A compendium and functional characterization of mammalian genes involved in adaptation to Arctic or Antarctic environments

Many mammals are well adapted to surviving in extremely cold environments. These species have likely accumulated genetic changes that help them efficiently cope with low temperatures. It is not known whether the same genes related to cold adaptation in one species would be under selection in another species. The aims of this study therefore were: to create a compendium of mammalian genes related to adaptations to a low temperature environment; to identify genes related to cold tolerance that have been subjected to independent positive selection in several species; to determine promising candidate genes/pathways/organs for further empirical research on cold adaptation in mammals

Medical student teaching in the UK: how well are newly qualified doctors prepared for their role caring for patients with cancer in hospital?

A number of studies have identified problems with undergraduate oncology teaching. We have investigated how well prepared newly qualified doctors (first foundation year, or FY1 doctors) are for treating patients with cancer. Twenty-five FY1 doctors and 15 senior doctors participated in interviews. We turned the emergent themes into a questionnaire for all 5143 UK FY1 doctors in 2005. The response rate was 43% (2062 responses). Sixty-one percent of FY1 doctors had received oncology teaching at medical school, but 31% recalled seeing fewer than 10 patients with cancer. Forty percent of FY1 doctors felt prepared for looking after patients with cancer. Sixty-five percent felt prepared for diagnosing cancer, 15% felt they knew enough about chemotherapy and radiotherapy, and 11% felt prepared for dealing with oncological emergencies. Respondents believed medical students should learn about symptom control (71%) and communication skills (41%). Respondents who had received oncology teaching were more likely to feel prepared for looking after patients with cancer (OR 1.52; 95% CI 1.14–2.04). Preparedness also correlated with exposure to patients with cancer (OR 1.48; 95% CI 1.22–1.79). We have found worryingly low levels of exposure of medical students to patients with cancer. First foundation year doctors lack knowledge about cancer care and symptom control. Oncologists should maintain involvement in undergraduate teaching, and encourage greater involvement of patients in this teaching

Primary ovarian cancer chemotherapy: current standards of care

Chemotherapy has been regarded as standard therapy for the majority of women with advanced epithelial ovarian cancer for several decades, with this role filled largely by the alkylating agents — used as monotherapy — until the mid-1980s. The activity of cisplatin in this disorder was established during the 1970s, and combinations of cisplatin and an alkylating agent were widely used during the late 1980s. However, further research prompted by continuing concerns over poor survival and tolerability led to the adoption of paclitaxel in combination with either cisplatin or carboplatin as first-line therapy in ovarian cancer during the 1990s. Most recent research has focused on further optimisation of these regimens to maximise clinical benefit while minimising toxicity, and investigations into alternative taxanes (e.g. docetaxel), other novel agents and new treatment schedules are ongoing

Self-care coping strategies in people with diabetes: a qualitative exploratory study

<p>Abstract</p> <p>Background</p> <p>The management of diabetes self-care is largely the responsibility of the patient. With more emphasis on the prevention of complications, adherence to diabetes self-care regimens can be difficult. Diabetes self-care requires the patient to make many dietary and lifestyle changes. This study will explore patient perceptions of diabetes self-care, with particular reference to the burden of self-care and coping strategies among patients.</p> <p>Methods</p> <p>A maximum variation sample of 17 patients was selected from GP practices and diabetes clinics in Ireland to include patients with types 1 and 2 diabetes, various self-care regimens, and a range of diabetes complications. Data were collected by in-depth interviews; which were tape-recorded and transcribed. The transcripts were analysed using open and axial coding procedures to identify main categories, and were reviewed by an independent corroborator. Discussion of the results is made in the theoretical context of the health belief, health value, self-efficacy, and locus of control frameworks.</p> <p>Results</p> <p>Patients' perceptions of their self-care varied on a spectrum, displaying differences in self-care responsibilities such as competence with dietary planning, testing blood sugar and regular exercise. Three patient types could be distinguished, which were labeled: "proactive manager," a patient who independently monitors blood glucose and adjusts his/her self-care regime to maintain metabolic control; "passive follower," a patient who follows his/her prescribed self-care regime, but does not react autonomously to changes in metabolic control; and "nonconformist," a patient who does not follow most of his/her prescribed self-care regimen.</p> <p>Conclusion</p> <p>Patients have different diabetes self-care coping strategies which are influenced by their self-care health value and consequently may affect their diet and exercise choices, frequency of blood glucose monitoring, and compliance with prescribed medication regimens. Particular attention should be paid to the patient's self-care coping strategy, and self-care protocols should be tailored to complement the different patient types.</p

