Testing the Enemy Release Hypothesis on tall-statured grasses in South Africa, using Arundo donax, Phragmites australis, and Phragmites mauritianus as models.

The Enemy Release Hypothesis (ERH) predicts that introduced plant species can escape herbivory and therefore have a competitive advantage over native plants, which are exposed to both generalist and specialist natural enemies. In this study, the ERH was explored using the invasive alien species, Arundo donax and two native tall-statured grasses, the cosmopolitan Phragmites australis and African endemic Phragmites mauritianus in South Africa. It was predicted that A. donax would have reduced species richness of herbivores compared with the native Phragmites spp., that it would be devoid of specialist herbivores and would thus be experiencing enemy escape in the adventive range. The herbivore assemblages were determined from both field surveys and a literature review. The assumptions of the ERH were for the most part not met; 13 herbivores were found on A. donax compared with 17 on P. australis and 20 on P. mauritianus. Arundo donax had two specialist herbivores from its native range, and shared native herbivores with Phragmites spp. Although A. donax had reduced species richness and diversity compared with that found in the native distribution, it has partially re-acquired a herbivore assemblage which is similar to that found on analogous native species. This suggests that enemy release may not fully explain the invasive success of A. donax in South Africa.

Beta blockers and improved progression-free survival in patients with advanced HER2 negative breast cancer: a retrospective analysis of the ROSE/TRIO-012 study.

BACKGROUND: Recent retrospective studies suggest that beta-adrenergic blocking drugs (BB) are associated with improved outcomes in patients with a range of cancers. Although limited and discordant data suggest that BB may increase overall survival (OS) in localized breast cancer (BC), there is no information on the effects of BB in women with advanced BC. PATIENTS AND METHODS: To explore the association between BB use and BC outcomes, we retrospectively reviewed ROSE/TRIO-012, a double-blinded, multinational phase III trial that randomized 1144 patients with HER2-negative advanced BC to first-line docetaxel in combination with ramucirumab or placebo. We compared progression-free survival (PFS), OS, overall response rate, and clinical benefit rate in patients who received BB to those who did not. RESULTS: 153/1144 (13%) patients received BB; 62% prior to enrolment and 38% began after enrolment. Median PFS in BB treated patients was longer than in patients who did not receive them (10.3 versus 8.3 months; HR 0.81; 95% CI 0.66-0.99; P = 0.038). Patients treated with BB only after enrolment had even higher median PFS (15.5 versus 8.3 months, P < 0.001). In the TNBC subset, median PFS was 13.0 months with BB, compared to 5.2 months without BB (HR 0.52; 95% CI 0.34-0.79; P = 0.002). The benefit of BB intake in PFS was independent of treatment-emergent hypertension (P = 0.476) but associated with treatment arm (P = 0.037). The test for interactions between BB and treatment arm was not significant (P = 0.276). No differences were seen in OS, overall response rate, or clinical benefit rate. A validation dataset analysis had consistent but less substantial improved outcomes for women with node positive operable breast cancer receiving BB in the BCIRG-005 trial. CONCLUSIONS: In this exploratory analysis, BB intake was associated with significant improvement in PFS, particularly in patients with TNBC and patients not previously exposed to BB. CLINICAL TRIAL NUMBER: NCT00703326.

Fibroblast activation and senescence in oral cancer.

There is now compelling evidence that the tumour stroma plays an important role in the pathogenesis of cancers of epithelial origin. The pre-eminent cell type of the stroma is carcinoma-associated fibroblasts. These cells demonstrate remarkable heterogeneity with activation and senescence being common stress responses. In this review, we summarise the part that these cells play in cancer, particularly oral cancer, and present evidence to show that activation and senescence reflect a unified programme of fibroblast differentiation. We report advances concerning the senescent fibroblast metabolome, mechanisms of gene regulation in these cells and ways in which epithelial cell adhesion is dysregulated by the fibroblast secretome. We suggest that the identification of fibroblast stress responses may be a valuable diagnostic tool in the determination of tumour behaviour and patient outcome. Further, the fact that stromal fibroblasts are a genetically stable diploid cell population suggests that they may be ideal therapeutic targets and early work in this context is encouraging.

Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy

Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients.

The opposing roles of NOTCH signalling in head and neck cancer: a mini review.

