bluuebunny/crossref_metadata_2025 huggingface dataset:
PALLIATIVE CARE BY THE COMMUNITY – MAXIMISING THE IMPACT OF VOLUNTEERS IN HOME CARE SERVICES
Authors: Hill M , Ockenden N , Morris S , Payne S
Published: February 2014

Introduction

The Volunteer Management in Palliative Care (VMPC) survey (67% response rate) revealed that 32% of hospices that involve volunteers do so within their home care service. This is considerably lower than in day care (90%), bereavement (79%) or inpatient care (74%). Moreover, community volunteering is considerably more developed in some other countries.

Aim(s) and method(s)

The paper aims to assess the impact of volunteering within community care and explore challenges and opportunities for expanding its role by drawing on data from the VMPC project which engaged 205 staff, volunteers, patients and relatives in primarily face-to-face individual interviews across eleven in-depth organisational case studies.

Results

As well as their time, the evidence shows that volunteers make substantial distinctive contributions to community care outcomes underpinned by their unique relationship with patients, relatives and the community. Substantial good practice learning included the need for specialist training and induction sessions; more flexible and comprehensive remote and contact management mechanisms to ensure volunteers are emotionally and practically supported; developing clear guidelines for volunteers, staff and patients to effectively manage boundary and attachment issues; and a more sophisticated understanding of risk. The lack of involvement of volunteers in community care is often driven by historical organisational conceptions of appropriate roles and fears of job substitution. Where volunteers have been successfully introduced these concerns have been sensitively confronted through engaging community care staff in role development and organisational change.

Conclusion(s)

There is considerable potential for increasing the role of volunteers in emotional, social and practical support roles in community care.
‘RING US IF YOU NEED US’: THE IMPORTANCE OF REASSURANCE TO FAMILY CAREGIVERS PROVIDING HOME-BASED END-OF-LIFE CARE
Authors: Dunn L , Byrne P , Lloyd-Williams M
Published: February 2014

Introduction

This research explores the experience of uncertainty and reassurance from the perspective of family carers.

Aim(s) and method(s)

To explore the phenomenological experience of providing end of life care for a family member with a life-limiting illness, at home. Fifty-one narrative interviews were conducted with bereaved family carers. Data was analysed using thematic structural analysis (Robichaux 2003; Riessman 2008).

Results

Uncertainty emerged as a key feature of the caregiving experience. Many carers were invited by community health care professionals to ‘ring us if you need us’. However, carers explained that they were reluctant to telephone about non-emergency issues. In some cases, this led to feelings of isolation, uncertainty about pain and symptom management and uncertainty as their relative approached death. By contrast, carers explained that they would feel more reassured if they had received additional contact from health and social care professionals to ‘check up’ on them and ‘see how they were doing’. Additionally, scheduled visits from community and district nurses were a great source of reassurance to many carers. Feelings of uncertainty were greatest in the days and hours approaching their relative's death.

Conclusion(s)

Health care professionals working in the community may have limited awareness of the important impact that their presence has in reassuring family caregivers and improving their confidence in caring. In addition, increased informal contact made by health and social care professionals may reduce carers' uncertainty in providing end-of-life care at home.
SUPPORTING PATIENTS TO ACHIEVE THEIR PREFERRED PLACE OF CARE AT THE END OF LIFE
Authors: Griggs C , Gleeson K
Published: February 2014

Introduction

Hospital deaths make up more than half of all deaths in England and Wales, despite the finding that the vast majority of patients express a preference for home death. The Royal Liverpool and Broadgreen University Hospitals Trust and Marie Curie Cancer Care have developed the role of Case Manager – End of Life Care (CM-EOLC) and created a Supported Discharge Service (SDS) to facilitate and support urgent and rapid discharges to home of deteriorating and dying patients.

Aim(s) and method(s)

To illustrate the impact of the role of CM-EOLC in RLBUHT and of SDS in enabling individuals to meet and remain in their PPC at the end of life.

Results

Pertinent information, including outcome data, is collected routinely for each patient referred to the service. Data between December 2012 to November 2013 was analysed and illustrates a 37% increase on the previous year in successful rapid discharges home to die. Forty-seven patients who were deteriorating quickly were also urgently discharged home. Forty-four patients received additional care from SDS enabling them to die at home. There were no readmissions to hospital for this cohort of patients.

Conclusion(s)

Through partnership working, the development of innovative new services and improving individual case management, patients who are nearing the end of their lives are being identified earlier. Patients are being discharged to their preferred place of care with additional support and care in the home environment enabling them to remain there for their last hours/days.
DO INDIVIDUALS WITH SEVERE MENTAL ILLNESS RECEIVE EQUITABLE CARE IN THE LAST YEAR OF LIFE?
Authors: Gola A
Published: February 2014

Introduction

Do individuals with severe mental illness receive equitable care in the last year of life? People living with severe mental illness (SMI) have higher morbidity rates compared to general population. This is partly explained by lifestyle factors; however there is emerging evidence that the increased prevalence rates of cancer and infectious diseases are also attributable to the lack of appropriate healthcare provision, including in the last year of life. For these patients, tasks to quantify the degree of under-use of medical care, as well as to draw health economic implications have been challenging for researchers.

