A new paradigm of genetic testing for hereditary breast/ovarian cancers

INTRODUCTION: Genetic risk factors and family history play an important role in breast cancer development. This review aimed to summarise the current genetic testing approach to hereditary breast/ovarian cancer. METHODS: A systematic literature review was performed by searching the PubMed database. Publications available online until January 2015 that addressed issues related to hereditary breast/ovarian cancer genetic counselling/testing were selected. The search terms used were 'familial breast/ovarian cancer', 'susceptibility genes', 'genetic counselling', and 'genetic testing'. The data extracted for this review were analysed by the authors, with a focus on genetic testing for hereditary breast/ovarian cancer. RESULTS: Although a greater proportion of inherited breast/ovarian cancers are due to the BRCA1 and BRCA2 mutations, a number of new genes have emerged as susceptibility candidates, including rare germline mutations in high penetrance genes, such as TP53 and PTEN, and more frequent mutations in moderate/low penetrance genes, such as PALB2, CHEK2 and ATM. Multi-gene testing, if used appropriately, is generally a more cost- and time-effective method than single-gene testing, and may increase the number of patients who can be offered personal surveillance, risk-reduction options, and testing of high-risk family members. CONCLUSIONS: Recent advances in molecular genetics testing have identified a number of susceptibility genes related to hereditary breast and/or ovarian cancers other than BRCA1 and BRCA2. The introduction of multi-gene testing for hereditary cancer has revolutionised the clinical management of high-risk patients and their families. Individuals with hereditary breast/ovarian cancer will benefit from genetic counselling/testing.published_or_final_versio

A regioselectivity switch in Pd-catalyzed hydroallylation of alkynes.

By exploiting the reactivity of a vinyl-Pd species, we control the regioselectivity in hydroallylation of alkynes under Pd-hydride catalysis. A monophosphine ligand and carboxylic acid combination promotes 1,5-dienes through a pathway involving isomerization of alkynes to allenes. In contrast, a bisphosphine ligand and copper cocatalyst favor 1,4-dienes via a mechanism that involves transmetalation. Our study highlights how to access different isomers by diverting a common organometallic intermediate

MiR-199a-5p confers tumor-suppressive role in triple-negative breast cancer

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Memory in humans and deep language models: Linking hypotheses for model augmentation

The computational complexity of the self-attention mechanism in Transformer models significantly limits their ability to generalize over long temporal durations. Memory-augmentation, or the explicit storing of past information in external memory for subsequent predictions, has become a constructive avenue for mitigating this limitation. We argue that memory-augmented Transformers can benefit substantially from considering insights from the memory literature in humans. We detail an approach to integrating evidence from the human memory system through the specification of cross-domain linking hypotheses. We then provide an empirical demonstration to evaluate the use of surprisal as a linking hypothesis, and further identify the limitations of this approach to inform future research.Comment: 5 figure

Independence in the Home: A Wearable Interface for a Person with Quadriplegia to Teleoperate a Mobile Manipulator

Teleoperation of mobile manipulators within a home environment can significantly enhance the independence of individuals with severe motor impairments, allowing them to regain the ability to perform self-care and household tasks. There is a critical need for novel teleoperation interfaces to offer effective alternatives for individuals with impairments who may encounter challenges in using existing interfaces due to physical limitations. In this work, we iterate on one such interface, HAT (Head-Worn Assistive Teleoperation), an inertial-based wearable integrated into any head-worn garment. We evaluate HAT through a 7-day in-home study with Henry Evans, a non-speaking individual with quadriplegia who has participated extensively in assistive robotics studies. We additionally evaluate HAT with a proposed shared control method for mobile manipulators termed Driver Assistance and demonstrate how the interface generalizes to other physical devices and contexts. Our results show that HAT is a strong teleoperation interface across key metrics including efficiency, errors, learning curve, and workload. Code and videos are located on our project website

Association of EP2 receptor and SLC19A3 in regulating breast cancer metastasis

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The long non-coding RNA HOTAIR is a critical epigenetic mediator of angiogenesis in diabetic retinopathy

