overall activity against SAHA as determined by Vmax/KM (16 ± 6.5, 7.1 ± 2.2, 33 ± 6.3, and 24 ± 2.4 nL·min−1.μg UGT protein−1, respectively), with UGT2B17 exhibiting the lowest KM (300 μmol/L) against SAHA of any UGT in vitro. Whereas the UGT1A8p.Ala173Gly variant exhibited a 3-fold (P < 0.005) decrease in glucuronidation activity against SAHA compared with wild-type UGT1A8, the UGT1A8p.Cys277Tyr variant exhibited no detectable glucuronidation activity; a similar lack of detectable glucuronidation activity was observed for the UGT1A10p.Gly139Lys variant. To analyze the effects of the UGT2B17 gene deletion variant (UGT2B17*2) on SAHA glucuronidation phenotype, human liver microsomes (HLM) were analyzed for glucuronidation activity against SAHA and compared with UGT2B17 genotype. HLM from subjects homozygous for UGT2B17*2 exhibited a 45% (P < 0.01) decrease in glucuronidation activity and a 75% (P < 0.002) increase in KM compared with HLMs from subjects homozygous for the wild-type UGT2B17*1 allele. Overall, these results suggest that several UGTs play an important role in the metabolism of SAHA and that UGT2B17-null individuals could potentially exhibit altered SAHA clearance rates with differences in overall response. [Cancer Res 2009;69(7):2981–9]
Induction of Prostaglandin E2 Pathway Promotes Gastric Hamartoma Development with Suppression of Bone Morphogenetic Protein Signaling
Authors: Oshima Hiroko , Itadani Hiraku , Kotani Hidehito , Taketo Makoto Mark , Oshima Masanobu
Published: March 2009

Mutations in bone morphogenetic protein (BMP) receptor 1A (BMPR1A) are responsible for a subset of cases of juvenile polyposis (JP) syndrome that develops hamartomatous tumors in the gastrointestinal tract. Mouse genetic studies have shown that suppression of BMP signaling in the intestines causes JP-type hamartoma development. Here, we generated K19-Nog transgenic mice expressing noggin, a BMP antagonist, in gastric epithelium. However, inhibition of BMP signaling did not cause gastric phenotypes. We thus crossed K19-Nog with K19-C2mE mice that expressed Ptgs2 and Ptges in the stomach to generate compound transgenic mice. Expression of Ptgs2 and Ptges results in prostaglandin E2 (PGE2) biosynthesis, and both enzymes are induced in most human gastrointestinal tumors. Importantly, K19-Nog/C2mE compound mice developed gastric hamartomas that were morphologically similar to those found in JP with mucin-containing dilated cysts and inflammatory infiltration. Notably, treatment of K19-Nog/C2mE mice with a cyclooxygenase-2 inhibitor, celecoxib, significantly reduced tumor size with suppression of angiogenesis, suggesting that induction of the PGE2 pathway together with inhibition of BMP signaling is required for gastric hamartoma development. Moreover, microarray analyses revealed that canonical Wnt signaling target genes were not induced in K19-Nog/C2mE hamartomas, indicating that BMP inhibition and PGE2 induction lead to gastric hamartoma development independent of the Wnt/β-catenin pathway. These results, taken together, suggest that the PGE2 pathway is an effective preventive target against BMP-suppressed gastric hamartomas, as well as for Wnt/β-catenin–activated adenocarcinomas. [Cancer Res 2009;69(7):2729–33]
Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer
Authors: Pernas Francisco G. , Allen Clint T. , Winters Mary E. , Yan Bin , Friedman Jay , Dabir Bhavana , Saigal Kunal , Mundinger Gerhard S. , Xu Xiaojiang , Morris John C. , Calvo Katherine R. , Van Waes Carter , Chen Zhong
Published: March 2009

Purpose: Gefitinib targeting of the epidermal growth factor receptor (EGFR) has shown limited activity in clinical trials of head and neck squamous cell carcinoma (HNSCC). To investigate the underlying molecular mechanism, the proteomic signatures and responses of EGFR and downstream signals have been studied in a panel of HNSCC cell lines and tumor specimens pre- and post-gefitinib treatment.

Experimental Design: The IC50 of gefitinib for HNSCC cell lines were determined using 3-(4,5-dmethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay. The effects of gefitinib on activation of EGFR and downstream signaling molecules were determined by Western blot, ELISA, and reverse-phase protein microarray (RPMA). The biomarkers involved in the signaling pathways were examined in HNSCC tumor specimens from patients in a phase I gefitinib trial.

Results: In vitro, gefitinib inhibited cell proliferation with differing IC50, and suppressed activation of EGFR and downstream signaling molecules protein kinase B (AKT), extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor κB. The drug sensitivity was statistically correlated with activation of phosphorylated AKT (p-AKT) and phosphorylated STAT3 (p-STAT3) detected by ELISA, and consistent with results measured by RPMA. In patient samples, a broad suppression of activation of EGFR and downstream signaling molecules was observed in a molecular responder patient, in contrast to a lack of inhibition or increased activation of biomarkers in different pathways in nonresponder patients.