Aim(s) and method(s)

To estimate whether people with SMI in the UK have poorer access to healthcare services in the last year of life. The analysis utilises the Heath Improvement Network, a UK primary care database with over 450 General practices. In the cohort study, we identify patients with and without SMI deceased due to cancers and infectious diseases and estimate the reduced likelihood of receiving adequate medical attention for patients with SMI, adjusting for various factors such as race and deprivation area. Patient, provider, and system-level factors are integrated to consider health outcomes in people with SMI.

Results

Compared to demographically similar general practice patients, people with SMI diagnosis have fewer recorded screening tests, lifestyle counselling and referrals for treatments. Furthermore, they frequently receive inadequate advice from healthcare professionals regarding modifiable risk factors. Disparities are also seen after medical hospitalizations.

Conclusion(s)

Fragmentation of healthcare produces poor outcomes for individuals with SMI. Health economic, clinical and research implications are drawn.
WHAT DO WE KNOW ABOUT THE END-OF-LIFE DECISION-MAKING EXPERIENCES OF PATIENTS WITH ADVANCED LUNG CANCER?
Authors: Roulston A
Published: February 2014

Introduction

Lung cancer is an unforgiving illness with most patients being diagnosed in the advanced stages of disease. How much do we really know about the range of end-of-life care decisions that patients encounter?

Aim(s) and method(s)

To explore end-of-life care decision-making by patients diagnosed with advanced lung cancer known to a community palliative care team in Northern Ireland.

Qualitative data were obtained during two individual interviews (mean duration 48 minutes) with 12 community patients diagnosed with advanced lung cancer. Llewellyn-Thomas' decision-making framework informed data collection and data were analysed using Interpretative Phenomenological Analysis and narrative analysis.

Results

Emergent themes mirrored an illness journey. (1) Beginnings: There's something not right, bad news, emotional responses and no way back; (2) Middles: Treatment decision-making, impact of treatment on quality of life and impact of illness on self, social relations and engagement with the physical world; (3) Endings: Preferred priorities for care, a good death, legacy, coping patterns and funeral wishes. Three cross-cutting themes were common: preciousness of time; importance of skilful communication, and maintenance of hope.

Conclusion(s)

This study offers insight into patients' experiences of living with advanced lung cancer, their daily navigation of decisions that surpassed our assumptions, and patient expectations of professionals. Despite knowing their inevitable fate, findings highlighted the importance of maintaining hope and exploring futures.
10 YEARS ON - HAS THE GOLD STANDARDS FRAMEWORK (GSF) INFLUENCED NURSING CARE OF PATIENTS WITH END OF LIFE CARE NEEDS IN THE COMMUNITY?
Authors: Meehan HC , Munday D
Published: February 2014

Introduction

District nurses (DN) play a key role in supporting patients with palliative care needs in the community. Gold Standards Framework (GSF) is a service improvement tool that was developed over 10 years ago for primary care, to enable GP practices to proactively support patients with palliative care needs.

Aim(s) and method(s)

This study explores the experiences of DNs working with practices that have implemented GSF and investigates their perceptions of how GSF has influenced provision of nursing care to patients with palliative care needs in the community. A qualitative methodology was used. Semi-structured interviews were undertaken with 8 DNs from one Trust. This Trust provided community nursing services to practices that had been early adopters of GSF.

Results

The results identified a number of benefits and challenges for DNs in working with GSF practices. The benefits included early referral of patients to district nursing, proactive provision of supportive nursing care, team working, improved communication and improved recognition of the DN role in end of life care. Challenges included supporting practices with varying levels of GSF adoption, working with variability of engagement by GPs within a practice, supporting more patients with palliative care needs in the community, lack of continuity when working with external providers.

Conclusion(s)

There was evidence that GSF had influenced DN roles. There was evidence of an emerging advocacy role for GSF, the development of a nursing model using the principles of GSF to provide proactive nursing care to patients and empowerment of DNs to embed and sustain GSF within a local area.
HELPING PEOPLE WITH VERY SEVERE COPD: FEASIBILITY STUDY OF A NOVEL COMMUNITY-BASED HOLISTIC INTERVENTION
Authors: Kendall M , Buckingham S , Ferguson S , Sheikh A , Murray SA , Boyd K , Pinnock H , MacNee W , Worth A , White P
Published: February 2014

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a major cause of death worldwide. Research shows people with severe COPD have unmet needs, and the traditional cancer palliative care model is not appropriate.

Aim(s) and method(s)

To pilot and evaluate HELP-COPD - a community-based proactive holistic assessment of needs. The intervention comprised a home visit by a respiratory nurse, following discharge from hospital after an exacerbation, to discuss social/psychological/spiritual/physical needs, provide advice/information and make further referrals. A HELP_COPD Action Plan was completed and given to the patient and general practitioner. Follow-up included three phone calls over six months.

Qualitative evaluation of HELP-COPD comprised interviews with participating patients, lay-carers and health professionals, alongside documentary analysis of completed action plans. Interviews were recorded, transcribed and entered into NVivo for thematic analysis.

