Drug delivery, biodistribution and anti-EGFR activity: theragnostic nanoparticles for simultaneous in vivo delivery of tyrosine kinase inhibitors and kinase activity biosensors.

In vivo delivery of small molecule therapeutics to cancer cells, assessment of the selectivity of administration, and measuring the efficacity of the drug in question at the molecule level, are important ongoing challenges in developing new classes of cancer chemotherapeutics. One approach that has the potential to provide targeted delivery, tracking of biodistribution and readout of efficacy, is to use multimodal theragnostic nanoparticles to deliver the small molecule therapeutic. In this paper, we report the development of targeted theragnostic lipid/peptide/DNA lipopolyplexes. These simultaneously deliver an inhibitor of the EGFR tyrosine kinase, and plasmid DNA coding for a Crk-based biosensor, Picchu-X, which when expressed in the target cells can be used to quantify the inhibition of EGFR in vivo in a mouse colorectal cancer xenograft model. Reversible bioconjugation of a known analogue of the tyrosine kinase inhibitor Mo-IPQA to a cationic peptide, and co-formulation with peptides containing both EGFR-binding and cationic sequences, allowed for good levels of inhibitor encapsulation with targeted delivery to LIM1215 colon cancer cells. Furthermore, high levels of expression of the Picchu-X biosensor in the LIM1215 cells in vivo allowed us to demonstrate, using fluorescence lifetime microscopy (FLIM)-based biosensing, that EGFR activity can be successfully suppressed by the tyrosine kinase inhibitor, released from the lipopolyplexes. Finally, we measured the biodistribution of lipopolyplexes containing 125I-labelled inhibitors and were able to demonstrate that the lipopolyplexes gave significantly higher drug delivery to the tumors compared with free drug.

Design, synthesis, and evaluation of peptide-imidazo[1,2-a]pyrazine bioconjugates as potential bivalent inhibitors of the VirB11 ATPase HP0525.

Helicobacter pylori (H. pylori) infections have been implicated in the development of gastric ulcers and various cancers: however, the success of current therapies is compromised by rising antibiotic resistance. The virulence and pathogenicity of H. pylori is mediated by the type IV secretion system (T4SS), a multiprotein macromolecular nanomachine that transfers toxic bacterial factors and plasmid DNA between bacterial cells, thus contributing to the spread of antibiotic resistance. A key component of the T4SS is the VirB11 ATPase HP0525, which is a hexameric protein assembly. We have previously reported the design and synthesis of a series of novel 8-amino imidazo[1,2-a]pyrazine derivatives as inhibitors of HP0525. In order to improve their selectivity, and potentially develop these compounds as tools for probing the assembly of the HP0525 hexamer, we have explored the design and synthesis of potential bivalent inhibitors. We used the structural details of the subunit-subunit interactions within the HP0525 hexamer to design peptide recognition moieties of the subunit interface. Different methods (cross metathesis, click chemistry, and cysteine-malemide) for bioconjugation to selected 8-amino imidazo[1,2-a]pyrazines were explored, as well as peptides spanning larger or smaller regions of the interface. The IC50 values of the resulting linker-8-amino imidazo[1,2-a]pyrazine derivatives, and the bivalent inhibitors, were related to docking studies with the HP0525 crystal structure and to molecular dynamics simulations of the peptide recognition moieties.

Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties.

Coenzyme A (CoA) is a highly selective inhibitor of the mitotic regulatory enzyme Aurora A kinase, with a novel mode of action. Herein we report the design and synthesis of analogues of CoA as inhibitors of Aurora A kinase. We have designed and synthesised modified CoA structures as potential inhibitors, combining dicarbonyl mimics of the pyrophosphate group with a conserved adenosine headgroup and different length pantetheine-based tail groups. An analogue with a -SH group at the end of the pantotheinate tail showed the best IC50, probably due to the formation of a covalent bond with Aurora A kinase Cys290.

Multi-modal imaging probe for assessing the efficiency of stem cell delivery to orthotopic breast tumours.

