Progressive resistance training and stretching following surgery for breast cancer: study protocol for a randomised controlled trial

Background: Currently 1 in 11 women over the age of 60 in Australia are diagnosed with breast cancer. Following treatment, most breast cancer patients are left with shoulder and arm impairments which can impact significantly on quality of life and interfere substantially with activities of daily living. The primary aim of the proposed study is to determine whether upper limb impairments can be prevented by undertaking an exercise program of prolonged stretching and resistance training, commencing soon after surgery. Methods/design: We will recruit 180 women who have had surgery for early stage breast cancer to a multicenter single-blind randomized controlled trial. At 4 weeks post surgery, women will be randomly assigned to either an exercise group or a usual care ( control) group. Women allocated to the exercise group will perform exercises daily, and will be supervised once a week for 8 weeks. At the end of the 8 weeks, women will be given a home-based training program to continue indefinitely. Women in the usual care group will receive the same care as is now typically provided, i.e. a visit by the physiotherapist and occupational therapist while an inpatient, and receipt of pamphlets. All subjects will be assessed at baseline, 8 weeks, and 6 months later. The primary measure is arm symptoms, derived from a breast cancer specific questionnaire (BR23). In addition, range of motion, strength, swelling, pain and quality of life will be assessed. Discussion: This study will determine whether exercise commencing soon after surgery can prevent secondary problems associated with treatment of breast cancer, and will thus provide the basis for successful rehabilitation and reduction in ongoing problems and health care use. Additionally, it will identify whether strengthening exercises reduce the incidence of arm swelling. Trial Registration: The protocol for this study is registered with the Australian Clinical Trials Registry (ACTRN012606000050550).

A late Pleistocene predator-accumulated avifauna from Kids Cave, West Coast, South Island, New Zealand

A fossil deposit excavated from the floor of Kids Cave, West Coast, South Island, New Zealand, is interpreted as having been primarily accumulated by New Zealand falcon Falco novaeseelandiae, with some contribution by Haast's eagle Harpagornis moorei. The fauna is rich: 3699 bones represented 41 bird species, two frog species, unspecified geckoes and skinks, and one bat species. Fossil deposition was mainly within the Last Glacial Maximum from about 22,000 cal yr bp to about 15,000 cal yr bp, with a marked change in sediment characteristics at the onset of the LGM's coldest period. Chronological control is given by three Uranium-series dates for a speleothem and radiocarbon AMS dating of four avian eggshell samples and one bone. The fauna is the first extensive predator accumulation of LGM age described from the West Coast of the South Island, and it indicates a palaeoenvironment of a mosaic of shrublands with forest patches. The onset of the coldest part of the LGM (Aurora 3 glacial advance, 19,500 - 19,000 cal yrs bp) saw marked climate cooling/drying affecting the site, but the avifauna indicates that although open-country taxa became more common in this period, some forest persisted nearby throughout the remainder of the LGM.

Developing a complex intervention to reduce time to presentation with symptoms of lung cancer

Background - Lung cancer is the commonest cause of cancer in Scotland and is usually advanced at diagnosis. Median time between symptom onset and consultation is 14 weeks, so an intervention to prompt earlier presentation could support earlier diagnosis and enable curative treatment in more cases. Aim - To develop and optimise an intervention to reduce the time between onset and first consultation with symptoms that might indicate lung cancer. Design and setting - Iterative development of complex healthcare intervention according to the MRC Framework conducted in Northeast Scotland. Method - The study produced a complex intervention to promote early presentation of lung cancer symptoms. An expert multidisciplinary group developed the first draft of the intervention based on theory and existing evidence. This was refined following focus groups with health professionals and high-risk patients. Results - First draft intervention components included: information communicated persuasively, demonstrations of early consultation and its benefits, behaviour change techniques, and involvement of spouses/partners. Focus groups identified patient engagement, achieving behavioural change, and conflict at the patient–general practice interface as challenges and measures were incorporated to tackle these. Final intervention delivery included a detailed self-help manual and extended consultation with a trained research nurse at which specific action plans were devised. Conclusion -The study has developed an intervention that appeals to patients and health professionals and has theoretical potential for benefit. Now it requires evaluation.