Results

23 patients, from two hospitals, completed action plans. 31 interviews were completed. Patients were generally positive, openly discussing concerns and coping strategies in all domains. Professionals considered the intervention feasible and potentially valuable. Actions included facilitating discussion with their GP on palliative use of opiates, reinforcing referral to pulmonary rehabilitation and providing details of local voluntary services. However, fewer unmet needs were identified than expected, and some patients declined proffered services/information. Participants highlighted overlap with discharge planning and case management provided by community teams.

Conclusion(s)

HELP COPD was feasible and generally welcomed by patients. Fewer actions were identified than anticipated due to a combination of inappropriate timing, reluctance to accept social services, duplication by existing services and long-term adaptation reducing recognition of need and of the seriousness of the condition.
THE EVIDENCE BASE OF QUALITY STATEMENTS ON ADVANCED DEMENTIA: A SYSTEMATIC REVIEW
Authors: Candy B , Elliott M , Jones L , Sampson E
Published: February 2014

Introduction

The National Institute for Health and Care Excellence (NICE) clinical guideline on dementia highlighted how people with dementia may not be able to access good quality palliative care (NICE 2007). Subsequently, the NICE Quality Standards Programme for Dementia provided quality statements for commissioners to guide the care of those with advanced dementia. However, the literature review supporting these statements identified little empirical evidence behind these. Since then new research on end of life care in dementia has been published.

Aim(s) and method(s)

To undertake a systematic review of the current evidence relevant to three NICE quality statements on care of people with advanced dementia: (1) advanced care planning; (2) assessment of palliative care needs; (3) a named care co-ordinator. We are searching four databases including EMBASE and other sources including expert consultation. We seek high quality quantitative and qualitative research. For the quantitative evidence, in our summation we are prioritising studies of comparative design. If there are randomised trials we will use as appropriate meta-analysis to combine the trials. For the qualitative evidence we are using thematic synthesis approaches as appropriate. All key stages are undertaken in duplicate.

Results

We will have completed our review by March 2014 and will summarise how well each quality statement is supported by evidence.

Conclusion(s)

This review will identify how robust these commissioning statements are with respect to the evidence that underlies them. We will be able to make recommendations on how the quality standards may be improved and made more effective in day to day practice.
Remote and rapid pathological diagnosis in a resource challenged unit
Authors: Carey P , Fudzulani R , Scholfield D , Chagaluka G , Tomoka T , Liombe G , Banda K , Wadehra V , Samarasinghe S , Molyneux E M , Bailey S
Published: February 2014

Malawi is one of the world's poorest countries, but despite this, has a dedicated paediatric oncology service. The service has been hampered by the inability to make a timely cytological diagnosis in the majority of patients. A telemedicine programme was commenced to help overcome this problem, and the results for the first 197 consecutive patients are described. The results are compared with the local reports where available. Most samples were fine needle aspirates (104/197–53%), but others included bone marrow aspirates, peripheral blood films and other fluid collections. A diagnosis was arrived at in 52% of the samples; there were 46 discordant results, 38 were when one or other of the local or distant teams were unable to make a diagnosis, and only 8 where the diagnoses of the 2 teams differed. Diagnoses were made and reports were compiled by the ‘distant’ team within 24 h and sent to the centre in Malawi. This simple telepathology initiative has had a positive impact on clinical management, and could be used in other less resourced centres twinned with better resourced ones.
Introduction of a manual vacuum aspiration service: a model of service within a NHS Sexual Health Service
Authors: Pillai Mary , Welsh Val , Sedgeman Kirsty , Gazet A Caroline , Staddon Juliet , Carter Helen
Published: February 2014

Background

We assessed the applicability, acceptability and cost implications of introducing the manual vacuum aspiration (MVA) technique with local anaesthesia for fully conscious first-trimester termination of pregnancy within our service and for our population.

Setting

The outpatient setting of a Pregnancy Advisory Service within a NHS Sexual Health Service.

Methods

Self-administered misoprostol and diclofenac, extra-amniotic local anaesthetic gel and paracervical mepivicaine prior to MVA. Routinely collected data were used to provide information on uptake, demographic details, timing, pain score, complications, contraceptive uptake, and economic implications for our service.

Results

MVA was chosen by 305/1681 potentially eligible women. Forty percent had the procedure on the day they attended for assessment. Seventy-nine percent gave a pain score of 3 or less out of 10. Complications occurred in six cases (2%); these included cervical rigidity, a false passage, retained products of conception, bleeding (more than 200 ml) and one allergic reaction. Eighty percent of women chose to commence a long-acting reversible contraception (LARC) method at the time of MVA. Operating theatre utilisation was reduced by one termination list per week and cost savings of around £60 000 per annum were realised.

