Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A.

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.

Neighborhood Social Cohesion Associates with Loneliness Differently among Older People According to Subjective Social Status.

OBJECTIVES: To examine whether neighborhood social cohesion can alleviate the negative impact of low subjective social status on feelings of loneliness. DESIGN: Cross-sectional study. SETTING: Community, Hong Kong. PARTICIPANTS: Older people who participated in a cohort study on osteoporosis and general health in Hong Kong (MrOs study). METHODS: Data were sourced from the 14-year follow-up data of the MrOs study. Loneliness was measured using the 6-item De Jong Gierveld Loneliness Scale. Neighborhood social cohesion was measured by the Hong Kong version of Neighborhood Cohesion Instrument. Linear regression models were used to examine the associations between neighborhood social cohesion and loneliness, controlled for age, sex, marital status, educational level, lifestyle, number of diseases, and maximum lifetime income. The analyses were stratified by subjective social status as measured by a 10-rung self-anchoring scale. RESULTS: 1,037 participants with a mean age of 83 years were included in the study, of whom 72%, 83%, and 64% were classified as at risk of overall loneliness, emotional loneliness, and social loneliness, respectively. Those who were classified as at risk of overall loneliness reported lower subjective social status and had lower levels of neighborhood social cohesion. Linear regression models showed that higher levels of neighborhood social cohesion were associated with lower levels of overall and social loneliness. Stratified analyses showed that the associations between neighborhood social cohesion and loneliness vary across subjective social status groups. Among those with low/middle social status ranking, higher levels of neighborhood social cohesion were associated with lower overall (low-ranking B=-0.111, p=0.001; middle-ranking B=-0.057, p=0.026) and social (low-ranking B=-0.093, p<0.001; middle-ranking B=-0.073, p<0.001) loneliness scores. Among those with high ranking, higher levels of neighborhood social cohesion were associated with lower overall (B=-0.099, p=0.041) and emotional (B=-0.056, p=0.017) loneliness scores, but the associations became insignificant when controlling for maximum lifetime income. CONCLUSIONS AND IMPLICATIONS: Neighborhood social cohesion may operate differently in different social ranking groups. Interventions to alleviate feelings of loneliness should be subjective social status specific.

Report from the 19th annual Western Canadian Gastrointestinal Cancer Consensus Conference; Winnipeg, Manitoba; 29-30 September 2017.

The 19th annual Western Canadian Gastrointestinal Cancer Consensus Conference (wcgccc) was held in Winnipeg, Manitoba, 29-30 September 2017. The wcgccc is an interactive multidisciplinary conference attended by health care professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer.

Cost-effectiveness of osteoporosis screening strategies for hip fracture prevention in older Chinese people: a decision tree modeling study in the Mr. OS and Ms. OS cohort in Hong Kong.

Despite the high costs of hip fracture, many governments provide limited support for osteoporosis screening. We demonstrated that osteoporosis screening by dual-energy X-ray absorptiometry (DXA) with or without pre-screening by Fracture Risk Assessment Tool (FRAX) or calcaneal ultrasound are more cost-effective than no screening in Chinese people aged 65 or over in Hong Kong. INTRODUCTION: To examine the cost-effective potential osteoporosis screening strategies for hip fracture prevention in Hong Kong. METHODS: Decision tree models were constructed to evaluate the cost per quality-adjusted life years (QALYs) of the different osteoporosis screening strategies followed by subsequent 5-year treatment with alendronate compared to no screening (but treat if a hip fracture occurs). The multiple osteoporosis screening strategies were composed of alternative tests and initiation age groups were evaluated with a 10-year horizon, and treatment were assigned if central dual-energy X-ray absorptiometry (DXA) T-score (at either the hip or spine) is - 2.5 or less. Strategies included DXA for all people and pre-screening with the Fracture Risk Assessment Tool (FRAX) at specific thresholds or by calcaneal quantitative ultrasonography (QUS) before taking DXA examination. All the model inputs were based on the Mr. OS and Ms. OS Hong Kong cohort; data are obtained from the Social Welfare Department or the published literature. RESULTS: All of the screening strategies, including the universal screening with DXA and the pre-screening with FRAX or QUS before DXA, were consistently more cost-effective than no screening for people aged 65 years old or over. One-way sensitivity analysis with a more optimistic assumption on treatment adherence or inclusion of other major osteoporotic fractures did not change the results materially. Probabilistic sensitivity analyses showed a dominant role of pre-screening with FRAX followed by subsequent osteoporosis drug treatment in people aged 70 years old or over in Hong Kong. CONCLUSIONS: Osteoporosis screening strategies based on DXA with or without pre-screening are more cost-effective compared to no screening for Chinese people aged 65 or over in Hong Kong.

Reductions in all-cause and cause-specific mortality among HIV-infected individuals receiving antiretroviral therapy in British Columbia, Canada: 2001-2012.