NOTCH signalling can exert oncogenic or tumour suppressive effects in both solid and haematological malignancies. Similar to T-cell acute lymphoblastic leukaemia (T-ALL), early studies suggested a pro-tumorigenic role of NOTCH in head and neck squamous cell carcinoma (HNSCC), mainly based on the increased expression levels of the genes within the pathway. Recently, data from exome sequencing analyses unexpectedly pointed to a tumour suppressor role for NOTCH in HNSCC by identifying loss-of-function mutations in the NOTCH1 gene in a significant proportion of patients. These data have questioned the accepted role of NOTCH in HNSCC and the possible rationale of targeting NOTCH in this disease. This review summarises the current information on NOTCH signalling in HNSCC and discusses how this pathway can apparently exert opposing effects within the same disease.

Cardiovascular MRI predicts 5-year adverse clinical outcome in heart transplant recipients.

Imaging recommendations for the follow-up of heart transplant recipients (HTRs) lack evidence justifying their prognostic value. Cardiovascular magnetic resonance imaging (CMRI) can characterize heart structure and function and has prognostic value in many myocardial diseases. We hypothesized that CMRI evaluation of cardiac allografts would predict adverse events. We performed CMRI on 60 HTRs evaluating biventricular size, function and myocardial scar. We performed survival analysis to identify independent predictors of cardiovascular (CV) death or hospitalization. Participants had a mean age of 51 ± 14 years, mean graft age of 3.5 years (±4) and 75% are male. Median follow-up time was 4.9 years with 22 CV hospitalizations and 7 CV deaths. A multivariable survival analysis of imaging and clinical variables identified myocardial scar (hazard ratio [HR] of 10.7, p = 0.005), right ventricular end- diastolic volume index (RVEDVI; 1.1/mL/m(2) , p = 0.001), graft age (HR = 1.2/year, p = 0.004) and previous allograft rejection (HR = 4.4, p = 0.006) as predictive of time to CV death or hospitalization. CMRI-derived myocardial scar and RVEDVI are independently associated with CV outcomes in HTRs.

Lysophosphatidic acid and calcitriol co-operate to promote human osteoblastogenesis: requirement of albumin-bound LPA.

Lysophosphatidic acid (LPA), a pleiotropic signalling lipid is assuming growing significance in osteoblast biology. Although committed osteoblasts from several mammalian species are receptive to LPA far less is known about the potential for LPA to influence osteoblast formation from their mesenchymal progenitors. An essential factor for both bone development and post-natal bone growth and homeostasis is the active metabolite of vitamin D3, calcitriol (D3). Previously we reported how a combination of LPA and D3 synergistically co-operated to enhance the differentiation of immature human osteoblasts. Herein we provide evidence for the formation of human osteoblasts from multiple, primary human bone marrow derived stromal (stem) cells (hBMSCs). Importantly osteoblast development from hBMSCs only occurred when LPA was administered as a complex with albumin, its natural carrier. Collectively our findings support a co-operative role of LPA and D3 in osteoblastogenesis, findings which may aid the development of novel treatment strategies for bone repair.

Mitochondrial DNA mutations in head and neck cancer are infrequent and lack prognostic utility.

BACKGROUND: Mitochondrial DNA (mtDNA) mutations occur in head and neck squamous cell carcinoma (HNSCC) and are most frequently detected in the displacement-loop (D-loop) region. The D-loop is considered to be important because it controls mitochondrial gene expression and mtDNA replication. There is currently no evidence that mtDNA mutations can be used as prognostic or predictive biomarkers in HNSCC. METHODS: We used denaturing high performance liquid chromatography to screen the entire mitochondrial genome of six oral squamous cell carcinoma-derived cell lines and then focused on detecting D-loop abnormalities in 34 HNSCC tissue samples. RESULTS: Mitochondrial DNA mutations are not ubiquitous in HNSCC because only half of the cell lines had detectable mtDNA abnormalities following screening of the entire mitochondrial genome and only 18% (6 of 34) of tissue samples had D-loop mutations. There was no correlation between D-loop mutations and determinates of clinical outcome; specifically, tumour stage and the expression of hypoxia-inducible genes included in a highly prognostic hypoxia metagene. CONCLUSIONS: Taken together, these data suggest that mtDNA D-loop mutations are stochastic events that may not significantly influence the biology of HNSCC and supports the hypothesis that mtDNA mutations in cancer represent bystander genotoxic damage as a consequence of tumour development and progression.

Hypoperfusion of segment 4 in right in situ split-liver transplantation.

