Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of cases of childhood precursor B-cell acute lymphoblastic leukemia. These abnormalities are too complex to engineer faithfully in animal models and are unrepresented in leukemia cell lines. As a resource for future functional and preclinical studies, we have created xenografts from the leukemic blasts of patients with intrachromosomal amplification of chromosome 21 and characterized them by in-vivo and ex-vivo luminescent imaging, flow immunophenotyping, and histological and ultrastructural analyses of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia-initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumor suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-cell acute lymphoblastic leukemia. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-cell acute lymphoblastic leukemia and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions.

Social vulnerability index for the older people-Hong Kong and New York City as examples.

Many world cities have suffered large-scale disasters, causing a significant loss of lives, property damage, and adverse social and economic impact. Those who are most vulnerable during and in the immediate aftermath of disaster crises are the elderly. Therefore, it is imperative to identify them and determine their specific needs in order to support them. Although several Social Vulnerability Indexes (SVIs) have been developed to assess different types of disaster vulnerability across geographic and population levels, few have been tailored to the older population. Building on the research of Gusmano et al., this study modifies and uses an SVI specifically designed to assess the vulnerability of older populations to emergencies and disasters across seven domains, namely, population size, institutionalization, poverty, living alone, disability, communication obstacles, and access to primary care. Moreover, it is acknowledged that availability of data largely depends on the local context and is always a barrier to production of indices across countries. The present study offers suggestions on how modifications can be made for local adaptation such that the SVI can be applied in different cities and localities. The SVI used in this study provides information to stakeholders in emergency preparedness, not only about natural disasters but also about health hazards and emergencies, which few existing SVI address.

Disruption to the FOXO-PRDM1 axis resulting from deletions of chromosome 6 in acute lymphoblastic leukaemia.

A common problem in the study of human malignancy is the elucidation of cancer driver mechanisms associated with recurrent deletion of regions containing multiple genes. Taking B-cell acute lymphoblastic leukaemia (B-ALL) and large deletions of 6q [del(6q)] as a model, we integrated analysis of functional cDNA clone tracking assays with patient genomic and transcriptomic data, to identify the transcription factors FOXO3 and PRDM1 as candidate tumour suppressor genes (TSG). Analysis of cell cycle and transcriptomic changes following overexpression of FOXO3 or PRDM1 indicated that they co-operate to promote cell cycle exit at the pre-B cell stage. FOXO1 abnormalities are absent in B-ALL, but like FOXO3, FOXO1 expression suppressed growth of TCF3::PBX1 and ETV6::RUNX1 B-ALL in-vitro. While both FOXOs induced PRDM1 and other genes contributing to late pre-B cell development, FOXO1 alone induced the key transcription factor, IRF4, and chemokine, CXCR4. CRISPR-Cas9 screening identified FOXO3 as a TSG, while FOXO1 emerged as essential for B-ALL growth. We relate this FOXO3-specific leukaemia-protective role to suppression of glycolysis based on integrated analysis of CRISPR-data and gene sets induced or suppressed by FOXO1 and FOXO3. Pan-FOXO agonist Selinexor induced the glycolysis inhibitor TXNIP and suppressed B-ALL growth at low dose (ID50 < 50 nM).

Acetylation of heat shock protein 20 (Hsp20) regulates human myometrial activity.

Phosphorylation of heat shock protein 20 (Hsp20) by protein kinase A (PKA) is now recognized as an important regulatory mechanism modulating contractile activity in the human myometrium. Thus agonists that stimulate cyclic AMP production may cause relaxation with resultant beneficial effects on pathologies that affect this tissue such as the onset of premature contractions prior to term. Here we describe for the first time that acetylation of Hsp20 is also a potent post-translational modification that can affect human myometrial activity. We show that histone deacetylase 8 (HDAC8) is a non-nuclear lysine deacetylase (KDAC) that can interact with Hsp20 to affect its acetylation. Importantly, use of a selective linkerless hydroxamic acid HDAC8 inhibitor increases Hsp20 acetylation with no elevation of nuclear-resident histone acetylation nor marked global gene expression changes. These effects are associated with significant inhibition of spontaneous and oxytocin-augmented contractions of ex vivo human myometrial tissue strips. A potential molecular mechanism by which Hsp20 acetylation can affect myometrial activity by liberating cofilin is described and further high-lights the use of specific effectors of KDACs as therapeutic agents in regulating contractility in this smooth muscle.