The Maudsley Early Onset Schizophrenia Study:The effect of age of onset and illness duration on fronto-parietal gray matter

Objective: In Early Onset Schizophrenia (EOS; onset before the 18th birthday) late brain maturational changes may interact with disease mechanisms leading to a wave of back to front structural changes during adolescence. To further explore this effect we examined the relationship between age of onset and duration of illness on brain morphology in adolescents with EOS. Subjects and methods: Structural brain magnetic resonance imaging scans were obtained from 40 adolescents with EOS. We used Voxel Based Morphometry and multiple regressions analyses, implemented in SPM, to examine the relationship between gray matter volume with age of onset and illness duration. Results: Age of onset showed a positive correlation with regional gray matter volume in the right superior parietal lobule (Brodmann Area 7). Duration of illness was inversely related to regional gray matter volume in the left inferior frontal gyrus (BA 11/47). Conclusions: Parietal gray matter loss may contribute to the onset of schizophrenia while orbitofrontal gray matter loss is associated with illness duration. © 2008 Elsevier Masson SAS. All rights reserved.

Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease

Poor maternal nutrition during pregnancy can alter postnatal phenotype and increase susceptibility to adult cardiovascular and metabolic diseases. However, underlying mechanisms are largely unknown. Here, we show that maternal low protein diet (LPD), fed exclusively during mouse preimplantation development, leads to offspring with increased weight from birth, sustained hypertension, and abnormal anxiety-related behavior, especially in females. These adverse outcomes were interrelated with increased perinatal weight being predictive of later adult overweight and hypertension. Embryo transfer experiments revealed that the increase in perinatal weight was induced within blastocysts responding to preimplantation LPD, independent of subsequent maternal environment during later pregnancy. We further identified the embryo-derived visceral yolk sac endoderm (VYSE) as one mediator of this response. VYSE contributes to fetal growth through endocytosis of maternal proteins, mainly via the multiligand megalin (LRP2) receptor and supply of liberated amino acids. Thus, LPD maintained throughout gestation stimulated VYSE nutrient transport capacity and megalin expression in late pregnancy, with enhanced megalin expression evident even when LPD was limited to the preimplantation period. Our results demonstrate that in a nutrient-restricted environment, the preimplantation embryo activates physiological mechanisms of developmental plasticity to stablize conceptus growth and enhance postnatal fitness. However, activation of such responses may also lead to adult excess growth and cardiovascular and behavioral diseases. © 2008 by the Society for the Study of Reproduction, Inc.

Nonparametric versus Parametric Statistical Approaches for Genetic Anticipation: The Pancreatic Cancer Case

2000 Mathematics Subject Classi cation: 62N01, 62N05, 62P10, 92D10, 92D30.

Reduced Androgen Receptor Expression Accelerates the Onset of ERBB2 Induced Breast Tumors in Female Mice

Androgen receptor (AR) is commonly expressed in both the epithelium of normal mammary glands and in breast cancers. AR expression in breast cancers is independent of estrogen receptor alpha (ERα) status and is frequently associated with overexpression of the ERBB2 oncogene. AR signaling effects on breast cancer progression may depend on ERα and ERBB2 status. Up to 30% of human breast cancers are driven by overactive ERBB2 signaling and it is not clear whether AR expression affects any steps of tumor progression in this cohort of patients. To test this, we generated mammary specific Ar depleted mice (MARKO) by combining the floxed allele of Ar with the MMTV-cre transgene on an MMTV-NeuNT background and compared them to littermate MMTV-NeuNT, Arfl/+ control females. Heterozygous MARKO females displayed reduced levels of AR in mammary glands with mosaic AR expression in ductal epithelium. The loss of AR dramatically accelerated the onset of MMTV-NeuNT tumors in female MARKO mice. In this report we show that accelerated MMTV-NeuNT-dependent tumorigenesis is due specifically to the loss of AR, as hormonal levels, estrogen and progesterone receptors expression, and MMTV-NeuNT expression were similar between MARKO and control groups. MMTV-NeuNT induced tumors in both cohorts displayed distinct loss of AR in addition to ERα, PR, and the pioneer factor FOXA1. Erbb3 mRNA levels were significantly elevated in tumors in comparison to normal mammary glands. Thus the loss of AR in mouse mammary epithelium accelerates malignant transformation rather than the rate of tumorigenesis.