Conclusions: Gefitinib sensitivity is correlated with p-AKT and p-STAT3 activation in HNSCC cell lines and tumor specimens. p-AKT and p-STAT3 could serve as potentially useful biomarkers and drug targets for further development of novel therapeutic agents for HNSCC.
microRNA-451 Regulates Macrophage Migration Inhibitory Factor Production and Proliferation of Gastrointestinal Cancer Cells
Authors: Bandres Eva , Bitarte Nerea , Arias Fernando , Agorreta Jackeline , Fortes Puri , Agirre Xabi , Zarate Ruth , Diaz-Gonzalez Juan A. , Ramirez Natalia , Sola Jesus J. , Jimenez Paula , Rodriguez Javier , Garcia-Foncillas Jesus
Published: March 2009

Purpose: microRNAs (miRNA) are small RNAs that function as post-transcriptional regulators of gene expression. Recent evidence has shown that some miRNAs can act as oncogenes or tumor suppressors. This study was conducted to evaluate the potential association of miRNA expression with clinical outcome in patients with gastric cancer.

Experimental Design: Expression of 250 human mature miRNAs was measured by real-time PCR on paraffin-embedded tumor samples of 21 patients with gastric cancer stage III uniformly treated with surgical resection followed by chemoradiation. We identified the miRNAs correlated with disease-free and overall survival times, and the results were evaluated including 24 other patients. In vitro cell proliferation and radiosensitivity studies were done to support clinical data.

Results: The results revealed that down-regulation of miR-451 was associated with worse prognosis. miR-451 was detected by in situ hybridization in epithelial cells and showed decreased expression in gastric and colorectal cancer versus nontumoral tissues. Overexpression of miR-451 in gastric and colorectal cancer cells reduced cell proliferation and increased sensitivity to radiotherapy. Microarray and bioinformatic analysis identified the novel oncogene macrophage migration inhibitory factor (MIF) as a potential target of miR-451. In fact, overexpression of miR-451 down-regulated mRNA and protein levels of MIF and decreased expression of reporter genes with MIF target sequences. Moreover, we found a significant inverse correlation between miR-451 and MIF expression in tumoral gastric biopsies.

Conclusions: These findings support the role of miR-451 as a regulator of cancer proliferation and open new perspectives for the development of effective therapies for chemoradioresistant cancers.
Expression of Hepatocyte Growth Factor and Its Receptor Met in Wilms' Tumors and Nephrogenic Rests Reflects Their Roles in Kidney Development
Authors: Vuononvirta Raisa , Sebire Neil J. , Messahel Boo , Perusinghe Nina , Reis-Filho Jorge S. , Pritchard-Jones Kathy , Vujanic Gordan M. , Jones Chris
Published: March 2009

Purpose: Hepatocyte growth factor (HGF) and its receptor Met are known to play diverse roles in both organogenesis and cancer. Wilms' tumor (WT) is a prototype for the link between abrogated development and neoplasia, with dysregulation of growth factor/receptor pathways playing key roles. Despite this, an understanding of the HGF/Met axis in the process is lacking.

Experimental Design: Observing copy number alterations at the loci for these genes in WTs and their precursor lesions nephrogenic rests, we examined protein expression by immunohistochemistry and investigated the effects of HGF on an in vitro model of kidney development.

Results: HGF was preferentially expressed in the blastemal cells of nephrogenic rests but not WTs. Met expression was infrequent and restricted to well-differentiated epithelial cells and stroma in both lesions. In an independent cohort of favorable histology WTs on a tissue microarray, HGF was expressed in 15 of 193 (8%) cases and correlated with a predominance of epithelial cells, whereas Met expression was observed in 25 of 179 (14%) cases and was associated with stromal subtypes. In a mouse mesonephric cell line model, we observed Met expression in culture conditions reflecting both mesenchymal and epithelial differentiation, whereas HGF was up-regulated in association with acquisition of a more epithelial-like phenotype. This could be mimicked by exogenous exposure of mesenchymal-like cells to recombinant HGF.

Conclusions: These data show that the relatively infrequent expression of HGF and Met in WT tumorigenesis reflects their roles in nephrogenesis, particularly the mesenchymal-to-epithelial transition, rather than a dependence on oncogenic signaling pathways.
Potentiation of a Topoisomerase I Inhibitor, Karenitecin, by the Histone Deacetylase Inhibitor Valproic Acid in Melanoma: Translational and Phase I/II Clinical Trial
Authors: Daud Adil I. , Dawson Jana , DeConti Ronald C. , Bicaku Elona , Marchion Douglas , Bastien Sem , Hausheer Frederick A. , Lush Richard , Neuger Anthony , Sullivan Daniel M. , Munster Pamela N.
Published: March 2009

Purpose: The novel topoisomerase I inhibitor karenitecin (KTN) shows activity against melanoma. We examined whether histone deacetylase inhibition could potentiate the DNA strand cleavage, cytotoxicity as well as the clinical toxicity, and efficacy of KTN in melanoma.

Experimental Design: Apoptosis, COMET, and xenograft experiments were carried out as described previously. A phase I/II trial of valproic acid (VPA) and KTN was conducted in patients with stage IV melanoma, with any number of prior therapies, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function.

Results: VPA pretreatment potentiated KTN-induced apoptosis in multiple melanoma cell lines and in mouse A375 xenografts. VPA increased KTN-induced DNA strand breaks. In the phase I/II trial, 39 patients were entered, with 37 evaluable for toxicity and 33 evaluable for response. Somnolence was the dose-limiting toxicity. The maximum tolerated dose for VPA was 75 mg/kg/d; at maximum tolerated dose, serum VPA was ∼200 μg/mL (1.28 mmol/L). At the dose expansion cohort, 47% (7 of 15) of patients had stable disease; median overall survival and time to progression were 32.8 and 10.2 weeks, respectively. Histone hyperacetylation was observed in peripheral blood mononuclear cells at maximum tolerated dose.

