bluuebunny/crossref_metadata_2025_split huggingface dataset:
Partial tyrosinase‐specific self tolerance by HLA‐A*0201‐restricted cytotoxic T lymphocytes in mice and man
Authors: Lotz Carina , Ferreira Edite Antunes , Drexler Ingo , Mutallib Sarah Abdel , Huber Christoph , Sutter Gerd , Theobald Matthias 
Published: June 2004

AbstractThe human tyrosinase (hTyr) (369–377) cytotoxic T lymphocyte (CTL) epitope is presented by malignant melanoma and various nontransformed cells in association with human leukocyte antigen (HLA)‐A*0201 (A2.1) and used for vaccination‐based immunotherapy of melanoma patients. Its mouse homologue, mTyr (369‐377), is naturally processed and bound by A2.1 with equivalent efficacy and thus enabled us to explore the effect of self tolerance on Tyr‐specific T cells in different lines of A2.1 transgenic (Tg) mice and man. We found that self Tyr‐reactive CTL in Tg mice and, importantly, in man were affected by partial tolerance resulting in only residual T lymphocytes of higher avidity for self Tyr along with low‐avidity T cells to be present in the periphery. Immunizing mice with the xenogeneic nonself Tyr peptide facilitated the generation of self Tyr‐reactive CTL. As compared to Tyr‐reactive CTL induced by high amounts of the self Tyr epitope, however, the nonself antigen (Ag) had no effect on improving the avidity of self Tyr‐specific mouse and human T cells. Depleting mice of CD25+ T cells with and without CTL‐associated Ag 4 (CTLA‐4) blockade demonstrated that tolerance of Tyr‐specific CTL was not regulated by CD4+CD25+ T regulatory cells (Treg) or CTLA‐4. Our studies have important implications for the design of anti‐Tyr‐based immunotherapeutics. © 2003 Wiley‐Liss, Inc.
Decreased pyruvate kinase M2 activity linked to cisplatin resistance in human gastric carcinoma cell lines
Authors: Yoo Byong Chul , Ku Ja‐Lok , Hong Sung‐Hye , Shin Young‐Kyoung , Park So Yeon , Kim Hark Kyun , Park Jae‐Gahb 
Published: June 2004

AbstractResistance to anticancer drugs is a major obstacle preventing effective treatment of disseminated cancers. Understanding the molecular basis to chemoresistance is likely to provide better treatment. Cell lines resistant to cisplatin or 5‐fluorouracil (5‐FU) were established from human gastric carcinoma cell lines SNU‐638 and SNU‐620. Comparative proteomics involving 2‐dimensional gel electrophoresis (2‐DE) and matrix‐associated laser desorption ionization‐mass spectroscopy (MALDI‐MS) was performed on protein extracts from these parental and drug‐resistant derivative lines to screen drug resistance‐related proteins. Pyruvate kinase M2 (PK‐M2) was identified as a protein showing lower expression in cisplatin‐resistant cells compared to parental cells. Consistent with this finding, PK‐M2 activity was also lower in cisplatin‐resistant cells. Suppression of PK‐M2 expression by antisense oligonucleotide resulted in acquired cisplatin resistance in SNU‐638 cells. Furthermore, PK‐M2 activity in 11 individual human gastric carcinoma cell lines positively correlated with cisplatin sensitivity. Taken together, PK‐M2 protein and activity levels were lower in cisplatin‐resistant human gastric carcinoma cell lines compared to their parental cell lines. Furthermore, suppression of PK‐M2 expression using antisense oligonucleotides increased cisplatin resistance. These data clearly link PK‐M2 and cisplatin resistance mechanisms. © 2003 Wiley‐Liss, Inc.
Association of kallikrein expression in nipple aspirate fluid with breast cancer risk
Authors: Sauter Edward R. , Lininger John , Magklara Angelika , Hewett John E. , Diamandis Eleftherios P. 
Published: June 2004