Assessing the information desire of patients with advanced cancer by providing information with a decision aid, which is evaluated in a randomized trial: a study protocol

Contains fulltext : 95653.pdf (publisher's version ) (Open Access)BACKGROUND: There is a continuing debate on the desirability of informing patients with cancer and thereby involving them in treatment decisions. On the one hand, information uptake may be hampered, and additional stress could be inflicted by involving these patients. On the other hand, even patients with advanced cancer desire information on risks and prognosis. To settle the debate, a decision aid will be developed and presented to patients with advanced disease at the point of decision making. The aid is used to assess the amount of information desired. Factors related to information desire are explored, as well as the ability of the medical oncologist to judge the patient's information desire. The effects of the information on patient well-being are assessed by comparing the decision aid group with a usual care group. METHODS/DESIGN: This study is a randomized controlled trial of patients with advanced colorectal, breast, or ovarian cancer who have started treatment with first-line palliative chemotherapy. The trial will consist of 100 patients in the decision aid group and 70 patients in the usual care group. To collect complete data of 170 patients, 246 patients will be approached for the study. Patients will complete a baseline questionnaire on sociodemographic data, well-being measures, and psychological measures, believed to predict information desire. The medical oncologist will judge the patient's information desire. After disease progression is diagnosed, the medical oncologist offers the choice between second-line palliative chemotherapy plus best supportive care (BSC) and BSC alone. Randomization will take place to determine whether patients will receive usual care (n = 70) or usual care and the decision aid (n = 100). The aid offers information about the potential risks and benefits of both treatment options, in terms of adverse events, tumour response, and survival. Patients decide for each item whether they desire the information or not. Two follow-up questionnaires will evaluate the effect of the decision aid. DISCUSSION: This study attempts to settle the debate on the desirability of informing patients with cancer. In contrast to several earlier studies, we will actually deliver information on treatment options to patients at the point of decision making

Disclosure of cancer diagnosis and prognosis: a survey of the general public's attitudes toward doctors and family holding discretionary powers

BACKGROUND: This study aimed to ask a sample of the general population about their preferences regarding doctors holding discretionary powers in relation to disclosing cancer diagnosis and prognosis. METHODS: The researchers mailed 443 questionnaires to registered voters in a ward of Tokyo which had a socio-demographic profile similar to greater Tokyo's average and received 246 responses (response rate 55.5%). We describe and analysed respondents' attitudes toward doctors and family members holding discretionary powers in relation to cancer diagnoses disclose. RESULTS: Amongst respondents who wanted full disclosure about the diagnosis without delay, 117 (69.6 %) respondents agreed to follow the doctor's discretion, whilst 111 (66.1 %) respondents agreed to follow the family member's decision. For respondents who preferred to have the diagnosis and prognosis withheld, 59 (26.5 %) agreed to follow the doctor's decision, and 79 (35.3 %) of respondents agreed with following family member's wishes. CONCLUSIONS: The greater proportion of respondents wants or permits disclosure of cancer diagnosis and prognosis. In patients who reveal negative attitudes toward being given a cancer disclosure directly, alternative options exist such as telling the family ahead of the patient or having a discussion of the cancer diagnosis with the patient together with the family. It is recommended that health professionals become more aware about the need to provide patients with their cancer diagnosis and prognosis in a variety of ways