Conclusion: VPA potentiates KTN-induced DNA strand breaks and cytotoxicity. VPA can be combined at 75 mg/kg/d for 5 days with full-dose KTN without overlapping toxicities. In metastatic poor prognosis melanoma, this combination is associated with disease stabilization in 47% of patients. Further testing of this combination appears warranted.
A Phase I Study with Neratinib (HKI-272), an Irreversible Pan ErbB Receptor Tyrosine Kinase Inhibitor, in Patients with Solid Tumors
Authors: Wong Kwok-K. , Fracasso Paula M. , Bukowski Ronald M. , Lynch Thomas J. , Munster Pamela N. , Shapiro Geoffrey I. , Jänne Pasi A. , Eder Joseph P. , Naughton Michael J. , Ellis Matthew J. , Jones Suzanne F. , Mekhail Tarek , Zacharchuk Charles , Vermette Jennifer , Abbas Richat , Quinn Susan , Powell Christine , Burris Howard A.
Published: March 2009

Purpose: The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors.

Experimental Design: Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration.

Results: Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease ≥24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non–small cell lung cancer patients.

Conclusion: The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.
Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma
Authors: Maréchal Raphaël , Mackey John R. , Lai Raymond , Demetter Pieter , Peeters Marc , Polus Marc , Cass Carol E. , Young James , Salmon Isabelle , Devière Jacques , Van Laethem Jean-Luc
Published: March 2009

Purpose: Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma and its use in combination with radiotherapy is under exploration. Human equilibrative nucleoside transporter 1 (hENT1) and human concentrative nucleoside transporter (hCNT) 1 and 3 are the major transporters responsible for 2′,2′-difluoro-2-deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine patients' outcome according to the expression of hENT1 and hCNT3 in tumoral cells after postoperative gemcitabine-based chemoradiation regimen.

Experimental Design: We studied tumor blocks from 45 pancreatic adenocarcinoma patients treated with gemcitabine-based chemoradiation after curative resection and assessed hENT1 and hCNT3 expression using immunohistochemistry.

Results: When adjusted for the effects of lymph node ratio and tumor diameter, patients with high hENT1 expression had significantly longer disease-free survival and overall survival (OS) than patients with low expression, whereas high hCNT3 expression was only associated with longer OS. In a combined analysis, patients with two favorable prognostic factors (hENT1high/hCNT3high expression) had a longer survival (median OS, 94.8 months) than those having one (median OS, 18.7 months) or no (median OS, 12.2 months) favorable prognostic factor.

Conclusions: Pancreatic adenocarcinoma patients with a high expression of hENT1 and hCNT3 immunostaining have a significantly longer survival after adjuvant gemcitabine-based chemoradiation. These biomarkers deserve prospective evaluation in patients receiving gemcitabine-based adjuvant therapy.
Tumor Microenvironment of Metastasis in Human Breast Carcinoma: A Potential Prognostic Marker Linked to Hematogenous Dissemination
Authors: Robinson Brian D. , Sica Gabriel L. , Liu Yi-Fang , Rohan Thomas E. , Gertler Frank B. , Condeelis John S. , Jones Joan G.
Published: March 2009

Purpose: Multiphoton-based intravital imaging has shown that invasive carcinoma cells in mouse and rat mammary tumors intravasate when associated with perivascular macrophages, identifying a potential tumor microenvironment of metastasis (TMEM). We define TMEM as the tripartite arrangement of an invasive carcinoma cell, a macrophage, and an endothelial cell. The aim of this study was to determine if TMEM density in human breast carcinoma samples predicts the development of systemic, hematogenous metastases.

Experimental Design: A case-control study of 30 patients who developed metastatic breast cancer and 30 patients without metastatic disease was done. Cases were matched to controls based on currently used prognostic criteria. Paraffin-embedded primary breast cancer samples were stained using a triple immunohistochemical method allowing simultaneous identification of carcinoma cells, macrophages, and endothelial cells. Two pathologists, blinded to outcome, evaluated the number of TMEM per 20 high-power fields.

Results: No association was seen between TMEM density and tumor size or grade, lymph node metastasis, lymphovascular invasion, or hormone receptor status. TMEM density was greater in the group of patients who developed systemic metastases compared with the patients with only localized breast cancer (median, 105 versus 50, respectively; P = 0.00006). For every 10-unit increase in TMEM density, the odds ratio for systemic metastasis was 1.9 (95% confidence interval, 1.1-3.4).

Conclusions: TMEM density predicted the development of systemic, hematogenous metastases. The ability of TMEM to predict distant metastasis was independent of lymph node status and other currently used prognosticators. Quantitation of TMEM may be a useful new prognostic marker for breast cancer patients.
The NFATc2 Gene Is Involved in a Novel Cloned Translocation in a Ewing Sarcoma Variant That Couples Its Function in Immunology to Oncology
Authors: Szuhai Károly , IJszenga Marije , de Jong Danielle , Karseladze Apollon , Tanke Hans J. , Hogendoorn Pancras C.W.
Published: March 2009

Purpose: Ewing sarcoma is an aggressive sarcoma and is the second most common bone sarcoma in childhood. Disease-specific t(11;22) (∼85-90%), t(21;22) (∼5-10%), or rarer variant translocations with the involvement of chromosome 22 (∼5%) are present. At the gene level, the EWSR1 gene fuses with FLI1, ERG, or other ETS transcription factor family members. Thus far, no Ewing sarcoma has been identified with a fusion to transcription factors other than ETS.