AbstractHuman kallikreins (hK) 2, 3, 6 and 10 are expressed in breast and prostate tissue. hK2 and hK3 (prostate‐specific antigen, PSA) are used to screen for prostate cancer. hK6 and hK10 are downregulated in breast cancer compared to normal breast tissue. We demonstrated that levels of PSA in nipple aspirate fluid (NAF) are lower in women with breast cancer than in normal women. We hypothesize that the expression of hK2, 3, 6 and 10 are related and important in detecting breast cancer. The goals of this study are to determine the level of expression of kallikreins in NAF and serum, the association of hK2, 3, 6 and 10 in NAF, and the association of each of the kallikreins with breast cancer. In NAF from 275 women, hK3, 6 and 10 were detectable in ≥ 90% and hK2 in 74% of samples analyzed. NAF levels were highest for hK6 and lowest for hK2, regardless of cancer and menopausal status. hK3 was detectable in 15/29 (52%) and hK2 in 0/29 serum samples collected from 6 women. hK2 and hK3 were concentrated in NAF vs. matched serum. The 4 kallikreins were associated with the exception of hK2 with hK6 or hK10. PSA levels were higher in normal pre‐ than postmenopausal subjects (but not women with breast cancer), whereas levels of hK2, 6 and 10 did not differ by menopausal status. hK2 and PSA were associated with both pre‐ and postmenopausal breast cancer; hK6 and 10 were not. hK2 and PSA were more associated with pre‐ than postmenopausal breast cancer. Using logistic regression, PSA and menopausal status provided the best model of breast cancer prediction, with a sensitivity of 91% and specificity of 39%. In conclusion, 4 kallikreins are expressed in NAF. hK2 and PSA, and hK6 and hK10 are highly associated. Higher premenopausal PSA levels suggest the influence of ovarian steroids. PSA shows the most promise in aiding in the early detection of breast cancer. © 2003 Wiley‐Liss, Inc.
Generation, immunologic characterization and antitumor effects of human monoclonal antibodies for carcinoembryonic antigen
Authors: Imakiire Takayuki , Kuroki Motomu , Shibaguchi Hirotomo , Abe Hironori , Yamauchi Yasushi , Ueno Aruto , Hirose Yumiko , Yamada Hiromi , Yamashita Yuichi , Shirakusa Takayuki , Ishida Isao , Kuroki Masahide 
Published: June 2004

AbstractWe generated fully human mAbs (HmAbs) to carcinoembryonic antigen (CEA) using the KM mouse, which carries a human chromosome 14 fragment containing the entire Ig H chain loci and human κ L chain segments in the mouse genome. Forty‐six hybridoma clones producing HmAbs to CEA were thus obtained by fusing the P3‐U1 mouse myeloma cells with splenocytes of the KM mice immunized with CEA. Among them, 22 clones produced HmAbs that reacted with CEA but not with 3 other CEA‐related cell adhesion molecule (CEACAM) family members, CEACAM1, CEACAM6 and CEACAM8. In 12 HmAbs examined, 8 were IgG4, 2 were IgG3, 1 was IgG2, and the other was IgG1. The affinity constants for CEA of these HmAbs were comparable to those of the previously prepared mouse anti‐CEA mAbs (MmAbs). BIAcore analyses revealed that 1 and 2 of the 22 HmAbs react with 2 epitopes defined by MmAbs on the domain N and the domain A1 or B1 of CEA, respectively. In the presence of human complement in vitro, 2 HmAbs tested showed substantial cytotoxicity, namely, 50–65%, against CEA‐expressing tumor cells. With human lymphokine‐activated killer cells in vitro, 3 HmAbs tested exhibited 40–65% Ab‐dependent cell‐mediated cytotoxicity against the tumor cells. Moreover, one of the HmAbs induced a significant inhibition of tumor growth when administered to mice xenografted with the CEA‐expressing cells. Considering their lack of immunogenicity to humans, these CEA‐specific HmAbs may be useful for immunotherapeutic approaches as well as for immunodiagnosis. © 2003 Wiley‐Liss, Inc.
Highly sensitive detection of the MGB1 transcript (mammaglobin) in the peripheral blood of breast cancer patients
Authors: Cerveira Nuno , Torres Lurdes , Rocha Patrícia , Bizarro Susana , Pereira Deolinda , Abreu Joaquim , Henrique Rui , Teixeira Manuel R. , Castedo Sérgio 
Published: June 2004

