bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Dendritic Cell Activity againstHistoplasma capsulatumIs Mediated via Phagolysosomal Fusion
Authors: Gildea Lucy A. , Ciraolo Georgianne M. , Morris Randal E. , Newman Simon L. 
Published: September 2005

ABSTRACTHistoplasma capsulatumis a fungal pathogen that requires the induction of cell-mediated immunity (CMI) for host survival. We have demonstrated that human dendritic cells (DC) phagocytoseH. capsulatumyeasts and, unlike human macrophages (Mø) that are permissive for intracellular growth, DC killed and degraded the fungus. In the present study, we sought to determine whether the mechanism(s) by which DC killHistoplasmais via lysosomal hydrolases, via the production of toxic oxygen metabolites, or both. Phagosome-lysosome fusion (PL-fusion) was quantified by using fluorescein isothiocyanate-dextran and phase and fluorescence microscopy and by electron microscopy with horseradish peroxidase colloidal gold to label lysosomes. Unlike Mφ,Histoplasma-infected DC exhibited marked PL-fusion. The addition of suramin toHistoplasma-infected DC inhibited PL-fusion and DC fungicidal activity. Incubation ofHistoplasma-infected DC at 18°C also concomitantly reduced PL-fusion and decreased the capacity of DC to kill and degradeH. capsulatumyeasts. Further, culture ofHistoplasma-infected DC in the presence of bafilomycin, an inhibitor of the vacuolar ATPase, did not block DC anti-Histoplasmaactivity, indicating that phagosome acidification was not required for lysosome enzyme activity. In contrast, culture ofHistoplasma-infected DC in the presence of inhibitors of the respiratory burst or inhibitors of NO synthase had little to no effect on DC fungicidal activity. These data suggest that the major mechanism by which human DC mediate anti-Histoplasmaactivity is through the exposure of yeasts to DC lysosomal hydrolases. Thus, DC can override one of the strategies used byH. capsulatumyeasts to survive intracellularly within Mø.
Induction of Protective Immunity to Anthrax Lethal Toxin with a Nonhuman Primate Adenovirus-Based Vaccine in the Presence of Preexisting Anti-Human Adenovirus Immunity
Authors: Hashimoto Masahiko , Boyer Julie L. , Hackett Neil R. , Wilson James M. , Crystal Ronald G. 
Published: September 2005

ABSTRACT

Prevention or therapy for bioterrorism-associated anthrax infections requires rapidly acting effective vaccines. We recently demonstrated (Y. Tan, N. R. Hackett, J. L. Boyer, and R. G. Crystal, Hum. Gene Ther.
14:
1673-1682, 2003) that a single administration of a recombinant serotype 5 adenovirus (Ad) vector expressing anthrax protective antigen (PA) provides rapid protection against anthrax lethal toxin challenge. However, approximately 35 to 50% of humans have preexisting neutralizing antibodies against Ad5. This study assesses the hypothesis that a recombinant adenovirus vaccine based on the nonhuman primate-derived serotype AdC7, against which humans do not have immunity, expressing PA (AdC7PA) will protect against anthrax lethal toxin even in the presence of preexisting anti-Ad5 immunity. Naive and Ad5-immunized BALB/c mice received (intramuscularly) 10
8
to 10
11
particle units (PU) of AdC7PA, Ad5PA (a human serotype Ad5-based vector expressing a secreted form of PA), or AdNull (an Ad5 vector with no transgene). Robust anti-PA immunoglobulin G and neutralizing antibodies were detected by 2 to 4 weeks following administration of AdC7PA to naive or Ad5 preimmunized mice, whereas low anti-PA titers were detected in Ad5-preimmunized mice following administration of Ad5PA. To assess protection in vivo, naive or mice previously immunized against Ad5 were immunized with AdC7PA or Ad5PA and then challenged with a lethal intravenous dose of
Bacillus anthracis
lethal toxin. Whereas Ad5PA protected naive mice against challenge with
B. anthracis
lethal toxin, Ad5PA was ineffective in mice that were previously immunized against Ad5. In contrast, AdC7PA functioned effectively not only to protect naive mice but also to protect Ad5-preimmunized mice, with 100% survival after lethal toxin challenge. These data suggest the nonhuman-based vector AdC7PA is an effective vaccine for the development of protective immunity against
B. anthracis
and importantly functions as a “sero-switch” base for an adenovirus vaccine to function in the context of preexisting anti-Ad immunity.
Identification of New Antigens in Visceral Leishmaniasis by Expression Cloning and Immunoblotting with Sera of Kala-Azar Patients from Bihar, India
Authors: Theinert Stephan M. , Basu Rajatava , Forgber Michael , Roy Syamal , Sundar Shyam , Walden Peter 
Published: September 2005

