Little information is available about health impacts of the North American Free Trade Agreement (NAFTA) traffic‐related pollution on residents near the major traffic corridors along the U.S.–Canadian border. Here we report on a 10 year (1991–2000) retrospective study of commercial traffic volumes across the Peace Bridge and health care use for asthma in a residential community, which serves as a conduit for traffic crossing between Fort Erie, Ontario, Canada, and Buffalo, New York. We hypothesized that commercial traffic pollution was impacting on residents in close proximity to the trade corridor. Commercial traffic volumes, hospital discharges for asthma, and outpatient visits to area hospitals and clinics were analyzed before and after implementation of NAFTA. Results showed a positive association between increased commercial traffic volume and increased health care use for asthma. Zip codes 14201 and 14213, which surround the Peace Bridge Plaza Complex (PBC), had the highest prevalence rates and health care use rates for asthma. Statistical analysis showed the findings to be significant (p < 0.05) in that residential proximity to the PBC was associated with greater hospital discharge rates for asthma. The findings were strongest (p < 0.000) in the zip codes where the PBC was located (14213) and the major highway I‐190 passed through (14201). A yearly excess of 230.2 adult asthma hospital discharges was associated with an increase in traffic volume during the period from 1991 to 1996 in the study area. This is in contrast to an overall decrease in the national rate of hospitalizations for asthma by 7.5% in the same period. The results suggest that NAFTA‐related commercial traffic has a negative health impact on asthmatics living in close proximity to the trade corridor. Health and social costs due to traffic pollution need to be included in cost estimates of transport decisions related to the NAFTA corridors. Similar health effects due to NAFTA traffic need to be studied at other U.S.–Canada border crossing points.
Chondroblastoma is an aggressive tumor of bone with the capacity for recurrence and metastasis. We sought to determine the prognostic factors that affect survival and local recurrence with particular emphasis on surgical technique and the anatomic constraints of the open physis. It was hypothesized that an open growth plate would impact the local recurrence rate negatively and be a primary determinant of treatment outcome. We retrospectively reviewed 82 consecutive patients treated at one institution. Intralesional treatment with meticulous curettage and bone graft resulted in local control in the majority of patients. Four local recurrences developed between 5 and 51 months. An open growth plate was not found to correlate with local recurrence. In most cases, the open physis did not considerably impact surgical technique. Although the median age of the patients was 16 years, the majority of patients had a closed or closing physis. Few patients had substantial growth remaining. A physeal-sparing operation was done in six patients, and no local recurrences were observed in this group. The factors that seemed to affect local recurrence included inadequate surgery and biologic aggressiveness of the tumor. Inadequate surgery was likely to be the cause of local recurrence in patients who presented after previous treatment elsewhere. Three patients who developed local recurrence manifested increased biologic aggressiveness of disease. These patients subsequently developed metastatic disease and malignant transformation of disease. All three patients died from their disease. Pelvic tumors tend to be biologically more aggressive and more apt to recur locally and metastasize to distant locations.Therapeutic Study, Level IV (case series). See the Guidelines for Authors for a complete description of levels of evidence.
Background Optimal cancer care requires a multidisciplinary approach. The purpose of the current study was to evaluate the impact of a multidisciplinary tumor board on the treatment plans of children with solid tumors. Procedures The records of 158 consecutive patients discussed at a formal multidisciplinary pediatric tumor board between July 2012 and April 2014 were reviewed. Treatment plans were based on clinical practice guidelines and on current Children's Oncology Group protocols. Alterations in radiologic, pathologic, surgical, and medical interpretations were analyzed to determine the impact on changes in recommendations for clinical management. Results Overall, 55 of 158 children (35%) had alterations in radiologic, pathologic, medical, or surgical interpretation of clinical data following multidisciplinary discussion. Of these, 64% had changes to the initial recommendation for clinical management. Review of imaging studies resulted in interpretation changes in 30 of 158 patients studied (19%), with 12 clinical management changes. Six of 158 patients (3.9%) had changes in pathologic interpretation, with four patients (2.5%) requiring treatment changes. In eight patients (5%), a change in medical management was recommended, while in 11 patients (7%) there were changes in surgical management that were based solely on discussion and not on interpretation of imaging or pathology. Conclusions Formal multidisciplinary review led to alterations in interpretation of clinical data in 35% of patients, and the majority led to changes in recommendations for treatment. Comprehensive multidisciplinary tumor board incorporated into the care of children with cancer provides additional perspectives for families and care providers when delineating optimal treatment plans.
Carcinoembryonic antigen (CEA) is a tumor marker for the clinical management of colorectal cancer (CRC). The elevated blood levels of CEA are associated with metastasis and poor prognosis in CRC. There is mounting evidence that CEA enhances the metastatic potential of cancer cells. CEA increases the ability of weakly metastatic CRC to colonize the liver and to develop spontaneous hematogeneous liver and lung metastases. CEA expression has also been related with resistance to cytotoxic chemotherapy and to anoikis, a form of apoptosis caused by detachment from cell matrix. Yet the mechanism of CEA mediated metastasis is only partially understood. The TGF-β (transforming growth factor beta) signaling pathway contributes to tumorigenesis by controlling several biological processes, including cell proliferation, differentiation, migration and apoptosis. It has been reported that TGF-β regulates CEA transcription and secretion, however, little is known about the effects of CEA on TGFβ signaling. Aims: Based on the above facts, we focused on the influence of CEA on the TGF-β signaling in both normal cells and colorectal cancer cells. Results: Our preliminary data showed that CEA directly interacted with TGF-β receptors. Overexpression of CEA blocked TGF-β induced SMAD3 phosphorylation, SMAD3 translocation to nuclear and the downregulation of c-myc transcription. Targeting CEA with anti-CEA antibody rescued TGFβ response in CRC cell lines with elevated CEA expression, thereby restoring the inhibitory effects of TGF-β on the proliferation of these cancer cells. Finally, in animal experiment, we found that CEA enhanced survival of colorectal cancer cell in both local colonization and liver metastasis. Conclusion: Since CEA is a well-characterized tumor-associated antigen that is frequently overexpressed in tumors, specific antibodies targeting CEA have been developed as a novel therapeutic approach for treatment of tumors expressing CEA on their surface. Based on our study, it may be helpful to combine CEA antibody and TGF-β to inhibit cancer cell proliferation and metastasis in some cases.