AbstractWe describe a new one‐step RT‐PCR assay for the detection of the mammaglobin (MGB1) gene transcript in the peripheral blood of breast cancer patients. With this approach, the MGB1 transcript could be detected in the peripheral blood of 22 of 54 (41%) breast cancer patients prior to any therapy. This method, using specific primers for cDNA synthesis, proved to be more sensitive (10−6 to 10−11, usually 10−7) than previously reported methodologies. This increased sensitivity was achieved without compromising specificity, as the MGB1 transcript was not detected in 38 blood samples of healthy donors and in only 1 of 18 blood samples of patients presenting with hematologic malignancies. A positive correlation was seen between MGB1 positivity and breast cancer stage: 0/3 (0%) in stage 0, 3/13 (23%) in stage I, 6/17 (35%) in stage II, 5/10 (50%) in stage III, 8/11 (73%) in stage IV (p = 0.003). The prognostic and therapeutic implications of MGB1 positivity by one‐step RT‐PCR in the peripheral blood of breast cancer patients, especially in clinically localized disease (stages I and II), should be evaluated after long‐term clinical follow‐up of these patients. © 2003 Wiley‐Liss, Inc.
The efficacy of ritonavir in the prevention of AIDS‐related Kaposi's sarcoma
Authors: Stebbing Justin , Portsmouth Simon , Nelson Mark , Mandalia Sundhiya , Kandil Hala , Alexander Nic , Davies Liz , Brock Cathryn , Bower Mark , Gazzard Brian 
Published: June 2004

AbstractAngiogenesis is thought to play a major role in the development of Kaposi's sarcoma (KS), considered by many to be a hyperplastic disorder caused in part by local production of inflammatory cytokines. The antiangiogenic effects of protease inhibitors, in particular ritonavir, have been suggested in laboratory work to lead to regression of KS, and recent data have shown the importance of ritonavir as a model of pharmaceutical development. As our clinical cohort data has shown that non‐nucleoside reverse transcriptase inhibitor‐based regimens are not inferior to protease inhibitor‐based therapy in the prevention of KS, we investigated the specific contribution of ritonavir to chemoprevention of this AIDS‐defining illness. In a logistic regression analysis, we found that ritonavir‐based therapy confers no advantages compared to other regimens in the prevention of KS. This is consistent with data suggesting that regression of KS is mediated by an overall improvement in immune function and not by the effects of specific antiretrovirals. © 2003 Wiley‐Liss, Inc.
Inhibition of human vascular endothelial cells proliferation by terbinafine
Authors: Ho Pei‐Yin , Liang Yu‐Chih , Ho Yuan‐Soon , Chen Chiung‐Tong , Lee Wen‐Sen 
Published: June 2004

AbstractWe have demonstrated previously that terbinafine (TB), an oral antifungal agent used in the treatment of superficial mycosis, suppresses proliferation of various cultured human cancer cells in vitro and in vivo by inhibiting DNA synthesis and activating apoptosis. In our study, we further demonstrated that TB at a range of concentrations (0–120 μM) dose‐dependently decreased cell number in cultured human umbilical vascular endothelial cells (HUVEC). Terbinafine was not cytotoxic at a concentration of 120 μM, indicating that it may have an inhibitory effect on the cell proliferation in HUVEC. The TB‐induced inhibition of cell growth rate is reversible. [3H]thymidine incorporation revealed that TB reduced the [3H]thymidine incorporation into HUVEC during the S‐phase of the cell‐cycle. Western blot analysis demonstrated that the protein levels of cyclin A, but not cyclins B, D1, D3, E, CDK2 and CDK4, decreased after TB treatment. The TB‐induced cell‐cycle arrest in HUVEC occurred when the cyclin‐dependent kinase 2 (CDK2) activity was inhibited just as the protein level of p21 was increased and cyclin A was decreased. Pretreatment of HUVEC with a p21 specific antisense oligonucleotide reversed the TB‐induced inhibition of [3H]thymidine incorporation. Taken together, these results suggest an involvement of the p21‐associated signaling pathway in the TB‐induced antiproliferation in HUVEC. Capillary‐like tube formation and chick embryo chorioallantoic membrane (CAM) assays further demonstrated the anti‐angiogenic effect of TB. These findings demonstrate for the first time that TB can inhibit the angiogenesis. © 2004 Wiley‐Liss, Inc.
Low urine osmolarity as a determinant of cisplatin‐induced nephrotoxicity
Authors: Polycarpe Emmanuel , Arnould Laurent , Schmitt Elise , Duvillard Laurence , Ferrant Emmanuelle , Isambert Nicolas , Duvillard Christian , Beltramo Jean‐Luc , Chevet Dominique , Chauffert Bruno 
Published: June 2004