ABSTRACT

Sera of kala-azar patients from Bihar, India, were used to identify
Leishmania donovani
antigens encoded by a phage expression library. Ten antigens were identified, five of which have not been described as leishmania antigens before. The antigens specifically react with sera of leishmania-infected patients but not of toxoplasma- or plasmodium-infected patients.
Digalactoside Expression in the Lipopolysaccharide of
Haemophilus influenzae
and Its Role in Intravascular Survival
Authors: Griffin Ruth , Bayliss Chris D. , Herbert Mark A. , Cox Andrew D. , Makepeace Katherine , Richards James C. , Hood Derek W. , Moxon E. Richard 
Published: September 2005

ABSTRACT

Digalactoside (galα-1-4 galβ) structures of the lipopolysaccharide (LPS) of
Haemophilus influenzae
are implicated in virulence. A confounding factor is that tetranucleotide repeats within the
lic2A
,
lgtC
, and
lex2
genes mediate phase-variable expression of the digalactosides. By deleting these repeats, we constructed recombinant strains of RM153 constitutively expressing either one or two LPS digalactosides. Expression of two digalactosides, rather than one, was associated with increased virulence of
H. influenzae
in vivo.
Antibodies to Conserved Pneumococcal Antigens Correlate with, but Are Not Required for, Protection against Pneumococcal Colonization Induced by Prior Exposure in a Mouse Model
Authors: Trzciński Krzysztof , Thompson Claudette , Malley Richard , Lipsitch Marc 
Published: September 2005

ABSTRACT

In mice following intranasal exposure to
Streptococcus pneumoniae
, protection against pneumococcal colonization was independent of antibody but dependent on CD4
+
T cells. Nonetheless, concentrations of antibodies to three conserved pneumococcal antigens correlated with protection against colonization. Concentrations of antibodies to conserved pneumococcal antigens may be correlates of protection without being effectors of protection.
Streptomycin-Dependent Exhibition of Cytokine-Inducing Activity in Streptomycin-DependentMycobacterium tuberculosisStrain 18b
Authors: Fukasawa Yutaka , Kawamura Ikuo , Uchiyama Ryosuke , Yamamoto Kazuhiro , Kaku Taijin , Tominaga Takanari , Nomura Takamasa , Ichiyama Satoshi , Ezaki Takayuki , Mitsuyama Masao 
Published: September 2005

ABSTRACTPeritoneal exudate cells of mice were stimulated with a streptomycin-dependentMycobacterium tuberculosisstrain, 18b. Gamma interferon production by natural killer cells depending on interleukin-12 and interleukin-18 was induced only in the presence of a high dose of streptomycin. This study suggested the requirement of active bacterial metabolism for this host response.
Mycobacterial Lipomannan Induces Matrix Metalloproteinase-9 Expression in Human Macrophagic Cells through a Toll-Like Receptor 1 (TLR1)/TLR2- and CD14-Dependent Mechanism
Authors: Elass Elisabeth , Aubry Laëtitia , Masson Maryse , Denys Agnès , Guérardel Yann , Maes Emmanuel , Legrand Dominique , Mazurier Joël , Kremer Laurent 
Published: September 2005

