Online ergonomics training programs have emerged as an efficient way to support office workers’ health, safety, and wellbeing. A scoping review was conducted to assess the design and user-related outcomes of current online office ergonomics training tested in the scientific literature and provided by Occupational Health and Safety (OHS) authorities. A systematic search of five databases and eighteen OHS authorities’ websites was conducted. Data on training details and content was extracted and tabulated. Design outcomes of satisfaction, usability and acceptability were recorded, as were user health-related and knowledge outcomes. A validated rubric for eLearning evaluation was used to assess the functional, technical, and pedagogical aspects of training programs provided by OHS authorities. Five articles were included, and reported on user-related outcomes: musculoskeletal health, ergonomics knowledge, and/or posture. None of the studies reported on design-related outcomes. Eight online training programs were identified in six OHS authorities in Australia (2), the USA (2) and Canada (2). All eight programs included information on workstation set-up and physical hazards while two included information on psychosocial hazards. These programs scored high in the technical (12/12) and accessibility (10.5/12) aspects, but lower on teaching (4/9), social (5/9) and cognitive (5.5/9) aspects. Online office ergonomics training tested in the literature seem to focus on user-related outcomes while OHS authorities training was more comprehensive and met design-related targets. Future collaboration between OHS authorities, the scientific community and end-users need to be considered to build robust evidence-based programs that address both the design and user-related outcomes.
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
At least 10% of the BRCA1/2 tests identify variants of uncertain significance (VUS) while the distinction between pathogenic variants (PV) and benign variants (BV) remains particularly challenging. As a typical tumor suppressor gene, the inactivation of the second wild-type (WT) BRCA1 allele is expected to trigger cancer initiation. Loss of heterozygosity (LOH) of the WT allele is the most frequent mechanism for the BRCA1 biallelic inactivation. To evaluate if LOH can be an effective predictor of BRCA1 variant pathogenicity, we carried out LOH analysis on DNA extracted from 90 breast and seven ovary tumors diagnosed in 27 benign and 55 pathogenic variant carriers. Further analyses were conducted in tumors with PVs yet without loss of the WT allele: BRCA1 promoter hypermethylation, next-generation sequencing (NGS) of BRCA1/2 , and BRCAness score. Ninety-seven tumor samples were analyzed from 26 different BRCA1 variants. A relatively stable pattern of LOH (65.4%) of WT allele for PV tumors was observed, while the allelic balance (63%) or loss of variant allele (15%) was generally seen for carriers of BV. LOH data is a useful complementary argument for BRCA1 variant classification.
Background Achieving the elimination of soil-transmitted helminth (STH) infections requires a sufficient understanding of the current epidemiological status of STH endemicity. We aimed to examine the status of STH in Myanmar – a country with the eighth highest STH prevalence in the world, 10 years after instigation of the national deworming programme. Methods In August 2016 we screened for STH infections using Kato Katz (KK) microscopy and real-time PCR (qPCR) in schoolchildren from the Bago Region township of Phyu, a STH sentinel site in Myanmar. Ten schools were randomly selected, and one stool sample each from a total of 264 students was examined. Prevalence and intensity of infection were calculated for each STH. Results High prevalence of STH was identified in the study area with 78.8% of the schoolchildren infected with at least one STH by qPCR, and 33.3% by KK. The most prevalent STH was Trichuris trichiura , diagnosed by both KK (26.1%) and qPCR (67.1%), followed by Ascaris lumbricoides (15.5% KK; 54.9% qPCR). No hookworm infections were identified by KK; however, the qPCR analysis showed a high prevalence of Ancylostoma sp. infection (29.6%) with few Necator americanus (1.1%) infections. Conclusions Despite bi-annual deworming of schoolchildren in the fourth-grade and below, STH prevalence remains stubbornly high. These results informed the expansion of the Myanmar National STH control programme to include all school-aged children by the Ministry of Health and Sports in 2017, however further expansion to the whole community should be considered along with improving sanitation and hygiene measures. This would be augmented by rigorous monitoring and evaluation, including national prevalence surveys.