Conclusions

The technique for fully conscious MVA was very suitable for our outpatient setting. It was associated with very low levels of pain and bleeding. The uptake of LARC was high, and particularly the ability to provide intrauterine contraception at MVA was associated with a very high uptake.
Proximal to distal approach in the treatment of tandem occlusions causing an acute stroke
Authors: Spiotta Alejandro M , Lena Jonathan , Vargas Jan , Hawk Harris , Turner Raymond D , Chaudry M Imran , Turk Aquilla S
Published: February 2014

Introduction

A tandem occlusion is a rare presentation of acute stroke that involves an occlusion of the internal carotid artery at the bifurcation with an intracranial middle cerebral artery occlusion. This study describes the experience at our institution in treating tandem occlusions with a proximal to distal approach in the acute stroke setting.

Methods

A retrospective review of acute strokes caused by tandem occlusions requiring thrombectomy were performed.

Results

16 cases were identified with a mean National Institutes of Health Stroke Scale score at presentation of 13.1±3.9. The proximal occlusion was crossed initially with a microwire in all cases. All carotid occlusions were treated with stenting, and intracranial vessel thrombectomy was performed with a variety of devices. Procedure related complications occurred in two (12.5%) patients. Eight patients (50%) achieved a good outcome (modified Rankin Scale score of 0–2).

Conclusions

A tandem occlusion of the carotid artery at the bifurcation with a concomitant intracranial occlusion is a relatively rare and complex presentation of acute stroke. We have found that addressing the proximal lesion first and covering it with a stent prior to performing distal thrombectomy appears to be a safe and effective option in the treatment algorithm.
Effect of rotation on plane waves in generalized thermomicrostretch elastic solid: comparison of different theories using finite element method
Authors: Othman Mohamed I.A. , Abbas Ibrahim A.
Published: February 2014

The present investigation is aimed at studying the effect of rotation on the thermomicrostretch elastic solid. The formulation is applied in the context of the generalized thermoelasticity Lord–Şhulman theory with one relaxation time and Green–Lindsay’s theory with two relaxation times, as well as the classical dynamical coupled theory. The problem has been solved numerically using a finite element method. Numerical results for the temperature distribution, the displacement components, the force stresses, the couple stresses, and the microstress distribution are represented graphically. The results indicate that the effects of rotation are very pronounced. Comparisons are made with the results in the presence and absence of rotation and in the presence and absence of microstretch constants between the two theories.
Relationship of the deformed hyperbolic Kratzer-like and Tietz potential energy models for diatomic molecules
Authors: Jia Chun-Sheng , Yi Liang-Zhong , Long Shi-Wen
Published: February 2014

Taking the dissociation energy and the equilibrium bond length as explicit parameters, we construct an improved form of the deformed hyperbolic Kratzer-like potential function for diatomic molecules. We show that the deformed hyperbolic Kratzer-like potential model is equivalent to the Tietz potential model for diatomic molecules. We observe that the Tietz potential is superior to the Morse potential in reproducing the interaction potential energy curve for the 23Πg state of the 7Li2 molecule.
Are terrestrial plumes from motionless plates analogues to Martian plumes feeding the giant shield volcanoes?
Authors: Meyzen Christine M. , Massironi Matteo , Pozzobon Riccardo , Zilio Luca Dal
Published: February 2014

On Earth, most tectonic plates are regenerated and recycled through convection. However, the Nubian and Antarctic plates could be considered as poorly mobile surfaces of various thicknesses that are acting as conductive lids on top of Earth's deeper convective system. Here, volcanoes do not show any linear age progression, at least not for the last 30 myr, but constitute the sites of persistent, focused, long-term magmatic activity rather than a chain of volcanoes, as observed in fast-moving plate plume environments. The melt products vertically accrete into huge accumulations. The residual depleted roots left behind by melting processes cannot be dragged away from the melting loci underlying the volcanoes, which may contribute to producing an unusually shallow depth of oceanic swells. The persistence of a stationary thick depleted lid slows down the efficiency of melting processes at shallow depths. Numerous characteristics of these volcanoes located on motionless plates may be shared by those of the giant volcanoes of the Tharsis province, as Mars is a one-plate planet. The aim of this chapter is to undertake a first inventory of these common features, in order to improve our knowledge of the construction processes of Martian volcanoes.
Why software engineering courses should include ethics coverage
Authors: Narayanan Arvind , Vallor Shannon
Published: February 2014

Encouraging students to become comfortable exercising ethical discernment in a professional context with their peers.
Cardiomyocyte glycophagy is regulated by insulin and exposure to high extracellular glucose
Authors: Mellor Kimberley M. , Varma Upasna , Stapleton David I. , Delbridge Lea M. D.
Published: February 2014