To expand the donor pool, split-liver transplantation has been implemented in recent years. In the classic technique, the arterial axis with the artery for segment 4 (S4) coming from the left hepatic artery (HA) is included with the right graft. To give a surgical advantage to pediatric recipients in our center, the left HA, the common HA, and the celiac trunk are generally retained with the left liver. Thus the artery for S4 is sacrificed. We compared the outcomes of S4 in 290 whole grafts (WG; group A) with 28 right in situ split-liver grafts (SSLG; group B), which were transplanted over the past 10 years (January 1999-December 2009). The rates of major biliary and of hemorrhagic complications were similar. In most of cases (16/24, 66%) S4, on computerized tomographic scan appeared to show signs of hypoperfusion, sometimes with a peripheral aspect of hyperperfusion in the arterial phase. S1 showed signs of hypoperfusion in only 2 cases. A biliary collection near the resection line present in 8 cases was treated in 6 of them with percutaneous drainage and in 2 with laparotomy. These complications did not influence graft or patient survival. Graft survivals at 1, 5, and 10 years for WG and SSLG were not different among the groups: 85%, 74%, and 66% vs 89%, 79%, and 63%, respectively (P = .8). Although our technique cannot be considered to be anatomically correct, the ischemia of S4 did not influence the outcome. The rate of retransplantations for hepatic artery thrombosis was 17.9% in RSSG and 3.4% in WG (P = .001), which was probably due at least in part to the insertion of interposition grafts.

The use of Nolvadex in the treatment of generic Tamoxifen-associated small joint arthralgia.

INTRODUCTION: Small joint arthralgia has been anecdotally reported for many years by women taking generic Tamoxifen (gT). However, it is a symptom that is absent from the side effect profile of the original Tamoxifen preparation Nolvadex. Our aim was to determine the prevalence of arthralgia in Tamoxifen users and to investigate whether it was associated with the excipient profile of the newer, generic formulations of Tamoxifen. METHODS: Women diagnosed with oestrogen receptor positive breast cancer between 2001 and 2005 were eligible. Those with new-onset arthralgia following commencement of gT were entered into a one year double crossover study. Patients were swapped from gT to Nolvadex for 6 months, the response noted, and then swapped back to gT for 6 months. RESULTS: Of 1020 new breast cancer patients, 918 (90%) were oestrogen receptor (OR) positive and were started on gT as part of their treatment. Of those, a total of 121 (13.2%) suffered with arthralgia. All 121 patients agreed to enter the study and swap treatment to Nolvadex for 6 months 114 patients (94.2%) had resolution of their arthralgia whilst on Nolvadex (p < 0.05). CONCLUSION: Our findings suggest that there is an arthralgia syndrome which is prevalent in women taking generic Tamoxifen preparations. Symptoms are abolished when Nolvadex is used instead of gT. This suggests that the excipient profiles are an important factor. We hypothesise that either the excipient profile of gT induces arthralgia, or an unknown excipient of Nolvadex has a protective effect.

Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation.

Oral squamous cell carcinoma (OSCC) is a lethal disease and early death usually occurs as a result of local invasion and regional lymph node metastases. Current treatment regimens are, to a certain degree, inadequate, with a 5-year mortality rate of around 50% and novel therapeutic targets are urgently required. Using expression microarrays, we identified the eps8 gene as being overexpressed in OSCC cell lines relative to normal oral keratinocytes, and confirmed these findings using RT-PCR and western blotting. In human tissues, we found that Eps8 was upregulated in OSCC (32% of primary tumors) compared with normal oral mucosa, and that expression correlated significantly with lymph node metastasis (P=0.032), suggesting a disease-promoting effect. Using OSCC cell lines, we assessed the functional role of Eps8 in tumor cells. Although suppression of Eps8 produced no effect on cell proliferation, both cell spreading and migration were markedly inhibited. The latter cell functions may be modulated through the small GTP-ase, Rac1 and we used pull-down assays to investigate the role of Eps8 in Rac1 signaling. We found that alphavbeta6- and alpha5beta1-integrin-dependent activation of Rac1 was mediated through Eps8. Knockdown of either Eps8 or Rac1, inhibited integrin-dependent cell migration similarly and transient expression of constitutively active Rac1 restored migration of cells in which Eps8 expression had been suppressed. We also showed that knockdown of Eps8 inhibited tumor cell invasion in an organotypic model of OSCC. These data suggest that Eps8 and Rac1 are part of an integrated signaling pathway modulating integrin-dependent tumour cell motility and identify Eps8 as a possible therapeutic target.

The chemical synthesis of discodermolide.