Abstract Liver regeneration, following partial hepatectomy (PHx), occurs through precisely controlled and synchronized cell proliferation, in which quiescent hepatocytes undergo one to two rounds of replication, with restoration of liver mass and function. We previously demonstrated that loss of the Smad3/4 adaptor protein β-2 spectrin (β2SP) is associated with faster entry into S phase, and hepatocellular cancer formation. These observations led us to further pursue the role of β2SP in cell cycle progression in vivo . Liver regeneration studies with PHx in β2SP+/− mice reveal a surprising and significant decrease in liver/body weight ratio at 48 hours after PHx in β2SP+/− mice in comparison to wildtype mice. At 48 hours after PHx we also observe decreased levels of cyclin E (2.4-fold, P < 0.05), Cdk1 (7.2-fold, P < 0.05), cyclin A, pRb (Ser249/Thr252), proliferative cell nuclear antigen (PCNA), cyclin D1 with elevated levels of pCdk1 (Thr14) (3.6-fold, P < 0.05). Strikingly, at 24 hours elevated levels of p53 (4-fold, P < 0.05), phospho-p53 (ser15 and ser20), and p21 (200-fold, P < 0.05) persisting to 48 hours after PHx further correlated with raised expression of the DNA damage markers pChk2 (Thr68) and γH2AX (S139). However, compromised cell cycle progression with loss of β2SP is not rescued by inhibiting p53 function, and that G2/M phase arrest observed is independent and upstream of p53. Conclusion : β2SP deficiency results in dysfunctional hepatocyte cell cycle progression and delayed liver regeneration at 48 hours after PHx, which is p53-independent. β2SP loss may increase susceptibility to DNA damage, impair cell cycle progression, and ultimately lead to hepatocellular cancer. (Hepatology 2011;)
Abstract At least 40% of hepatocellular cancers (HCC) are clonal, suggesting that HCC may develop from malignant transformation of liver progenitor/stem cells. Several signaling pathways, including IL-6/STAT3 and TGF-β are known to be involved in stem cell renewal, differentiation and survival, and are commonly deregulated in HCC. We have previously demonstrated that human and mouse HCC tissues with aberrant TGF-β signaling show increased expression of STAT3. Moreover, down-regulation of the IL-6/STAT3 pathway in a TGF-β disrupted mouse model (β2SP+/−) by crossing with itih4—/— (Inter-alpha-trypsin inhibitor-heavy chain-4) mice resulted in a significant decrease in the incidence of HCC. Aims: This led us to hypothesize that the TGF-β signaling pathway is a strong candidate pathway for the transition from progenitor to differentiated cells and its disruption may activate the stem cell renewal IL-6/STAT3 pathway. We proceeded to investigate the role of key TGF-β signaling components, including the key Smad3/4 adaptor protein β2SP and Smad3, in the regulation of STAT3 expression. Methods and Results: First, using early passage mouse embryonic fibroblasts (MEFs) from wild type and β2SP−/− embryos, we demonstrate a four-fold increase in STAT3 mRNA by RT-PCR (p<0.001). Moreover, we demonstrate that overexpression of β2SP by transfection or inhibition of β2SP expression by siRNA in several HCC cell lines results in STAT3 suppression or induction, respectively, suggesting that β2SP and the TGF-β signaling pathway regulate STAT3 transcription. Then, using ChiP assay, we demonstrate that β2SP and Smad3 are bound to the STAT3 promoter only following TGF-β stimulation. To then further define the molecular mechanism of TGF-β-mediated STAT3 transcriptional regulation, we then used mutational analysis and demonstrate two transcription factor binding sites within the STAT3 promoter, the cAMP-responsive element (CRE) and STAT3 binding (SBE) sites, are essential for TGF-β-mediated regulation of the STAT3 transcription. Subsequent, electrophoresis mobility shift assays (EMSA) demonstrate that the CRE-binding protein ATF-2, Smad3, and β2SP proteins are major components of the TGF-β-mediated STAT3 transcriptional suppressor complex. Conclusion: These experiments demonstrate a clear link between the TGF-β and IL-6/STAT3 signaling pathways. TGF-β suppression of STAT3 transcription is mediated by a complex including [[Unsupported Character - ]]β2SP, Smad3 and ATF-2 at the CRE site of the STAT3 promoter. Inactivation of TGF-β signaling via disruption of β2SP decreases STAT3 suppression and suggests a potential mechanism for malignant transformation in TGF-β deficient progenitor/stem cells. STAT3 may also present an important target for new therapeutics in transformed cancer progenitor/stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3913.