AbstractCisplatin is widely used in the treatment of human tumors, but it is a nephrotoxic drug. Early pragmatic clinical trials have shown that cisplatin‐induced renal toxicity is greatly reduced through the use of high hydration, a large NaCl supply and mannitol infusion, but the precise mechanisms of these nephroprotective measures are not fully understood. We show here an increase in the cisplatin uptake and cytotoxicity on 56/10 A1 human glomerular and HK‐2 human tubular cells when the drug incubation was performed in a hypotonic phosphate‐buffered saline solution or in human urine (“drag in” transport hypothesis). When 4 mg/kg cisplatin was intraperitoneally injected in rats in 20 ml of a hypotonic 4 g/l NaCl solution, the platinum accumulation increased in both the cortex and papilla but not in the subcutaneously grafted colon tumors when compared to rats injected with cisplatin in normal or hyperosmotic solutions (9 and 14 g/l NaCl, respectively). The urea and creatinine blood levels were significantly increased, and more apoptotic cells were detected by the caspase‐3 cleavage and TUNEL assays in the tubular cells of rats treated with cisplatin in a hypotonic solution compared to animals that received normal or hypertonic solutions. Osmolarity was sometimes low in urine from patients receiving an intravenous hydration for a cisplatin treatment or from healthy volunteers who were given an oral hydration with a 50 g/l glucose solution. Our results show that low urine osmolarity could be a major determinant in the increase of cisplatin‐induced nephrotoxicity and justify the widely used concurrent infusion of osmotically active substances during intravenous hydration. © 2004 Wiley‐Liss, Inc.
Glycine‐extended gastrin induces matrix metalloproteinase‐1‐ and ‐3‐mediated invasion of human colon cancer cells through type I collagen gel and Matrigel
Authors: Baba Miyako , Itoh Kazuyuki , Tatsuta Masaharu 
Published: June 2004