The marine sponge-derived polyketide discodermolide is a potent antimitotic agent that represents a promising natural product lead structure in the treatment of cancer. Discodermolide shares the same microtubule-stabilising mechanism of action as Taxol(®), inhibits the growth of solid tumours in animal models and shows synergy with Taxol. The pronounced cytotoxicity of discodermolide, which is maintained against cancer cell lines that display resistance to Taxol and other drugs, combined with its scarce availability from its natural source, has fuelled significant academic and industrial interest in devising a practical total synthesis as a means of ensuring a sustainable supply for drug development. This chapter surveys the various total syntheses of discodermolide that have been completed over the period 1993-2007, focusing on the strategies employed for introduction of the multiple stereocentres and achieving control over the alkene geometry, along with the various methods used for realising the pivotal fragment couplings to assemble progressively the full carbon skeleton. This dedicated synthetic effort has triumphed in removing the supply problem for discodermolide, providing sufficient material for extensive biological studies and enabling its early stage clinical development, as well as facilitating SAR studies for lead optimisation.

Managing the 2-week wait for breast patients.

INTRODUCTION: Published data suggest that the 2-week wait system and triple assessment at one fast-track clinic visit is an out-dated method of capturing disease from a referral population. These studies report up to 32% of breast cancer coming from routine referrals. It has been recommended, therefore, that all breast referrals should be seen within 2 weeks. The sheer volume of referrals are likely to prevent this target being achieved. The aim of this study was to analyse the performance of our fast-track system. PATIENTS AND METHODS: The Birmingham Heartlands and Solihull fast-track clinics were set up in 1999 with a prospective audit system. The data from this audit were retrospectively analysed and cross-referenced with the cancer data base to determine the referral origin of breast cancers from November 1999 to February 2005. RESULTS: A total of 14,303 (fast-track, n = 6678; routine referral, n = 7625) patients were seen over a 5-year period. Overall, 1095 cancers (91.8% of the total) came from the fast-track clinics which had a pick-up rate of 16.4% compared with 98 cancers (8.2% of the total) and a pick-up rate of 1.3% for routine referrals (P < 0.001). The appropriateness of fast-track referral was also analysed which showed that 14.4% of cancers were detected if the referral criteria were met compared to 0.55% if they were inappropriate (P < 0.001). CONCLUSIONS: The traditional fast-track, triple assessment breast clinic is an efficient and well-structured way of diagnosing disease. We recommend that the two system referral pattern should continue.

Lisinopril-induced acute pancreatitis.

Drugs are an uncommon but well-recognised cause of acute pancreatitis and new agents of drug-induced pancreatitis continue to be reported. We describe only the 10th reported case of lisinopril-induced pancreatitis in a young female patient.

Menopausal symptoms in women treated for breast cancer: the prevalence and severity of symptoms and their perceived effects on quality of life.

OBJECTIVES: To determine, first, the prevalence and severity of various symptoms related to estrogen deficiency in women within a few years of receiving treatment for breast cancer, second, how women perceive the effects of these symptoms on their quality of life and, third, what measures have been taken to relieve vasomotor symptoms. METHODS: Two hundred women (aged 29-65 years) who had received treatment for breast cancer within the last 5 years were included in this cross-sectional survey. Information was collected about their breast cancer treatment, menopausal symptoms (Menopausal Rating Scale), the perceived effects of menopausal symptoms on their and their partner's quality of life and any treatments they were receiving for hot flushes. RESULTS: All but one woman reported at least one symptom related to the menopause (95.9% vasomotor; 83.3% psychological; 89.7% somatic). Current treatment with tamoxifen or previous chemotherapy did not influence the prevalence or the severity of hot flushes. Current antidepressant treatment was, however, significantly associated with a higher prevalence and severity of most menopausal symptoms, including hot flushes and sweats (p = 0.008). The severity of hot flushes and sweats was significantly correlated with self-assessed effects on overall quality of life (r(s) = 0.47); 56.4% of the respondents believed that menopausal symptoms had affected their partner's quality of life, the strongest correlations being with severity of sexual symptoms (r(s) = 0.56) and vaginal dryness (r(s) = 0.5). Only 21% of women experiencing hot flushes were receiving any treatment for hot flushes, with most women describing no knowledge or poor knowledge of treatment options. CONCLUSIONS: The majority of women receiving treatment for breast cancer report menopausal symptoms, which negatively correlate, not only with their own, but also with their partner's quality of life. Most women experiencing hot flushes are not receiving treatment due to lack of both awareness and confidence in the existing treatment options.

TGF-beta signal transduction in oro-facial health and non-malignant disease (part I).

