Heterocyclic boronic acids display sialic acid selective binding in a hypoxic tumor relevant acidic environment.

Boronic acids are well known for their ability to reversibly interact with the diol groups found in sugars and glycoproteins. However, they are generally indiscriminate in their binding. Herein we describe the discovery of a group of heterocyclic boronic acids demonstrating unusually high affinity and selectivity for sialic acids (SAs or N-acetylneuraminic acid), which are sugar residues that are intimately linked with tumor growth and cancer progression. Remarkably, these interactions strengthen under the weakly acidic pH conditions associated with a hypoxic tumoral microenvironment. In vitro competitive binding assays uncovered a significantly higher ability of 5-boronopicolinic acid, one of the derivatives identified in this work as a strong SA-binder, to interact with cell surface SA in comparison to a gold-standard structure, 3-propionamidophenylboronic acid, which has proven to be an efficient SA-binder in numerous reports. This structure also proved to be suitable for further chemical conjugation with a well-preserved SA-binding capability. These findings suggest an attractive alternative to other ongoing boronic acid based chemistry techniques aiming to achieve tumor-specific chemotherapies and diagnoses.

siRNA-mediated silencing of PD-1 ligands enhances tumor-specific human T-cell effector functions.

Adoptive cell therapy using tumor-specific T cells is a promising strategy for treating patients with malignancy. However, accumulating evidences have demonstrated that optimal function of tumor-reactive T cells is often attenuated by negative regulatory signal(s) delivered through receptors, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and their cognate ligands. Although systemic blocking of these molecules needs careful attention on the risk of uncontrolled immune activation, selective inhibition of negative signals in tumor-specific T cells by their genetic modification is an attractive approach to overcome immunological suppression in cancer patients. Here, we demonstrate the improved effector functions of tumor-specific CD4(+) and CD8(+) human T cells by small interfering RNA (siRNA) -mediated silencing of PD-1 ligands, PD-L1 or PD-L2. Tumor antigen MAGE-A4-specific human T-cell clones upregulated the expression of PD-1 ligands upon activation. siRNA-mediated knockdown of PD-L1 or -L2 enhanced the interferon-γ production and antigen-specific cytotoxicity of these cells. Peripheral blood mononuclear cells transduced with a retroviral vector encoding MAGE-A4-specific T-cell receptor α/ß chains also increased their effector functions by this modification. These results suggest that siRNA-mediated knockdown of PD-1 ligands is an attractive strategy to inhibit a negative regulatory mechanism of tumor-specific T cells resulting in enhanced efficacy of adoptive T-cell therapy of cancer using genetically modified autologous lymphocytes.

Lung diseases directly associated with rheumatoid arthritis and their relationship to outcome.

The outcome and cause of death of each lung disease directly associated with rheumatoid arthritis (RA-LD) have been poorly investigated. A retrospective study was conducted of 144 patients with RA-LD, in whom the median follow-up period after the initial visit for a respiratory examination was 4.5 yrs. A total of 57 patients were identified with usual interstitial pneumonia (UIP), 31 with bronchiectasis, 16 with nonspecific interstitial pneumonia (NSIP), 11 with bronchiolitis, five with organising pneumonia (OP), five with diffuse alveolar damage (DAD) and 19 with combined disease. The 5-yr survival rates were 36.6% in the UIP group, 87.1% in the bronchiectasis group, 93.8% in the NSIP group, 88.9% in the bronchiolitis group, 60.0% in the OP group and 20.0% in the DAD group. Survival of patients with DAD was worse than that of patients with UIP. Overall, survival of patients with UIP was worse than that of patients with bronchiectasis, NSIP or bronchiolitis. Of the 144 patients, 71 (49.3%) died, of whom 58 (81.7%) died due to respiratory lesions. Of patients with RA-LD, patients with DAD experienced the highest mortality, and the survival of patients with UIP was worse than that of patients with NSIP.

Toll-like receptors and immune regulation: implications for cancer therapy.