AbstractThe effects of glycine‐extended gastrin (G‐Gly) on the invasion by colon cancer cells through stromal extracellular matrix and the role of metalloproteinases (MMPs) in this invasion were investigated. We found that 10−9–10−6 M G‐Gly significantly increased the invasiveness of 2 human colon cancer cell lines, LoVo and HT‐29, both expressing the G‐Gly‐specific binding site but little gastrin/CCK‐B receptor (gastrin receptor). LoVo cells expressed MMP‐1, ‐2, ‐3 and ‐9. An amount of 10−7 M G‐Gly enhanced collagenase MMP‐1 expression. Overexpression of enhanced green fluorescent protein (EGFP)‐fused MMP‐1 in LoVo cells, by cDNA transfection, enhanced invasiveness through type I collagen gel. Immunofluorescence study revealed that G‐Gly increased the number of cytoplasmic vesicles containing MMP‐1, some vesicles being released from the cells. The MMP‐1 vesicles contained one of the ubiquitous coat proteins, Golgi‐localized, γ‐adaptin ear‐containing, ARF‐binding proteins‐2 (GGA‐2). MMP‐1 also colocalized with CD147 (EMMPRIN, an extracellular matrix metalloproteinase inducer in adjacent stromal cells). It was suggested that G‐Gly increased the number of vesicles containing MMP‐1 and that MMP‐1 interacted with CD147 to increase invasion. G‐Gly significantly enhanced the production of MMP‐3, an activator of MMP‐1 and ‐9, as well as gelatinase MMP‐9 activity. The G‐Gly‐mediated MMP‐9 increase was inhibited by treatment with anti‐MMP‐3 IgG and MMP‐3 siRNA. Furthermore, G‐Gly increased the proMMP‐2 level, although no activated MMP‐2 was found in conditioned medium in either the presence or the absence of G‐Gly. By contrast, gastrin (10−7 M) had no effect on the levels of these MMPs or the invasiveness of colon cancer cells in type I collagen gel and Matrigel. These effects of G‐Gly on the activity and expression of MMPs and the invasiveness of colon cancer cells were inhibited by treating the cells with a broad‐spectrum metalloproteinase inhibitor (CGS27023A) and nonselective gastrin/CCK receptor antagonists (proglumide and benzotript). But a gastrin/CCK‐B receptor antagonist (YM022) did not inhibit the increased invasion by G‐Gly. Together, these results demonstrate that G‐Gly renders colon cancer cells more invasive by increasing MMP‐1 and MMP‐3 expressions via the putative G‐Gly receptor and would thus be a good molecular target in a clinical setting. © 2004 Wiley‐Liss, Inc.
mTHPC‐mediated photodynamic therapy for early oral squamous cell carcinoma
Authors: Hopper Colin , Kübler Alexander , Lewis Harry , Tan I. Bing , Putnam Graham ,   the Foscan 01 Study Group
Published: June 2004

AbstractSurgery and radiotherapy are standard treatments for early oral squamous cell carcinoma, both resulting in good tumour control. However, neither of these modalities is without consequent functional or cosmetic impairment, and there are patients in whom both are contraindicated. Furthermore, there is a significant risk of metachronous tumours developing in the oral cavity, and salvage or retreatment with either surgery or radiotherapy poses difficulties. Photodynamic therapy (PDT) offers the potential for improved functional and cosmetic outcomes, while achieving comparable tumour control. We conducted an open‐label, multicentre study to assess the efficacy and safety of meta‐tetrahydroxyphenylchlorin (mTHPC) in patients with early oral cancer. One hundred twenty‐one patients received intravenously administered mTHPC, followed 96 hr later by illumination of the tumour surface with 652 nm laser light. Of these patients, 114 were protocol compliant. A complete tumour response was achieved in 85% of protocol‐compliant patients (97 of 114 patients). A complete response was maintained in 85% of responders at 1 year and in 77% at 2 years. One‐ and 2‐year actuarial survival rates were 89% and 75%, respectively. In the opinion of the investigators, tumour clearance was accompanied by excellent cosmetic and functional results, without impact on the patients' performance status. Mild‐to‐moderate pain at the treatment site, a recognised side effect of PDT in the oral cavity, was reported by 82% of patients but was manageable with appropriate analgesia. Mild‐to‐moderate skin photosensitivity reactions were reported for 13% of patients. mTHPC offers an effective alternative treatment for early oral squamous cell carcinoma. It is associated with excellent functional and cosmetic results and can be used in conjunction with other standard therapies. © 2004 Wiley‐Liss, Inc.
C8orf4 is a transforming growth factor B induced transcript downregulated in metastatic colon cancer
Authors: Friedman Joshua B. , Brunschwig Elaine B. , Platzer Petra , Wilson Keith , Markowitz Sanford D. 
Published: June 2004

