Estrogen-receptor (ER) and progesterone-receptor (PR) expression levels in breast cancer, which have been principally compared via binomial descriptors, can vary widely across tumors. We sought to ...characterize ER and PR expression levels using semi-quantitative analyses of receptor staining in germline pathogenic variant (PV) carriers of cancer predisposition genes.
We conducted a retrospective chart review of patients who underwent germline genetic testing for cancer predisposition genes at a tertiary cancer center genetics clinic. We performed comparisons of semi-quantitative ER and PR percentage staining levels across carriers and non-carriers of cancer predisposition genes.
Breast cancers from BRCA1 PV carriers expressed significantly lower ER (15.2% vs 78.2%, p < 0.001) and lower PR (6.8% vs 41.1%, p < 0.001) staining compared to non-PV carriers. Similarly, breast cancers of BRCA2 (66.7% vs 78.2%, p = 0.005) and TP53 (50.6% vs 78.2%, p = 0.015) PV tumors also displayed moderate decreases in ER staining. Conversely, CHEK2 tumors displayed higher ER (93.1% vs 78.2%, p = 0.005) and PR (72% vs 48.8%, p = 0.001) staining when compared to non-PV carriers. We observed a wide range of dispersion across the ER and PR staining levels of the carriers and noncarriers. ER and PR ranges of dispersion of CHEK2 tumors were uniquely narrower than all other groups.
The findings of our study suggest that precise expression levels of ER and PR in breast cancers can vary widely. These differences are further augmented when comparing expression staining across PV and non-PV carriers, suggesting potentially unique tumorigenesis and progression pathways influenced by germline cancer predisposition genes.
microRNAs (miRNAs) are critical to heart development and disease. Emerging research indicates that regulated precursor processing can give rise to an unexpected diversity of miRNA variants. We ...subjected small RNA from murine HL-1 cardiomyocyte cells to next generation sequencing to investigate the relevance of such diversity to cardiac biology. ∼40 million tags were mapped to known miRNA hairpin sequences as deposited in miRBase version 16, calling 403 generic miRNAs as appreciably expressed. Hairpin arm bias broadly agreed with miRBase annotation, although 44 miR* were unexpectedly abundant (>20% of tags); conversely, 33 -5p/-3p annotated hairpins were asymmetrically expressed. Overall, variability was infrequent at the 5' start but common at the 3' end of miRNAs (5.2% and 52.3% of tags, respectively). Nevertheless, 105 miRNAs showed marked 5' isomiR expression (>20% of tags). Among these was miR-133a, a miRNA with important cardiac functions, and we demonstrated differential mRNA targeting by two of its prevalent 5' isomiRs. Analyses of miRNA termini and base-pairing patterns around Drosha and Dicer cleavage regions confirmed the known bias towards uridine at the 5' most position of miRNAs, as well as supporting the thermodynamic asymmetry rule for miRNA strand selection and a role for local structural distortions in fine tuning miRNA processing. We further recorded appreciable expression of 5 novel miR*, 38 extreme variants and 8 antisense miRNAs. Analysis of genome-mapped tags revealed 147 novel candidate miRNAs. In summary, we revealed pronounced sequence diversity among cardiomyocyte miRNAs, knowledge of which will underpin future research into the mechanisms involved in miRNA biogenesis and, importantly, cardiac function, disease and therapy.
As a global health emergency, the rapid spread of the novel coronavirus disease (COVID-19) led to the implementation of widespread restrictions (e.g., quarantine, physical/social distancing ...measures). However, while these restrictions reduce the viral spread of COVID-19, they may exacerbate behavioural and cognitive symptoms in dementia patients and increase pressure on caregiving. Here, we aimed to assess the impact of COVID-19 and related restrictions on both carers and people living with dementia across the world. We conducted an international survey (Australia, Germany, Spain, and the Netherlands) to assess the impact of COVID-19 on carers and people living with dementia. People with dementia experienced worsened neuropsychiatric symptoms since the outbreak of COVID-19, most commonly, depression, apathy, delusions, anxiety, irritability, and agitation. Regression analyses revealed that limited understanding of the COVID-19 situation and not living with the carer was associated with worsened neuropsychiatric symptoms. Carers also reported a decline in their own mental health, increased stress and reduced social networks as a result of COVID-19 and related restrictions. Regression analyses revealed uncertainty about the future and loneliness were associated with worsened carer mental health. Findings from this study will inform strategies for the development of support services and compassionate protocols that meet the evolving needs of those living with dementia and their carers.