Identifying service needs from the users and service providers' perspective: a focus group study of Chinese elders, health and social care professionals.

AIM: This is a preliminary study to identify older people service needs in Hong Kong from the users' and service providers' perspective. BACKGROUND: As the Hong Kong population is ageing rapidly, it is important to identify the needs for care of older people. Although a wide variety of medical and social services have been provided to meet the needs of older people, there has been little evaluation from the users' or service providers' perspective regarding what the needs are and how well current service provisions match their needs. In recent years the importance of patient-centred care has been emphasised, where patient's expectation of care has been given a central role in guiding and improving the provision of health. However few studies have been carried out with respect to services for older people. DESIGN: To identify the service needs, a focus group study was conducted. Both service providers and older people were interviewed. This preliminary study used a qualitative research method to identify older people's service needs, generating rich information which could be used to inform older people care service development. METHOD: Data were collected by conducting eight focus group discussions. The focus group interviews were audio-taped. Interviews were then transcribed and themes were identified. RESULTS: The study identified several areas for improvement in services for older people, covering adequacy, accessibility and affordability of medical services, coordination of health and social care, quality of long-term care, negative perceptions and training needs. Some themes such as service adequacy and negative staff attitudes occurred in both older people and health professional focus groups. The themes of fast access, continuity of care and smooth transition, affordability, provision of information of available health and social services appear to be universal as these have also been identified in similar studies in other countries. CONCLUSION: In addition to other objective outcomes, such as duration of stay in hospital or re-admission rates after hospital discharges, changes in service provisions towards improvement should be evaluated from the users as well as professional care providers' perspectives. RELEVANCE TO CLINICAL PRACTICE: Areas of improvement in service delivery include timely access, continuity, affordability, better coordination of health and social care, quality of care particularly in the long-term residential care setting and healthcare professionals' communication and caring skills and attitude.

Quality of end-of-life care for non-cancer patients in a non-acute hospital.

AIMS AND OBJECTIVES: Few surveys have been carried out documenting the quality of life for non-cancer patients in general district hospitals reaching the final trajectory towards death. We carried out a survey of 80 patients facing the final stages of their chronic illness as well as their carers and hospital staff. BACKGROUND: With increasing life expectancy, a large majority of patients are older, where palliative care principles for patients with cancer are equally applicable. Few surveys have been carried out documenting the quality of life for non-cancer patients in general district hospitals reaching the final trajectory towards death in terms of patients' and carers' perspective, compared with the more extensive literature for patients with cancer. DESIGN: Survey. METHODS: Assessment tools include symptom check list, geriatric depression scale, Chinese Death Anxiety Inventory and the McGill Quality of Life Questionnaire for patients; SF-12 and the Chinese cost of care index for informal carers; and the Chinese Maslach Bumout and Death Anxiety Inventories for hospital staff. RESULTS: Lower-limb weakness (92·5%), fatigue (86·2%), oedema (85%), dysphagia (58·2%) and pain (48·8%) were the most common symptoms in this group of patients. The mean Chinese Caregiver Stress Index score was 45·93 (SD 6·45) (maximum score = 80). For staff, the mean SF-12 physical component score was lower than the Hong Kong population average. CONCLUSION: The findings suggest that there is room for improvement in the quality of end-of-life care. Relevance to clinical practice. Patients in the final stages of many chronic illnesses have high prevalence of symptoms comparable to those of patients with cancer. Raising awareness and improving training for all health care professionals, formulating guidelines and care pathways and incorporating quality of care as key performance indicators are measures to improve the quality of end-of-life care.

The living experience of losing genetic continuity: Concealment tendency in Chinese recipients of donor-assisted conception.