ABSTRACTLipomannans (LM) from various mycobacterial species were found to induce expression and secretion of the matrix metalloproteinase 9 (MMP-9) both in human macrophage-like differentiated THP-1 cells and in primary human macrophages. Inhibition studies using antireceptor-neutralizing antibodies are indicative of a Toll-like receptor 1 (TLR1)/TLR2- and CD14-dependent signaling mechanism. Moreover, LM was shown to down-regulate transcription of the metalloproteinase inhibitor TIMP-1, a major endogenous MMP-9 regulator.
An Angiogenesis Inhibitor E7820 Shows Broad-Spectrum Tumor Growth Inhibition in a Xenograft Model
Authors: Semba Taro , Funahashi Yasuhiro , Ono Naoto , Yamamoto Yuji , Sugi Naoko Hata , Asada Makoto , Yoshimatsu Kentaro , Wakabayashi Toshiaki 
Published: September 2005

Abstract
We reported previously that an angiogenesis inhibitor, E7820, inhibits in vitro tube formation of human umbilical vein endothelial cell through the suppression of integrin α2 expression. Here we describe the antiangiogenic and antitumor effects of E7820 in mice and discuss the feasibility of using platelet integrin α2 expression on platelets as a biological marker of the efficacy of E7820. Oral administration of E7820 significantly inhibited basic fibroblast growth factor-induced angiogenesis in Matrigel implants and human colon WiDr tumor-induced angiogenesis in a dorsal air sac model. Twice-daily treatment with E7820 clearly inhibited the s.c. tumor growth of seven tumor cell lines derived from human colon, breast, pancreas, and kidney, and completely suppressed the growth of human pancreatic KP-1 and human colon LoVo cell lines. Moreover, E7820 significantly inhibited the growth of KP-1 and human colon tumor Colo320DM cells orthotopically implanted in the pancreas and cecum, respectively. The efficacy of E7820 was comparable in the s.c. and orthotopic transplantation models. Immunohistochemical analyses using anti-CD31 antibody showed that E7820 significantly reduced microvessel density in orthotopically implanted KP-1 tumor. E7820 reduced integrin α2 expression on a megakaryocytic cell line, Dami cells, induced by phorbol 12-myristate 13-acetate treatment. It also decreased the expression level of integrin α2 on platelets withdrawn from mice bearing s.c. KP-1 tumor at a dosage close to that affording antitumor activity. These data demonstrate that E7820 showed a broad-spectrum antitumor effect in mice through inhibition of angiogenesis and indicate that the decrease of integrin α2 on platelets might serve as a biological marker for the antitumor efficacy of E7820.
Prognostic Significance of Activated Akt Expression in Pancreatic Ductal Adenocarcinoma
Authors: Yamamoto Shinji , Tomita Yasuhiko , Hoshida Yoshihiko , Morooka Takaya , Nagano Hiroaki , Dono Keizo , Umeshita Koji , Sakon Masato , Ishikawa Osamu , Ohigashi Hiroaki , Nakamori Shoji , Monden Morito , Aozasa Katsuyuki 
Published: September 2005