Toll-like receptors (TLRs) function as pathogen pattern recognition molecules that sensor and initiate innate and adaptive immune responses against microbes and cancer cells. Recognition of pathogen-derived ligands by TLRs expressed on many types of cells, including dendritic cells and T cells, triggers the nuclear factor (NF)-kappaB and type-1 interferon pathways, leading to the production of proinflammatory cytokines that are essential in stimulating CD4(+) T cells to differentiate to T helper (Th) 1, Th2 Th17 and regulatory T (Treg) cells. Recent studies indicate that Treg cells play a critical role in suppressing immune responses and inducing immune tolerance to cancer and infectious diseases. Of particular interest, the human TLR8 signaling pathway is essential for reversing the suppressive function of Treg cells. Thus, TLRs regulate cancer immunity and tolerance through innate immune responses mediated by Treg, dendritic and other immune cells. In this review, we focus on the current understanding of TLRs and Treg cells with emphasis on their roles in cancer immunity. Related information on non-TLR immune receptors will be briefly discussed.

Radiotherapy negates the effect of retroperitoneal nonclosure for prevention of lymphedema of the legs following pelvic lymphadenectomy for gynecological malignancies: an analysis from a questionnaire survey.

Using patient questionnaires, we studied the long-term effect of leaving the peritoneum open on the incidence of lymphedema of the legs in patients following pelvic lymphadenectomy for gynecological malignancies. The patients were retrospectively assigned to one of two groups, depending on whether the retroperitoneum was closed or left open at surgery. Three years after surgery, we obtained valid questionnaire responses from 101 patients (43 cervical, 46 endometrial, and 12 ovarian cancers) in the closure group and 83 patients (34 cervical, 40 endometrial, and 9 ovarian cancers) in the nonclosure group. In patients' self-analysis, the overall incidence of lymphedema of the legs was significantly lower in the nonclosure group than in the closure group (25.3% and 50.5%, respectively; P<0.01). The incidence of lymphedema of the legs was significantly increased by postoperative radiotherapy. Especially in the nonclosure group, the incidence of lymphedema was only 15.8% in patients who did not have radiotherapy, but it increased significantly (44.4%) (P<0.05) when patients underwent radiotherapy. In conclusion, this questionnaire survey suggested that leaving the retroperitoneum open after lymphadenectomy is significantly effective in reducing the incidence of leg lymphedema, which impairs patients' quality of life more than expected by physicians.

Melanoma differentiation-associated gene-7 (mda-7)/interleukin (IL)-24 induces anticancer immunity in a syngeneic murine model.

Previous studies have shown that the human melanoma differentiation-associated gene-7 (mda-7)/interleukin-24 (IL-24) has tumor-suppressor activity in vitro and in vivo. Additionally, in vitro studies using human peripheral blood mononuclear cells indicate that mda-7/IL-24 has TH1 cytokine-like activity. However, the individual properties of mda-7/IL-24 have been previously examined separately. Thus, there is not a single study that has examined both, antitumor and proimmune properties of mda-7/IL-24. Furthermore, the tumor suppressive activity and the cytokine activity of mda-7/IL-24 have not been previously tested in an immunocompetent setting. We therefore in the present study evaluated the antitumor and immune properties of mda-7/IL-24 in a murine syngeneic tumor model. In vitro, adenovirus-mediated mda-7 gene (Ad-mda7) transfer to murine fibrosarcoma (UV2237m; MCA16) and normal (10T1/2) cells significantly inhibited growth (P=0.001) and induced apoptosis in tumor cells but not in normal cells. In vivo, intratumoral administration of Ad-mda7 resulted in significant inhibition of tumor growth (P<0.05), with a subset of mice showing complete tumor regression. We next evaluated the immune potentiation activity of Ad-mda7 in a cancer vaccine model. UV2237m cells transfected with Ad-mda7 and injected into syngeneic immunocompetent C3H mice were unable to grow; however, they did grow in immunocompromised nude mice. These tumor-free C3H mice, when challenged with parental tumor cells experienced no tumor growth, suggesting induction of systemic immunity. Moreover, splenocytes prepared from vaccinated C3H mice demonstrated higher proliferative activity and produced elevated levels of TH1 cytokines compared with those from control mice. An in vitro subset analysis of splenocytes from vaccinated mice demonstrated a significant increase in the CD3(+)CD8(+) but not the CD3(+)CD4(+) cell population (P=0.019). Thus Ad-mda7 treatment of syngeneic tumors induces tumor cell death and promotes immune activation, leading to anticancer immunity.

