Global impact of aberrant splicing on human gene expression levels.

Alternative splicing (AS) is pervasive in human genes, yet the specific function of most AS events remains unknown. It is widely assumed that the primary function of AS is to diversify the proteome, however AS can also influence gene expression levels by producing transcripts rapidly degraded by nonsense-mediated decay (NMD). Currently, there are no precise estimates for how often the coupling of AS and NMD (AS-NMD) impacts gene expression levels because rapidly degraded NMD transcripts are challenging to capture. To better understand the impact of AS on gene expression levels, we analyzed population-scale genomic data in lymphoblastoid cell lines across eight molecular assays that capture gene regulation before, during, and after transcription and cytoplasmic decay. Sequencing nascent mRNA transcripts revealed frequent aberrant splicing of human introns, which results in remarkably high levels of mRNA transcripts subject to NMD. We estimate that ~15% of all protein-coding transcripts are degraded by NMD, and this estimate increases to nearly half of all transcripts for lowly-expressed genes with many introns. Leveraging genetic variation across cell lines, we find that GWAS trait-associated loci explained by AS are similarly likely to associate with NMD-induced expression level differences as with differences in protein isoform usage. Additionally, we used the splice-switching drug risdiplam to perturb AS at hundreds of genes, finding that ~3/4 of the splicing perturbations induce NMD. Thus, we conclude that AS-NMD substantially impacts the expression levels of most human genes. Our work further suggests that much of the molecular impact of AS is mediated by changes in protein expression levels rather than diversification of the proteome.

APOE Gene Associated with Dementia-Related Traits, Depression, and Anxiety in the Hispanic Population.

Alzheimer's disease (AD), a main cause of dementia, is commonly seen in aging populations with a strong genetic component. AD is one of the most common neurodegenerative disorders; it is a genetically and clinically heterogeneous disease. Specific demographic factors and genetic variants have been identified in non-Hispanic populations; however, limited studies have observed the Hispanic population. Therefore, we focused on investigating a known gene, APOE, associated with AD-related phenotypes and two psychiatric diseases (depression and anxiety) within the U.S. Hispanic population in our current study. A total of 1382 subjects were studied based on data collected from the Texas Alzheimer's Research and Care Consortium (TARCC, N = 1320) and the Initial Study of Longevity and Dementia from the Rio Grande Valley (ISLD-RGV, N = 62). Questionnaires regarding demographics, medical history, and blood/saliva samples were collected. We genotyped the APOE gene. The current findings indicated that APOE-ε4 was associated with not only AD (p < 0.0001) but also with anxiety (p < 0.0001) and depression (p = 0.0004). However, APOE-ε3 was associated with depression (p = 0.002) in the Hispanic population. We provide additional evidence in which APOE-ε4 increased the risk for AD in Hispanics. For the first time, APOE alleles show increased risks for anxiety and depression in Hispanics. Further research is warranted to confirm the current findings.

Outcomes of comprehensive geriatric assessment and surgical management in head and neck cancers of the elderly: an observational study.

AIM: The aims of this study were to assess the survival benefit of optimal vs suboptimal management in elderly patients presenting with upper aerodigestive tract (UADT) cancer for which surgery was the standard of care, and determine if comprehensive geriatric assessment (CGA) was a prognostic factor for survival. MATERIALS AND METHODS: This single-center retrospective cohort study was conducted from January 2014 to December 2018. Included patients were aged 70 or older at the time of diagnosis, and presented with UADT cancer with a theoretical indication for curative-intent surgery according to international guidelines. RESULTS: A total of 188 patients were included, with a median age of 78 years. Treatment included surgery in 67.6% of cases and was considered optimal in 60.6% of patients. The overall 3-year survival was 55.2%, and was significantly better in case of optimal vs suboptimal treatment (74.5% vs 25.8%, p < 0.001). In univariate analysis, factors associated with a significantly improved 3-year survival included surgery (p < 0.001), age < 80 years, performance status < 2 and G8 score > 14. In multivariate analysis, CGA was associated with a better survival. CONCLUSIONS: In patients aged over 70 presenting with UADT cancer for which the standard of care is surgery, an optimal management is associated with better overall survival. Receiving a CGA seems to provide a survival benefit in patients with a G8 score ≤ 14, through an optimization of the care pathway before and after the cancer treatment.