Mechanisms of initial cell fate decisions differ among species. To gain insights into lineage allocation in humans, we derived ten human embryonic stem cell lines (designated UCSFB1-10) from single ...blastomeres of four 8-cell embryos and one 12-cell embryo from a single couple. Compared with numerous conventional lines from blastocysts, they had unique gene expression and DNA methylation patterns that were, in part, indicative of trophoblast competence. At a transcriptional level, UCSFB lines from different embryos were often more closely related than those from the same embryo. As predicted by the transcriptomic data, immunolocalization of EOMES, T brachyury, GDF15 and active β-catenin revealed differential expression among blastomeres of 8- to 10-cell human embryos. The UCSFB lines formed derivatives of the three germ layers and CDX2-positive progeny, from which we derived the first human trophoblast stem cell line. Our data suggest heterogeneity among early-stage blastomeres and that the UCSFB lines have unique properties, indicative of a more immature state than conventional lines.
Introduction: Growing research has shown the negative impact of social isolation on the health and psychological well-being of individuals with dementia and their carers. This study investigated the ...effectiveness of a psychosocial intervention for dementia carers during a lockdown period of the COVID-19 pandemic. Methods: Twenty-three family carers of individuals diagnosed with dementia living in the community were recruited and provided with an online psychoeducation toolkit that aims to improve health literacy, management of social and behavioural symptoms in dementia, carer social engagement, and coping skills. Carers were divided into “mild” or “moderate” groups based on the disease severity of the person with dementia they cared for. Outcome measures including distress and severity of neuropsychiatric symptoms, carer self-efficacy and burden, social network, and feelings of loneliness were assessed at baseline and 2 weeks later. Results: Carers in the moderate group reported higher levels of distress (p = 0.001) and severity (p < 0.001) of neuropsychiatric symptoms and greater carer burden (p = 0.003) than carers in the mild group. Following the intervention, both groups reported increased social networks (p = 0.001). In addition, carers in the moderate group reported significantly reduced distress for neuropsychiatric symptoms (p = 0.013), enhanced carer self-efficacy for controlling upsetting thoughts (p = 0.040), and decreased loneliness (p = 0.023). Conclusions: This study demonstrated that psychosocial interventions improve outcomes for carers of individuals with dementia, particularly those caring for individuals with greater disease severity. Findings from this study will inform the development of support services that meet the evolving needs of individuals with dementia and their carers in social isolation, during and in a post-pandemic context.
Accumulating evidence suggests that interventions to de-implement low-value services are urgently needed. While medical societies and educational campaigns such as Choosing Wisely have developed ...several guidelines and recommendations pertaining to low-value care, little is known about interventions that exist to de-implement low-value care in oncology settings. We conducted this review to summarize the literature on interventions to de-implement low-value care in oncology settings.
We systematically reviewed the published literature in PubMed, Embase, CINAHL Plus, and Scopus from 1 January 1990 to 4 March 2021. We screened the retrieved abstracts for eligibility against inclusion criteria and conducted a full-text review of all eligible studies on de-implementation interventions in cancer care delivery. We used the framework analysis approach to summarize included studies' key characteristics including design, type of cancer, outcome(s), objective(s), de-implementation interventions description, and determinants of the de-implementation interventions. To extract the data, pairs of authors placed text from included articles into the appropriate cells within our framework. We analyzed extracted data from each cell to describe the studies and findings of de-implementation interventions aiming to reduce low-value cancer care.
Out of 2794 studies, 12 met our inclusion criteria. The studies covered several cancer types, including prostate cancer (n = 5), gastrointestinal cancer (n = 3), lung cancer (n = 2), breast cancer (n = 2), and hematologic cancers (n = 1). Most of the interventions (n = 10) were multifaceted. Auditing and providing feedback, having a clinical champion, educating clinicians through developing and disseminating new guidelines, and developing a decision support tool are the common components of the de-implementation interventions. Six of the de-implementation interventions were effective in reducing low-value care, five studies reported mixed results, and one study showed no difference across intervention arms. Eleven studies aimed to de-implement low-value care by changing providers' behavior, and 1 de-implementation intervention focused on changing the patients' behavior. Three studies had little risk of bias, five had moderate, and four had a high risk of bias.
This review demonstrated a paucity of evidence in many areas of the de-implementation of low-value care including lack of studies in active de-implementation (i.e., healthcare organizations initiating de-implementation interventions purposefully aimed at reducing low-value care).