Stem cells have been utilised as anti-cancer agents due to their ability to home to and integrate within tumours. Methods to augment stem cell homing to tumours are being investigated with the goal of enhancing treatment efficacy. However, it is currently not possible to evaluate both cell localisation and cell viability after engraftment, hindering optimisation of therapy. In this study, luciferase-expressing human adipocyte-derived stem cells (ADSCs) were incubated with Indium-111 radiolabelled iron oxide nanoparticles to produce cells with tri-modal imaging capabilities. ADSCs were administered intravenously (IV) or intracardially (IC) to mice bearing orthotopic breast tumours. Cell fate was monitored using bioluminescence imaging (BLI) as a measure of cell viability, magnetic resonance imaging (MRI) for cell localisation and single photon emission computer tomography (SPECT) for cell quantification. Serial monitoring with multi-modal imaging showed the presence of viable ADSCs within tumours as early as 1-hour post IC injection and the percentage of ADSCs within tumours to be 2-fold higher after IC than IV. Finally, histological analysis was used to validate engraftment of ADSC within tumour tissue. These findings demonstrate that multi-modal imaging can be used to evaluate the efficiency of stem cell delivery to tumours and that IC cell administration is more effective for tumour targeting.

The impact of irritable bowel syndrome on health-related quality of life in women with polycystic ovary syndrome.

BACKGROUND: The objectives of this study were to compare the prevalence and quality of life (QOL) of irritable bowel syndrome (IBS) in women with polycystic ovary syndrome (PCOS) compared with healthy women. METHODS: This was a case-control study of 201 women recruited at an infertility clinic in Iran. The control group were healthy women (n = 100) and the comparison group, women with PCOS (n = 101). Data were collected by clinical Rome III criteria to determine the IBS, Bristol scale for stool consistency and IBS QOL. RESULTS: The reporting of IBS symptoms were higher in PCOS (20.7%) than control group (11%) (P = 0.05). The IBS QOL score in the IBS + PCOS group was lower than other groups (IBS+ non PCOS, non IBS + PCOS, non IBS+ non PCOS; scores in food avoidance and worries about health domains were significant (P < 0.01). CONCLUSIONS: We conclude that having PCOS and an increased level of LH/FSH tends to cause IBS symptoms. IBS + PCOS women experience significant impaired quality of life scores particularly in relation to worries about health and food avoidance. These results offer further insights into IBS in PCOS women and their functional status and wellbeing.

The impact of depression, self-esteem, and body image on sleep quality in patients with PCOS: a cross-sectional study.

BACKGROUND: To date, some factors associated with quality of sleep in patients with PCOS have been identified. Previous studies have mainly focused on limited psychological variables related to sleep disorder without evaluating them in a comprehensive framework. OBJECTIVE: The aim of the present study was to evaluate the impact of predictive factors on the sleep quality of PCOS patients using structural equation modeling (SEM). MATERIAL AND METHODS: The present study is a case control that is done in an infertility clinic in Hormozgan, Iran. The case group (n = 201) consisted of women with PCOS and the control group (n = 199) was healthy women whose partners had male infertility. All the women recruited to the study completed the Hospital Anxiety and Depression Scale, the Body Image Concern Investigation, the Rosenberg Self-esteem Scale, and the Pittsburgh Sleep Quality Index on attendance at the Hormozgan Infertility Clinic. Direct and indirect relationship between clinical signs, psychological situation, self-esteem, and body image was studied as independent predictors of sleep quality using structural equation modeling. RESULTS: Compared with the control group, there was a lower sleep quality in women with PCOS in all fields, especially subjective sleep quality (P < 0.05), daytime function (P = 0.001), and use of sleep medication (P = 0.003). The strongest effect from a psychological variable on sleep quality was body image which had negative impact on sleep quality of patients with PCOS. CONCLUSION: Our study showed that body image plays an important role in the sleep quality of women with PCOS.

Comparing pregnancy, childbirth, and neonatal outcomes in women with different phenotypes of polycystic ovary syndrome and healthy women: a prospective cohort study.

The aim of this study was to compare pregnancy, childbirth, and neonatal outcomes in women with different phenotypes of polycystic ovary syndrome (PCOS) with healthy women. A prospective cohort study from the beginning to the end of pregnancy for 41 pregnant women with PCOS (case) and 49 healthy pregnant women (control) was completed. Based on the presence or absence of menstrual dysfunction (M), hyperandrogenism (HA), and polycystic ovaries (PCO) on ultrasound, the PCOS (case) group were divided into three phenotypes (HA + PCO (n = 22), M + PCO (n = 9), HA + M+PCO (n = 10). Pre-eclampsia, gestational diabetes, and lower birth weight among newborns were significantly higher in the PCOS case group compared to the control group especially in the phenotype HA + M+PCO (p < .05). High BMI (ß = 2.40; p=.03) was the strongest predictor of pre-eclampsia in patients with PCOS. High androgen levels (free androgen index) (ß = 13.71, 3.02; p < .05), was the strongest predictor of developing diabetes during pregnancy and reduced birth weight baby, respectively.These results suggest that PCOS, particularly in phenotype HA + M+PCO (p < .05), is a risk factor for adverse pregnancy and neonatal outcomes including gestational diabetes, pre-eclampsia, and reduced weight babies.

