CD95-mediated tumor recognition by CD4+ effector cells in a murine mammary model

The authors examined cellular mechanisms involved in anti-tumor reactivity induced by the murine MT-9G1 mammary tumor line, which was transduced to secrete granulocyte macrophage-colony-stimulating factor (GM-CSF). Compared with the parental MT-901 tumor, MT-9G1 subcutaneous tumors elicited an influx of CD4+ cells and dendritic cells. Secondary in vitro activation of tumor-draining lymph node cells with anti-CD3 and interleukin-2 resulted in effector cells that can mediate regression of established pulmonary metastases after adoptive transfer. In vivo depletion of T-cell subsets showed that tumor regression required CD4+ tumor-draining lymph node cells rather than CD8+ cells. The activated CD4+ cells expressed CD95L and mediated lysis of CD95+ MT-901 tumor cells, which were major histocompatibility complex class II negative. The CD4+ cells also released GM-CSF in response to tumor stimulation. A Fas fusion protein inhibited tumor lysis and GM-CSF release by the CD4+ cells. These studies document an alternate pathway by which CD4+ immune cells may recognize major histocompatibility complex class II-deficient tumors in which CD95L-bearing T cells induced an anti-tumor response mediated via CD95L:CD95.     

Effects of tumor necrosis factor-alpha on the in vitro maturation of tumor-reactive effector T cells

Culture methods that enhance the anti-tumor reactivity of primed T cells would be important in adoptive immunotherapy of cancer. Using several different syngeneic murine tumor models, the authors evaluated the effects of tumor necrosis factor-alpha (TNF-alpha) exposure on tumor-draining lymph node (TDLN) cells during in vitro activation. Mice were inoculated with weakly immunogenic (i.e., MCA 205, MCA 207 sarcoma) or the poorly immunogenic (i.e., D5 melanoma) tumor cells, and TDLN cells were harvested 9 or 10 days later for activation by an anti-CD3/interleukin-2 culture procedure. Human recombinant TNF-alpha (25 ng/mL) added during the activation culture resulted in a two-fold increase in interferon-gamma release (type 1 response) and a significant reduction of interleukin-10 (type 2 response) after tumor antigen stimulation. In an adoptive transfer model, TNF-alpha-cultured TDLN cells mediated significantly greater regression of established tumor than did TDLN cells cultured in the absence of TNF-alpha in five of five experiments. Neutralization of interleukin-10 monoclonal antibody further augmented the therapeutic efficacy of TNF-alpha-cultured TDLN cells. These studies document the ability of TNF-alpha to selectively promote a type 1 over a type 2 response in a bulk population of tumor-primed T cells during in vitro activation.     

Roles of cyclooxygenase-2 and prostaglandin E receptors in gastric mucosal defense in <Emphasis Type="Italic">Helicobacter pylori</Emphasis>-infected mice

Background/Aim: Helicobacter pylori (H. pylori) induces cyclooxygenase-2 (COX-2) expression. The aim of this study was to assess the roles of COX-2 and PGE₂ receptors (EPs) in gastric defense in H. pylori-infected mice. Methods: Gastric lesions were induced by oral administration of 0.15 N HCl in 60 % ethanol (HCl/EtOH) to mice infected with H. pylori, and macroscopically evaluated 30 min later. Mice were administered NS-398 (COX-2 selective inhibitor) concomitantly with selective EP agonists 4 hours before HCl/EtOH challenge. Results: H. pylori infection prevented the gastric damage induced by HCl/EtOH, and this protective effect was abolished by NS-398. Selective agonists of EP1, EP2, and EP4, but not the EP3 agonist, reversed the inhibitory effect of NS-398 on prevention of damage by H. pylori infection. The EP4 agonist and EP2/EP4 agonists inhibited the increase in TNF-α mRNA expression and neutrophilic infiltration caused by NS-398, respectively. Conclusion: COX-2-derived PGE₂ may play an important role in resistance to HCl/EtOH damage in H. pylori-infected mice by activating EP1, EP2, and EP4. Received 1 August 2006; accepted 21 August 2006     

Oncolytic viral therapy for cervical and ovarian cancer cells by Sindbis virus AR339 strain.