Background To report a case of Fuchs’ adenoma occurring in an eye with a large choroidal melanoma. We have reviewed the literature to describe the clinical presentation, ultrasound characteristics and pathological features of these entities. Case presentation A 69-year-old Caucasian man presented with vision loss from a large choroidal melanoma. Enucleation showed an incidental Fuchs’ adenoma in the same eye. Whole-exome sequence analysis was also performed on the patient’s blood and melanoma, which showed a rarely-reported ATRX mutation. Conclusions Fuchs’ adenoma is an under-diagnosed benign age-related hyperplasia of the non-pigmented ciliary epithelium (NPCE). Given its location and characteristics, it can be mistaken for choroidal melanoma and clinicians are reminded how to differentiate between these pathologies and that they may co-exist.
Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional ( p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic ( p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity.
Microglia are implicated in most neurodegenerative diseases. Here, we present a robust and efficient protocol to differentiate monocyte-derived microglia-like cells (MDMi) from whole blood. The protocol consists of three parts. The first part will describe two methods for PBMC isolation. This will be followed by MDMi differentiation, and lastly, the characterization of MDMi by immunocytochemistry. MDMi can be used to investigate microglial-related responses in various age-related neurodegenerative diseases and can be applied to drug testing on a personalized basis. For complete details on the use and execution of this protocol, please refer to Quek et al. (2022).
Background Electroencephalogram (EEG) monitoring is recommended as routine in newborn neurocritical care to facilitate early therapeutic decisions and outcome predictions. EEG's larger-scale implementation is, however, hindered by the shortage of expertise needed for the interpretation of spontaneous cortical activity, the EEG background. We developed an automated algorithm that transforms EEG recordings to quantified interpretations of EEG background and provides simple intuitive visualisations in patient monitors. Methods In this method-development and proof-of-concept study, we collected visually classified EEGs from infants recovering from birth asphyxia or stroke. We used unsupervised learning methods to explore latent EEG characteristics, which guided the supervised training of a deep learning-based classifier. We assessed the classifier performance using cross-validation and an external validation dataset. We constructed a novel measure of cortical function, brain state of the newborn (BSN), from the novel EEG background classifier and a previously published sleep-state classifier. We estimated clinical utility of the BSN by identification of two key items in newborn brain monitoring, the onset of continuous cortical activity and sleep-wake cycling, compared with the visual interpretation of the raw EEG signal and the amplitude-integrated (aEEG) trend. Findings We collected 2561 h of EEG from 39 infants (gestational age 35·0–42·1 weeks; postnatal age 0–7 days). The external validation dataset included 105 h of EEG from 31 full-term infants. The overall accuracy of the EEG background classifier was 92% in the whole cohort (95% CI 91–96; range 85–100 for individual infants). BSN trend values were closely related to the onset of continuous EEG activity or sleep-wake cycling, and BSN levels showed robust difference between aEEG categories. The temporal evolution of the BSN trends showed early diverging trajectories in infants with severely abnormal outcomes. Interpretation The BSN trend can be implemented in bedside patient monitors as an EEG interpretation that is intuitive, transparent, and clinically explainable. A quantitative trend measure of brain function might harmonise practices across medical centres, enable wider use of brain monitoring in neurocritical care, and might facilitate clinical intervention trials. Funding European Training Networks Funding Scheme, the Academy of Finland, Finnish Pediatric Foundation (Lastentautiensäätiö), Aivosäätiö, Sigrid Juselius Foundation, HUS Children's Hospital, HUS Diagnostic Center, National Health and Medical Research Council of Australia.