Near-infrared dual bioluminescence imaging in mouse models of cancer using infraluciferin.

Bioluminescence imaging (BLI) is ubiquitous in scientific research for the sensitive tracking of biological processes in small animal models. However, due to the attenuation of visible light by tissue, and the limited set of near-infrared bioluminescent enzymes, BLI is largely restricted to monitoring single processes in vivo. Here we show, that by combining stabilised colour mutants of firefly luciferase (FLuc) with the luciferin (LH2) analogue infraluciferin (iLH2), near-infrared dual BLI can be achieved in vivo. The X-ray crystal structure of FLuc with a high-energy intermediate analogue, 5'-O-[N-(dehydroinfraluciferyl)sulfamoyl] adenosine (iDLSA) provides insight into the FLuc-iLH2 reaction leading to near-infrared light emission. The spectral characterisation and unmixing validation studies reported here established that iLH2 is superior to LH2 for the spectral unmixing of bioluminescent signals in vivo; which led to this novel near-infrared dual BLI system being applied to monitor both tumour burden and CAR T cell therapy within a systemically induced mouse tumour model.

Pelvic floor dysfunction and polycystic ovary syndrome.

The purpose of this study was to compare the prevalence of pelvic floor dysfunction (PFD) symptoms in patients with and without polycystic ovary syndrome (PCOS) and among different PCOS phenotypes. This was a case-control study. All participants were assessed using ultrasonography to determine the presence or absence of polycystic ovaries (PCO) and allocated to the case or control group (having healthy females whose husbands were diagnosed with male infertility). The case group was then further subdivided into the three phenotypes according to the presence or absence of menstrual dysfunction (M), hyperandrogenism (HA) and PCO on ultrasonography. Pelvic floor dysfunction was assessed by the Pelvic Floor Distress Inventory-20 (PFDI-20). Briefly, the reported pelvic organ prolapse (POP) symptoms were higher in PCOS group (p = 0.05). The mean PFD score in the HA + M + PCO group was higher compared to other phenotypes although the difference did not reach significant level (p > 0.05). However, there was a significant positive correlation between luteinising hormone (LH) level and the POP symptom portion of the PFDI-20 (p < 0.05). The reported POP symptoms were higher in PCOS group especially in HA + M + PCO phenotype. The findings suggest that higher levels of LH might correlate to symptoms of POP.

Exercise: A Path to Wellness During Adjuvant Chemotherapy for Breast Cancer?

BACKGROUND: Breast cancer treatment can represent a threat to a patient's wellness. The role of exercise in perceived wellness in women with breast cancer merits further study. OBJECTIVE: The objective of this study was to describe how exercise is perceived by women to influence their physical and psychosocial wellness at the time they were receiving chemotherapy. METHODS: Five focus group interviews with a total of 27 women with early-stage breast cancer were conducted. Prior to the focus groups, the women had participated in an exercise intervention during chemotherapy treatment. RESULTS: Three themes emerged from the analysis: exercise shapes feelings of psychological wellness; exercise stimulates feelings of physical wellness; and exercise influences social wellness. The women reported feeling stronger in a psychological sense after exercising, that the strength exercise improved their upper-limb functioning, and that engaging in exercise triggered social support and interactions. CONCLUSIONS: Exercise during breast cancer treatment is perceived to enhance the patients' wellness on several dimensions and in particular psychological wellness. Exercise might support the patients' efforts to restore their sense of wellness and enhance their level of daily life functioning. IMPLICATIONS FOR PRACTICE: Cancer nurses should promote exercise as a wellness-fostering intervention during chemotherapy treatment. Focusing on how exercise can contribute to feelings of wellness may help women with breast cancer choose exercise as a health-promoting activity that contributes to their recovery.

Factors perceived to influence exercise adherence in women with breast cancer participating in an exercise programme during adjuvant chemotherapy: a focus group study.