Integration of modeling and simulation into hospital-based decision support systems guiding pediatric pharmacotherapy

<p>Abstract</p> <p>Background</p> <p>Decision analysis in hospital-based settings is becoming more common place. The application of modeling and simulation approaches has likewise become more prevalent in order to support decision analytics. With respect to clinical decision making at the level of the patient, modeling and simulation approaches have been used to study and forecast treatment options, examine and rate caregiver performance and assign resources (staffing, beds, patient throughput). There us a great need to facilitate pharmacotherapeutic decision making in pediatrics given the often limited data available to guide dosing and manage patient response. We have employed nonlinear mixed effect models and Bayesian forecasting algorithms coupled with data summary and visualization tools to create drug-specific decision support systems that utilize individualized patient data from our electronic medical records systems.</p> <p>Methods</p> <p>Pharmacokinetic and pharmacodynamic nonlinear mixed-effect models of specific drugs are generated based on historical data in relevant pediatric populations or from adults when no pediatric data is available. These models are re-executed with individual patient data allowing for patient-specific guidance via a Bayesian forecasting approach. The models are called and executed in an interactive manner through our web-based dashboard environment which interfaces to the hospital's electronic medical records system.</p> <p>Results</p> <p>The methotrexate dashboard utilizes a two-compartment, population-based, PK mixed-effect model to project patient response to specific dosing events. Projected plasma concentrations are viewable against protocol-specific nomograms to provide dosing guidance for potential rescue therapy with leucovorin. These data are also viewable against common biomarkers used to assess patient safety (e.g., vital signs and plasma creatinine levels). As additional data become available via therapeutic drug monitoring, the model is re-executed and projections are revised.</p> <p>Conclusion</p> <p>The management of pediatric pharmacotherapy can be greatly enhanced via the immediate feedback provided by decision analytics which incorporate the current, best-available knowledge pertaining to dose-exposure and exposure-response relationships, especially for narrow therapeutic agents that are difficult to manage.</p

High mutation rates explain low population genetic divergence at copy-number-variable loci in Homo sapiens

Copy-number-variable (CNV) loci differ from single nucleotide polymorphic (SNP) sites in size, mutation rate, and mechanisms of maintenance in natural populations. It is therefore hypothesized that population genetic divergence at CNV loci will differ from that found at SNP sites. Here, we test this hypothesis by analysing 856 CNV loci from the genomes of 1184 healthy individuals from 11 HapMap populations with a wide range of ancestry. The results show that population genetic divergence at the CNV loci is generally more than three times lower than at genome-wide SNP sites. Populations generally exhibit very small genetic divergence (G(st) = 0.05 ± 0.049). The smallest divergence is among African populations (G(st) = 0.0081 ± 0.0025), with increased divergence among non-African populations (G(st) = 0.0217 ± 0.0109) and then among African and non-African populations (G(st) = 0.0324 ± 0.0064). Genetic diversity is high in African populations (~0.13), low in Asian populations (~0.11), and intermediate in the remaining 11 populations. Few significant linkage disequilibria (LDs) occur between the genome-wide CNV loci. Patterns of gametic and zygotic LDs indicate the absence of epistasis among CNV loci. Mutation rate is about twice as large as the migration rate in the non-African populations, suggesting that the high mutation rates play dominant roles in producing the low population genetic divergence at CNV loci

Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious?