Background Bangladesh has reduced malaria incidence and mortality by over 75% between 2010 and 2020. Widespread long-lasting insecticidal net (LLIN) distribution and use is one of the measures responsible for this success. Recalcitrant malaria hotspots within the Chittagong Hill Tracts districts suggest important drivers of malaria risk may remain uncharacterized. Methods Towards understanding how household-level human behaviour impacts exposure to mosquitoes, parallel human landing catches and human behavioural observations were conducted in four households for 6 months (May–October) over the rainy season in the Bandarban District. Analysis quantifies spatiotemporal human behaviour-adjusted exposure to Anopheles with and without LLINs. Results This small-scale operational study demonstrates that human spatial and temporal presence along with LLIN use drives exposure to Anopheles . Though the four households had both outdoor and indoor exposure, especially in the evening (1800–2000 h) and early morning (0400–0500 h), data points to household-based heterogeneity in malaria exposure even with similar LLIN access. Conclusion Incorporating human behaviour into exposure estimates can be used to understand the efficacy and limitations of local vector control strategies and identify gaps in protection, as well as where present intervention strategies may be optimized.
More than 100 arboviruses, almost all of which have an RNA genome, cause disease in humans. RNA viruses are causing unprecedented health system challenges worldwide, many with little or no specific therapies or vaccines available. Certain species of mosquito can carry dengue virus (DENV), Zika virus (ZIKV) and yellow fever virus (YFV), where co-infection of these viruses has occurred. Here, we found that purified synthetic defective interfering particles (DIPs) derived from DENV type 2 (DENV-2) strongly suppressed replication of the aforementioned viruses, respiratory syncytial virus (RSV) and also the novel emerging virus SARS-CoV-2 in human cells. DENV DIPs produced in bioreactors, purified by column chromatography, and concentrated are virus-like particles that are about half the diameter of a typical DENV particle, but with similar ratios of the viral structural proteins envelope and capsid. Overall, DIP-treated cells inhibited DENV, ZIKV, YFV, RSV, and SARS-CoV-2 by at least 98% by mechanisms which included interferon (IFN)-dependent cellular antiviral responses. IMPORTANCE DIPs are spontaneously derived virus mutants with deletions in genes that block viral replication. DIPs play important roles in modulation of viral disease, innate immune responses, virus persistence and virus evolution. Here, we investigated the antiviral activity of highly purified synthetic DIPs derived from DENV, which were produced in bioreactors. DENV DIPs purified by column chromatography strongly inhibited five different RNA viruses, including DENV, ZIKV, YFV, RSV, and SARS-CoV-2 in human cells. DENV DIPs inhibited virus replication via delivery of a small, noninfectious viral RNA that activated cellular innate immunity, resulting in robust type 1 interferon responses. The work here presents a pathway for DIP production which is adaptable to Good Manufacturing Practice, so that their preclinical testing should be suitable for evaluation in subjects.
Background: Smoking cessation is an important screening component, but the evidence base to inform implementation is lacking. We report longitudinal smoking behavior in an Australian screening cohort and examine predictor variables associated with continued smoking. Methods: Healthy current or former smokers (quit less than 15 years and ≥30-pack year smoking history) aged 60-74 years underwent CT screening at baseline, year 1 and year 2. Participants received brief smoking cessation advice and generic Quitline materials. Smoking status was self-reported every 6 months for 5 years. Mediators of smoking behavior, adjusted for sociodemographic, health and scan variables were explored using logistic regression modeling. Results: Two hundred thirty-five participants were analyzed. One hundred eight (46%) were current smokers at enrolment. At baseline, current smokers' mean Fagerström Test for Nicotine Dependence was 4.9, and they had higher levels of lung cancer-specific distress and passive smoke exposure than former smokers. At 36 months, 33% of baseline smokers achieved sustained (≥6 months) smoking abstinence. Five (4%) former smokers relapsed at any point during the study. Continued smoking was positively associated with greater nicotine dependence and smoking pack-years, and negatively associated with cardiovascular disease, stroke, and lung cancer family history. Conclusions: This study provides the first data on smoking cessation rates in Australian lung cancer screenees and supports screening as a teachable moment. We identify several factors that identify smokers who may require more intensive smoking cessation interventions and could be used to develop effective smoking cessation as part of lung cancer screening, tailored to individual risk profiles.