Experimental Design: Using molecular tools such as multicolor fluorescence in situ hybridization and array comparative genomic hybridization, a ring chromosome containing chromosomes 20 and 22 was identified in four Ewing sarcoma cases. The breakpoint was mapped with (fiber-) fluorescence in situ hybridization and reverse transcription-PCR followed by sequencing of the fusion partners.

Results: Molecular karyotyping showed the translocation and amplification of regions of chromosomes 20q13 and 22q12. Cloning of the breakpoint showed an in-frame fusion between the EWSR1 and NFATc2 genes, resulting in loss of the NH2-terminal, calcineurin-dependent control region and an intact active domain of NFATc2 controlled by the transactivation domains of EWSR1.

Conclusion: A new translocation involving EWSRI and NFATc2 was cloned. NFATc2 is a transcription factor that is not a member of the ETS family and functions in T-cell differentiation and immune response. Direct involvement of NFATc2 has not yet been observed in oncogenesis. We show that due to the shared sequence recognition of NFATc2 and the ETS family, shared transcriptional control is possible using activating protein complex 1.
Transcriptional Activation of the Mixed Lineage Leukemia–p27Kip1 Pathway by a Somatostatin Analogue
Authors: Horiguchi Kazuhiko , Yamada Masanobu , Satoh Tetsurou , Hashimoto Koshi , Hirato Junko , Tosaka Masahiko , Yamada Shozo , Mori Masatomo
Published: March 2009

Purpose: Mixed lineage leukemia (MLL) is a histone methyltransferase that activates gene transcription and associates with menin. In multiple endocrine neoplasia type 1 (Men1), a mutation of menin caused decreased expression of the p27Kip1 and p18Ink4C genes and deregulated cell growth. We hypothesized that the same pathway might be involved in sporadic pituitary adenomas.

Experimental Design: mRNA levels for MLL, Men1, p27Kip1, and p18Ink4C were measured in specimens of several sporadic pituitary adenomas, and a search for clinical parameters revealed that octreotide treatment affected the level of expression of some genes tested. To study molecular mechanisms, we cloned and characterized the MLL promoter region and used small interfering RNA for MLL and specific inhibitors for signal transduction pathways.

Results: A strong correlation between MLL and p27Kip1 mRNA levels was observed in prolactinomas and growth hormone–secreting adenomas, and these levels were attenuated except in growth hormone–secreting adenomas treated with a somatostatin analogue, octreotide. Conversely, the patients treated with octreotide showed high levels of MLL-p27Kip1 mRNA. Experiments in vitro showed that octreotide increased MLL and p27Kip1 protein and mRNA levels, and overexpression of MLL induced a marked increase in p27Kip1promoter activity. Furthermore, octreotide stimulated the promoter activity of the MLL gene through phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. In addition, incubation with an inhibitor for methyltransferase, MTA, and knockdown of MLL completely inhibited the octreotide-induced expression of p27Kip1.

Conclusions: The MLL-p27Kip1 pathway was down-regulated in the pituitary adenomas, and octreotide increased the p27Kip1 level, at least in part, by sequential transcriptional stimulation of the MLL and p27Kip1 genes through phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways.
Telomerase-Specific Virotheranostics for Human Head and Neck Cancer
Authors: Kurihara Yuji , Watanabe Yuichi , Onimatsu Hideki , Kojima Toru , Shirota Tatsuo , Hatori Masashi , Liu Dong , Kyo Satoru , Mizuguchi Hiroyuki , Urata Yasuo , Shintani Satoru , Fujiwara Toshiyoshi
Published: March 2009

Purpose: Long-term outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) remain unsatisfactory despite advances in combination of treatment modalities. SCCHN is characterized by locoregional spread and it is clinically accessible, making it an attractive target for intratumoral biological therapies.

Experimental Design: OBP-301 is a type 5 adenovirus that contains the replication cassette in which the human telomerase reverse transcriptase promoter drives expression of the E1 genes. OBP-401 contained the replication cassette and the green fluorescent protein (GFP) gene. The antitumor effects of OBP-301 were evaluated in vitro by the sodium 30-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay and in vivo in an orthotopic xenograft model. Virus spread into the lymphatics was also orthotopically assessed by using OBP-401.

Results: Intratumoral injection of OBP-301 resulted in the shrinkage of human SCCHN tumors orthotopically implanted into the tongues of BALB/c nu/nu mice and significantly recovered weight loss by enabling oral ingestion. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Moreover, whole-body fluorescent imaging revealed that intratumorally injected OBP-401 could visualize the metastatic lymph nodes, indicating the ability of the virus to traffic to the regional lymphatic area and to selectively replicate in neoplastic lesions, resulting in GFP expression and cell death in metastatic lymph nodes.