APOE Gene Associated with Cholesterol-Related Traits in the Hispanic Population.

Genetic variants in the apolipoprotein E (APOE) gene are associated with lipid metabolism and lipid-related traits in the non-Hispanic population. There have been limited studies regarding the association between the APOE gene and hypercholesterolemia in the Hispanic population; therefore, our aim for this study is to examine the APOE gene's associations with cholesterol level and its related phenotypes. The APOE gene consists of three different alleles, ε2, ε3, and ε4, with ε4 being associated with dementia and cardiovascular diseases. A total of 1,382 subjects were collected from the Texas Alzheimer's Research and Care Consortium (TARCC, N = 1320) and the Initial Study of Longevity and Dementia from the Rio Grande Valley (ISLD-RGV, N = 62). Questionnaires on demographics, medical history, and blood/saliva samples were collected and APOE genotypes were performed. We observed allele frequencies of the APOE ε3 (96.7%), ε4 (22.6%) and ε2 (6.8%) alleles, respectively. Multivariable logistic regression revealed a significant association between the APOE ε4 allele and hypercholesteremia (p = 1.8 × 10-4) in our studied Hispanic population. We prove for the first time, that the APOE ε4 allele increases the risk for hypercholesterol in Hispanics. Further research is needed to confirm and supports our current findings.

Impact of a comprehensive geriatric assessment on decision-making in older patients with hematological malignancies.

OBJECTIVE: Hematological treatment decisions in older adults with hematological malignancies are complex. Our objective is to study the impact of a comprehensive geriatric assessment on hematological treatment decision in older patients and the factors associated with change in treatment plan. METHODS: We conducted a cross-sectional analysis of patients aged 65 years and above with hematological malignancies, hospitalized between 2008 and 2019 at the University Cancer Institute of Toulouse. They were assessed by a geriatrician/nurse team using a comprehensive geriatric assessment (CGA). A penalized logistic regression model with elastic net regularization was used to identify factors associated with change in hematological treatment plan. RESULTS: A total of 424 patients were included. Main hematological malignancies were lymphoma (36.1 %), acute myeloid leukemia (26.9 %) and myelodysplastic syndrome (19.8%). Change in hematological treatment plan was suggested after CGA for 92 patients (21.7%). Factors associated with change in treatment plan were functional impairment according to ADL and IADL scale, mobility impairment, the presence of comorbidity defined by the Charlson score >1 and increasing age. CONCLUSION: A CGA has a significant impact on hematological treatment decision in older patients. Functional and mobility impairment, comorbidities and age are predictive factors of change in treatment plan.

Hedgehog-FGF signaling axis patterns anterior mesoderm during gastrulation.

The mechanisms used by embryos to pattern tissues across their axes has fascinated developmental biologists since the founding of embryology. Here, using single-cell technology, we interrogate complex patterning defects and define a Hedgehog (Hh)-fibroblast growth factor (FGF) signaling axis required for anterior mesoderm lineage development during gastrulation. Single-cell transcriptome analysis of Hh-deficient mesoderm revealed selective deficits in anterior mesoderm populations, culminating in defects to anterior embryonic structures, including the pharyngeal arches, heart, and anterior somites. Transcriptional profiling of Hh-deficient mesoderm during gastrulation revealed disruptions to both transcriptional patterning of the mesoderm and FGF signaling for mesoderm migration. Mesoderm-specific Fgf4/Fgf8 double-mutants recapitulated anterior mesoderm defects and Hh-dependent GLI transcription factors modulated enhancers at FGF gene loci. Cellular migration defects during gastrulation induced by Hh pathway antagonism were mitigated by the addition of FGF4 protein. These findings implicate a multicomponent signaling hierarchy activated by Hh ligands from the embryonic node and executed by FGF signals in nascent mesoderm to control anterior mesoderm patterning.

Systematic Comparison of High-throughput Single-Cell and Single-Nucleus Transcriptomes during Cardiomyocyte Differentiation.