Observational studies suggest that 25-hydroxy vitamin D (25(OH)D) concentration is inversely associated with pain. However, findings from intervention trials are inconsistent. We assessed the effect of vitamin D supplementation on pain using data from a large, double-blind, population-based, placebo-controlled trial (the D-Health Trial). 21,315 participants (aged 60-84 years) were randomly assigned to a monthly dose of 60,000 IU vitamin D3 or a matching placebo. Pain was measured using the 6-item Pain Impact Questionnaire (PIQ-6), administered 1, 2 and 5 years after enrollment. We used regression models (linear for continuous PIQ-6 score and log-binomial for binary categorizations of the score, namely 'some or more pain impact' and 'presence of any bodily pain') to estimate the effect of vitamin D on pain. We included 20,423 participants who completed ≥1 PIQ-6. In blood samples collected from 3943 randomly selected participants (∼800 per year) the mean (SD) 25(OH)D concentrations were 77 (SD 25) and 115 (SD 30) nmol/L in the placebo and vitamin D groups, respectively. Most (76%) participants were predicted to have 25(OH)D concentration >50 nmol/L at baseline. The mean PIQ-6 was similar in all surveys (∼50.4). The adjusted mean difference in PIQ-6 score (vitamin D cf placebo) was 0.02 (95% CI, -0.20 to 0.25). The proportion of participants with some or more pain impact and with presence of bodily pain was also similar between groups (both prevalence ratios 1.01, 95% CI 0.99 to 1.03). In conclusion, supplementation with 60,000 IU of vitamin D3 per month had negligible effect on bodily pain.
Information about the prevalence of photodermatoses is lacking, despite their substantial impact on life quality. Our objective was to systematically review the literature to establish what is known regarding prevalence and incidence of photodermatoses. We searched Medline, CINAHL and Embase from inception to 2021 to identify original population-based studies in the English literature reporting the prevalence and/or incidence of photodermatoses. Information was extracted according to geographical location and risk of bias was assessed using a 10-point risk of bias tool for prevalence studies. Primary outcome was the population prevalence of photodermatoses. Prevalence data for polymorphic light eruption (PLE) was used to calculate the global pooled prevalence of PLE. Twenty-six studies were included; 15 reported prevalence of photodermatoses based on samples of the general population and 11 on prevalence and/or incidence from national and international registry data. The general population studies involved PLE (9 studies), unspecified photosensitivity (2), actinic prurigo (2), juvenile spring eruption (1), chronic actinic dermatitis (1), and variegate porphyria (1), while registry studies reported on cutaneous porphyrias and genophotodermatoses (9 and 2 studies, respectively). Worldwide the prevalence of PLE between countries ranged from 0.65% (China) to 21.4% (Ireland). The pooled estimated prevalence of PLE was 10% (95% CI 6%-15%) among the general population (n=19,287), and PLE prevalence increased with distance from the equator (r=0.78, p<0.001). While several photodermatoses are rare, photosensitivity can be prevalent at wide-ranging world locations, including Egypt where photosensitivity was found in 4% of children and 10% of adults. This study showed that PLE is highly prevalent in many populations and that its prevalence shows a highly significant correlation with increasing northerly or southerly latitude. Available population-based studies for photodermatoses suggest they can be prevalent at a range of world locations; more attention is required to this area.
Background: Enteral nutrition (EN) is often required in patients with head and neck cancer (HNSCC); however, initiation criteria is limited or inconsistent. This study aimed to describe the relationship of treatment toxicities and requirement for EN and investigate toxicity and baseline characteristics association with EN duration. Methods: Acute toxicities and baseline characteristics were collected from patients with HNSCC (n = 110) undergoing H-IMRT. Percentage EN contributing to estimated requirements and EN duration were measured. Results: The threshold for patients needing ≥50% of estimated requirements via EN increased from week 3 to 4 for grade ≥2 oral/pharyngeal mucositis, dysgeusia, thick saliva and nausea, and for grade 3 dysphagia. Patients with grade 2-3 dysphagia had a reduced risk of ceasing EN compared to those with grade 0-1 dysphagia. Conclusions: Using acute toxicities in clinical practice may be a useful tool to inform prompt initiation of EN prior to decline in nutritional status and anticipate EN duration.