Conclusions: These results illustrate the potential of telomerase-specific oncolytic viruses for a novel therapeutic and diagnostic approach, termed theranostics, for human SCCHN.
Limited Amounts of Dendritic Cells Migrate into the T-Cell Area of Lymph Nodes but Have High Immune Activating Potential in Melanoma Patients
Authors: Verdijk Pauline , Aarntzen Erik H.J.G. , Lesterhuis W. Joost , Boullart A.C. Inge , Kok Ellemieke , van Rossum Michelle M. , Strijk Simon , Eijckeler Femke , Bonenkamp Johannes J. , Jacobs Joannes F.M. , Blokx Willeke , vanKrieken J. Han J.M. , Joosten Irma , Boerman Otto C. , Oyen Wim J.G. , Adema Gosse , Punt Cornelis J.A. , Figdor Carl G. , de Vries I. Jolanda M.
Published: March 2009

Purpose: The success of immunotherapy with dendritic cells (DC) to treat cancer is dependent on effective migration to the lymph nodes and subsequent activation of antigen-specific T cells. In this study, we investigated the fate of DC after intradermal (i.d.) or intranodal (i.n.) administration and the consequences for the immune activating potential of DC vaccines in melanoma patients.

Experimental Design: DC were i.d. or i.n. administered to 25 patients with metastatic melanoma scheduled for regional lymph node resection. To track DC in vivo with scintigraphic imaging and in lymph nodes by immunohistochemistry, cells were labeled with both [111In]-indium and superparamagnetic iron oxide.

Results: After i.d. injection, maximally 4% of the DC reached the draining lymph nodes. When correctly delivered, all DC were delivered to one or more lymph nodes after i.n. injection. Independent of the route of administration, large numbers of DC remained at the injection site, lost viability, and were cleared by infiltrating CD163+ macrophages within 48 hours. Interestingly, 87 ± 10% of the surviving DC preferentially migrated into the T-cell areas, where they induced antigen-specific T-cell responses. Even though more DC reached the T-cell areas, i.n. injection of DC induced similar antigen-specific immune responses as i.d. injection. Immune responses were already induced with <5 × 105 DC migrating into the T-cell areas.

Conclusions: Monocyte-derived DC have high immune activating potential irrespective of the route of vaccination. Limited numbers of DC in the draining lymph nodes are sufficient to induce antigen-specific immunologic responses.
The Role of Microbiota in Allergy
Authors: Kalliomäki Marko
Published: March 2009

The hygiene hypothesis links the growing epidemic of clinical manifestations of allergy, atopic eczema, allergic rhinoconjunctivitis and asthma to reduced exposure to microbes at an early age as a result of environmental changes in the industrialized world. These include improved sanitation and living conditions, vaccinations and antimicrobial therapy, together with declining family size and changes in dietary intake. The discovery of three subgroups of regulatory T cells has revolutionized the original immunological basis of the hygiene hypothesis, the so-called T helper 1/T helper 2 paradigm. In a case of defective oral tolerance allergy ensues. Recent experimental and clinical findings clearly indicate that both the development and maintenance of oral tolerance is dependent on these immunosuppressive regulatory T cells. Moreover, gut microbiota has been demonstrated to be crucial for the appropriate expression and function of the regulatory T cells, thus connecting microbiota closely to allergy. Indeed, many of the cross-sectional studies have shown a different composition of gut microbiota in children with atopic eczema and healthy controls. Most of the published prospective follow-up studies so far have also found that alterations in gut microbiota precede development of allergy. Changes in the amount of bifidobacteria, clostridia and Escherichia coli have been the most common findings in these studies. There has been, however, considerable variation in the settings of different prospective studies, making it difficult to interpret probable causes for variable results. The future studies addressing the issue should not only use novel molecular techniques of gut microbiota assessment, but also take into consideration several other aspects discussed in this paper.
Gut Microbiota, Obesity and Diabetes
Authors: Bibiloni Rodrigo , Membrez Mathieu , Chou Chieh Jason
Published: March 2009

The growing epidemic of obesity is no longer restricted to developed countries. In 2005, the World Health Organization alerted that there were approximately 400 million obese adults worldwide, and approximately 20 million children worldwide were overweight. Obesity is a complex health issue with serious consequences such as type 2 diabetes, cardiovascular diseases, and others. Behavioral, genetic and environmental factors have been addressed as contributing factors for overweight and obesity. Recent evidence indicates that the community of microorganisms that dwell in the gut, known as the gut microbiota, can influence nutrient absorption and energy storage. The microbiotic composition has been shown to differ between obese and lean mice and humans alike, suggesting that modulation of the gut microbiotic composition offers a new avenue for the treatment of obesity and overweight. This review revises the available scientific evidence supporting these speculations. Recent results obtained from studies focusing on the contributions of gut microbiota to diabetes are also summarized in this review.
Diagnóstico de la colestasis neonatal
Authors: Girard Muriel , Lacaille Florence
Published: March 2009

La colestasis es un proceso frecuente en los recién nacidos (1 de cada 2.500 nacidos vivos) y los niños pequeños. Comprende numerosas etiologías, en ocasiones con pronósticos ominosos. En caso de colestasis neonatal, la actitud más importante consiste en observar el color de las deposiciones y excluir la atresia biliar, que debe ser tratada quirúrgicamente antes del día 45 de vida. La atresia biliar representa casi el 50% de los casos de colestasis neonatal, cuyas demás causas son numerosas. Algunos casos pueden ser tratados satisfactoriamente, como la tirosinemia de tipo I o los errores congénitos de las síntesis de ácidos biliares. No obstante, en la mayoría de los casos no existe tratamiento específico y la enfermedad evoluciona hacia la cirrosis o la insuficiencia hepática, que requiere un trasplante hepático. En la actualidad, aunque los resultados del trasplante hepático son satisfactorios, se trata de una intervención difícil con frecuentes efectos secundarios. En el futuro, el análisis y el mejor conocimiento de los mecanismos de las diferentes enfermedades colestáticas podría permitir el establecimiento de otros tratamientos como el trasplante de hepatocitos o la terapia génica, capaces de aportar nuevas perspectivas para los niños.
Síndromes colestáticos familiares
Authors: Thompson Richard
Published: March 2009