Neoadjuvant chemotherapy (NACT) is a term originally used to describe the administration of chemotherapy preoperatively before surgery. The original rationale for administering NACT or so-called induction chemotherapy to shrink or downstage a locally advanced tumour, and thereby facilitate more effective local treatment with surgery or radiotherapy, has been extended with the introduction of more effective combinations of chemotherapy to include reducing the risks of metastatic disease. It seems logical that survival could be lengthened, or organ preservation rates increased in resectable tumours by NACT. In rectal cancer NACT is being increasingly used in locally advanced and nonmetastatic unresectable tumours. Randomised studies in advanced colorectal cancer show high response rates to combination cytotoxic therapy. This evidence of efficacy coupled with the introduction of novel molecular targeted therapies (such as Bevacizumab and Cetuximab), and long waiting times for radiotherapy have rekindled an interest in delivering NACT in locally advanced rectal cancer. In contrast, this enthusiasm is currently waning in other sites such as head and neck and nasopharynx cancer where traditionally NACT has been used. So, is NACT in rectal cancer a real advance or just history repeating itself? In this review, we aimed to explore the advantages and disadvantages of the separate approaches of neoadjuvant, concurrent and consolidation chemotherapy in locally advanced rectal cancer, drawing on theoretical principles, preclinical studies and clinical experience both in rectal cancer and other disease sites. Neoadjuvant chemotherapy may improve outcome in terms of disease-free or overall survival in selected groups in some disease sites, but this strategy has not been shown to be associated with better outcomes than postoperative adjuvant chemotherapy. In particular, there is insufficient data in rectal cancer. The evidence for benefit is strongest when NACT is administered before surgical resection. In contrast, the data in favour of NACT before radiation or chemoradiation (CRT) is inconclusive, despite the suggestion that response to induction chemotherapy can predict response to subsequent radiotherapy. The observation that spectacular responses to chemotherapy before radical radiotherapy did not result in improved survival, was noted 25 years ago. However, multiple trials in head and neck cancer, nasopharyngeal cancer, non-small-cell lung cancer, small-cell lung cancer and cervical cancer do not support the routine use of NACT either as an alternative, or as additional benefit to CRT. The addition of NACT does not appear to enhance local control over concurrent CRT or radiotherapy alone. Neoadjuvant chemotherapy before CRT or radiation should be used with caution, and only in the context of clinical trials. The evidence base suggests that concurrent CRT with early positioning of radiotherapy appears the best option for patients with locally advanced rectal cancer and in all disease sites where radiation is the primary local therapy

Bone Marrow Stromal Cells Modulate Mouse ENT1 Activity and Protect Leukemia Cells from Cytarabine Induced Apoptosis

BACKGROUND: Despite a high response rate to chemotherapy, the majority of patients with acute myeloid leukemia (AML) are destined to relapse due to residual disease in the bone marrow (BM). The tumor microenvironment is increasingly being recognized as a critical factor in mediating cancer cell survival and drug resistance. In this study, we propose to identify mechanisms involved in the chemoprotection conferred by the BM stroma to leukemia cells. METHODS: Using a leukemia mouse model and a human leukemia cell line, we studied the interaction of leukemia cells with the BM microenvironment. We evaluated in vivo and in vitro leukemia cell chemoprotection to different cytotoxic agents mediated by the BM stroma. Leukemia cell apoptosis was assessed by flow cytometry and western blotting. The activity of the equilibrative nucleoside transporter 1 (ENT1), responsible for cytarabine cell incorporation, was investigated by measuring transport and intracellular accumulation of (3)H-adenosine. RESULTS: Leukemia cell mobilization from the bone marrow into peripheral blood in vivo using a CXCR4 inhibitor induced chemo-sensitization of leukemia cells to cytarabine, which translated into a prolonged survival advantage in our mouse leukemia model. In vitro, the BM stromal cells secreted a soluble factor that mediated significant chemoprotection to leukemia cells from cytarabine induced apoptosis. Furthermore, the BM stromal cell supernatant induced a 50% reduction of the ENT1 activity in leukemia cells, reducing the incorporation of cytarabine. No protection was observed when radiation or other cytotoxic agents such as etoposide, cisplatin and 5-fluorouracil were used. CONCLUSION: The BM stroma secretes a soluble factor that significantly protects leukemia cells from cytarabine-induced apoptosis and blocks ENT1 activity. Strategies that modify the chemo-protective effects mediated by the BM microenvironment may enhance the benefit of conventional chemotherapy for patients with AML