2016 Vol. 30, No. 5
2016, 30(5): 353-360. doi: 10.7555/JBR.30.20150107
Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is a leading cause of cancer-related death in the US, with a dismal median survival of 6 months. Thus, there is an urgent unmet need to identify ways to diagnose and to treat this deadly cancer. Although a number of genetic changes have been identified in pancreatic cancer, their mechanisms of action in tumor development, progression and metastasis are not completely understood. Hedgehog signaling, which plays a major role in embryonic development and stem cell regulation, is known to be activated in pancreatic cancer; however, specific inhibitors targeting the smoothened molecule failed to improve the condition of pancreatic cancer patients in clinical trials. Furthermore, results regarding the role of Hh signaling in pancreatic cancer are controversial with some reporting tumor promoting activities whereas others tumor suppressive actions. In this review, we will summarize what we know about hedgehog signaling in pancreatic cancer, and try to explain the contradicting roles of hedgehog signaling as well as the reason(s) behind the failed clinical trials. In addition to the canonical hedgehog signaling, we will also discuss several non-canonical hedgehog signaling mechanisms.
Alzheimer's disease (AD) is a prevalent and debilitating neurodegenerative disorder in the elderly. The etiology of AD has not been fully defined and currently there is no cure for this devastating disease. Compelling evidence sug-gests that the immune system plays a critical role in the pathophysiology of AD. Autoantibodies against a variety- of molecules have been associated with AD. The roles of these autoantibodies in AD, however, are not well -understood.This review attempts to summarize recent findings on these autoantibodies and explore their potential as diagnostic/ prognostic biomarkers for AD, their roles in the pathogenesis of AD, and their implications in the development of effective immunotherapies for AD.
This study investigated the therapeutic effects of renal denervation on cardiac systolic function after myocardial infarction (MI) in rats and the mechanism involved. Fifty male SD rats were randomly assigned to the sham group (n = 15), the MI group (n = 20), and the MI plus renal denervation group (n = 15). MI was established through thoracotomic ligation of the anterior descending artery. Renal denervation was achieved by laparotomic stripping of the renal arterial adventitial sympathetic nerve, approximately 3 mm from the abdominal aorta. Left ventricular function and hemodynamics were measured several weeks following MI. The left ventricular systolic function of the MI group was significantly reduced and the systolic blood pressure (SBP) remarkably declined. In rats with MI treated with renal denervation, the left ventricular ejection fraction (EF), fractional shortening (FS) and SBP markedly improved compared with the MI group. However, heart rate and fibrosis decreased significantly. These findings suggest that renal denervation has therapeutic effects on post-MI cardiac dysfunction. These effects are associated with increased left ventricular ejection fraction (LVEF) and SBP, as well as reduced heart rate and fibrosis. This may represent a new approach to the treatment of post-MI remodeling and subsequent heart failure.
Epinephrine is often used for the treatment of patients with heart failure, low cardiac output and cardiac arrest. It can acutely improve hemodynamic parameters; however, it does not seem to improve longer term clinical outcomes. Therefore, we hypothesized that epinephrine may induce unfavorable changes in gene expression of cardiomyocyte. Thus, we investigated effects of epinephrine exposure on the mediation or modulation of gene expression of cultured cardiomyocytes at a genome-wide scale. Our investigation revealed that exposure of cardiomyocytes to epinephrine in an in vitro environment can up-regulate the expression of angiopoietin-2 gene (+ 2.1 times), and down-regulate the gene expression of neuregulin 1 ( – 3.7 times), plasminogen activator inhibitor-1 ( – 2.4 times) and SPARC-related modular calcium-binding protein-2 ( – 4.5 times). These changes suggest that epinephrine exposure may induce inhibition of angiogenesis-related gene expressions in cultured rat cardiomyocytes. The precise clinical significance of these changes in gene expression, which was induced by epinephrine exposure, warrants further experimental and clinical investigations.