Abstract
Purpose: Akt is a serine/threonine kinase that plays a central role in tumorigenesis. Among the members of Akt family, Akt2 is associated with the development of human cancers. The present study was designed to clarify the prognostic significance of Akt2 and activated Akt expression in pancreatic ductal adenocarcinoma (PDAC). In addition, activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and the proliferation activity of tumor cells detected by Ki-67 immunohistochemistry were examined.
Experimental Design: Immunohistochemical analysis was performed on paraffin-embedded specimens from 65 patients with PDAC; 36 males and 29 females with ages ranging from 48 to 79 years (median, 66 years) of age. Expression levels of Akt2, phosphorylated Akt (p-Akt), and phosphorylated ERK 1/2 (p-ERK 1/2) were categorized as either weaker (low intensity) or equal to stronger (high intensity) compared with those in the endothelial cells of the same specimens. For Ki-67 immunohistochemistry, cases were divided into two groups: level 1, Ki-67 labeling index (LI), &lt;20%; level 2, Ki-67 LI, ≥20%.
Results: Twenty-six (42.6%), 28 (45.9%), 39 (63.9%), and 46 (75.4%) of the tumors showed high intensity of Akt2, p-Akt, and p-ERK 1/2 expression, and Ki-67 LI level 2, respectively. A significant positive correlation was observed between Akt2 and p-Akt expression (P &lt; 0.01). Multivariate analysis revealed that p-Akt expression, Ki-67 LI, and histological differentiation are independent prognosticators for PDAC.
Conclusions: p-Akt expression is a significant prognostic indicator for PDAC. Inhibition of Akt is a possible molecular approach for treatment of PDAC.
Loss of Heterozygosity at the Thymidylate Synthase (TS) Locus on Chromosome 18 Affects Tumor Response and Survival in Individuals Heterozygous for a 28-bp Polymorphism in theTSGene
Authors: Uchida Kazumi , Hayashi Kazuhiko , Kawakami Kazuyuki , Schneider Sylke , Yochim Ji Min , Kuramochi Hidekazu , Takasaki Ken , Danenberg Kathleen D. , Danenberg Peter V. 
Published: September 2005

AbstractThymidylate synthase (TS), the target enzyme of the fluoropyrimidine class of drugs, has a 28-bp repeat polymorphism in the promoter region that has been associated with response of tumors to 5-fluorouracil-based therapy. Patients homozygous for the double repeat (2R/2R) in the TS gene have an overall better outcome from treatment than patients homozygous for the triple repeat (3R/3R). However, due to loss of heterozygosity at the TS locus on chromosome 18 in cancer cells, heterozygous 2R/3R individuals can acquire the 2R/loss or the 3R/loss genotype in their tumors. The purpose of this study was to determine whether the response of colorectal cancer to fluoropyrimidine therapy is associated with the resulting tumor TS genotype when loss of heterozygosity occurs in tumor DNA. A total of 30 colorectal cancer patients treated with the fluoropyrimidine-based combination S-1, all of whom had stage IV disease, were studied. The response rate to S-1 in this group of patients was 13 of 30 (43%). The heterozygous 2R/3R genotype was found in 22 of 30 normal tissues, whereas 10 (45%) of the matched cancer tissues showed only the 2R-sequence band (2R/loss), and 7 cancer tissues (32%) showed only the 3R-sequence band (3R/loss). The response rate of the 2R/loss tumor genotype patients was 80% (8 of 10) compared with 14% (1 of 7) in the 3R/loss genotype group (P = 0.029). Patients with tumor 3R/loss genotypes had significantly lower survival than 2R/loss genotypes. Heterozygous patients with a 2R/loss tumor genotype had the same survival as 2R/2R patients, whereas patients with a 2R/3R tumor genotype had a short survival similar to homozygous 3R/3R genotypes. These results show that: (a) response to 5-fluorouracil-based therapy is determined by tumor genotype; and (b) the 3R repeat is a direct negative determinant of outcome.
Novel Temperature-Sensitive Liposomes with Prolonged Circulation Time
Authors: Lindner Lars H. , Eichhorn Martin E. , Eibl Hansjoerg , Teichert Nicole , Schmitt-Sody Marcus , Issels Rolf D. , Dellian Marc 
Published: September 2005