Samples can be prone to ascertainment and attrition biases. The Australian Genetics of Depression Study is a large publicly recruited cohort (n = 20,689) established to increase the understanding of depression and antidepressant treatment response. This study investigates differences between participants who donated a saliva sample or agreed to linkage of their records compared to those who did not. We observed that older, male participants with higher education were more likely to donate a saliva sample. Self-reported bipolar disorder, ADHD, panic disorder, PTSD, substance use disorder, and social anxiety disorder were associated with lower odds of donating a saliva sample, whereas anorexia was associated with higher odds of donation. Male and younger participants showed higher odds of agreeing to record linkage. Participants with higher neuroticism scores and those with a history of bipolar disorder were also more likely to agree to record linkage whereas participants with a diagnosis of anorexia were less likely to agree. Increased likelihood of consent was associated with increased genetic susceptibility to anorexia and reduced genetic risk for depression, and schizophrenia. Overall, our results show moderate differences among these subsamples. Most current epidemiological studies do not search for attrition biases at the genetic level. The possibility to do so is a strength of samples such as the AGDS. Our results suggest that analyses can be made more robust by identifying attrition biases both on the phenotypic and genetic level, and either contextualising them as a potential limitation or performing sensitivity analyses adjusting for them.
Importance An increasing number of people develop more than 1 primary melanoma, yet to date, no population-based prospective cohort studies have reported on risk factors for developing first vs second primary melanomas. Objective To compare the clinical characteristics of first and second melanomas and then to estimate the relative risks of developing 1 vs multiple melanomas associated with demographic, phenotypic, sun exposure, and genetic factors. Design, Setting, and Participants This population-based prospective cohort study included men and women aged 40 to 69 years recruited in 2011 and followed up until December 2018 in Queensland, Australia. Data analysis was performed from February to July 2022. Exposures Self-reported information about demographic, phenotypic, and sun exposure measures captured using a survey completed at baseline, and polygenic risk score for melanoma. Main Outcomes and Measures Incident first or second primary melanoma diagnosis, and histologic and clinical characteristics thereof. The Wei-Lin-Weissfeld model for recurrent events was used to estimate the association of each factor with the risks of first and second primary melanoma. Results A total of 38 845 patients (mean [SD] age at baseline, 56.1 [8.2] years; 17 775 men and 21 070 women) were included in the study. During a median follow-up period of 7.4 years, 1212 (3.1%) participants had a single primary melanoma diagnosis, and 245 (0.6%) had a second primary melanoma diagnosis. Second melanomas were more likely than first melanomas to be in situ; for invasive tumors, second melanomas were more likely to be thin (ie, ≤1 mm) than first melanomas. Having many moles at age 21 years (self-reported using visual scoring tool) was more strongly associated with second (hazard ratio [HR], 6.36; 95% CI, 3.77-10.75) than first primary melanoma (HR, 3.46; 95% CI, 2.72-4.40) ( P value for difference between the HRs = .01). A high genetic predisposition (ie, polygenic risk score in tertile 3) was also more strongly associated with second (HR, 3.28; 95% CI, 2.06-5.23) than first melanoma (HR, 2.06; 95% CI, 1.71-2.49; P = .03). Second melanomas were more strongly associated with a history of multiple skin cancer excisions (HR, 2.63; 95% CI, 1.80-3.83) than first melanomas (HR, 1.86; 95% CI, 1.61-2.16; P = .05). For all other phenotypic characteristics and sun exposure measures, similarly elevated associations with first vs second melanomas were observed. Conclusions and Relevance Findings of this cohort study suggest that within the general population, the presence of many nevi and having a high genetic predisposition to melanoma were associated with the highest risks of developing second primary melanomas.