Chemical composition of Late Cenozoic volcanic and volcaniclastic deposits from the western Woodlark Basin area, SW Pacific

Tephra fallout layers and volcaniclastic deposits, derived from volcanic sources around and on the Papuan Peninsula, form a substantial part of the Woodlark Basin marine sedimentary succession. Sampling by the Ocean Drilling Program Leg 180 in the western Woodlark Basin provides the opportunity to document the distribution of the volcanically-derived components as well as to evaluate their chronology, chemistry, and isotope compositions in order to gain information on the volcanic sources and original magmatic systems. Glass shards selected from 57 volcanogenic layers within the sampled Pliocene-Pleistocene sedimentary sequence show predominantly rhyolitic compositions, with subordinate basaltic andesites, basaltic trachy-andesites, andesites, trachy-andesites, dacites, and phonolites. It was possible to correlate only a few of the volcanogenic layers between sites using geochemical and age information apparently because of the formation of strongly compartmentalised sedimentary realms on this actively rifting margin. In many cases it was possible to correlate Leg 180 volcanic components with their eruption source areas based on chemical and isotope compositions. Likely sources for a considerable number of the volcanogenic deposits are Moresby and Dawson Strait volcanoes (D'Entrecasteaux Islands region) for high-K calc-alkaline glasses. The Dawson Strait volcanoes appear to represent the source for five peralkaline tephra layers. One basaltic andesitic volcaniclastic layer shows affinities to basaltic andesites from the Woodlark spreading tip and Cheshire Seamount. For other layers, a clear identification of the sources proved impossible, although their isotope and chemical signatures suggest similarities to south-west Pacific subduction volcanism, e.g. New Britain and Tonga- Kermadec island arcs. Volcanic islands in the Trobriand Arc (for example, Woodlark Island Amphlett Islands and/or Egum Atoll) are probable sources for several volcaniclastic layers with ages between 1.5 to 3 Ma. The Lusancay Islands can be excluded as a source for the volcanogenic layers found during Leg 180. Generally, the volcanogenic layers indicate much calc-alkaline rhyolitic volcanism in eastern Papua since 3.8 Ma. Starting at 135 ka, however, peralkaline tephra layers appear. This geochemical change in source characteristics might reflect the onset of a change in geotectonic regime, from crustal subduction to spreading, affecting the D'Entrecasteaux Islands region. Initial 143Nd/144Nd ratios as low as 0.5121 and 0.5127 for two of the tephra layers are interpreted as indicating that D'Entrecasteaux Islands volcanism younger than 2.9 Ma occasionally interacted with the Late Archean basement, possibly reflecting the mobilisation of the deep continental crust during active rift propagation.

Late Pliocene variations of the Mediterranean outflow

Late Pliocene changes in the advection of Mediterranean Outflow Water (MOW) derivates were reconstructed at northeast Atlantic DSDP/ODP sites 548 and 982 and compared to records of WMDW at West Mediterranean Site 978. Neodymium isotope (epsilon-Nd) values more positive than ~10.5/~ 11 reflect diluted MOW derivates that spread almost continuously into the northeast Atlantic from 3.7 to 2.55 Ma, reaching Rockall Plateau Site 982 from 3.63 to 2.75 Ma. From 3.4 to 3.3 Ma average MOW temperature and salinity increased by 2°-4 °C and ~1 psu both at proximal Site 548 and distal Site 982. The rise implies a rise in flow strength, coeval with a long-term rise in both west Mediterranean Sea surface salinity by almost 2 psu and average bottom water salinity (BWS) by ~1 psu, despite inherent uncertainties in BWS estimates. The changes were linked with major Mediterranean aridification and a drop in African monsoon humidity. In contrast to model expectations, the rise in MOW salt discharge after 3.4 Ma did not translate into improved ventilation of North Atlantic Deep Water, since it possibly was too small to significantly influence Atlantic Meridional Overturning Circulation. Right after ~2.95 Ma, with the onset of major Northern Hemisphere Glaciation, long-term average bottom water temperature (BWT) and BWS at Site 548 dropped abruptly by ~5 °C and ~1-2 psu, in contrast to more distal Site 982, where BWT and BWS continued to oscillate at estimates of ~2 °C and 1.5-2.5 psu higher than today until ~2.6 Ma. We relate the small-scale changes both to a reduced MOW flow and to enhanced dilution by warm waters of a strengthened North Atlantic Current temporarily replacing MOW derivates at Rockall Plateau.

A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division.