AbstractHyperthermia increases the efficiency of various chemotherapeutic drugs and is administered as an adjunct to chemotherapy for the treatment of cancer patients. The temperature-dependent effect can be strongly increased by the use of temperature-sensitive liposomes in combination with regional hyperthermia, which specifically releases the entrapped drug in the heated tumor tissue. The novel lipid 1.2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG), which is closely related to the naturally occurring 1.2-dipalmitoyl-sn-glycero-3-phosphoglycerol, in combination with 1.2-dipalmitoyl-sn-glycero-3-phosphocholine and 1.2-distearoyl-sn-glycero-3-phosphocholine provides long-circulating temperature-sensitive liposomes with favorable properties under mildly hyperthermic conditions (41–42°C). DPPGOG facilitates temperature-triggered drug release from these liposomes (diameter, 175 nm) and leads to a substantially prolonged plasma half-life for the encapsulated drug with t1/2 = 9.6 h in hamsters and t1/2 = 5.0 h in rats. Quantitative fluorescence microscopy of amelanotic melanoma grown in the transparent dorsal skin fold chamber of hamsters demonstrated a favorable drug accumulation in heated tissue after i.v. application of these liposomes (42°C for 1 h). The mean area under the curve for tissue drug concentration was increased by more than sixfold by application of the new liposomes compared with nonliposomal drug delivery. In summary, we present a new DPPGOG-based liposomal formulation enabling long circulation time combined with fast and efficient drug release under mild hyperthermia. This adds positively to the results with lipid-grafted polyethylenglycol used thus far in temperaturesensitive liposomes and widens the possibilities for clinical applications.
Determinants of Rapamycin Sensitivity in Breast Cancer Cells
Authors: Noh Woo-Chul , Mondesire Wallace H. , Peng Junying , Jian Weiguo , Zhang Haixia , Dong JinJiang , Mills Gordon B. , Hung Mien-Chie , Meric-Bernstam Funda 
Published: September 2005

Abstract
Purpose: Rapamycin inhibits the serine-threonine kinase mammalian target of rapamycin (mTOR), blocking phosphorylation of p70 S6 kinase (S6K1) and 4E-binding protein 1 (4E-BP1) and inhibiting protein translation and cell cycle progression. Rapamycin and its analogues are currently being tested in clinical trials as novel-targeted anticancer agents. Although rapamycin analogues show activity in clinical trials, only some of the treated patients respond. The purpose of this study is to identify determinants of rapamycin sensitivity that may assist the selection of appropriate patients for therapy.
Experimental Design: Breast cancer cell lines representing a spectrum of aberrations in the mTOR signaling pathway were tested for rapamycin sensitivity. The expression and phosphorylation state of multiple components of the pathway were tested by Western blot analysis, in the presence and absence of rapamycin.
Results: Cell proliferation was significantly inhibited in response to rapamycin in 12 of 15 breast cancer cell lines. The ratio of total protein levels of 4E-BP1 to its binding partner eukaryotic initiation factor 4E did not predict rapamycin sensitivity. In contrast, overexpression of S6K1, and phosphorylated Akt independent of phosphatase and tensin homologue deleted from chromosome 10 status, were associated with rapamycin sensitivity. Targeting S6K1 and Akt with small interfering RNA and dominant-negative constructs, respectively, decreased rapamycin sensitivity. Rapamycin inhibited the phosphorylation of S6K1, ribosomal S6 protein, and 4E-BP1 in rapamycin-resistant as well as -sensitive cells, indicating that its ability to inhibit the mTOR pathway is not sufficient to confer sensitivity to rapamycin. In contrast, rapamycin treatment was associated with decreased cyclin D1 levels in the rapamycin-sensitive cells but not in rapamycin-resistant cells.
Conclusions: Overexpression of S6K1 and expression of phosphorylated Akt should be evaluated as predictors of rapamycin sensitivity in breast cancer patients. Furthermore, changes in cyclin D1 levels provide a potential pharmacodynamic marker of response to rapamycin.
Phase II Randomized Trial of Autologous Formalin-Fixed Tumor Vaccine for Postsurgical Recurrence of Hepatocellular Carcinoma
Authors: Kuang Ming , Peng Bao G. , Lu Ming D. , Liang Li J. , Huang Jie F. , He Qiang , Hua Yun P. , Totsuka Saeri , Liu Shu Q. , Leong Kam W. , Ohno Tadao 
Published: September 2005

