Adenoma multiplicity in irradiated Apc(Min) mice is modified by chromosome 16 segments from BALB/c

Ionizing radiation (IR) is a well-characterized carcinogen in humans and mice. The BALB/c mouse strain is unusually sensitive to IR-induced tissue damage and cancer development in a range of organs, suggestive of a partial defect in DNA damage response. This has been confirmed by finding BALB/c-specific functional polymorphism in Prkdc, a gene on mouse chromosome 16 that encodes the catalytic subunit of DNA-dependent protein kinase. Prkdc(BALB) has been associated with increased susceptibility to IR-induced mammary and lymphatic neoplasia. Here, we provide evidence that chromosome 16 segments from BALB/c interact with Apc(Min) (multiple intestinal neoplasia) and specifically enhance IR-induced adenoma development in the upper part of the small intestine.     

The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Results of National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials B-04 and B-06

BACKGROUND: In the current study, the authors compared the incidence of subsequent primary lung carcinoma in patients with breast carcinoma who received radiotherapy as part of their treatment and in those patients who did not. The patients were participants in two large National Surgical Adjuvant Breast and Bowel Project (NSABP) breast carcinoma trials, B-04 and B-06, which prospectively randomized women to either undergo surgery alone or to undergo surgery and postoperative radiotherapy. METHODS: The NSABP trial B-04 (1971-1974) randomized patients to undergo radical mastectomy versus total (simple) mastectomy and radiotherapy to the chest wall, axilla, and supraclavicular and internal mammary lymph node areas. For patients with a clinically uninvolved axilla, there was a third randomization arm: total mastectomy without radiotherapy. The B-06 trial (1976-1984) randomized patients between those undergoing total mastectomy versus lumpectomy versus those undergoing lumpectomy and breast irradiation, with all patients undergoing an axillary lymph node dissection. The records of all patients who developed a recurrence in the lung or a new primary lung tumor were reviewed to determine the incidence and laterality of confirmed and probable primary lung carcinoma. RESULTS: For the 1665 evaluable patients on the NSABP B-04 trial (mean follow-up of 21.4 years), there was a total of 23 subsequent confirmed and probable ipsilateral or contralateral primary lung carcinomas. In those patients who had received comprehensive postmastectomy radiotherapy, there was a statistically significant increase in the incidence of these new primary tumors (P = 0.029). With regard to the development of confirmed new primary ipsilateral lung carcinoma alone, the incidence was statistically significantly increased (P = 0.013) in those patients who had received radiotherapy as part of their treatment, and when confirmed and probable ipsilateral lung carcinomas were analyzed, there was a strong trend toward a statistically significant increase in those patients who had received radiotherapy (P = 0.066). For the 1850 evaluable patients on the NSABP trial B-06 (mean follow-up of 19.0 years), there was a total of 30 second primary lung carcinomas but no increase in either ipsilateral or contralateral primary tumors of the lung in those patients who had received radiotherapy. CONCLUSIONS: Extensive postmastectomy irradiation of the chest wall and regional lymphatic node areas, with consequent exposure of a greater volume of lung to higher doses as administered in the NSABP B-04 trial compared with postlumpectomy breast irradiation in the NSABP B-06 trial, was associated with an increased incidence of subsequent primary lung tumors, both ipsilateral and contralateral.     

MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine

MBD4 was originally identified through its methyl binding domain, but has more recently been characterized as a thymine DNA glycosylase that interacts with the mismatch repair (MMR) protein MLH1. In vivo, MBD4 functions to reduce the mutability of methyl-CpG sites in the genome and mice deticient in MBD4 show increased intestinal tumorigenesis on an Apc(Min/+) background. As MLH1 and other MMR proteins have been functionally linked to apoptosis, we asked whether MBD4 also plays a role in mediating the apoptotic response within the murine small intestine. Mice deficient for MBD4 showed significantly reduced apoptotic responses 6 h following treatment with a range of cytotoxic agents including gamma-irradiation, cisplatin, temozolomide and 5-fluorouracil (5-FU). This leads to increased clonogenic survival in vivo in Mbd4(-/-) mice following exposure to either 5-FU or cisplatin. We next analysed the apoptotic response to 5-FU and temozolomide in doubly mutant Mbd4(-/-), Mlh1(-/-) mice but observed no additive decrease. The results imply that MBD4 and MLH1 lie in the same pathway and therefore that MMR-dependent apoptosis is mediated through MBD4. MBD4 deficiency also reduced the normal apoptotic response to gamma-irradiation, which we show is independent of Mlh1 status (at least in the murine small intestine), so suggesting that the reliance upon MBD4 may extend beyond MMR-mediated apoptosis. Our results establish a novel functional role for MBD4 in the cellular response to DNA damage and may have implications for its role in suppressing neoplasia.     

Severe acute respiratory syndrome: lessons from Singapore

An outbreak of severe acute respiratory syndrome (SARS) occurred in Singapore in March 2003. To illustrate the problems in diagnosing and containing SARS in the hospital, we describe a case series and highlight changes in triage and infection control practices that resulted. By implementing these changes, we have stopped the nosocomial transmission of the virus.An outbreak of severe acute respiratory syndrome (SARS) was first recognized in Singapore on March 12, 2003. The index patient was hospitalized at Tan Tock Seng Hospital, which has since become the country’s designated SARS hospital. The patient infected 20 other people (including patients and healthcare workers), who subsequently became the sources for secondary spread of the infection (1). As of June 12, 2003, a total of 206 cases and 31 deaths attributed to SARS had been reported in Singapore.We describe the important lessons learned during the triage and containment of SARS at the National University Hospital, Singapore. Both involved expanding isolation criteria to include all patients with undifferentiated fever (even in the absence of respiratory symptoms or chest x-ray changes), improving contact-tracing methods, enforcing the use of fit-tested personal protective equipment in all patient-care areas, avoiding aerosol-generating procedures, and carefully monitoring all healthcare workers for fever or respiratory symptoms. We also highlight the impact of these measures on preventing the entry and nosocomial spread of infection.     