OBJECTIVES: Since 2006, the British Columbia HIV/AIDS Drug Treatment Program (DTP) has expanded enrolment and dramatically increased its number of participants. We examined the effect this expansion has had on the underlying cause of death in HIV-infected individuals. METHODS: We analysed data from participants aged 18 years and older in the DTP to measure 2-year mortality rates and causes of death from 2001 to 2012. We conducted tests of trend for all-cause and cause-specific mortality, and compared demographics and characteristics of individuals. Cox proportional hazard models were used to determine the risk of death. RESULTS: A total of 8185 participants received antiretroviral therapy (ART) during the study period. Mortality declined from 3.88 per 100 person-years (PY) in 2001-2002 to 2.15 per 100 PY in 2011-2012 (P = 0.02). There were significant decreases in HIV-related deaths (2.34 to 0.56 per 100 PY; P = 0.02) and deaths attributable to chronic liver disease (0.20 to 0.09 per 100 PY; P = 0.01), cardiovascular disease (0.24 to 0.05 per 100 PY; P = 0.03) and suicides (0.47 to 0 per 100 PY; P = 0.003). Multivariate models, adjusted for age, gender, history of injecting drug use, AIDS diagnoses and baseline CD4 cell counts, demonstrated that initiation of ART in all time periods after 2001-2002 was independently associated with reduced mortality (P < 0.001). CONCLUSIONS: We observed declines in HIV-related mortality and certain non-HIV-related causes of death among participants in the BC DTP from 2001 to 2012. These findings suggest that there may be broader benefits to the increasingly liberal HIV treatment guidelines, including reductions in death caused by cardiovascular disease and chronic liver disease.

Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes.

The splicing factor SF3B1 is the most frequently mutated gene in myelodysplastic syndromes (MDS), and is strongly associated with the presence of ring sideroblasts (RS). We have performed a systematic analysis of cryptic splicing abnormalities from RNA sequencing data on hematopoietic stem cells (HSCs) of SF3B1-mutant MDS cases with RS. Aberrant splicing events in many downstream target genes were identified and cryptic 3' splice site usage was a frequent event in SF3B1-mutant MDS. The iron transporter ABCB7 is a well-recognized candidate gene showing marked downregulation in MDS with RS. Our analysis unveiled aberrant ABCB7 splicing, due to usage of an alternative 3' splice site in MDS patient samples, giving rise to a premature termination codon in the ABCB7 mRNA. Treatment of cultured SF3B1-mutant MDS erythroblasts and a CRISPR/Cas9-generated SF3B1-mutant cell line with the nonsense-mediated decay (NMD) inhibitor cycloheximide showed that the aberrantly spliced ABCB7 transcript is targeted by NMD. We describe cryptic splicing events in the HSCs of SF3B1-mutant MDS, and our data support a model in which NMD-induced downregulation of the iron exporter ABCB7 mRNA transcript resulting from aberrant splicing caused by mutant SF3B1 underlies the increased mitochondrial iron accumulation found in MDS patients with RS.

Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells.

The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34(+) cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicing/processing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34(+) cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

Tenofovir-based alternate therapies for chronic hepatitis B patients with partial virological response to entecavir.

Entecavir (ETV) is a first-line antiviral therapy for treating chronic hepatitis B (CHB); however, some patients have suboptimal response to ETV. Currently, there are limited data on how to approach these patients. Therefore, our aim was to compare the effectiveness of two alternate therapies--tenofovir (TDF) monotherapy and combination therapy of ETV+TDF--in CHB patients with ETV partial virological response. We conducted a retrospective study of 68 patients who had partial virological response to ETV, defined as having detectable HBV DNA following at least 12 months of ETV, and were switched to TDF monotherapy (n = 25) or ETV+TDF (n = 43). Patients were seen in seven US liver/community-based clinics and started on ETV between 2005 and 2009. The majority of patients were male; the vast majority were Asian and had positive hepatitis B e antigen (HBeAg). Patients in both groups had similar pretreatment characteristics. Complete viral suppression (CVS) rates with TDF monotherapy and ETV+TDF were similar after 6 months (71% vs 83%, P = 0.23) and 12 months (86% vs 84%, P = 0.85), and there was no statistically significant difference in CVS rates even when only patients with higher HBV DNA levels at switch (>1000 IU/mL) were evaluated. Multivariate analysis indicated that ETV+TDF was not an independent predictor of CVS compared to TDF monotherapy (OR = 1.19, P = 0.63). In conclusion, TDF monotherapy and ETV+TDF are comparable in achieving CVS in CHB patients with partial virological response to ETV. Long-term alternate therapy with one pill (TDF monotherapy) vs two pills (ETV+TDF) could lead to lower nonadherence rates and better treatment outcomes.

Evaluating use of neutral electrolyzed water for cleaning near-patient surfaces.