Characterization of 17beta-hydroxysteroid dehydrogenase type 4 in human ovarian surface epithelial cells.

The human ovarian surface epithelium (hOSE) is a single layer of mesothelial-type primitive epithelial cells that are potential estrogen targets. It has been reported that hOSE cells can produce estrogen. However, the mechanisms that regulate estrogen level(s) in hOSE cells are not yet known. To elucidate the enzymes involved in these reactions, we examined gene expression of 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) in primary hOSE (POSE) and OSE2a cells using RT-PCR. We found that POSE cells and cells of the immortalized hOSE line, OSE2a, bidirectionally converted estrone (E1) and 17beta-estradiol (E2). Both cell types expressed mRNA for 17beta-HSD type 1 (17beta-HSD1), suggesting that the enzyme is involved in the E1 to E2 conversion. Interestingly, both cells expressed 17beta-HSD4 mRNA but not 17beta-HSD2 mRNA. We prepared an antibody against the carboxyl terminal of 17beta-HSD4 (anti-17beta-HSD4 antibody), which recognized the 80 and 48 kDa proteins in POSE and OSE2a cells based on immunoblot analysis. Furthermore, immunohistochemical study revealed the presence of 17beta-HSD4 in hOSE cells in the human ovary. These results suggest that 17beta-HSD4 is involved in estrogen inactivation and may protect against an excessive accumulation of E2 in hOSE cells.

Effect of cis-diammine dichloroplatinum on vascular endothelial growth factor expression in uterine cervical carcinoma.

PURPOSE OF INVESTIGATION: In this study, we investigated the effects of cis-diammine dichloroplatinum (CDDP) on VEGF mRNA expression and VEGF production in uterine cervical carcinoma tissues obtained from patients with locally advanced disease and in CaSki cells cultured in vitro. METHODS: VEGF in cultured CaSki cells and in the culture media was measured using a sensitive enzyme-linked immunosorbent assay (ELISA) before and 24 h, 48 h and 72 h after 3 h exposure to CDDP. VEGF mRNA expression in CaSki cells was assessed by the semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) before and 24 h and 48 h after 3 h exposure to CDDP. We also examined the effect of CDDP on microvessel counts in uterine cervical carcinoma tissues obtained before and after high-dose CDDP intraarterial chemotherapy. Immunohistochemical staining using a monoclonal antibody against CD34 was carried out with cervical carcinoma tissue specimens, and microvessel counts were quantified by counting vessels. RESULTS: CDDP treatment resulted in significant increases in not only VEGF concentrations in cultured CaSki cells and culture media but also in VEGF mRNA expression levels in cultured CaSki cells in a time-dependent and dose-dependent manner compared to untreated controls (p < 0.05, n = 5). On the other hand, VEGF concentrations and microvessel counts in cervical carcinoma tissues were significantly lower in cases with complete response (CR) and partial response (PR), compared to those before treatment (p < 0.05, n = 5 ). By contrast, in cases with no change (NC) to CDDP, both VEGF concentrations and microvessel counts did not decrease and rather showed a somewhat increase compared with levels prior to the treatment. CONCLUSIONS: These results suggest that CDDP-induced increases in VEGF production by cervical carcinoma cells may stimulate angiogenesis in the tumor lesion after CDDP treatment.