Abstract
Purpose: We conducted a Phase II clinical trial with randomized patients to determine whether autologous formalin-fixed tumor vaccine (AFTV) protects against postsurgical recurrence of hepatocellular carcinoma (HCC).
Experimental Design: Forty-one patients with HCC who had undergone curative resection were randomly allocated to the vaccine treatment (n = 19) or no adjuvant control group (n = 22). Three intradermal vaccinations were administered at 2-week intervals beginning 4–6 weeks after hepatic resection. A delayed-type hypersensitivity test was performed before and after vaccination. Primary and secondary end points are recurrence-free survival and overall survival, respectively. Observation continued until the majority of surviving patients had lived &gt;12 months after the curative resection.
Results: In a median follow-up of 15 months, the risk of recurrence in vaccinated patients was reduced by 81% (95% confidence interval, 33–95%; P = 0.003). Vaccination significantly prolonged the time to first recurrence (P = 0.003) and improved recurrence-free survival (P = 0.003) and overall survival rates (P = 0.01). AFTV played a significant role in preventing recurrence in patients with small tumors. Adverse effects were limited to grade 1 or 2 skin toxicities such as erythema, dry desquamation, and pruritus.
Conclusions: AFTV therapy is a safe, feasible, and effective treatment for preventing postoperational recurrence of HCC. Patients with low tumor burdens benefit from the treatment. This treatment should be advanced to a large-scale randomized trial.
Resveratrol Suppresses the Angiogenesis and Tumor Growth of Gliomas in Rats
Authors: Tseng Sheng-Hong , Lin Swei-Ming , Chen Jin-Cherng , Su Yen-Hao , Huang Hsin-Yi , Chen Chia-Kang , Lin Po-Yin , Chen Yun 
Published: September 2005

Abstract
Purpose: We wanted to investigate the antitumor effects and effect on angiogenesis of resveratrol in rat RT-2 gliomas.
Experimental Design: RT-2 glioma cells were treated with resveratrol, and then cytotoxicity was assayed, apoptosis was measured by flow-activated cell sorter flow cytometry, and expression of vascular endothelial growth factor was measured by reverse transcription-PCR. Tumor size, animal survival time, and survival rate were followed in resveratrol-treated rats with s.c. or intracerebral gliomas. Furthermore, in vitro proliferation was assayed to explore the effect of resveratrol on the proliferation of ECV304 human umbilical vein endothelial cells. Expression of CD31 in resveratrol-treated gliomas was followed immunohistochemically to study the effect of resveratrol on the glioma-induced angiogenesis.
Results: Resveratrol was demonstrated to exert cytotoxic effects and induce glioma cell apoptosis in a concentration- and time-dependent manner (P &lt; 0.05). Resveratrol (40 mg/kg/day) exerted significant antitumor effects on s.c. tumors, including slower tumor growth rate, longer animal survival time, and higher animal survival rate (P &lt; 0.05). In contrast, resveratrol affected intracerebral tumors at only an increased dose (100 mg/kg/day), prolonging animal survival (P &lt; 0.05) without affecting survival rate. The expression of vascular endothelial growth factor in the glioma cells and the proliferation of ECV304 cells were inhibited by resveratrol in a concentration-dependent manner. Immunohistochemical analyses showed that the s.c. gliomas from resveratrol-treated rats had fewer microvessel densities than did control rats (P &lt; 0.01).
Conclusions: Resveratrol caused significant glioma cell cytotoxicity and apoptosis, exerted antitumor effects on the s.c. and intracerebral gliomas, and inhibited angiogenesis in s.c. gliomas. Thus, resveratrol might be considered a possible treatment strategy for gliomas.