El término ‘familiar’ es, en realidad, desafortunado. Aunque en la definición se incluye la palabra ‘hereditario’, la inferencia es que tendrá que aparecer habitualmente en otros miembros de la familia. En muchos de los procesos que se describen en este artículo esto a menudo no sucede y, por este motivo, las condiciones ‘familiares’ pueden ser pasadas por alto cuando se alcanza un diagnóstico. La colestasis es definida de manera diferente por médicos, anatomopatólogos y bioquímicos. Además, lo que se entiende por hepatopatía colestática varía muy frecuentemente entre los hepatólogos pediatras y los hepatólogos de adultos. No obstante, los mecanismos patogenéticos son cada vez más similares. La atresia biliar, que es la hepatopatía colestática más frecuente que afrontan los pediatras, es llamativamente diferente de la mayoría de las enfermedades, dado que parece no ser equivalente a ‘inicio tardío’ y casi nunca es familiar. En la actualidad se han constituido varias colaboraciones internacionales con la esperanza de superar estos obstáculos (http://www.barcnetwork.org/, http://www.orpha.net/nestasso/EFBAR/, http://www.biliary-atresia.com/index_frameset_ebar.html). De manera cotidiana, los hepatólogos pediatras tienen que vérselas con un grupo de lactantes cuya ictericia tiene una causa que no es fácilmente evidente. En muchos aspectos esto ha empeorado por el conocimiento adquirido desde hace tiempo de que una proporción significativa mejorará espontáneamente mientras que otros evolucionarán desfavorablemente. En los primerísimos meses de vida todavía tenemos dificultades para prever los desenlaces de ciertos pacientes. La causa subyacente, por lo menos en el grupo con desenlace ominoso, se está haciendo ahora evidente en un número creciente de casos. La mayoría de las mejoras en nuestra comprensión de este grupo de niños se han producido como consecuencia de los progresos en nuestro conocimiento de la etiología genética. También ha llegado a ser evidente que la hepatopatía colestática genética no se limita sólo a los pediatras. Sólo ahora se ha llegado a aclarar la medida exacta en la cual la genética contribuye a la enfermedad de ‘inicio tardío’.
Neue Entwicklungen bei der hormonellen Stimulation
Authors: Griesinger G. , Diedrich K.
Published: March 2009

Die ovarielle Stimulation ist integraler Bestandteil der In-vitro- Fertilisation (IVF)-Behandlung und trägt wesentlich zur Effizienz des Verfahrens bei. In nicht unerheblichem Ausmass verursacht die ovarielle Stimulation jedoch auch Behandlungsrisiken, Nebenwirkungen sowie finanzielle und psychische Belastungen, sodass eine Weiterentwicklung der gängigen Stimulationsprotokolle notwendig ist. In einer selektiven Literaturübersicht werden ausgewählte, neue Entwicklungen bei der ovariellen Stimulation diskutiert. Zur Prävention eines ovariellen Überstimulationssyndroms im Rahmen der IVF kann humanes Choriongonadotropin durch eine Bolusgabe eines Gonadorelin (GnRH)-Agonisten zur Auslösung der finalen Eizellreifung ersetzt werden. Dieses Vorgehen ist nur im GnRH-Antagonisten-Protokoll möglich und zeigt in mehreren Studien ein sehr gutes Potenzial zur Prävention des ovariellen Hyperstimulationssyndroms bei Risikopatientinnen. Zur Verringerung der Injektionshäufigkeit von Follikel stimulierendem Hormon (FSH) wurde ein lang wirksames FSH-Molekül (carboxyterminales Peptid, FSH-CTP) entwickelt. Phase-III-Daten zeigen, dass FSH-CTP (150 und 100 μg) über mehrere Tage wirkt und ähnlich effektiv und sicher wie die tägliche FSH-Verabreichung im Rahmen der ovariellen Stimulation zur IVF ist. Oral verfügbare Luteinisierungshormon- und FSH-Mimetika werden seit geraumer Zeit entwickelt. Eine Anwendung beim Menschen ist bisher nicht publiziert, und die verfügbaren Erkenntnisse entstammen In-vitro-Versuchen und Tierexperimenten.
Polkörperdiagnostik
Authors: Montag M. , van der Ven K. , van der Ven H.
Published: March 2009