Transient increase in squamous cell carcinoma antigen expression in cultured cervical carcinoma CaSki cells in response to exposure to cis-diamminedichloroplatinum.

The present study was conducted to elucidate the molecular mechanism underlying the transient increase in circulating squamous cell carcinoma antigen (SCC Ag) levels in response to CIS-diamminedichloroplatinum (CDDP) infusion using an in vitro model. The uterine cervical squamous carcinoma CaSki cells were cultured for 72 h after 3 h exposure to 5.0 microg/ml CDDP. The effects of CDDP exposure on the proliferative activity and apoptosis in cultured CaSki cells were determined by bromodeoxyuridine (BrdU) uptake and cell counting and by the TUNEL assay, respectively. SCC Ag levels in cultured CaSki cells and culture media were determined with the use of SCC-RIA kit. The expression of SCC Ag-1 mRNA and SCC Ag-2 mRNA in cultured CaSki cells was assessed using semiquantitative RT-PCR with Southern blot analysis. The number of BrdU-positive CaSki cells significantly decreased 6 h after exposure to CDDP, whereas the apoptosis-positive rate of cultured CaSki cells significantly increased 12 h after the CDDP exposure. The number of cultured CaSki cells significantly decreased 72 h after the CDDP exposure. The total SCC Ag protein levels in both cultured CaSki cells and the culture media after the 3-hour CDDP exposure increased in a time-dependent manner during the subsequent incubation for 48 h. Semiquantitative RT-PCR revealed that the expression levels of both SCC Ag-1 and SCC Ag-2 mRNA increased (1.7- and 2.7-fold, respectively) 12 h after the exposure to CDDP relative to those before the subsequent cultures. Exposure of uterine cervical squamous carcinoma CaSki cells to CDDP resulted in a transient increase in SCC Ag protein and mRNA expression in those cells during the initial 12 h after the exposure, being associated with decreased proliferative activity and increased apoptosis of those cells.

Role of SEREX-defined immunogenic wild-type cellular molecules in the development of tumor-specific immunity.

Recognition of altered self-antigens in tumor cells by lymphocytes forms the basis for antitumor immune responses. The effector cells in most experimental tumor systems are CD8(+) T cells that recognize MHC class I binding peptides derived from molecules with altered expression in tumor cells. Although the need for CD4(+) helper T cells in regulating CD8(+) T cells has been documented, their target epitopes and functional impact in antitumor responses remain unclear. We examined whether broadly expressed wild-type molecules in murine tumor cells eliciting humoral immunity contributed to the generation of CD8(+) T cells and protective antitumor immune responses to unrelated tumor-specific antigens [mutated ERK2 (mERK2) and c-erbB2/HER/neu (HER2)]. The immunogenic wild-type molecules, presumably dependent on recognition by CD4(+) helper T cells, were defined by serological analysis of recombinant cDNA expression libraries (SEREX) using tumor-derived lambda phage libraries screened with IgG antibodies of hosts bearing transplanted 3-methylchoranthrene-induced tumors. Coimmunization of mice with plasmids encoding SEREX-defined murine wild-type molecules and mERK2 or HER2 led to a profound increase in CD8(+) T cells specific for mERK2 or HER2 peptides. This heightened response depended on CD4(+) T cells and copresentation of SEREX-defined molecules and CD8(+) T cell epitopes. In tumor protection assays, immunization with SEREX-defined wild-type molecules and mERK2 resulted in an inhibition of pulmonary metastasis, which was not achieved by immunization with mERK2 alone.

Limitations of successive transradial approach in the same arm: the Japanese experience.

The transradial approach (TRA) has been used for diagnostic and interventional cardiology. It has not previously been determined how many times the same radial artery can be cannulated without complications. A total of 812 patients (502 men and 310 women) underwent angiography or angioplasty via the TRA between 1997 and 1999 at our institution with a total of 1,438 procedures. Sheaths were 5 (55%) or 6 Fr (45%). Dropout rates of 3.5% and 7.9% were found at the second TRA attempt in the men and the women, respectively. Of the 62 TRA failures, 56 (90%) were due to narrowing or occlusion of the radial artery after the previous TRA procedure. A third TRA procedure was possible in 90% of the men and 80% of the women. A fifth TRA procedure was possible in 70% of the men and 50% of the women. The dropout rates for TRA increased as successive punctures were performed. This was primarily due to vessel narrowing and occlusion occurring as a function of multiple punctures.