PURPOSE: Recently, the application of replication-competent viruses has been studied as anticancer agents. Sindbis virus (SIN) is an RNA virus that belongs to the Alphavirus genus in the Togaviridae virus family. The AR339 strain of SIN has not been reported to induce any serious disease to humans. EXPERIMENTAL DESIGN: In this study, we evaluated the feasibility of the replication-competent SIN AR339 strain as an agent for cervical and ovarian cancer therapy. RESULTS: SIN infection was able to induce cytopathic effects and apoptosis in two cervical cancer cells (HeLaS3 and C33A) and three ovarian cancer cells (HOC-1, HAC-2, and OMC-3) but not in normal human keratinocytes in vitro. The analysis of cell viability, virus protein synthesis, and viral growth showed the cancer-specific cytotoxicity and virus growth of SIN. In nude mice, i.t. and i.v. inoculation of SIN resulted in significant regression of established cervical tumors implanted at their backs. Histologic studies revealed that systemic treatment with the single injection of SIN induces necrosis within tumors at a remote site. In the metastasis model of ovarian cancer, suppression of ascites formation was observed in nude mice with i.p. SIN treatment. By using an in vivo green fluorescent protein imaging system, we also showed that systemic treatment with SIN targeted tumors specifically. CONCLUSIONS: Our study suggested that SIN AR339 strain has a possibility as a novel agent for human cervical and ovarian cancer therapy.     

Effects of occupational metallic mercury vapour exposure on suppressor-inducer (CD4+CD45RA+) T lymphocytes and CD57+CD16+ natural killer cells

Objectives: To examine the effects of metallic mercury vapour on the cellular and humoral immune system. Methods: We measured T lymphocyte and natural killer (NK) cell subpopulations, B lymphocytes, and serum immunoglobulins (i.e. IgG, IgA and IgM) together with total T (CD3+) lymphocytes and total lymphocytes in blood samples from 20 male, fluorescent-lamp makers (mercury workers) and the same number of gender-, age- and smoking-matched controls. Urinary concentrations of inorganic mercury (UHg) in the 20 workers ranged from 1.8 to 163.5 (mean 44.8) μg/l. They had been exposed to mercury vapour for 4 to 62 (mean 31) months. Results: Numbers of CD4+CD45RA+ (suppressor-inducer) T lymphocytes and total CD4+ T lymphocytes in the mercury workers were significantly smaller than those in the controls (paired-sample t-test, P < 0.01). The number of CD57+CD16+ NK cells was inversely correlated with UHg. Conclusion: It is suggested that numbers of CD4+CD45RA+ T lymphocytes and CD57+CD16+ NK cells are inversely affected by exposure to metallic mercury vapour in workers, with an average urinary inorganic mercury concentration of 45 μg/l being found. Received: 7 September 1999 / Accepted: 6 May 2000     

Radioisotope cisternographic study on intracranial arachnoid cyst (author's transl)

The dynamics of the CSF circulation in six cases of intracranial arachnoid cysts was examined by RI cisternography suing 0.5 to 1.0 mCi of 169Yb DTPA or 50 to 100 microCi of 131I HSA injected into the lumbar subarachnoid space. Serial scintigrams were obtained with rectilineal scintillation scanner at 2, 4, 6, 24 and 48 hours after injection. The communication of the cavity of arachnoid cyst and subarachnoid space was recognized in all cases. The cysts were best visualized at 24 hours in most cases. Four patterns of the entry and stasis of RI in cysts were observed as follows, 1) rapid filling of RI into the cyst and delayed clearance, 2) both rapid filling and clearance, 3) slow filling and delayed clearance, 4) no filling.     

Risk factors associated with onset of urinary incontinence in a community-dwelling elderly population: a 4-year follow-up study