The roles of long non-coding RNAs (lncRNAs) in regulating cancer and stem cells are being increasingly appreciated. Its diverse mechanisms provide the regulatory network with a bigger repertoire to increase complexity. Here we report a novel LncRNA, Lnc34a, that is enriched in colon cancer stem cells (CCSCs) and initiates asymmetric division by directly targeting the microRNA miR-34a to cause its spatial imbalance. Lnc34a recruits Dnmt3a via PHB2 and HDAC1 to methylate and deacetylate the miR-34a promoter simultaneously, hence epigenetically silencing miR-34a expression independent of its upstream regulator, p53. Lnc34a levels affect CCSC self-renewal and colorectal cancer (CRC) growth in xenograft models. Lnc34a is upregulated in late-stage CRCs, contributing to epigenetic miR-34a silencing and CRC proliferation. The fact that lncRNA targets microRNA highlights the regulatory complexity of non-coding RNAs (ncRNAs), which occupy the bulk of the genome.

Clay-mineral composition and biogenic opal content of Late Neogene to Quaternary sediments of the Antarctic Peninsula region

Clay-mineral composition and biogenic opal content in upper Miocene to Quaternary drift sediments recovered at two Ocean Drilling Program (ODP) sites from the continental rise in the Bellingshausen Sea had been analyzed in order to reconstruct the climatic and glacial history of the Antarctic Peninsula. The clay mineral composition at both sites is dominated by smectite, illite, and chlorite, and alternates between a smectite-enriched and a chlorite-enriched assemblage throughout the last 9.3 my. The spatial distribution of clay minerals in Holocene sediments west of the Antarctic Peninsula facilitates the identification of particular source areas, and thus the reconstruction of transport pathways. The similarity to clay mineral variations reported from upper Quaternary sequences suggests that the short-term clay-mineralogical fluctuations in the ODP cores reflect glacial-interglacial cyclicity. Thus, repeated ice advances and retreats in response to a varying size of the Antarctic Peninsula ice cap are likely to have occurred throughout the late Neogene and Quaternary. The clay minerals in the drift sediments exhibit only slight long-term variations, which are caused by local changes in glacial erosion and in supply of source rocks, rather than by major climatic changes. The opal records at the ODP sites are dominated by long-term variations since the late Miocene. We infer that the opal content in the drift sediments, although it is influenced by dissolution in the water column and the sediment column and by the burial with lithogenic detritus, provides a signal of paleoproductivity. Because the annual sea-ice coverage is regarded as the main factor controlling biological productivity, the opal signal helps to reconstruct paleoceanographic changes in the Bellingshausen Sea. Slightly enhanced opal deposition during the late Miocene indicates slightly warmer climatic conditions in the Antarctic Peninsula area than at present. During the early Pliocene, enhanced opal deposition in the Pacific sector of the Southern Ocean and coinciding high opal concentrations in sedimentary sequences from the Atlantic and Indian sectors document a strong reduction of sea-ice cover and relatively warm climatic conditions. Thereby, the early onset of the Pliocene warmth in the Bellingshausen Sea points to a positive feedback of regional Antarctic climate on the global thermohaline circulation. A decrease of opal deposition between 3.1 and 2.6 Ma likely reflects sea-ice expansion in response to reduced supply of northern-sourced deep-waters to the Southern Ocean, caused by the onset of Northern Hemisphere glaciation. Throughout the Quaternary, a relatively constant level of opal deposition on the Antarctic continental margin indicates relatively stable climatic conditions.