AbstractTransforming growth factor (TGF) β mediates a tumor suppressor pathway in human colon epithelial cells. We were interested in identifying and characterizing novel genes regulated by the TGFβ pathway in the colon. We employed expression microarrays to identify transcripts induced by TGFβ in Vaco 330, a colon adenoma cell line. We then used expression microarrays to determine which of these TGFβ induced transcripts are down‐regulated in metastatic colon cancer. Northern analysis and real‐time reverse transcription PCR confirmed and quantified our findings from the microarrays. These analyses highlighted C8orf4 as induced by TGFβ in colon cells. Moreover, C8orf4 is expressed in most normal colon mucosa samples, and is not expressed in most colon cancer metastases or colon cancer cell lines. Colon cancer primary tumors showed reduced expression of C8orf4 relative to normal mucosa, possibly reflecting contributions of C8orf4 expression in stromal cells. C8orf4 is a gene regulated by TGFβ signaling and loss in advanced colon cancer suggests C8orf4 may play a role in colon cell differentiation or growth regulation. © 2004 Wiley‐Liss, Inc.
Altered mode of allelic replication accompanied by aneuploidy in peripheral blood lymphocytes of prostate cancer patients
Authors: Dotan Zohar A. , Dotan Aviva , Ramon Jacob , Avivi Lydia 
Published: June 2004

AbstractReplication timing of the genetic material is a highly programmed process correlated with expression, stability and methylation capacity. An important aspect of that timing is the temporal order of allelic replication: a synchronous mode for biallelically expressed genes and an asynchronous for monoallelically expressed genes. Previous studies showed that malignancy is associated with changes in the inherent mode of allelic replication, and even normal cells of cancer patients display alterations in the replication of various genes. Using fluorescence in situ hybridization (FISH), we checked whether allelic‐replication mode differentiates cancer patients from healthy individuals. We focused on prostate cancer (CAP), the most common diagnosed cancer and the second leading cause of cancer death in men over 50 years old. Five nonrelated genes and a nontranscribed DNA sequence associated with chromosomal segregation were used in our study. All 6 tested loci displayed in peripheral blood lymphocytes stimulated with phytohemagglutinin (PHA) of CAP patients loss of their inherent temporal order of allelic replication, coupled with aneuploidy, the outcome of chromosome malsegregation. The replication‐timing modification is a reversible epigenetic alteration, evidenced by our ability to resurrect the normal pattern in all 6 tested loci by introducing an inhibitor of methyl transferase. On the other hand, the methylation‐blocking agent failed to obliterate aneuploidy. The replication alteration accompanied by aneuploidy, detected in peripheral blood cells, distinguishes between CAP patients and individuals with benign prostate hyperplasia (BPH; a common disorder in elderly men) better than the routinely used blood marker, the prostate‐specific antigen (PSA). © 2004 Wiley‐Liss, Inc.
Microsatellite analysis of serum DNA in patients with head and neck cancer
Authors: Nawroz‐Danish Homaira , Eisenberger Claus F. , Yoo George H. , Wu Li , Koch Wayne , Black Carri , Ensley John F. , Wei Wei‐Zen , Sidransky David 
Published: June 2004

AbstractWe have shown previously that microsatellite alterations in serum DNA was predictive of distant metastasis in a study with 21 primary head and neck squamous cell carcinoma patients. To further investigate serum microsatellite alterations as a prognostic tool, we carried out microsatellite analysis of serum DNA with 10 markers on 152 patients with head and neck cancer. Forty‐five percent (68/152) of patients had microsatellite alterations of serum DNA identical to corresponding tumor DNA. In 16 patients that had distant metastasis, 11 patients had a positive serum test (microsatellite alterations detectable in their serum DNA with one or more markers). The difference in distant metastasis rates between the negative and positive serum tests (6.0% [5/84] vs. 16.2% [11/68], RR = 2.7) was clinically significant and almost reached statistical significance (p = 0.06). When the analysis was restricted to patients with recurrent disease, a positive serum test correlated with those who developed distant metastasis (p = 0.04). Other parameters, such as development of recurrence, stage of the cancer, disease‐free survival and overall survival, were not associated with a positive serum test. Detecting tumor DNA in serum by microsatellite analysis may help identify patients at risk for distant metastasis. Therefore, circulating tumor cells may contribute to the presence of tumor DNA in the serum. In the future if a serum test is positive, therapeutic approaches may by intensified, such as platinum‐based chemoradiation, to reduce distant failures. © 2004 Wiley‐Liss, Inc.