This study explored how Chinese women with donor-assisted conception experienced loss of genetic continuity and managed donor-assisted conception-related information. Through Interpretative Phenomenological Analysis, a thematic framework on women's beliefs, motivation, and behaviors in information management was constructed. Contrary to the Western trend toward disclosure, it was found that Chinese women strongly preferred to conceal, in order to protect their family members, the parent-child relationship, and family stability. Participants' strong preference was also indicated in specific behaviors that ensure information concealment. The findings of this study may contribute toward the development of culturally sensitive clinical guidelines for counseling practice that supports infertile couples' decision-making.

An exploration of anticipatory grief in advanced cancer patients.

BACKGROUND AND OBJECTIVES: Research on anticipatory grief (AG) has been more focused on the experience of relatives than the terminally ill patients. This study will present qualitative 'thick descriptions' of advanced cancer patient's experience of AG and explore how it is experienced in the family context. METHOD: Seven advanced incurable cancer patients (median 58 years) were recruited from the day hospice and five patients comprised the final sample. Participants were invited to attend focus groups and individual interviews to discuss their experience of terminal illness, thoughts and feelings related to AG and how they cope with losses and grief in the family. Qualitative transcripts were analyzed using interpretative phenomenological analysis. RESULT: Two inter-related themes of AG were identified. The first main theme 'subjective experience of AG' comprises confrontations with death and multiple losses; and resistance against death and loss. The second main theme 'experience of AG in the family' explored the patient's role in the family interaction patterns and interpersonal processes. CONCLUSION: An understanding in the subjective experience of AG in terminally ill patients and their experience of AG in the family may contribute to the development of psychotherapeutic interventions. The generative role of the patient in the family grief process is also highlighted.

A pilot study on the effectiveness of anticipatory grief therapy for elderly facing the end of life.

This pilot study evaluates the benefits of anticipatory grief therapy (AGT) for day hospice patients and long-term care (LTC) residents with cancer and non-malignant chronic diseases. Twenty-six elderly people (69.2 percent female; average age 81.8 years) participated in experiential, expressive activities and discussions during AGT. The McGill Quality of Life Questionnaire-Hong Kong version and the 15-item Geriatrics Depression Scale (Chinese version) were administered immediately before and after AGT, and at a four-week follow-up. Focus groups were held to collect qualitative feedback. Significant post-AGT improvements were found in physical (Z = -2.12, p < 0.05), psychological (Z = -2.22, p < 0.05), and total quality of life measures (Z = -2.66, p < 0.01), and in depression levels (Z = -2.49, p < 0.05). Emergent qualitative themes included grief and existential concerns, pros and cons of reminiscence, reflection and affirmation of meaning through expressive art, perceived benefits of AGT, and comments and suggestions for improving AGT in the future. We conclude that AGT delivered in both day hospice and LTC settings could be acceptable, feasible, and useful for elderly people facing the end of life.

Handicap and its determinants of change in stroke survivors: one-year follow-up study.

BACKGROUND AND PURPOSE: Stroke, a major health issue affecting the elderly, limits their participation in society. The aim of this study was to investigate changes in stroke survivors' handicap levels and to identify their determinants in the subacute phase from 3 months to 1 year. METHODS: Data were collected from a prospective cohort of 303 Chinese stroke survivors with the use of questionnaires, including the Lawton Instrumental Activities of Daily Living-Chinese Version (IADL-CV), Barthel Index, Chinese Mini-Mental State Examination, Chinese Geriatric Depression Scale, and the Chinese version of the London Handicap Scale. RESULTS: A total of 297 and 268 patients were successfully followed up at 6 and 12 months, respectively. Whereas IADL remained unchanged throughout, we found an improvement in Barthel Index but a deterioration in the Chinese Geriatric Depression Scale score at 12 months. Multilevel modeling revealed improvements in the mobility and social integration handicap domains and a deterioration in the orientation domain at 12 months. Overall handicap remained unchanged. At 12 months, depression was most significantly and independently associated with poststroke handicap, and advanced old age alone (>80 years) was associated with clinically significant deterioration in handicap. CONCLUSIONS: Even though IADL remained static at 1 year, mobility and social integration handicap dimensions can be improved in the early community phase after stroke. Nonphysical factors such as depression were confirmed to be significantly associated with handicap. Rehabilitation should target the high-risk group of very elderly stroke survivors who were 4 times more likely to deteriorate in handicap.