Polkörperdiagnostik (PKD) ist eine Methode zur indirekten genetischen Analyse von Eizellen. Polkörper sind Nebenprodukte des meiotischen Zellzykluses, die für die weitere embryonale Entwicklung keine Bedeutung haben. Die Biopsie der Polkörper kann durch mechanisches Zonadrilling oder durch laserassistierte Zonaeröffnung in kürzester Zeit durchgeführt werden. Der väterliche Anteil an der genetischen Konstitution des entstehenden Embryos kann mit der PKD nicht diagnostiziert werden. Der überwiegende Einsatz der PKD erfolgt zum Nachweis von mütterlichen Aneuploidien und Translokationen in Eizellen. Für diese Indikationen ist die PKD eine Alternative zur Entnahme von Blastomeren, da die Integrität des Embryos durch die PKD nicht gestört wird. Neue Entwicklungen im Bereich der molekulargenetischen Diagnostik werden auch die PKD beeinflussen und möglicherweise in naher Zukunft eine umfassendere Diagnose ermöglichen.
An Evidence-Based Perspective to the Medical Treatment of Male Infertility: A Short Review
Authors: Ghanem Hussein , Shamloul Rany
Published: March 2009

Introduction: Evidence-based medicine (EBM) is the integration of best research evidence with clinical expertise and patient preferences and values. Aim: This narrative review aims to assist the physicians to make informed decisions based on the best available evidence in the area of male infertility and the patients’ own preferences and values. Methods: In this review we present the current state of knowledge and uncertainties about the medical management of male infertility. We describe the best available evidence from systematic reviews, randomized controlled studies and observational studies where appropriate. Results: Data from the literature suggest that gonadotropin treatment of male infertility can lead to a significant increase in pregnancy rates, however larger studies are needed to confirm such findings. Studies including combinations of antiestrogens, antioxidants and androgens are promising but need confirmation with further research. Conclusions: Most current combination therapies consist of orphan medications without industry support. Andrology research centers and other dedicated departments and units need to conduct randomized controlled trials of sufficient duration, sample number and robust design for groups most likely to benefit from antiestrogens, L-carnitine, antioxidants, and combination therapy. The ease of administration, low cost and mild side effects of antiestrogens justify their utility despite insufficient evidence of effect as monotherapies. Randomized controlled trials assessing other forms of medical therapy and combination therapy are available but are still in the preliminary stages.
Comparison of HoLEP and TURP in Terms of Efficacy in the Early Postoperative Period and Perioperative Morbidity
Authors: Mavuduru R.M. , Mandal A.K. , Singh S.K. , Acharya N. , Agarwal M. , Garg S. , Kumar S.
Published: March 2009

Objectives: We conducted this study to compare the safety and efficacy of transurethral resection of the prostate (TURP) and holmium laser prostatectomy. Methods: A total of 30 patients eligible for surgery for symptomatic benign prostatic hyperplasia were included in the study. They were randomized into two groups of 15 each. The patients were evaluated at 3 weeks, 3 and 9 months. Results: Preoperative parameters were comparable between the 2 groups. The mean operative time was longer in the holmium laser enucleation of prostate (HoLEP) group (53 ± 9.84 vs. 43 ± 9.36 min; p = 0.001). The intraoperative adverse events were comparable. The mean traction time (26.80 ± 5.9 vs. 19.60 ± 3.6 h; p = 0.0001), irrigation time (30 ± 7.68 vs. 19.40 ± 1.15 h; p = 0.0001), and duration of indwelling catheter (78.20 ± 17.84 vs. 46.42 ± 14.25 h; p = 0.0001) were significantly less in the HoLEP group as compared to the TURP group. Two patients (13.66%) in the TURP group had significant hematuria. Two patients in the HoLEP group vs. none in the TURP group developed urinary incontinence (p < 0.05). Significant improvements were observed in IPSS score, PFRs and PVRs in both the groups and maintained at 9 months. Conclusions: HoLEP is safe and effective in the surgical management of benign prostatic hyperplasia, with the advantage of reduced intraoperative hemorrhage and perioperative morbidity.
Usefulness of Naftopidil for Dysuria in Benign Prostatic Hyperplasia and Its Optimal Dose – Comparison between 75 and 50 mg
Authors: Oh-oka Hitoshi
Published: March 2009

Background/Objectives: The clinical usefulness and optimal dose of naftopidil were evaluated and discussed in 100 patients with benign prostatic hyperplasia without urinary retention. Methods: Naftopidil was administered once in the morning in a dose of 75 mg for 6 weeks; following washout for 1 week, a reduced dose of 50 mg was administered for another 6 weeks. Subjective and objective symptoms were clinically evaluated. Results: Significant improvements were observed in nocturia, IPSS, QOL index, Qmax, Qave, and % postvoid residual urine volume after administration of 75 mg as well as 50 mg. Comparison of the results obtained after administration of 75 and 50 mg revealed improvement only in bladder compliance. Among the items of the IPSS, ‘nocturia’, ‘less than two hours urination’, ‘weak urinary stream’ and ‘sensation of not emptying bladder’ improved, after administration of 75 as well as 50 mg. The bladder compliance aggravated to 13.6, from 22.1 ml/cm H2O after administration of 50 mg. Conclusions: Naftopidil could have superior effects in benign prostatic hyperplasia patients whose complaints are storage and voiding symptoms, especially nocturia of three times or more, as well as in patients with low compliance bladder and detrusor overactivity. The recommended dose seems to be 50 mg.
Toll-Free Telephone Medical Information on Nocturnal Enuresis: The First Italian Experience over a Two-Year Period
Authors: Ferrara Pietro , Nicoletti Alessandro , Emmanuele Valentina , Chiozza Maria Laura , Aceto Gabriella , Del Gado Roberto , Caione Paolo
Published: March 2009