AIMS AND OBJECTIVES: To explore factors influencing exercise adherence among women with breast cancer while following an exercise programme. BACKGROUND: Earlier research shows that women with breast cancer decrease physical activity following the cancer diagnosis and that adhering to exercise interventions can be a challenge. Research is needed to identify motivational factors and barriers for exercise adherence among women during treatment for breast cancer. DESIGN: This was a qualitative study to explore patient's perceptions of the challenges to exercise adherence during a randomised, controlled trial. METHODS: Twenty-seven women with early-stage breast cancer were purposively sampled for focus group interviews during 2011-2012 from their participation in the exercise intervention group during 2010-2012. Five focus groups were performed, and data analysis was completed using the systematic text condensation method. RESULTS: During the focus group study, five main themes were identified, which described factors participants perceived to influence their adherence to exercise during chemotherapy: 'side effects of breast cancer treatment as a barrier to exercise', 'restoring and maintaining normality in daily life motivates exercise', 'other valued activities compete with exercise', 'constructive support enhances exercise' and 'positive beliefs about efficacy and outcomes motivate exercise'. CONCLUSION: Adherence to exercise in women with breast cancer is challenged by internal and external conditions and may be improved by attention to the impact of treatment side effects and by supporting patient self-efficacy towards changing health behaviour. RELEVANCE TO CLINICAL PRACTICE: Nurses should be aware that exercise adherence could be a challenge among women with breast cancer. They should help identify obstacles to exercise for women and ways to overcome them, as well as support them in their beliefs that they are capable of changing their health behaviour.

Cervical screening and the aftermath of childhood sexual abuse: are clinical staff trained to recognise and manage the effect this has on their patients?

AIMS AND OBJECTIVES: To evaluate the training needs and awareness of childhood sexual abuse amongst clinical staff taking cervical screening samples in one inner city primary care trust. BACKGROUND: Studies exploring sexual abuse and nonparticipation in cervical screening have demonstrated that women can experience re-traumatisation if care during examinations is insensitive to their particular needs. DESIGN: This was a mixed methods, service evaluation in three phases. METHODS: A literature review, a questionnaire to cervical screening staff in an inner city primary care trust and a focus group of four staff drawn from questionnaire respondents to explore themes raised in the questionnaire data. RESULTS: Data analysis of both quantitative and qualitative data showed that clinical staff underestimated the frequency of childhood sexual abuse although they were aware of the difficulties and reluctance some women experience undergoing gynaecological examinations. When women did disclose childhood sexual abuse or when staff suspected a history of childhood sexual abuse, staff reported feeling unsure of how they should proceed. There was no support or clinical supervision, and unmet training needs were identified. CONCLUSIONS: Nurses expressed anxiety around the potential of the screening test to cause more harm than good and at their inability to provide more help than listening. Staff wanted support and further training after completing their cervical screening training course to assist in their provision of sensitive care to patients who have experienced childhood sexual abuse. RELEVANCE TO CLINICAL PRACTICE: Whilst our results cannot be generalised to a wider population, they may be meaningful for the community of cervical screening takers. We argue that screening staff require further training and professional support (clinical supervision) to increase their confidence when providing safe and sensitive practice for childhood sexual abuse survivors. If staff feel more confident and competent when responding to disclosure of childhood sexual abuse in screening situations, women who have experienced childhood sexual abuse might participate in the screening programme more readily.

The social construction of cancer chemotherapy toxicity: the case of Taiwan.

BACKGROUND: Chemotherapy toxicity hinders cancer treatment outcomes. Healthcare professionals educated in biomedical-oriented systems tend to label patients who refuse or discontinue chemotherapy as "noncompliant." How diverse discourses in public texts related to chemotherapy toxicity, which may significantly shape patients' actions, has not been formally explored. OBJECTIVE: The aims of this study were to explore the 2 dominant discourses in Taiwan related to chemotherapy toxicity within their sociocultural context and to ascertain how chemotherapy toxicity is constructed in the texts of journals and newspapers. METHODS: Public, medical, and nursing texts about chemotherapy from 1950 to 2010 were collected and analyzed using Foucaultian discourse analytical techniques; juxtaposing dominant and marginalized discourses, we identified cultural themes. RESULTS: In traditional Chinese medicine, toxic chemotherapy drugs are believed to interfere with circulation of energy flow and blood and to disturb the harmony of yin/yang in the body. Findings indicate that biomedical and traditional Chinese medical doctors do not agree about the best management of chemotherapy toxicity. Moreover, lay knowledge and patient voices regarding chemotherapy toxicity are often ignored in medical discourses. CONCLUSIONS: Cultural beliefs and covert power relations between diverse medical traditions shape patients' experiences of chemotherapy toxicity. The preferential use by patients of traditional Chinese medicine over biomedicine to manage chemotherapy toxicity sustains its pivotal role. IMPLICATIONS FOR PRACTICE: The disparity of perceptions between healthcare professionals and patients regarding chemotherapy toxicity needs to be thoroughly assessed. Thus, culturally specific nursing care models may be developed.