Super high-dose intraarterial cisplatin infusion under percutaneous pelvic perfusion with extracorporeal chemofiltration for advanced uterine cervical carcinoma: I. Analysis for pharmacokinetics, tumor response, and toxicity of platinum.

The present study was designed to elucidate the clinical feasibility of a new intraarterial infusion system with an extracorporeal charcoal chemofiltration circuit, which is expected to achieve a super high-dose cisplatin pelvic perfusion with a limited systemic exposure to platinum. After inferior vena cava isolation was percutaneously achieved by balloon catheter technique, cisplatin (140-240 mg/m2) was administered by selective intrauterine arterial infusion, with inferior and superior gluteal arterial embolization. The platinum-containing blood was pumped through an extracorporeal charcoal chemofiltration circuit. Pharmacokinetics, tumor response, and toxicity of platinum under this system were studied in 14 patients with locally advanced uterine cervical carcinoma. Extracorporeal charcoal filters significantly (p < 0.05) reduced the prefilter area under concentration-time curve of plasma-free platinum by 86.7 +/- 5.2% at postfilter site and 76.3 +/- 6.6% at peripheral circulation, respectively. Although all adverse effects were mild under this system, tumor response and tissue platinum concentrations were augmented dose dependently with the administration of cisplatin. The extracorporeal chemofiltration system achieved a super high-dose cisplatin pelvic perfusion with the minimal adverse effects, allowing further cisplatin dose escalation with further augmented tumor response. This will contribute to the reduction in the extent of disease of locally advanced uterine cervical carcinoma.

Super high-dose intraarterial cisplatin infusion under percutaneous pelvic perfusion with extracorporeal chemofiltration for advanced uterine cervical carcinoma: II. Its impact on clinical response and subsequent surgery.

The present pilot study was conducted to investigate the clinical efficacy of super high-dose intraarterial cisplatin infusion with percutaneous pelvic perfusion under extracorporeal chemofiltration (PPPEC) for locally advanced uterine cervical carcinoma. Cisplatin (140-240 mg/m2) was infused in uterine arteries in a neoadjuvant setting in 20 patients under the PPPEC system twice during a 2-week interval. Fourteen of 17 patients in whom reduction of the disease (tumor downstaging) was confirmed underwent radical surgery. Despite the tumor downstaging, the remaining three patients had poor PS and the other three showed insufficient stage regression. Clinical responses, histologic responses, and surgical review were studied. The rate of overall tumor response (complete response plus partial response), tumor downstaging, overall histologic response, and radical surgery performance after the second course of PPPEC were 95.0%, 85.0%, 95.0%, and 70.0%, respectively. Curative surgery, defined as negative carcinoma cells in surgical margins, was achieved in 85.7% of the cases, whereas the rate of complete surgery defined as negative carcinoma cells both in surgical margins and regional lymph nodes was 42.9%. With 42 months of median follow-up time, 3 of the 14 surgical patients died of the original disease, and the remaining 9 patients are in recurrence-free survival, whereas 2 patients are alive with disease. PPPEC achieved a high frequency of rapid tumor downstaging of locally advanced uterine cervical carcinoma without severe adverse effects and resulted in the favorable performance of the subsequent radical surgery and prognosis.

Sesaminol from sesame seed induces apoptosis in human lymphoid leukemia Molt 4B cells.