PURPOSE. Diabetic retinopathy (DR) remains a pressing issue worldwide. Abnormal angiogenesis is a distinct vascular lesion in DR, and research has established that vascular endothelial growth factor A (VEGF-A) is a primary mediator of such changes. However, limitations in current anti-VEGF therapies suggest that our understanding of molecular networks underlying ocular angiogenesis remains far from complete. Based on our long non-coding RNA (lncRNA) array analyses, HOX antisense intergenic RNA (HOTAIR) was identified as one of the top upregulated lncRNAs in high glucose-cultured human retinal endothelial cells (HRECs). Given the well-documented roles of HOTAIR in cancer, no studies have examined the epigenetic implications of HOTAIR in DR, and we investigated such relationships herein. METHODS. We used HRECs exposed to various glucose concentrations and epigenetic modulators to examine HOTAIR, angiogenic, and DR-related molecular markers. Oxidative stress, angiogenesis, and mitochondrial dysfunction were assessed. Retinal tissues of diabetic rodents and the vitreous humor and serum of patients with proliferative DR were also investigated. RESULTS. Hyperglycemia significantly augmented HOTAIR expression in HRECs and promoted angiogenesis, oxidative damage, and mitochondrial aberrations. Similarly, vitreous humor and serum from proliferative DR patients and retinas from diabetic animals demonstrated increased HOTAIR expression compared to non-diabetic controls. HOTAIR knockdown protected against glucose-induced increases of angiogenic and diabetesassociated molecules in the retina. Mechanistically, we showed that HOTAIR exerts its capabilities by preventing oxidative stress and modulating epigenetic pathways involving histone methylation, histone acetylation, DNA methylation, and transcription factors. CONCLUSIONS. Our findings suggest that HOTAIR is a critical lncRNA in the pathogenesis of DR and may potentially be important for diagnostic and therapeutic targeting

Trajectories and predictors of the long-term course of low back pain: cohort study with 5-year follow-up

Low back pain (LBP) is a major health challenge globally. Research has identified common trajectories of pain over time. We aimed to investigate whether trajectories described in one primary care cohort can be confirmed in another, and to determine the prognostic value of factors collected 5 years prior to the identification of the trajectory. The study was carried out on 281 patients who had consulted primary care for LBP, at that point completed a baseline questionnaire, and then returned a questionnaire at 5-years follow-up plus at least 3 (of 6) subsequent monthly questionnaires. Baseline factors were measured using validated tools. Pain intensity scores from the 5-year follow-up and monthly questionnaires were used to assign participants into 4 previously derived pain trajectories (no or occasional mild, persistent mild, fluctuating, persistent severe), using latent class analysis. Posterior probabilities of belonging to each cluster were estimated for each participant. The posterior probabilities for the assigned clusters were very high (>0.90) for each cluster except for the smallest 'fluctuating' cluster (0.74). Lower social class and higher pain intensity were significantly associated with a more severe trajectory 5-years later, as were patients' perceptions of the greater consequences and longer duration of pain, and greater passive behavioural coping. LBP trajectories identified previously appear generalizable. These allow better understanding of the long-term course of LBP and effective management tailored to individual trajectories needs to be identified

The presence of broadly neutralizing anti-SARS-CoV-2 RBD antibodies elicited by primary series and booster dose of COVID-19 vaccine

Antibody-mediated immunity plays a key role in protection against SARS-CoV-2. We characterized B-cell-derived anti-SARS-CoV-2 RBD antibody repertoires from vaccinated and infected individuals and elucidate the mechanism of action of broadly neutralizing antibodies and dissect antibodies at the epitope level. The breadth and clonality of anti-RBD B cell response varies among individuals. The majority of neutralizing antibody clones lose or exhibit reduced activities against Beta, Delta, and Omicron variants. Nevertheless, a portion of anti-RBD antibody clones that develops after a primary series or booster dose of COVID-19 vaccination exhibit broad neutralization against emerging Omicron BA.2, BA.4, BA.5, BQ.1.1, XBB.1.5 and XBB.1.16 variants. These broadly neutralizing antibodies share genetic features including a conserved usage of the IGHV3-53 and 3–9 genes and recognize three clustered epitopes of the RBD, including epitopes that partially overlap the classically defined set identified early in the pandemic. The Fab-RBD crystal and Fab-Spike complex structures corroborate the epitope grouping of antibodies and reveal the detailed binding mode of broadly neutralizing antibodies. Structure-guided mutagenesis improves binding and neutralization potency of antibody with Omicron variants via a single amino-substitution. Together, these results provide an immunological basis for partial protection against severe COVID-19 by the ancestral strain-based vaccine and indicate guidance for next generation monoclonal antibody development and vaccine design