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"Davidson, Patricia"
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Nuclear envelope rupture and repair during cancer cell migration
During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we investigated mammalian tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increased with cell confinement and with depletion of nuclear lamins, NE proteins that structurally support the nucleus. Cells restored NE integrity using components of the endosomal sorting complexes required for transport III (ESCRT III) machinery. Our findings indicate that cell migration incurs substantial physical stress on the NE and its content and requires efficient NE and DNA damage repair for cell survival.
Journal Article
Dying in the hospital setting: A systematic review of quantitative studies identifying the elements of end-of-life care that patients and their families rank as being most important
Background:
The majority of expected deaths occur in hospitals where optimal end-of-life care is not yet fully realised, as evidenced by recent reviews outlining experience of care. Better understanding what patients and their families consider to be the most important elements of inpatient end-of-life care is crucial to addressing this gap.
Aim and design:
This systematic review aimed to ascertain the five most important elements of inpatient end-of-life care as identified by patients with palliative care needs and their families.
Data sources:
Nine electronic databases from 1990 to 2014 were searched along with key internet search engines and handsearching of included article reference lists. Quality of included studies was appraised by two researchers.
Results:
Of 1859 articles, 8 met the inclusion criteria generating data from 1141 patients and 3117 families. Synthesis of the top five elements identified four common end-of-life care domains considered important to both patients and their families, namely, (1) effective communication and shared decision making, (2) expert care, (3) respectful and compassionate care and (4) trust and confidence in clinicians. The final domains differed with financial affairs being important to families, while an adequate environment for care and minimising burden both being important to patients.
Conclusion:
This review adds to what has been known for over two decades in relation to patient and family priorities for end-of-life care within the hospital setting. The challenge for health care services is to act on this evidence, reconfigure care systems accordingly and ensure universal access to optimal end-of-life care within hospitals.
Journal Article
Fear of falling is as important as multiple previous falls in terms of limiting daily activities: a longitudinal study
Background
Fear of falling and previous falls are both risk factors that affect daily activities of older adults. However, it remains unclear whether they independently limit daily activities accounting for each other.
Methods
We used the data from Round 1 (Year 1) to Round 5 (Year 5) of the National Health and Aging Trends Study. We included a total of 864 community-dwelling participants who provided data on previous falls, fear of falling and limited activities from Year 1 to Year 5 and had no limited daily activities at Year 1 in this study. Previous falls and fear of falling were ascertained by asking participants how many falls they had in the past year and whether they had worried about falling in the last month. Limited daily activities included any difficulties with mobility (e.g., going outside), self-care (e.g., eating), and household activities (e.g., laundering). Generalized estimation equation models were used to examine whether previous falls and fear of falling independently predicted development of limited daily activities adjusting covariates.
Results
Participants were mainly between 65 and 79 years old (83 %), male (57 %), and non-Hispanic White (79 %). Among participants who had multiple falls in Year 1, 19.1-31 %, 21.4-52.4 %, and 11.9-35.7 % developed limitations in mobility, self-care, and household activities during Year 2 to Year 5, respectively. Among those who had fear of falling in Year 1, 22.5-41.3 %, 30.0-55.0 %, and 18.8-36.3 % developed limitations in mobility, self-care, and household activities during Year 2 to Year 4, respectively. Fear of falling independently predicted limitations in mobility (Incidence rate ratio [IRR]: 1.79, 95 % CI: 1.44, 2.24), self-care (IRR: 1.25, 95 % CI: 1.08, 1.44) and household activities (IRR: 1.39, 95 % CI: 1.08, 1.78) after adjusting for previous falls and covariates. Multiple previous falls independently predicted limitations in mobility (IRR: 1.72, 1.30, 2.27), self-care (IRR: 1.40, 95 % CI: 1.19, 1.66) and household activities (IRR: 1.36, 95 % CI: 1.01, 1.83) after adjusting fear of falling and covariates.
Conclusions
Fear of falling seems to be as important as multiple previous falls in terms of limiting older adults’ daily activities.
Journal Article
Elements of Effective Interventions for Addressing Intimate Partner Violence in Latina Women: A Systematic Review
Intimate partner violence remains a global problem and is of particular concern in Latina diasporas.
To identify effective elements of interventions to address intimate partner violence in Latina women.
The systematic review was undertaken according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We focused the search on intervention studies assessing intimate partner violence as an outcome measure and on publications in English and Spanish from the last 11 years (2004-2015).
Despite the scope of the problem, from the 1,274 studies screened only four met the search criteria and only a single study included an exclusive Latino population. Of the four interventions, one was only as effective as the control treatment. Heterogeneity of study populations and designs prohibited meta-analytic methods.
Theoretically derived interventions that are gender specific, culturally appropriate, target mutual aid through group dynamics, and that are developed collaboratively with the target population are likely to be most effective.