Disturbed systemic glycemic and insulinemic status elicits cardiomyocyte metabolic stress and altered glucose handling. In diabetes, pathological myocardial glycogen accumulation occurs. Recently, evidence of a specific myocardial autophagic degradation pathway for glycogen (“glycophagy”) has been reported, differentiated from the more well-characterized protein “macrophagy” pathway. The goal of this study was to identify potential mechanisms involved in cardiac glycogen accumulation, glycophagy, and macrophagy regulation using cultured neonatal rat ventricular myocytes (NRVMs). In NRVMs, insulin-induced Akt phosphorylation was evident with 5 mM-glucose conditions (∼2.3-fold increased). Under high-glucose (30 mM) conditions, insulin-augmented phosphorylation was not observed. Accumulation of glycogen was observed in response to insulin only in high-glucose conditions (∼2-fold increase). Increased expression of the glycophagy marker starch-binding domain-containing protein-1 (STBD1, 25% increase) was observed under high-glucose and insulin conditions. Expression levels of the macrophagy markers p62 and light chain protein 3BII:I were not increased by insulin at either glucose level. Preliminary results from hearts of streptozotocin-treated diabetic rats are supportive of the findings obtained in NRVMs, suggesting diabetes induced elevated expression of STBD1 and of an additional glycophagy marker GABA(A) receptor-associated protein-like 1. Confocal microscopy demonstrated that light chain protein 3B and STBD1 immunomarkers were not colocalized in NRVMs. These findings provide the first evidence that cardiomyocyte glycophagy induction occurs under the influence of insulin and is responsive to extracellular high glucose. This study suggests that the regulation of glycogen content and glycophagy induction in the cardiomyocyte may be linked, and it is speculated that glycogen pathology in diabetic cardiomyopathy has glycophagic involvement.
Investigations of the Navβ1b sodium channel subunit in human ventricle; functional characterization of the H162P Brugada syndrome mutant
Authors: Yuan Lei , Koivumäki Jussi T. , Liang Bo , Lorentzen Lasse G. , Tang Chuyi , Andersen Martin N. , Svendsen Jesper H. , Tfelt-Hansen Jacob , Maleckar Molly , Schmitt Nicole , Olesen Morten S. , Jespersen Thomas
Published: February 2014

Brugada syndrome (BrS) is a rare inherited disease that can give rise to ventricular arrhythmia and ultimately sudden cardiac death. Numerous loss-of-function mutations in the cardiac sodium channel Nav1.5 have been associated with BrS. However, few mutations in the auxiliary Navβ1–4 subunits have been linked to this disease. Here we investigated differences in expression and function between Navβ1 and Navβ1b and whether the H162P/Navβ1b mutation found in a BrS patient is likely to be the underlying cause of disease. The impact of Navβ subunits was investigated by patch-clamp electrophysiology, and the obtained in vitro values were used for subsequent in silico modeling. We found that Navβ1b transcripts were expressed at higher levels than Navβ1 transcripts in the human heart. Navβ1 and Navβ1b coexpressed with Nav1.5 induced a negative shift on steady state of activation and inactivation compared with Nav1.5 alone. Furthermore, Navβ1b was found to increase the current level when coexpressed with Nav1.5, Navβ1b/H162P mutated subunit peak current density was reduced by 48% (−645 ± 151 vs. −334 ± 71 pA/pF), V1/2 steady-state inactivation shifted by −6.7 mV (−70.3 ± 1.5 vs. −77.0 ± 2.8 mV), and time-dependent recovery from inactivation slowed by >50% compared with coexpression with Navβ1b wild type. Computer simulations revealed that these electrophysiological changes resulted in a reduction in both action potential amplitude and maximum upstroke velocity. The experimental data thereby indicate that Navβ1b/H162P results in reduced sodium channel activity functionally affecting the ventricular action potential. This result is an important replication to support the notion that BrS can be linked to the function of Navβ1b and is associated with loss-of-function of the cardiac sodium channel.
Downregulation of L-type Ca2+channel in rat mesenteric arteries leads to loss of smooth muscle contractile phenotype and inward hypertrophic remodeling
Authors: Kudryavtseva Olga , Herum Kate Møller , Dam Vibeke Secher , Straarup Marthe Simonsen , Kamaev Dmitry , Briggs Boedtkjer Donna M. , Matchkov Vladimir V. , Aalkjær Christian
Published: February 2014

L-type Ca2+channels (LTCCs) are important for vascular smooth muscle cell (VSMC) contraction, as well as VSMC differentiation, as indicated by loss of LTCCs during VSMC dedifferentiation. However, it is not clear whether loss of LTCCs is a primary event underlying phenotypic modulation or whether loss of LTCCs has significance for vascular structure. We used small interference RNA (siRNA) transfection in vivo to investigate the role of LTCCs in VSMC phenotypic expression and structure of rat mesenteric arteries. siRNA reduced LTCC mRNA and protein expression in rat mesenteric arteries 3 days after siRNA transfection to 12.7 ± 0.7% and 47.3 ± 13%, respectively: this was associated with an increased resting intracellular Ca2+concentration ([Ca2+]i). Despite the high [Ca2+]i, the contractility was reduced (tension development to norepinephrine was 3.5 ± 0.2 N/m and 0.8 ± 0.2 N/m for sham-transfected and downregulated arteries respectively; P < 0.05). Expression of contractile phenotype marker genes was reduced in arteries downregulated for LTCCs. Phenotypic changes were associated with a 45% increase in number of VSMCs and a consequent increase of media thickness and media area. Ten days after siRNA transfection arterial structure was again normalized. The contractile responses of LTCC-siRNA transfected arteries were elevated in comparison with matched controls 10 days after transfection. The study provides strong evidence for causal relationships between LTCC expression and VSMC contractile phenotype, as well as novel data addressing the complex relationship between VSMC contractility, phenotype, and vascular structure. These findings are relevant for understanding diseases, associated with phenotype changes of VSMC and vascular remodeling, such as atherosclerosis and hypertension.
Inhibition of endocytosis exacerbates TNF-α-induced endothelial dysfunction via enhanced JNK and p38 activation
Authors: Choi Hyehun , Nguyen Hong N. , Lamb Fred S.
Published: February 2014

Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine that causes endothelial dysfunction. Endocytosis of TNF-α receptors (TNFR) precedes endosomal reactive oxygen species (ROS) production, which is required for NF-κB activation in vascular smooth muscle cells. It is unknown how endocytosis of TNFRs impacts signaling in endothelial cells. We hypothesized that TNF-α-induced endothelial dysfunction is induced by both endosomal and cell surface events, including NF-κB and mitogen-activated protein kinases (MAPKs) activation, and endocytosis of the TNFR modifies signaling. Mesenteric artery segments from C57BL/6 mice were treated with TNF-α (10 ng/ml) for 22 h in tissue culture, with or without signaling inhibitors (dynasore for endocytosis, SP600125 for JNK, SB203580 for p38, U0126 for ERK), and vascular function was assessed. Endothelium-dependent relaxation to acetylcholine (ACh) was impaired by TNF-α, and dynasore exacerbated this, whereas JNK or p38 inhibition prevented these effects. In cultured endothelial cells from murine mesenteric arteries, dynasore potentiated JNK and p38 but not ERK phosphorylation and promoted cell death. NF-κB activation by TNF-α was decreased by dynasore. JNK inhibition dramatically increased both the magnitude and duration of TNF-α-induced NF-κB activation and potentiated intercellular adhesion molecule-1 (ICAM-1) activation. Dynasore still inhibited NF-κB activation in the presence of SP600125. Thus TNF-α-induced endothelial dysfunction is both JNK and p38 dependent. Endocytosis modulates the balance of NF-κB and MAPK signaling, and inhibition of NF-κB activation by JNK limits this pro-proliferative signal, which may contribute to endothelial cell death in response to TNF-α.
Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure
Authors: Sun Dong , Cuevas Azita J. , Gotlinger Katherine , Hwang Sung Hee , Hammock Bruce D. , Schwartzman Michal L. , Huang An
Published: February 2014

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid via cytochrome P450 (CYP)/epoxygenases. EETs possess cardioprotective properties and are catalyzed by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs) that lack vasoactive property. To date, the role of sEH in the regulation of myogenic response of resistant arteries, a key player in the control of blood pressure, remains unknown. To this end, experiments were conducted on sEH-knockout (KO) mice, wild-type (WT) mice, and endothelial nitric oxide synthase (eNOS)-KO mice treated with t-TUCB, a sEH inhibitor, for 4 wk. sEH-KO and t-TUCB-treated mice displayed significantly lower blood pressure, associated with significantly increased vascular EETs and ratio of EETs/DHETs. Pressure-diameter relationships were assessed in isolated and cannulated gracilis muscle arterioles. All arterioles constricted in response to increases in transmural pressure from 60 to 140 mmHg. The myogenic constriction was significantly reduced, expressed as an upward shift of pressure-diameter curve, in arterioles of sEH-KO and t-TUCB-treated eNOS-KO mice compared with their controls. Removal of the endothelium, or treatment of the vessels with PPOH, an inhibitor of EET synthase, restored the attenuated pressure-induced constriction to the levels similar to those observed in their controls but had no effects on control vessels. No difference was observed in the myogenic index, or in the vascular expression of eNOS, CYP2C29 (EET synthase), and CYP4A (20-HETE synthase) among these groups of mice. In conclusion, the increased EET bioavailability, as a function of deficiency/inhibition of sEH, potentiates vasodilator responses that counteract pressure-induced vasoconstriction to lower blood pressure.
A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors
Authors: Angevin Eric , Tabernero Josep , Elez Elena , Cohen Steven J. , Bahleda Rastilav , van Laethem Jean-Luc , Ottensmeier Christian , Lopez-Martin Jose A. , Clive Sally , Joly Florence , Ray-Coquard Isabelle , Dirix Luc , Machiels Jean-Pascal , Steven Neil , Reddy Manjula , Hall Brett , Puchalski Thomas A. , Bandekar Rajesh , van de Velde Helgi , Tromp Brenda , Vermeulen Jessica , Kurzrock Razelle
Published: February 2014

Purpose: This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors.

Experimental Design: In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non–small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks.

Results: Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1–45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade ≥3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ≥3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade ≥3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased ≥1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed.