The exposure of human lymphoid leukemia Molt 4B cells to sesaminol, a component of sesame oil led to both growth inhibition and the induction of apoptosis. Morphological change showing apoptotic bodies was observed in the cells treated with sesaminol. The fragmentation of DNA by sesaminol to oligonucleosomal-sized fragments that are characteristics of apoptosis was observed to be concentration- and time-dependent. These findings suggest that growth inhibition of Molt 4B cells by sesaminol results from the induction of apoptosis in the cells.

Sesamolin from sesame seed inhibits proliferation by inducing apoptosis in human lymphoid leukemia Molt 4B cells.

The exposure of human lymphoid leukemia Molt 4B cells to sesamolin, a component of sesame seed led to both growth inhibition and the induction of apoptosis. Morphological change showing apoptotic bodies was observed in the cells treated with sesamolin. The fragmentation of DNA by sesamolin to oligonucleosomal-sized fragments that are characteristics of apoptosis was observed to be concentration- and time-dependent. These findings suggest that growth inhibition of Molt 4B cells by sesamolin results from the induction of apoptosis in the cells.

Clinical characteristics of acute pulmonary thromboembolism in Japan: results of a multicenter registry in the Japanese Society of Pulmonary Embolism Research.

BACKGROUND: Although the incidence of acute pulmonary thromboembolism (APTE) has been increasing in Japan, patient characteristics, management strategies, and outcome have not yet been assessed in large series. HYPOTHESIS: The present study was designed to investigate the current status of APTE in Japan. METHODS: Of a total of 533 registry patients with pulmonary thromboembolism, 309 with APTE were analyzed with respect to clinical symptoms and signs, predisposing factors, diagnostic procedures, estimation of deep venous thrombosis, treatment, and clinical course. RESULTS: Main risk factors were recent major surgery, cancer, prolonged immobilization, and obesity; only a few patients had coagulopathy and 36% were in cardiogenic shock at presentation. The majority of registry patients underwent lung scans or pulmonary angiography; 30% were diagnosed only by lung scanning. Venous ultrasonography was used in only 34 patients, while 188 patients underwent at least one diagnostic procedure for deep venous thrombosis. Thrombolysis was more frequently performed in patients with cardiogenic shock, and only a few patients received thromboembolectomy. In-hospital mortality rate was 14%. In patients with cardiogenic shock, the mortality rate was reduced by thrombolysis. The predictors of in-hospital mortality were male gender, cardiogenic shock, cancer, and prolonged immobilization. CONCLUSIONS: The patients in this registry had almost the same findings as those in Western patients, except for some points that had the possibility of demonstrating a difference between Westerners and Japanese in the development of APTE. These results can prove especially helpful in planning prospective, randomized trials that will clarify the impact of widely used treatment modalities on the outcome of patients with APTE.

[Correlation of DNA copy number changes to malignancy in oral squamous cell carcinomas by comparative genomic hybridization].

To compare clinical and histopathological findings to tumor DNA copy number changes, comparative genomic hybridization (CGH) was performed on 18 primary oral squamous cell carcinomas. Copy number increases were most frequently observed on 8q, 3q, 13q, 11p, and 11q, while copy number decreases most frequently on 10q, 1p, 18q, 9p, and 19q. Copy number changes in relationship to WHO grading were examined with the result that DNA copy number increase on chromosome 6p23-25 was characteristically observed in the groups of Grade II and Grade III, and DNA copy number decreases on chromosomes 9p21 and 11p11-13 were observed in the same groups. Furthermore, comparison of DNA copy number changes to TNM classification indicated that the decreases on chromosomes 1p36 and 10q25-26 might be related to tumor progression. Moreover, the relationship of DNA amplification or deletion to metastasis was investigated. It was found that the majority of the metastasis-positive tumors showed increases on 3q26 and 17q12-21 and showed decreases on chromosome 18q21. The data suggested that these DNA copy number changes on each chromosome in the three categories might be associated with tumor cell differentiation, tumor size, and lymph node metastasis.

Sesamin and episesamin induce apoptosis in human lymphoid leukemia Molt 4B cells.