Journal Article
Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer
Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher
LMNA
expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.
Journal Article
Nuclear Deformability Constitutes a Rate-Limiting Step During Cell Migration in 3-D Environments
Cell motility plays a critical role in many physiological and pathological settings, ranging from wound healing to cancer metastasis. While cell migration on 2-dimensional (2-D) substrates has been studied for decades, the physical challenges cells face when moving in 3-D environments are only now emerging. In particular, the cell nucleus, which occupies a large fraction of the cell volume and is normally substantially stiffer than the surrounding cytoplasm, may impose a major obstacle when cells encounter narrow constrictions in the interstitial space, the extracellular matrix, or small capillaries. Using novel microfluidic devices that allow observation of cells moving through precisely defined geometries at high spatial and temporal resolution, we determined nuclear deformability as a critical factor in the cells’ ability to pass through constrictions smaller than the size of the nucleus. Furthermore, we found that cells with reduced levels of the nuclear envelope proteins lamins A/C, which are the main determinants of nuclear stiffness, passed significantly faster through narrow constrictions during active migration and passive perfusion. Given recent reports that many human cancers have altered lamin expression, our findings suggest a novel biophysical mechanism by which changes in nuclear structure and composition may promote cancer cell invasion and metastasis.
Journal Article
Effects of facilitated family case conferencing for advanced dementia: A cluster randomised clinical trial
Palliative care planning for nursing home residents with advanced dementia is often suboptimal. This study compared effects of facilitated case conferencing (FCC) with usual care (UC) on end-of-life care.
A two arm parallel cluster randomised controlled trial was conducted. The sample included people with advanced dementia from 20 Australian nursing homes and their families and professional caregivers. In each intervention nursing home (n = 10), Palliative Care Planning Coordinators (PCPCs) facilitated family case conferences and trained staff in person-centred palliative care for 16 hours per week over 18 months. The primary outcome was family-rated quality of end-of-life care (End-of-Life Dementia [EOLD] Scales). Secondary outcomes included nurse-rated EOLD scales, resident quality of life (Quality of Life in Late-stage Dementia [QUALID]) and quality of care over the last month of life (pharmacological/non-pharmacological palliative strategies, hospitalization or inappropriate interventions).
Two-hundred-eighty-six people with advanced dementia took part but only 131 died (64 in UC and 67 in FCC which was fewer than anticipated), rendering the primary analysis under-powered with no group effect seen in EOLD scales. Significant differences in pharmacological (P < 0.01) and non-pharmacological (P < 0.05) palliative management in last month of life were seen. Intercurrent illness was associated with lower family-rated EOLD Satisfaction with Care (coefficient 2.97, P < 0.05) and lower staff-rated EOLD Comfort Assessment with Dying (coefficient 4.37, P < 0.01). Per protocol analyses showed positive relationships between EOLD and staff hours to bed ratios, proportion of residents with dementia and staff attitudes.
FCC facilitates a palliative approach to care. Future trials of case conferencing should consider outcomes and processes regarding decision making and planning for anticipated events and acute illness.
Australian New Zealand Clinical Trial Registry ACTRN12612001164886.
Journal Article
Delirium prevalence, incidence, and implications for screening in specialist palliative care inpatient settings: A systematic review
Background:
Delirium is a serious neuropsychiatric syndrome frequently experienced by palliative care inpatients. This syndrome is under-recognized by clinicians. While screening increases recognition, it is not a routine practice.
Aim and design:
This systematic review aims to examine methods, quality, and results of delirium prevalence and incidence studies in palliative care inpatient populations and discuss implications for delirium screening.
Data sources:
A systematic search of the literature identified prospective studies reporting on delirium prevalence and/or incidence in inpatient palliative care adult populations from 1980 to 2012. Papers not in English or those reporting the occurrence of symptoms not specifically identified as delirium were excluded.
Results:
Of the eight included studies, the majority (98.9%) involved participants (1079) with advanced cancer. Eight different screening and assessment tools were used. Delirium incidence ranged from 3% to 45%, while delirium prevalence varied, with a range of: 13.3%–42.3% at admission, 26%–62% during admission, and increasing to 58.8%–88% in the weeks or hours preceding death. Studies that used the Diagnostic and Statistical Manual–Fourth Edition reported higher prevalence (42%–88%) and incidence (40.2%–45%), while incidence rates were higher in studies that screened participants at least daily (32.8%–45%). Hypoactive delirium was the most prevalent delirium subtype (68%–86% of cases).
Conclusion:
The prevalence and incidence of delirium in palliative care inpatient settings supports the need for screening. However, there is limited consensus on assessment measures or knowledge of implications of delirium screening for inpatients and families. Further research is required to develop standardized methods of delirium screening, assessment, and management that are acceptable to inpatients and families.
Journal Article