Infections are identified as the most common preventable cause of death in pediatric oncology patients. Assessing and stratifying risk of infections are essential to prevent infection in these patients. To date, no tool can fulfill this demand in China. This study aimed to develop a nursing work-based and Chinese-specific tool for pediatric nurses to assess risk of infection in oncology patients. This research was a modified Delphi study. Based on a literature review, a 37-item questionnaire rating on a 0–5 scale was developed. Twenty-four experts from 8 hospitals in 6 provinces of China were consulted for three rounds. Consensus for each item in the first round was defined as: the rating mean was > 3 and the coefficient of variation (CV) was < 0.5. Consensus for each item in the second round was defined as CV < 0.3. Consensus among experts was defined as: P value of Kendall's coefficient of concordance (W) < 0.05. After three rounds of consultation, a two-part tool was developed: the Immune Status Scale (ISS) and the Checklist of Risk Factors of Infection (CRFI). There were 5 items in the ISS and 14 in the CRFI. Based on the ISS score, nurses could stratify children into the low-risk and high-risk groups. For high-risk children, nurses should screen risk factors of infection every day by the CRFI, and twice weekly for low-risk children. Further study is needed to verify this tool's efficacy.
New insights into estrogenic regulation of O6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O6-benzylguanine indicates fresh avenues for therapy
2016, 30(5): 393-410. doi: 10.7555/JBR.30.20160040
Endocrine therapy using estrogen receptor-α (ER-α) antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O6-methylguanine DNA methyltransferase (MGMT), a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines (MCF-7, T47D) and ER- negative cell lines (MDAMB-468, MDAMB-231), and established inhibitors of ER-α and MGMT, namely, ICI-182,780 (Faslodex) and O6-benzylguanine, respectively, were used to study MGMT- ER interactions. The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements (EREs) and two antioxidant-responsive elements (AREs). MGMT expression was upregulated by estrogen, downregulated by tamoxifen in Western blot and promoter-linked reporter assays. Similarly, both transient and stable transfections of Nrf-2 (nuclear factor-erythroid 2-related factor-2) increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this drug-resistance determinant. Of the different ER-α antagonists tested, the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose, time and ER-α dependent manner, similar to O6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O6-benzylguanine also induced a specific loss of ER-α and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-α and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-α proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced the cytotoxicity of MGMT-targeted alkylating agents, namely, temozolomide and BCNU by 3 to 4-fold in ER-α positive cells, but not in ER–negative cells. We conclude that MGMT and ER-α proteins exist as a complex and are co-targeted for ubiquitin-conjugation and subsequent proteasomal degradation. The findings offer a clear rationale for combining alkylating agents with endocrine therapy.
In the present study, we reported our experience with partial aortic root remodeling for root reconstruction in patients with acute type A dissection, which involves in non-coronary sinus and/or the right coronary sinus with just one trimmed Dacron graft. Between February 2001 and May 2010, we performed partial aortic root remode-ling in 40 patients, who underwent emergency surgical intervention. The dissected sinuses were excised leaving a 3-5 mm rim of the aortic wall from the attached aortic valve cusps. A short piece (4-5 cm) of collagen coated woven polyester vascular prosthesis was trimmed with one or two "tongues" to reconstruct the non-coronary sinus and/ or the right coronary sinus, but without using separated patches. Additional procedures were including hemi-arch replacement in 11 patients, and total arch replacement plus stent-elephant trunk in 20 patients. The mean follow-up time was 36.4±3.6 months. In-hospital mortality was only 5.0% (2/40); furthermore, 3 (8.6%) patients underwent re-operation of the aortic valve and 2 (5.7%) patients died during follow-up. At the end of follow-up, trivial or no aortic regurgitation was found in 33 patients, but mild aortic regurgitation was found in 2 patients. Our data suggest that the early and mid-term results of partial aortic root remodeling were favorable, and it restored valve durability and function. Thus, the use of technique for root reconstruction in patients with acute type A dissection should be vigorously encouraged.