Laparoscopic surgery for endometrial cancer: a phenomenological study.

AIM: This paper is a report of a study of women's perspectives on the experience of laparoscopic surgery for endometrial cancer. BACKGROUND: Laparoscopic surgery is increasingly used to treat early endometrial cancer. It is associated with low levels of morbidity and is considered safe as cancer surgery, but research on quality of life and women's experiences is limited. METHOD: Heideggerian hermeneutic phenomenology was used to explore the experiences of 14 women who had undergone the procedure in two English cancer centres between February 2008 and July 2009. In-depth interviews were taped, transcribed and analysed using Colaizzi's framework. FINDINGS: A phenomenological description was produced from five identified themes: having cancer, transfer of responsibility to the surgeon, information and support, independence, and normality. The experience of laparoscopic surgery was overshadowed by the presence of cancer. Fear and lack of knowledge played an important role in entrusting the surgeon with the responsibility for decision-making. Individual, unmet information needs focused on the practicalities of treatment and being in an unfamiliar situation and environment. Loss of control and vulnerability were associated with illness and surgery, but early postoperative mobility and reduced pain, facilitated rapid return to independence and maintained a sense of normality. CONCLUSION: Healthcare professionals should deliver care in early endometrial cancer in a way that recognizes the significance of the cancer diagnosis, the role of the surgeon in decision-making and the need for practical information. Women with endometrial cancer should have access to treatments that reduce dependency and maintain normality.

An exploration of the influences on clinical decision making and the culture of blood transfusion practise in cancer-related anaemia using an ethnographic methodology.

PURPOSE: This study seeks to explore the cultural practises, which shape the culture of transfusion, and to identify the key elements, which influence clinical decision making in blood transfusion in haemato-oncology and lung cancer patients. METHODS: The assessment and decision making processes for blood transfusion were explored using fieldwork observation, six patient and nine clinician interviews based on ethnographic methodology. Data were analysed using thematic analysis. RESULTS: First, the findings suggested that despite anaemia and transfusion being ubiquitous in this cancer setting, it sits low in the hierarchy of clinical concerns (The unimportance of anaemia). Second, there is a great deal of uncertainty surrounding the diagnosis and management of this clinical problem; but this uncertainty was acknowledged by both patients and clinicians (Acknowledging uncertainty). Third, clinicians and to some extent patients, are socialised into the practise of the sub-discipline (Socialisation in practise). Fourth, the haemoglobin level was used as a distinct fragment of information on which to assess for the presence of anaemia and base the decision to treat with blood transfusion (Disaggregation of the body). CONCLUSION: The management of anaemia is not a priority in this setting; however, by understanding the complexity of factors for variation in practise in the clinical context, new models for learning transfusion skills can be developed. Furthermore, different collaborative groups could be organised to develop optimal transfusion practises, for example to include nurse-prescribing of blood components or by developing patient-centred decision making systems.

An evaluation of dependency assessment: experiences of staff, patients and carers in a UK hospice.

AIM: To evaluate the experiences of health-care professionals, service users and carers of service users from a UK hospice in relation to dependency assessment. DESIGN: Qualitative evaluation. SAMPLE: Purposive, convenience sample of hospice staff, patients receiving hospice services and carers of patients receiving hospice services. METHODS: Focus group interviews with hospice staff and carers of hospice service users. Individual interviews with patients. RESULTS: Staff felt the tool used produced inaccurate results, in part because of omissions in content. They did not perceive the data produced affected working practice, e.g. staffing levels. Patients described unobtrusive assessment and stated their needs were met. Carers reported feelings of isolation. They also described differing information and support needs from the patients. CONCLUSION: Further research is required to improve the validity of dependency data collection. Further investigation of carer assessment is also justified.