The exposure of human lymphoid leukemia Molt 4B cells to sesamin and episesamin which were isolated from unroasted sesame seed oil and identified by MS, and 1H and 13C-NMR, led to both growth inhibition and the induction of programmed cell death (apoptosis). Morphological change showing apoptotic bodies was observed in the Molt 4B cells treated with sesamin and episesamin. The fragmentations by sesamin and episesamin of DNA to oligonucleosomal-sized fragments that are characteristics of apoptosis were observed to be concentration-dependent, respectively. Moreover, the amount of the DNA fragments in the sesamin-treated cells was increased from 2 days, while that in the episesamin-treated cells was elevated at 3 days after addition of the compounds. These findings suggest that growth inhibitions by sesamin and episesamin of Molt 4B cells result from the induction of apoptosis in the cells.

Bone marrow-derived dendritic cells incorporate and process hydrophobized polysaccharide/oncoprotein complex as antigen presenting cells.

We have previously shown that a novel hydrophobized polysaccharide/oncoprotein complex vaccine can induce immune responses against the HER2/neu/c-erbB2 (HER2) expressing tumors. Bone marrow-derived dendritic cells (DCs), as antigen presenting cells (APCs), are the first candidates for presentation of tumor antigens. The aim of this study was to see whether DCs are able to elicit antigen specific host immune responses by stimulating the proliferation of T cells after exposure to cholesteryl group bearing pullulan (CHP) and HER2 protein complex. Vaccination by CHP-HER2 complex was as effective as cholesteryl group bearing mannan (CHM) and HER2 complex on which we reported previously. Immunization of mice with HER2 expressing CMS17HE tumor cells generated both CD4+ T cells and CD8+ T cells reactive with CHP-HER2 complex pretreated DCs. In addition, immunization with either CHP-HER2 complex or HER2 protein alone could also generate both CD4+ T cells and CD8+ T cells specifically reactive with CHP-HER2 complex pretreated DCs. The complete rejection of tumors occurred when immunization with CHP-HER2 complex pretreated DCs was started 10 days after tumor inoculation. Therefore, bone marrow-derived DCs pretreated with hydrophobized polysaccharide/oncoprotein complex are a powerful tool for enhancing the effectiveness of oncoprotein for anti-tumor vaccination, opening new options for immune cell therapy.

An elevation of stem cell factor in patients with hyperthyroid Graves' disease.

Graves' disease is an autoimmune disorder characterized by the presence of antibodies against thyrotropin receptor (TRAb). Stem cell factor (SCF), derived from bone marrow, is known to promote lymphohematopoiesis. To investigate the relation between the alteration in plasma levels of SCF, thyroid hormone status, and TRAb measured by thyrotropin binding inhibition (TBI), 13 untreated, 21 treated, and 4 relapsed hyperthyroid Graves' disease patients, 21 patients with Hashimoto's thyroiditis, 6 patients with subacute thyroiditis, and 11 control subjects were examined. In untreated hyperthyroid Graves' disease patients, serum levels of thyroxine (T4) and triiodothyronine decreased rapidly by methimazole treatment, and TBI decreased progressively, but variably. Simultaneously, the elevated plasma levels of SCF decreased gradually and progressively. The plasma levels of SCF correlated curvilinearly with the serum levels of T4. In 4 patients with relapsed hyperthyroid Graves' disease, TBI was marginally positive in 3 patients and negative in 1, but plasma levels of SCF were elevated significantly in all 4 patients. In patients with subacute thyroiditis and Hashimoto's thyroiditis with or without T4 replacement, plasma levels of SCF did not differ from that of controls. These findings indicate that the elevation of plasma levels of SCF relates to the longstanding thyrotoxic state and that short-term thyrotoxicosis does not significantly affect plasma levels of SCF. It remains to be determined whether the elevation in plasma levels of SCF is induced by excess thyroid hormone, reflecting the hypermetabolic state, or whether the elevation of plasma levels of SCF contributes to stimulation of lymphocytes producing TRAb.