Burnout and alcohol problems among urban transit operators in San Francisco

Although occupational burnout has been linked with numerous psychosomatic symptoms and mental health problems, few studies have examined the association between burnout and substance use. This study assessed the contribution of burnout (Emotional Exhaustion--Maslach Burnout Inventory) to the risk of alcohol dependence and alcohol-related harm among a sample of urban transit operators. The study population consisted of 993 current drinkers who participated in the 1993-1995 San Francisco Muni Health and Safety Study. A series of multivariate logistic regression models were developed to analyze the association between burnout and risk of alcohol problems after adjustment for seniority, sociodemographic factors, and mean daily ounces of ethanol. The results indicate that burnout is associated with elevated risk of alcohol dependence (odds ratio [OR] = 1.03; 95% confidence interval [CI] = 1.01, 1.06). The association between burnout and alcohol-related harm, however, was attenuated. These findings suggest that transit operators with higher levels of burnout may be at increased risk for alcohol problems, particularly alcohol dependence. The temporal relationship between the development of burnout and the onset of alcohol problems among occupational cohorts warrants further investigation.     

Granulocyte-macrophage colony-stimulating factor gene-transfected autologous tumor cell vaccine: focus[correction to fcous] on non-small-cell lung cancer

Traditionally, non-small-cell lung cancer (NSCLC) is not thought of as an immunosensitive malignancy. However, recent clinical results with GVAX, a granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced autologous tumor vaccine, may suggest otherwise. This review summarizes immune-induced activity caused by GM-CSF protein and GM-CSF gene-transfected vaccines. Initial indication of use for GM-CSF protein (sargramostim) was to improve neutrophil recovery following cytotoxic chemotherapy. However, several trials involving patients with hematologic malignancy demonstrated improvement in survival related to delayed disease progression in patients receiving sargramostim in combination with chemotherapy. Subsequently, others explored potential antitumor activity with sargramostim in a variety of trials. Results did not consistently demonstrate sufficient antitumor activity to justify routine use of sargramostim as an anticancer agent. Preclinical work with GM-CSF gene-transfected vaccines, however, did demonstrate significant activity, thereby justifying clinical investigation. Patients with metastatic NSCLC who had previously failed chemotherapy demonstrated response to GVAX (3 of 33 complete responses) and dose-related improvement in survival (471 days vs. 174 days).     

mda-7 (IL-24) Inhibits growth and enhances radiosensitivity of glioma cells in vitro via JNK signaling

Despite therapeutic interventions including surgery, chemotherapy and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. MDA-7 (IL-24), when expressed via a recombinant replication defective adenovirus, Ad.mda-7, has profound anti-proliferative and cytotoxic effects in a variety of tumor cells, but not in non-transformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cells. Ad.mda-7 reduced the proliferation of rodent and human glioma cells in MTT assays and in colony formation assays. The anti-proliferative effects of Admda-7 were enhanced by radiation in a greater than additive fashion. In vitro, this cellular change correlated with enhanced cell numbers in G1/G0 and G2/M phases of the cell cycle, implying Ad.mda-7 radiosensitizes tumor cells in a cell cycle-independent manner. The radiosensitizing effects were not observed in cultures of non-transformed primary astrocytes. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. Ad.mda-7 enhanced p38 and ERK1/2 activity but did not alter JNK or Akt activity. Irradiation of cells expressing MDA-7 suppressed ERK1/2 activity and dramatically enhanced JNK1/2 activity without altering either Akt or p38 activity. Inhibition of JNK1/2, but not p38, signaling abolished the radiosensitizing properties of MDA-7. Inhibition of neither ERK1/2 nor PI3K signaling enhanced the anti-proliferative effects of Ad.mda-7, whereas combined inhibition of both pathways enhanced cell killing, suggesting that ERK and PI3K signaling can be protective against MDA-7 lethality.     

Conditioned medium from hypoxic cytotrophoblasts alters arterial function

OBJECTIVE: Our goal was to test the hypothesis that cytotrophoblasts, under low oxygen tension, release substances that affect vascular behavior. STUDY DESIGN: We studied the vascular response to the vasoconstrictors phenylephrine (receptor dependent) and potassium (receptor independent), the relaxation response to methacholine, and the vasomotor behavior of isolated resistance (mesenteric) arteries from early pregnant rats after incubation in conditioned medium from first-trimester cytotrophoblasts, maintained in standard or hypoxic (2%; 14 mm Hg) culture conditions. RESULTS: After incubation in medium from hypoxic cytotrophoblasts, arterial segments were more responsive to phenylephrine and to potassium-induced constriction but were less responsive to methacholine, and the vasomotor activity was increased compared with that found in vessels incubated in control medium. CONCLUSIONS: These changes in vascular behavior are similar to those reported in isolated arteries from women with preeclampsia. These studies provide evidence which suggests that the link between abnormal placentation and maternal vascular abnormality in preeclampsia is the elaboration of vasoactive factors by cytotrophoblasts in response to hypoxia.