A comprehensive reference map of all cell types in the human body is necessary for improving our understanding of fundamental biological processes and in diagnosing and treating disease. High-throughput single-cell RNA sequencing techniques have emerged as powerful tools to identify and characterize cell types in complex and heterogeneous tissues. However, extracting intact cells from tissues and organs is often technically challenging or impossible, for example in heart or brain tissue. Single-nucleus RNA sequencing provides an alternative way to obtain transcriptome profiles of such tissues. To systematically assess the differences between high-throughput single-cell and single-nuclei RNA-seq approaches, we compared Drop-seq and DroNc-seq, two microfluidic-based 3' RNA capture technologies that profile total cellular and nuclear RNA, respectively, during a time course experiment of human induced pluripotent stem cells (iPSCs) differentiating into cardiomyocytes. Clustering of time-series transcriptomes from Drop-seq and DroNc-seq revealed six distinct cell types, five of which were found in both techniques. Furthermore, single-cell trajectories reconstructed from both techniques reproduced expected differentiation dynamics. We then applied DroNc-seq to postmortem heart tissue to test its performance on heterogeneous human tissue samples. Our data confirm that DroNc-seq yields similar results to Drop-seq on matched samples and can be successfully used to generate reference maps for the human cell atlas.

Low lean mass and chemotherapy toxicity risk in the elderly: the Fraction study protocol.

BACKGROUND: Half of cancer cases occur in patients aged 70 and above. Majority of older patients are eligible for chemotherapy but evidence for treating this population is sparse and severe toxicities affect more than half of them. Determining prognostic biomarkers able to predict poor chemotherapy tolerance remains one of the major issues in geriatric oncology. Ageing is associated with body composition changes (increase of fat mass and loss of lean mass) independently of weight-loss. Previous studies suggest that body composition parameters (particularly muscle mass) may predict poor chemotherapy tolerance. However, studies specifically including older adults on this subject remain sparse and the majority of them study body composition based on computed tomography (CT) scanner (axial L3 section) muscle mass estimation. This method is to date not validated in elderly cancer patients. METHODS: This trial (Fraction) will evaluate the discriminative ability of appendicular lean mass measured by dual-energy X-ray absorptiometry (DXA) to predict severe toxicity incidence in older cancer-patients treated with first-line chemotherapy. DXA is considered the gold standard in body composition assessment in older adults. Patient's aged ≥70 diagnosed with solid neoplasms or lymphomas at a locally advanced or metastatic stage treated for first-line chemotherapy were recruited. Patients completed a pre-chemotherapy assessment that recorded socio-demographics, tumor/treatment variables, laboratory test results, geriatric assessment variables (function, comorbidity, cognition, social support and nutritional status), oncological risk scores and body composition with DXA. Appendicular lean mass was standardized using evidence based international criteria. Participants underwent short follow-up geriatric assessments within the first 3 months, 6 months and a year after inclusion. Grade 3 to 5 chemotherapy-related toxicities, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) were assessed at each chemotherapy cycle. DISCUSSION: The finding that body composition is associated with poor tolerance of chemotherapy could lead to consider these parameters as well as improve current decision-making algorithms when treating older adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02806154 registered on October 2016.

Bronchial colonisation in patients with lung cancer: a prospective study.

Bronchial colonisation is frequently reported in patients with lung cancer, and has a potential impact on therapeutic management and prognosis. We aimed to prospectively define the prevalence and nature of bronchial colonisation in patients at the time of diagnosing lung cancer. 210 consecutive patients with lung cancer underwent a flexible bronchoscopy for lung cancer. The type and frequency of bacterial, mycobacterial and fungal colonisation were analysed and correlated with the patients' and tumours' characteristics. Potential pathogens were found in 48.1% of samples: mainly the Gram-negative bacilli Escherichia coli (8.1%), Haemophilus influenzae (4.3%) and Enterobacter spp. (2.4%); Gram-positive cocci, Staphylococcus spp. (12.9%) and Streptococcus pneumoniae (3.3%); atypical mycobacteria (2.9%); Candida albicans (42.9%); and Aspergillus fumigatus (6.2%). Aged patients (p=0.02) with chronic obstructive pulmonary disease (p=0.008) were significantly more frequently colonised; however, tumour stage, atelectasis, bronchial stenosis and abnormalities of chest radiography were not associated with a higher rate of colonisation. Squamous cell carcinoma tended to be more frequently colonised than other histological subtypes. Airway colonisation was reported in almost half of patients presenting with lung cancer, mainly in fragile patients, and was significantly associated with worse survival (p=0.005). Analysing colonisation status of patients at the time of diagnosis may help improve the management of lung cancer.