Purpose: The aim of the study is to promote, through this toll-free number (TFN) service, a health communication program providing information on nocturnal enuresis (NE) and related problems by a subspecialty-trained physician and to collect the callers’ characteristics too. All phone calls were scheduled to data collections. Methods: The telephone service operated as follows: the TFN was available from March 1 to May 31, 2000, and from April 1 to June 30, 2001. People called the free telephone line and received information needs. Results: A total of 12,806 calls were received by the help line during the two study periods (7,046 in 2000 and 5,760 in 2001). Of the calls, 61% came from subjects with NE without pharmacological or non-pharmacological treatment, 16% (2000) and 13% (2001) came from subjects >12 years old. Conclusions: A TFN for NE can be both accessible and effective in order to provide information on NE and related problems. Finally, such a service should be included in a national program to improve health and well-being.
Distribution of High Chromogranin A Serum Levels in Patients with Nonmetastatic and Metastatic Prostate Adenocarcinoma
Authors: Sciarra Alessandro , Di Silverio Franco , Autran Ana Maria , Salciccia Stefano , Gentilucci Alessandro , Alfarone Andrea , Gentile Vincenzo
Published: March 2009

Objectives: We analyzed the incidence of elevated serum levels of chromogranin A (CgA) (as marker of neuroendocrine activity) in nonmetastatic and metastatic prostate cancer populations. Material and Methods: 264 consecutive men with nonmetastatic prostate adenocarcinoma considered for radical prostatectomy (group 1) and 89 consecutive men with metastatic prostate adenocarcinoma (group 2) represented our population. In all 353 cases a blood sample for the determination of serum total PSA and CgA levels was obtained (RIA). Two different cut-off for elevated serum CgA levels were used: >60 and >90 ng/ml. Results: In group 1, 35.0% of cases presented CgA levels >60 ng/ml and 6.4% >90 ng/ml. In group 2, 100% of cases presented CgA levels >60 ng/ml and 69.7% >90 ng/ml. The OR for CgA level >60 and >90 ng/ml significantly increased from nonmetastatic to metastatic cases (p = 0.0001). In group 1 the percentage of cases with CgA >60 ng/ml was 29.6% in Gleason score ≤7 (3 + 4) and 46.4% in Gleason score ≥7 (4 + 3) (p = 0.0001). In group 2, the percentage of cases with CgA >90 ng/ml was 51.8% in Gleason score ≤7 (3 + 4) and 77.4% in Gleason score ≥7 (4 + 3) (p = 0.0028). Conclusions: We describe a significant incidence of elevated serum levels of CgA either in nonmetastatic (using 60 ng/ml as cut-off) or in metastatic (using 90 ng/ml as cut-off) prostate adenocarcinoma cases.
Sclerotherapy of the Pampiniform Plexus with Modified Marmar Technique in Children and Adolescents
Authors: Carmignani Luca , Casellato Stefano , Galasso Giacomo , Bozzini Giorgio , Spinelli Matteo , Dell’Agnola Carlo Alberto , Rocco Francesco
Published: March 2009

Aims: Treatment of varicocele in children is a debated problem for which no validated guidelines exist. Several techniques have been proposed to solve this problem. The aim of this study was to evaluate the effectiveness and applicability of a modified Marmar technique in the treatment of varicocele in children and adolescents. Methods:From April 2004 to September 2005, we evaluated 25 patients between the ages of 9 and 18 (mean 14.4) years, who suffered from left-sided varicocele with concomitant testicular hypotrophy. The diagnosis was ascertained clinically and with scrotal color Doppler ultrasound using the Dubin and Amelar classification. In 2 cases phimosis was also present. The operation was performed according to a modified Marmar technique, using embolization of the pampiniform plexus with 2 ml of 3% polidocanol. Patients underwent clinical evaluation and scrotal color Doppler ultrasound at 1 week and 3 and 6 months. Results: The mean duration of the operation was 42 min. At 1 week after surgery no persistence of varicocele was found. In 1 patient, edema of the spermatic cord occurred for about 2 months with spontaneous regression, in 1 patient homolateral hydrocele was observed. At 6 months no other complications were reported. No case of testicular atrophy was observed. Conclusions: The technique described has already been validated in the adult population, and although we present only a small number of cases, the operation proved easy to perform, safe, of low cost and can be considered a valid alternative to the microsurgical technique in children and adolescents.
Serum Adipocytokine Levels in Prostate Cancer Patients
Authors: Arisan Elif Damla , Arisan Serdar , Atis Gokhan , Palavan-Unsal Narcin , Ergenekon Erbil
Published: March 2009

Introduction: We estimated the circulating levels of adipocytokines such as adiponectin and leptin in nonobese nondiabetic prostate cancer (PCa) patients and compared the results with controls and benign prostate hyperplasia (BPH) patients. Material and Methods: Fifty patients with PCa, 20 patients with BPH and 50 healthy volunteers were entered into the study. Their blood samples were investigated for adipocytokines with the ELISA method. Results: Adiponectin levels were determined as 8.9 and 5.5 μg/ml for the same patients. Leptin concentration was 14.78 ng/ml in organ-confined PCa patients, and 15.24 ng/ml in advanced PCa patients. In control patients, adiponectin and leptin levels were 18.4 and 12.98 ng/ml, respectively. Conclusion: Serum adipocytokine levels of PCa patients were significantly different from those of controls and BPH patients who were not obese or diabetic. Therefore, further molecular investigation of these adipocytokines will help understand the mechanism.