Background: Most antihypertensives can induce dermal photosensitivity, which may increase melanoma risk. However, corroborating evidence is limited. We examined the associations between use of antihypertensives and melanoma risk. Methods: A nationwide nested case-control study was conducted using data from the Cancer Registry of Norway, the National Registry and the Norwegian Prescription Database in 2004-15. Ten controls were randomly selected for each melanoma case, matched on sex and birth year. The study included 12 048 cases and 117 895 controls. We estimated rate ratios (RRs) with 95% confidence intervals (CIs). All analyses were adjusted for ambient ultraviolet radiation (UVR). We additionally performed active comparator analyses, and sensitivity analyses by only including new users, distinguishing between exclusive and mixed users, allowing for different latency periods, and subgroup analyses by melanoma subtype and clinical stage. Results: Compared with non-use, we observed a slightly increased melanoma risk in users of diuretics (RR 1.08, CI 1.01-1.15), calcium-channel blockers (RR 1.10, CI 1.04-1.18) and drugs affecting the renin-angiotensin system (RR 1.10, CI 1.04-1.16), but not for beta blockers (RR 0.97, CI 0.92-1.03). We found no heterogeneity of associations by melanoma subtype or clinical stage and no dose-response relationship between the cumulative defined daily doses (DDDs) and melanoma. No interaction was found between cumulative DDDs and ambient UVR. Conclusions: Weak associations, with lack of a dose-response relationship and lack of interactions with ambient UVR, in the DDD analysis in this nationwide study do not support a causal relationship between antihypertensives and melanoma risk.
Purpose: To determine whether cannabidiol (CBD) oil can improve symptom distress in patients with advanced cancer receiving palliative care. Methods: Participants were adults with advanced cancer and symptom distress (Edmonton Symptom Assessment Scale [ESAS] total score of ≥ 10/90) who received titrated CBD oil 100 mg/mL, 0.5 mL once daily to 2 mL three times a day, or matched placebo for 28 days. The primary outcome was ESAS total symptom distress score (TSDS) at day 14. Response was defined as a decrease in TSDS by ≥ 6 at day 14. Secondary outcomes were ESAS TSDS over time, individual symptom scores, patient-determined effective dose, opioid use, Global Impression of Change, depression, anxiety, quality of life, and adverse events. Results: Of the 144 patients randomly assigned, the planned sample size of 58 participants on CBD and 63 on placebo reached the primary analysis point (day 14). The unadjusted change in TSDS from baseline to day 14 was -6.2 (standard deviation, 14.5) for placebo and -3.0 (standard deviation, 15.2) for CBD with no significant difference between arms (P = .24). Similarly, there was no detected difference in proportion of responders (placebo: 37 of 63 [58.7%], CBD: 26 of 58 [44.8%], P = .13). All components of ESAS improved (fell) over time with no difference between arms. The median dose of participant-selected CBD was 400 mg per day with no correlation with opioid dose. There was no detectable effect of CBD on quality of life, depression, or anxiety. Adverse events did not differ significantly between arms apart from dyspnea that was more common with CBD. Most participants reported feeling better or much better at days 14 (53% CBD and 65% placebo) and 28 (70% CBD and 64% placebo). Conclusion: CBD oil did not add value to the reduction in symptom distress provided by specialist palliative care alone.
Chemotherapy-resistant acute myeloid leukemia (AML), frequently driven by clonal evolution, has a dismal prognosis. A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockouts involving AraC metabolism and genes that regulate cell cycle arrest (cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53) as contributing to resistance. In human AML cohorts, reduced expression of CDKN2A conferred inferior overall survival and CDKN2A downregulation occurred at relapse in paired diagnosis-relapse samples, validating its clinical relevance. Therapeutically targeting the G1S cell cycle restriction point (with CDK4/6 inhibitor, palbociclib and KAT6A inhibitor, WM-1119, to upregulate CDKN2A) synergized with chemotherapy. Additionally, direct promotion of apoptosis with venetoclax, showed substantial synergy with chemotherapy, overcoming resistance mediated by impaired cell cycle arrest. Altogether, we identify defective cell cycle arrest as a clinically relevant contributor to chemoresistance and identify rationally designed therapeutic combinations that enhance response in AML, potentially circumventing chemoresistance.
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