The transforming growth factor-beta (TGF-beta) family of cytokines consists of multi-functional polypeptides that regulate a variety of cell processes, including proliferation, differentiation, apoptosis, extracellular matrix elaboration, angiogenesis, and immune suppression, among others. In so doing, TGF-beta plays a key role in the control of cell behavior in both health and disease. In this report, we review what is known about the mechanisms of activation of the peptide, together with details of TGF-beta signal transduction pathways. This review summarizes the evidence implicating TGF-beta in normal physiological processes of the craniofacial complex-such as palatogenesis, tooth formation, wound healing, and scarring-and then evaluates its role in non-malignant disease processes such as scleroderma, submucous fibrosis, periodontal disease, and lichen planus.

The role of TGF-beta in epithelial malignancy and its relevance to the pathogenesis of oral cancer (part II).

The role of transforming growth factor-beta (TGF-beta) in epithelial malignancy is complex, but it is becoming clear that, in the early stages of carcinogenesis, the protein acts as a potent tumor suppressor, while later, TGF-beta can function to advance tumor progression. We review the evidence to show that the pro-oncogenic functions of TGF-beta are associated with (1) a partial loss of response to the ligand, (2) defects of components of the TGF-beta signal transduction pathway, (3) over-expression and/or activation of the latent complex, (4) epithelial-mesenchymal transition, and (5) recruitment of signaling pathways which act in concert with TGF-beta to facilitate the metastatic phenotype. These changes are viewed in the context of what is known about the pathogenesis of oral cancer and whether this knowledge can be translated into the development of new therapeutic modalities.

Metastatic dissemination of human malignant oral keratinocyte cell lines following orthotopic transplantation reflects response to TGF-beta 1.

This study examined the behaviour of nine human malignant oral keratinocyte cell lines following orthotopic transplantation to the floor of the mouth of athymic mice. Tumourigenesis, local spread, and metastatic dissemination were correlated with known cellular responses to transforming growth factor-beta 1 (TGF-beta 1). Six of nine cell lines were tumourigenic; four of these cell lines showed local spread which was characterized by vascular and bone invasion. Metastatic spread was uncommon, with only 9% of animals with primary tumours developing metastases and these were almost exclusively found in the regional lymph nodes; there was one pulmonary metastasis and no liver deposits. Tumour cell behaviour did not reflect the clinical stage of the original tumours. Cell lines that were resistant to TGF-beta 1-induced growth inhibition were more likely to form primary tumours, exhibit local spread, and metastasize than cells that were growth-inhibited by the ligand. The data demonstrate that tumourigenicity and tumour behaviour in this orthotopic mouse model varied between cell lines and that the pattern of local invasion and metastasis was similar to that seen in human oral cancer. Furthermore, cell lines that were refractory to the growth inhibitory effects of TGF-beta 1 behaved more aggressively than cells that underwent ligand-induced cell-cycle arrest.

Functional significance of MMP-2 and MMP-9 expression by human malignant oral keratinocyte cell lines.

This study examined the expression of MMP-2 and MMP-9 in normal and human malignant oral keratinocytes. The expression of pro-MMP-2 and pro-MMP-9 was heterogeneous in the malignant cell lines. Normal oral keratinocytes expressed less pro-MMP-2 and more pro-MMP-9 than their malignant counterparts. Cells that expressed high levels of both MMP-2 and MMP-9 showed the greatest degree of invasion through Matrigel in vitro compared to cells with either low or variable levels of these enzymes; normal keratinocytes were non-invasive in these conditions. The degree to which the cells invaded through Matrigel was similar to their motility in the absence of Matrigel and was not influenced by the activation of the pro-enzymes or the inhibition of enzyme activity using a chemical inhibitor of gelatinases. Cells were transplanted orthotopically to athymic mice and demonstrated a variable capacity not only to form tumours at the site of inoculation but, also, to metastasise; normal oral keratinocytes were non-tumorigenic. There was no correlation between the expression of either MMP-2 or MMP-9 and the tumorigenic/metastatic phenotype. The results emphasise the limitations of correlating in vitro and in vivo assays of tumour cell behaviour and suggest that invasion/motility in vitro may be a distinct phenotype from tumorigenicity/metastasis in vivo.

Homeopathy: what is it and is it of value in the care of patients with cancer?

The underlying principles of homeopathy include treating 'like with like' by remedies which are potentized by serial dilution and succussion. These distinguish homeopathy from other forms of alternative or complementary therapy. Conventional scientific wisdom dictates that homeopathy should have no effect above and beyond placebo but experiments on ultra-high dilutions of solutes together with some clinical data suggest the intriguing possibility that it might do in some circumstances. However, most clinical evidence comes from treating relatively minor self-limiting diseases and little comes from treating life-threatening disorders such as cancer. This paper explains the principles of homeopathy and reviews the data on its use in cancer care.