OBJECTIVE: This study aimed to monitor the microbiological effect of cleaning near-patient sites over a 48-hour period with a novel disinfectant, electrolyzed water. SETTING: One ward dedicated to acute care of the elderly population in a district general hospital in Scotland. METHODS: Lockers, left and right cotsides, and overbed tables in 30 bed spaces were screened for aerobic colony count (ACC), methicillin-susceptible Staphylococcus aureus (MSSA), and methicillin-resistant S. aureus (MRSA) before cleaning with electrolyzed water. Sites were rescreened at varying intervals from 1 to 48 hours after cleaning. Microbial growth was quantified as colony-forming units (CFUs) per square centimeter and presence or absence of MSSA and MRSA at each site. The study was repeated 3 times at monthly intervals. RESULTS: There was an early and significant reduction in average ACC (360 sampled sites) from a before-cleaning level of 4.3 to 1.65 CFU/cm(2) at 1 hour after disinfectant cleaning ( P < .0001). Average counts then increased to 3.53 CFU/cm(2) at 24 hours and 3.68 CFU/cm(2) at 48 hours. Total MSSA/MRSA (34 isolates) decreased by 71% at 4 hours after cleaning but then increased to 155% (53 isolates) of precleaning levels at 24 hours. CONCLUSIONS: Cleaning with electrolyzed water reduced ACC and staphylococci on surfaces beside patients. ACC remained below precleaning levels at 48 hours, but MSSA/MRSA counts exceeded original levels at 24 hours after cleaning. Although disinfectant cleaning quickly reduces bioburden, additional investigation is required to clarify the reasons for rebound contamination of pathogens at near-patient sites.

Orolingual angioedema after alteplase therapy of acute ischaemic stroke: incidence and risk of prior angiotensin-converting enzyme inhibitor use.

BACKGROUND AND PURPOSE: Orolingual angioedema (OA) is an uncommon but potentially life-threatening complication of treatment with recombinant tissue plasminogen activator (rt-PA; alteplase) during acute ischaemic stroke. This study aimed to determine the incidence of rt-PA-related OA in an Asian stroke population and the risk of pre-stroke anti-hypertensive drug use for development of this complication. METHODS: A multi-center stroke registry was used to identify the pre-stroke medications of acute ischaemic stroke patients receiving intravenous rt-PA from January 2002 to December 2013. The clinical manifestations of rt-PA-related OA were recorded and the incidence of this complication was determined. The risks of pre-stroke use of different anti-hypertensive agents for the occurrence of rt-PA-related OA were determined from this study and from a meta-analysis. RESULTS: A total of 559 patients received intravenous rt-PA over a 12-year period. Five patients (two males) developed OA after rt-PA administration. The incidence of OA amongst these patients was 0.89% (95% confidence interval 0.29%-2.09%), which was lower than that obtained by meta-analysis (1.9%). Amongst pre-stroke anti-hypertensive medications, angiotensin-converting enzyme (ACE) inhibitors were found in this study to have the highest relative risk for rt-PA-related OA (17.1; 95% confidence interval 3.0-96.9). Meta-analysis also revealed that pre-stroke use of ACE inhibitors was associated with a high relative risk of OA after intravenous rt-PA (12.9; 95% confidence interval 4.5-37.0). CONCLUSIONS: The incidence of rt-PA-related OA in the Asian population is lower than that in the Caucasian population. Pre-stroke use of ACE inhibitors significantly increases the risk of this complication.

Modelling clinical progression and health care utilization of HIV-positive patients in British Columbia prior to death.

OBJECTIVES: The extent to which clinical progression of HIV-positive patients leads to an increase in health care utilization, especially prior to their death, is unknown. Thus, we modelled trends in CD4 cell count and emergency department utilization and the likelihood of an emergency department visit leading to a transfer to an acute care-level facility prior to a patient's death from nonaccidental causes. METHODS: Eligible patients initiated highly active antiretroviral therapy (HAART) in British Columbia between August 1996 and June 2006 (n = 457). Patients were followed until their death, which occurred on or before 30 June 2007 (period in which the emergency department visit data were available). Trends were modelled using generalized mixed effects. RESULTS: Patients experienced a significantly steep decline in CD4 cell count and a corresponding increase in the number of emergency department visits and transfers to acute-level facilities in the 5 years prior to death. For every 6-month interval prior to death, the CD4 cell count decreased by 13.22 cells/µL, the risk of experiencing an emergency department visit increased by 9%, and among those ever admitted, the odds ratio of being transferred to an acute care-level facility increased by 3%. CONCLUSIONS: We showed that patients experienced a steep decline in CD4 cell count, which was associated with an increase in health care utilization prior to their death. These findings highlight the substantial residual avoidable burden that unsuccessfully managed HIV disease poses, even in the HAART era. Further strategies to enhance sustained and successful engagement in care are urgently needed to mitigate high health care utilization.