East Asians (EAs) experience worse metabolic health outcomes compared to other ethnic groups at lower body mass indices; however, the potential role of the gut microbiota in contributing to these ...health disparities remains unknown. We conducted a multi-omic study of 46 lean and obese East Asian and White participants living in the San Francisco Bay Area, revealing marked differences between ethnic groups in bacterial richness and community structure. White individuals were enriched for the mucin-degrading
. East Asian subjects had increased levels of multiple bacterial phyla, fermentative pathways detected by metagenomics, and the short-chain fatty acid end-products acetate, propionate, and isobutyrate. Differences in the gut microbiota between the East Asian and White subjects could not be explained by dietary intake, were more pronounced in lean individuals, and were associated with current geographical location. Microbiome transplantations into germ-free mice demonstrated stable diet- and host genotype-independent differences between the gut microbiotas of East Asian and White individuals that differentially impact host body composition. Taken together, our findings add to the growing body of literature describing microbiome variations between ethnicities and provide a starting point for defining the mechanisms through which the microbiome may shape disparate health outcomes in East Asians.
Harmful algal bloom (HAB) events that lead to paralytic shellfish poisoning, fish fatalities, and seawater discolouration have been documented in Sabah’s coastal waters. Studies on nutrient analysis ...during HAB have been carried out periodically in Sabah’s waters; however, observation on variations of environmental parameters, primarily colour-producing agents’ (CPAs) concentrations, associated with HAB have not been carried out. Hence, this study aims to document environmental parameters and the CPAs over a period of 1 year. The study was conducted along the coastal waters of Sepanggar Bay, Malaysia, where
in-situ
environmental parameters and sea surface water samples were collected every month for 1 year of monitoring from November 2018 until December 2019. During the study period, the following three HAB events were reported: the first bloom (Bloom Event 1, BE1) in November 2018, the second bloom (Bloom Event 2, BE2) in July 2019, and the third bloom (Bloom Event 3, BE3) in October 2019, all of which were dominated by
Margalefidinium polykrikoides
species. Two HAB species,
M. polykrikoides
and
Pyrodinium bahamense
var.
compressum,
found in the BE3 were ten times higher than the previous two bloom events. The measured environmental parameters indicated a similar fluctuation in both bloom and non-bloom events. However, during BE3, the CPAs parameters showed larger values. Based on the 1-year monitoring, the fluctuating trend of the recorded environmental parameters exhibited no discernible pattern during pre- and post-bloom occurrences in the studied area. Chlorophyll
-a
and CDOM, on the other hand, increased during bloom occurrences as compared to non-bloom readings.
Pluripotent stem cells are derived from culture of early embryos or the germline and can be induced by reprogramming of somatic cells. Barriers to reprogramming that stabilize the differentiated ...state and have tumor suppression functions are expected to exist. However, we have a limited understanding of what such barriers might be. To find novel barriers to reprogramming to pluripotency, we compared the transcriptional profiles of the mouse germline with pluripotent and somatic cells, in vivo and in vitro. There is a remarkable global expression of the transcriptional program for pluripotency in primordial germ cells (PGCs). We identify parallels between PGC reprogramming to pluripotency and human germ cell tumorigenesis, including the loss of LATS2, a tumor suppressor kinase of the Hippo pathway. We show that knockdown of LATS2 increases the efficiency of induction of pluripotency in human cells. LATS2 RNAi, unlike p53 RNAi, specifically enhances the generation of fully reprogrammed iPS cells without accelerating cell proliferation. We further show that LATS2 represses reprogramming in human cells by post-transcriptionally antagonizing TAZ but not YAP, two downstream effectors of the Hippo pathway. These results reveal transcriptional parallels between germ cell transformation and the generation of iPS cells and indicate that the Hippo pathway constitutes a barrier to cellular reprogramming.
INTRODUCTION
Some people with dementia develop changes in behaviour and cognition that may lead to interactions with police or the legal system. However, large, prospective case–control studies ...examining these behaviours are lacking.
METHODS
One hundred and forty‐four people with dementia and 53 controls completed the Misdemeanours and Transgressions Screener.
RESULTS
Criminal risk behaviours were reported in: 65.6% of behavioural‐variant frontotemporal dementia, 46.2% of right‐lateralised semantic dementia, and 27.0% of Alzheimer's disease patients. In 19.1% of patients these behaviours led to contact with police or authority figures. Compared to controls, people with dementia showed higher rates of physical assault (p = 0.024), financial/professional recklessness (p = 0.009), and inappropriate behaviours (p = 0.052).
DISCUSSION
Criminal risk behaviours are common across dementia subtypes and may be one of the first clinical signs of frontotemporal dementia. Further research to understand how to balance risk minimisation with an individual's liberties as well as the inappropriate criminalisation of people with dementia is needed.
Highlights
The Misdemeanours and Transgressions Screener is a new tool to assess criminal risk behaviours.
Forty‐seven percent of patients with dementia show criminal risk behaviour after dementia onset.
Behaviours included verbal abuse, traffic violations, physical assault.
New onset of criminal risk behaviours >50 years is a clinical sign for frontotemporal dementia.
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