Conclusions: Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks. Clin Cancer Res; 20(8); 2192–204. ©2014 AACR.
The Phosphoinositide 3-Kinase α Selective Inhibitor BYL719 Enhances the Effect of the Protein Kinase C Inhibitor AEB071 in GNAQ/GNA11-Mutant Uveal Melanoma Cells
Authors: Musi Elgilda , Ambrosini Grazia , de Stanchina Elisa , Schwartz Gary K.
Published: February 2014

G-protein mutations are one of the most common mutations occurring in uveal melanoma activating the protein kinase C (PKC)/mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K)/AKT pathways. In this study, we described the effect of dual pathway inhibition in uveal melanoma harboring GNAQ and GNA11 mutations via PKC inhibition with AEB071 (sotrastaurin) and PI3K/AKT inhibition with BYL719, a selective PI3Kα inhibitor. Growth inhibition was observed in GNAQ/GNA11-mutant cells with AEB071 versus no activity in wild-type cells. In the GNAQ-mutant cells, AEB071 decreased phosphorylation of myristoylated alanine-rich C-kinase substrate, a substrate of PKC, along with ERK1/2 and ribosomal S6, but persistent AKT activation was present. BYL719 had minimal antiproliferative activity in all uveal melanoma cell lines, and inhibited phosphorylation of AKT in most cell lines. In the GNA11-mutant cell line, similar effects were observed with ERK1/2 inhibition, mostly inhibited by BYL719. With the combination treatment, both GNAQ- and GNA11-mutant cell lines showed synergistic inhibition of cell proliferation and apoptotic cell death. In vivo studies correlated with in vitro findings showing reduced xenograft tumor growth with the combination therapy in a GNAQ-mutant model. These findings suggest a new therapy treatment option for G-protein–mutant uveal melanoma with a focus on specific targeting of multiple downstream pathways as part of combination therapy. Mol Cancer Ther; 13(5); 1044–53. ©2014 AACR.
Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma
Authors: Knutson Sarah K. , Kawano Satoshi , Minoshima Yukinori , Warholic Natalie M. , Huang Kuan-Chun , Xiao Yonghong , Kadowaki Tadashi , Uesugi Mai , Kuznetsov Galina , Kumar Namita , Wigle Tim J. , Klaus Christine R. , Allain Christina J. , Raimondi Alejandra , Waters Nigel J. , Smith Jesse J. , Porter-Scott Margaret , Chesworth Richard , Moyer Mikel P. , Copeland Robert A. , Richon Victoria M. , Uenaka Toshimitsu , Pollock Roy M. , Kuntz Kevin W. , Yokoi Akira , Keilhack Heike
Published: February 2014

Mutations within the catalytic domain of the histone methyltransferase EZH2 have been identified in subsets of patients with non-Hodgkin lymphoma (NHL). These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. We have previously reported the discovery of EPZ005678 and EPZ-6438, potent and selective S-adenosyl-methionine-competitive small molecule inhibitors of EZH2. Although both compounds are similar with respect to their mechanism of action and selectivity, EPZ-6438 possesses superior potency and drug-like properties, including good oral bioavailability in animals. Here, we characterize the activity of EPZ-6438 in preclinical models of NHL. EPZ-6438 selectively inhibits intracellular lysine 27 of histone H3 (H3K27) methylation in a concentration- and time-dependent manner in both EZH2 wild-type and mutant lymphoma cells. Inhibition of H3K27 trimethylation (H3K27Me3) leads to selective cell killing of human lymphoma cell lines bearing EZH2 catalytic domain point mutations. Treatment of EZH2-mutant NHL xenograft-bearing mice with EPZ-6438 causes dose-dependent tumor growth inhibition, including complete and sustained tumor regressions with correlative diminution of H3K27Me3 levels in tumors and selected normal tissues. Mice dosed orally with EPZ-6438 for 28 days remained tumor free for up to 63 days after stopping compound treatment in two EZH2-mutant xenograft models. These data confirm the dependency of EZH2-mutant NHL on EZH2 activity and portend the utility of EPZ-6438 as a potential treatment for these genetically defined cancers. Mol Cancer Ther; 13(4); 842–54. ©2014 AACR.
Birinapant (TL32711), a Bivalent SMAC Mimetic, Targets TRAF2-Associated cIAPs, Abrogates TNF-Induced NF-κB Activation, and Is Active in Patient-Derived Xenograft Models
Authors: Benetatos Christopher A. , Mitsuuchi Yasuhiro , Burns Jennifer M. , Neiman Eric M. , Condon Stephen M. , Yu Guangyao , Seipel Martin E. , Kapoor Gurpreet S. , LaPorte Matthew G. , Rippin Susan R. , Deng Yijun , Hendi Mukta S. , Tirunahari Pavan K. , Lee Yu-Hua , Haimowitz Thomas , Alexander Matthew D. , Graham Martin A. , Weng David , Shi Yigong , McKinlay Mark A. , Chunduru Srinivas K.
Published: February 2014