This retrospective study investigated the impact of endplate fracture on postoperative vertebral height loss and kyphotic deformity in 144 patients with osteoporotic vertebral compression fracture (OVCF), who received balloon kyphoplasty. Patients were divided into four groups: Group 1 had no superior endplate fracture, Group 2 had frac-tures on the anterior portion of the superior endplate, Group 3 had fractures on the posterior portion of the superior endplate, and Group 4 had complete superior endplate fractures. Anterior and middle vertebral body height, vertebral compression ratio, vertebral height loss rate, and kyphosis Cobb angle of each patient were measured and visual analogue scale (VAS) and Oswestry disability index (ODI) scores were recorded. The anterior vertebral height and kyphosis deformity of all groups significantly improved after the surgery, whereas substantial anterior vertebral height loss and increased Cobb angle were observed in all patients at the last follow-up. Although the vertebral height loss rate and the Cobb angle in Group 2, 3 and 4 were larger compared with Group 1 at the last follow-up, only the vertebral height loss rate in Group 4 and the increase in the Cobb angle in Group 2 and 4 were statistically different from those in Group 1. The VAS and ODI scores in all groups measured after the surgery and at the last follow-up were significantly lower compared with preoperative scores, but there was no significant difference among these groups. Balloon kyphoplasty significantly improved vertebral fracture height and kyphosis. Vertebral height loss and increased kyphotic deformity were observed in OVCF patients with endplate fractures after the surgery. Postoperative aggravation of kyphosis was observed in Group 2. Furthermore, severe vertebral height loss and increased kyphotic deformity were confirmed in Group 4 after the surgery. Our results suggested that postoperative vertebral height loss and aggravation of kyphosis may be associated with biomechanical changes in the vertebral body caused by endplate fracture. Therefore, surgery should not only restore compressed vertebral body height and correct kyphosis, but also correct the deformity of endplate to achieve an effective treatment of OVCF patients with endplate fracture.
Aspartame, a "first generation sweetener", is widely used in a variety of foods, beverages, and medicine. The FDA has determined the acceptable daily intake (ADI) value of aspartame to be 50 mg/kg$day, while the JECFA (Joint FAO/WHO Expert Committee on Food Additives) has set this value at 40 mg/kg of body weight/day. Safety issues have been raised about aspartame due to its metabolites, specifically toxicity from methanol and/or its systemic metabolites formaldehyde and formic acid. The immune system is now recognized as a target organ for many xenobiotics, such as drugs and chemicals, which are able to trigger unwanted apoptosis or to alter the regulation of apoptosis. Our previous studies has shown that oral administration of aspartame [40 mg/(kg$day)] or its metabolites for 90 days increased oxidative stress in immune organs of Wistar albino rats. In this present study, we aimed to clarify whether aspartame consumption over a longer period (90-days) has any effect on the expression of hsp70, bcl-2 and bax at both mRNA transcript and protein expression levels in immune organs. We observed that oral administration of aspartame for 90 days did not cause any apparent DNA fragmentation in immune organs of aspartame treated animals; however, there was a significant increase in hsp70 expression, apart from significant alteration in bcl-2 and bax at both mRNA transcript and protein expression level in the immune organs of aspartame treated animals compared to controls. Hence, the results indicated that hsp70 levels increased in response to oxidative injury induced by aspartame metabolites; however, these metabolites did not induce apoptosis in the immune organs. Furthermore, detailed analyses are needed to elucidate the precise molecular mechanisms involved in these changes.
Anorectal malignant melanoma is a very rare but lethal disease. Patients with anorectal malignant melanoma commonly complain for changes in bowel habits and rectal bleeding. Therefore, anorectal malignant melanoma is often misdiagnosed as hemorrhoids, polyp or rectal cancer. Surgery is the mainstay of treatment for patients with anorectal malignant melanoma. However, whether abdominoperineal resection or wide local excision is the most appropriate surgical approach is still a controversial issue. Recently, with the great development of laparoscopic techniques, more and more operations can be performed by laparoscopic techniques. However, laparoscopic abdom-inoperineal resection for management of anorectal malignant melanoma has been rarely reported. In this study, we reported 4 patients with anorectal malignant melanoma underwent laparoscopic abdominoperineal resection. The outcomes of these patients were relatively good during a long time follow-up. Meanwhile, we reviewed the relevant studies with particular focus surgical treatment.