ROLE OF STAT1 AND CXCL10 IN THE TUMOUR IMMUNE MICROENVIRONMENT OF HIGH-GRADE SEROUS OVARIAN CANCER

High-grade serous ovarian cancer (HGSC) is the most prevalent epithelial ovarian cancer characterized by late detection, metastasis and resistance to chemotherapy. Previous studies on the tumour immune microenvironment in HGSC identified STAT1 and CXCL10 as the most differentially expressed genes between treatment naïve chemotherapy resistant and sensitive tumours. Interferon-induced STAT1 is a transcription factor, which induces many genes including tumour suppressor genes and those involved in recruitment of immune cells to the tumour immune microenvironment (TME), including CXCL10. CXCL10 is a chemokine that recruits tumour infiltrating lymphocytes (TILs) and exhibits angiostatic function. The current study was performed to determine the effects of differential STAT1 and CXCL10 expression on HGSC disease progression and TME. STAT1 expression and intratumoural CD8+ T cells were evaluated as prognostic and predictive biomarkers via immunohistochemistry on 734 HGSC tumours accrued from the Terry Fox Research Institute-Canadian Ovarian Experimental Unified Resource. The combined effect of STAT1 expression and CD8+ TIL density was confirmed as prognostic and predictive companion biomarkers in the second independent biomarker validation study. Significant positive correlation between STAT1 expression and intratumoral CD8+ TIL density was observed. The effects of enforced CXCL10 expression on HGSC tumour growth, vasculature and immune tumour microenvironment were studied in the ID8 mouse ovarian cancer cell engraftment in immunocompetent C57BL/6 mice. Significant decrease in tumour progression in mice injected with ID8 CXCL10 overexpressing cells compared to mice injected with ID8 vector control cells was observed. Multiplexed cytokine analysis of ascites showed differential expression of IL-6, VEGF and CXCL9 between the two groups. Endothelial cell marker staining showed differences in tumour vasculature between the two groups. Immune transcriptomic profiling identified distinct expression profiles in genes associated with cytokines, chemokines, interferons, T cell function and apoptosis between the two groups. These findings provide evidence that STAT1 is an independent biomarker and in combination with CD8+ TIL density could be applied as novel immune-based biomarkers in HGSC. These results provide the basis for future studies aimed at understanding mechanisms underlying differential tumour STAT1 and CXCL10 expression and its role in pre-existing tumour immunologic diversity, thus potentially contributing to biomarker guided immune modulatory therapies.

Acceptance of relapse fears in breast cancer patients: effects of an act-based abridged intervention

Objective: Relapse fear is a common psychological scar in cancer survivors. The aim of this study is to assess the effects of an abridged version of Acceptance and Commitment Therapy (ACT) in breast cancer patients.Method: An open trial was developed with 12 non-metastatic breast cancer patients assigned to 2 conditions, ACT and waiting list. Interventions were applied in just one session and focused on the acceptance of relapse fears through a ‘defusion’ exercise. Interference and intensity of fear measured through subjective scales were collected after each intervention and again 3 months later. Distress, hypochondria and ‘anxious preocupation’ were also evaluated through standardized questionnaires.Results: The analysis revealed that ‘defusion’ contributed to decrease the interference of the fear of recurrence, and these changes were maintained three months after intervention in most subjects. 87% of participants showed clinically significant decreases in interference at follow-up sessions whereas no patient in the waiting list showed such changes. Statistical analysis revealed that the changes in interference were significant when comparing pre, post and follow-up treatment, and also when comparing ACT and waiting list groups. Changes in intensity of fear, distress, anxious preoccupation and hypochondria were also observed.Conclusions: Exposure through ‘defusion’ techniques might be considered a useful option for treatment of persistent fears in cancer patients. This study provides evidence for therapies focusing on psychological acceptance in cancer patients through short, simple and feasible therapeutic methods.

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment (Review)

Background

It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non-pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis.
Objectives

To evaluate the cognitive effects, non-cognitive effects, duration and safety of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments).
Search methods

We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015.
Selection criteria

Randomised controlled trials (RCTs) of non-pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult-onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non-melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied.
Data collection and analysis

Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta-analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well-being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes.
Main results

Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer-assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed- and immediate- memory), subjectively reported cognitive function and mental well-being. Compensatory strategy training demonstrated improvements on objectively assessed delayed-, immediate- and verbal-memory, self-reported cognitive function and spiritual quality of life (QoL). The meta-analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well-being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) -0.59 to 0.83; I2= 67%) or two months post-intervention (SMD - 0.21, 95% CI -0.89 to 0.47; I2 = 63%) or on mental well-being two months post-intervention (SMD -0.38, 95% CI -1.10 to 0.34; I2 = 67%). Lower mental well-being immediately post-intervention appeared to be observed in patients who received compensatory strategy training compared to wait-list controls (SMD -0.57, 95% CI -0.98 to -0.16; I2 = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear.
Authors' conclusions

Overall, the, albeit low-quality evidence may be interpreted to suggest that non-pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi-site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer.

A Qualitative Assessment of Breast Cancer Advocates in Bolivia, Colombia, Ecuador and Peru

Thesis (Master's)--University of Washington, 2016-06