The acquisition of apoptosis resistance is a fundamental event in cancer development. Among the mechanisms used by cancer cells to evade apoptosis is the dysregulation of inhibitor of apoptosis (IAP) proteins. The activity of the IAPs is regulated by endogenous IAP antagonists such as SMAC (also termed DIABLO). Antagonism of IAP proteins by SMAC occurs via binding of the N-terminal tetrapeptide (AVPI) of SMAC to selected BIR domains of the IAPs. Small molecule compounds that mimic the AVPI motif of SMAC have been designed to overcome IAP-mediated apoptosis resistance of cancer cells. Here, we report the preclinical characterization of birinapant (TL32711), a bivalent SMAC-mimetic compound currently in clinical trials for the treatment of cancer. Birinapant bound to the BIR3 domains of cIAP1, cIAP2, XIAP, and the BIR domain of ML-IAP in vitro and induced the autoubiquitylation and proteasomal degradation of cIAP1 and cIAP2 in intact cells, which resulted in formation of a RIPK1:caspase-8 complex, caspase-8 activation, and induction of tumor cell death. Birinapant preferentially targeted the TRAF2-associated cIAP1 and cIAP2 with subsequent inhibition of TNF-induced NF-κB activation. The activity of a variety of chemotherapeutic cancer drugs was potentiated by birinapant both in a TNF-dependent or TNF-independent manner. Tumor growth in multiple primary patient–derived xenotransplant models was inhibited by birinapant at well-tolerated doses. These results support the therapeutic combination of birinapant with multiple chemotherapies, in particular, those therapies that can induce TNF secretion. Mol Cancer Ther; 13(4); 867–79. ©2014 AACR.
Aurora Kinase Inhibition Induces PUMA via NF-κB to Kill Colon Cancer Cells
Authors: Sun Jing , Knickelbein Kyle , He Kan , Chen Dongshi , Dudgeon Crissy , Shu Yongqian , Yu Jian , Zhang Lin
Published: February 2014

Aurora kinases play a key role in mitosis and are frequently overexpressed in a variety of tumor cells. Inhibition of aurora kinases results in mitotic arrest and death of cancer cells, and has been explored as an anticancer strategy. However, how aurora inhibition kills cancer cells is poorly understood. In this study, we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, in colorectal cancer cells irrespective of p53 status. Deficiency in PUMA increased polyploidy, improved cell survival, and abrogated mitochondria-mediated apoptosis induced by aurora kinase inhibitors. In response to aurora kinase inhibition, PUMA was directly activated by p65 through the canonical NF-κB pathway following AKT inhibition. Furthermore, PUMA was necessary for the chemosensitization and in vivo antitumor effects of aurora kinase inhibitors in colon cancer cells. These results suggest that PUMA induction mediates the apoptotic response to mitotic arrest imposed by aurora kinase inhibition, and may be a useful indicator for the anticancer activity of aurora kinase inhibitors. Mol Cancer Ther; 13(5); 1298–308. ©2014 AACR.
Streptavidin: A Novel Immunostimulant for the Selection and Delivery of Autologous and Syngeneic Tumor Vaccines
Authors: Weir Chris , Hudson Amanda L. , Moon Elizabeth , Ross Angus , Alexander Miles , Peters Lyndsay , Langova Veronika , Clarke Stephen J. , Pavlakis Nick , Davey Ross , Howell Viive M.
Published: February 2014

Induction of antitumor immunity using autologous tumor proteins is an attractive approach to cancer therapy. However, better methods and stimulants to present these autologous proteins back to the immune system are needed. Here, we identify streptavidin as a novel carrier protein and stimulant, and test the efficacy of both syngeneic (rat) and autologous vaccines (dogs) using streptavidin in combination with reduced soluble tumor proteins. Initial syngeneic vaccine studies in the 9L rat glioma model were used to optimize vaccine dose and selectivity. Cytokine and blood analysis was used to monitor the response. Rats receiving two vaccinations of syngeneic tumor vaccine demonstrated a statistically significant (P < 0.05) survival advantage compared with controls (adjuvant only). Notably, vaccination also led to remission rates of between 30% and 60% in the aggressive 9L glioma model. Antibodies to streptavidin were detected in the serum of vaccinated rats; however, antibody levels did not correlate with the response. The cytokine TNF-α was upregulated in vaccine-treated rats, whereas ICAM1 was downregulated. After engraftment, vaccinated rats maintained CD4+, CD8+ T cells, and total lymphocyte levels closer to normal baseline than those in the controls. Twenty-five dogs treated with autologous vaccine preparations using streptavidin as a stimulant showed no adverse reactions, irrespective of additional chemotherapy and other medications. In this study, we developed a novel method for producing syngeneic and autologous vaccines using streptavidin selectivity and immunogenicity. These vaccines show efficacy in the 9L glioma rat model. Safety was also demonstrated in canine patients presenting with cancer treated with autologous vaccine. Cancer Immunol Res; 2(5); 469–79. ©2014 AACR.
Improved Techniques for Endoscopic Mucosal Resection (EMR) in Colorectal Adenoma
Authors: Sold Moritz , Kähler Georg
Published: February 2014

Background: Endoscopic therapy of colorectal adenomas and early cancers is a standard method. Besides oncological criteria, the method is limited by polyp location, size, and texture. Method: Based on the current literature, technical modifications and developments in endoscopic mucosal resection are described. Results: Numerous approaches exist to improve the conditions of resection, including optimisation of mucosal elevation and modification of techniques, tools, and devices. Conclusion: Endoscopic therapy of sessile and flat colorectal polyps remains a challenge. Some of the presented modifications can help to address this challenge.