OBJECTIVE: To estimate the risk factors associated with onset of urinary incontinence in a rural community-dwelling elderly population. METHODS: The study area, village N in Akita Prefecture, is a rural community in which a baseline survey of TMIG-LISA (Tokyo Metropolitan Institute of Gerontology, Longitudinal and Interdisciplinary Study on Aging) was undertaken in 1996. Among the baseline subjects, 760 (314 males and 446 females) community-dwelling elderly people aged over 65, who did not suffer from urinary incontinence at entry of the survey were selected. This cohort has been followed for four years by multi-dimensional medical examination including interviews and physical performance tests, conducted on a yearly basis using similar methods to these for the baseline survey. RESULTS: After the 4-year follow-up, the incidence of urinary incontinence was 7.0% (22/314) in men and 12.3% (55/446) in women. The urinary incontinence group (UIG) had a significantly higher age and lower level of functional fitness at baseline for both sexes. In the UIG, the men but not the women had significantly lower serum levels of albumin and total cholesterol. By the logistic model, age (per 1-year increase: OR = 1.23, 95%CI: 1.11-1.38), and serum albumin (per 0.1 g/dl increase: OR = 0.70, 95%CI: 0.54-0.88) in men; and grip strength (per 1-kg increase: OR = 0.92, 95%CI: 0.86-0.98), social role (per 1-point decrease: OR = 1.81, 95%CI: 1.19-2.73), BMI (per 1-kg/m2 increase: OR = 1.10, 95%CI: 1.01-1.20) and smoking status (never smoker = 1.00, 3 = current smoker: OR = 7.53, 95%CI: 1.36-41.63) in women were independent variables significantly associated with onset of urinary incontinence. CONCLUSIONS: Lifestyle and functional fitness are significantly associated with onset of urinary incontinence in this population. Our findings suggest that intervention programs are needed to improve pelvic floor muscle and to provide social support for the elderly.     

Trends for stroke incidence, severity, and prognosis in a rural community with a long-term stroke prevention program

OBJECTIVE: To examine the benefit of a long-term community-based stroke prevention program, we explored 35 years of surveillance data of stroke incidence for residents in a rural area in Japan. METHOD: The surveyed community was Ikawa town (population in 2000 was 6,116) in Akita prefecture, where a community-based stroke prevention program has been conducted since 1963. Incidence rates and numbers of stroke episodes, proportions for loss of consciousness and motor paralysis at onset, proportions for each seriousness category (A: death within one day after onset, B: death during 2-7 days after onset, C: survival more than 8 days after onset with complete hemiparesis, D: survival more than 8 days after onset with incomplete or no hemiparesis), and one-year survival rates and activity of daily living were investigated for 1964-69, 1970-79, 1980-89 and 1990-98. RESULTS: Stroke incidence declined 66% and 64% among the 30-69 years age group and 70 years over age group, respectively between 1964-69 and 1990-98. Incident numbers of stroke episodes declined 41% among those aged 30-69 years and, while it increased 100% in the 70 years over age group, this was much less than the increase rate of 271% rated for the corresponding aged population growth over time. In the 30-69 years age group, the proportion of patients with no loss of consciousness at onset increased from 53-64% during the former three periods to 79% in 1990-98. The proportion of patients with no motor paralysis also increased progressively over the study periods and the proportions for A or B categories in the seriousness classification decreased between 1964-69 and 1990-98 while the proportion in the D category increased between 1980-89 and 1990-98. One-year survival rates increased from 71% and 36% in 1964 to 86% and 61% in 1990-98 among the 30-69 years age group and 70 years over age group, respectively. With both, the numbers of totally dependent patients at one-year after onset, did not change significantly over time, despite the marked increase in the population of risk. CONCLUSION: The present study showed that a long-term community-based stroke prevention program can not only decrease stroke incidence and number of episodes, but also reduce the likelihood of severe stroke attack and improve prognosis, thereby suppressing the increase of totally dependent patients expected from growth of the old population in the community.     

Spontaneous rupture of pancreatic metastasis from renal cell carcinoma

We report the case of a 53-year-old female who was admitted for sudden abdominal pain. Her right kidney was resected in 1993 due to renal cell carcinoma. Abdominal computed tomography performed in September 2002, while she was placed under observation, revealed a tumor 40 mm in size that extended from the head to the body of the pancreas. Abdominal ultrasonography on admission indicated retention of ascites, and the aspirated ascites was bloody. Based on this result, spontaneous rupture of a pancreatic tumor was strongly suspected. On abdominal contrast-enhanced computed tomography, multiple tumors were clearly visualized in the pancreas. Angiography revealed high-density tumor in the early arterial phase. The results of endocrinological tests were normal. Accordingly, the patient was diagnosed with multiple pancreatic metastases of renal cell carcinoma, and total pancreatectomy was performed. Histopathologically, the tumor resected was clear cell carcinoma and corresponded to the renal cell carcinoma resected in 1993. This is a rare case of pancreatic metastasis of renal cell carcinoma that resulted in spontaneous rupture 9 years after nephrectomy.