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Background: Long noncoding RNAs (lncRNAs) have surpassed the number of protein-coding genes, yet the majority have no known function. We previously discovered 844 lncRNAs that were genetically linked to breast cancer through genome-wide association studies (GWAS). Here, we show that a subset of these lncRNAs alter breast cancer risk by modulating cell proliferation, and provide evidence that a reduced expression on one lncRNA increases breast cancer risk through aberrant DNA replication and repair. Methods: We performed pooled CRISPR-Cas13d-based knockdown screens in breast cells to identify which of the 844 breast cancer-associated lncRNAs alter cell proliferation. We selected one of the lncRNAs that increased cell proliferation, KILR, for follow-up functional studies. KILR pull-down followed by mass spectrometry was used to identify binding proteins. Knockdown and overexpression studies were performed to assess the mechanism by which KILR regulates proliferation. Results: We show that KILR functions as a tumor suppressor, safeguarding breast cells against uncontrolled proliferation. The half-life of KILR is significantly reduced by the risk haplotype, revealing an alternative mechanism by which variants alter cancer risk. Mechanistically, KILR sequesters RPA1, a subunit of the RPA complex required for DNA replication and repair. Reduced KILR expression promotes breast cancer cell proliferation by increasing the available pool of RPA1 and speed of DNA replication. Conversely, KILR overexpression promotes apoptosis in breast cancer cells, but not normal breast cells. Conclusions: Our results confirm lncRNAs as mediators of breast cancer risk, emphasize the need to annotate noncoding transcripts in relevant cell types when investigating GWAS variants and provide a scalable platform for mapping phenotypes associated with lncRNAs. [ABSTRACT FROM AUTHOR]

The article discusses a study comparing the use of a laryngeal mask airway (LMA) versus tracheal intubation for surfactant administration in preterm infants. The study found that the LMA had a lower failure rate compared to tracheal intubation and demonstrated non-inferiority in terms of the primary outcome. The LMA method was found to be more user-friendly and required less training. However, the study's small sample size and methodological differences between groups limit the generalizability of the results. Further research is needed before these findings can be adopted into routine practice. [Extracted from the article]

The article discusses the management of patent ductus arteriosus (PDA) in extreme preterm infants. PDA is a common condition in these infants and its treatment is a subject of debate. The article presents the findings of the Baby-OSCAR trial, which compared early treatment with ibuprofen to placebo. The trial found that early treatment with ibuprofen did not reduce the risk of death or bronchopulmonary dysplasia. The article concludes that there is no evidence to support early treatment with ibuprofen for PDA in extreme preterm infants and that it may be more harmful than the condition itself. [Extracted from the article]

The article discusses a randomized controlled trial that compared the use of higher versus standard nasal continuous positive airway pressure (nCPAP) for extubation of extremely preterm infants. The study found that using a higher nCPAP level of 10cmH2O reduced the rate of extubation failure compared to standard nCPAP. However, there was no significant difference in rates of bronchopulmonary dysplasia (BPD) between the two groups. The authors suggest that further research is needed to evaluate the safety and efficacy of higher post-extubation nCPAP levels on important outcomes for clinicians and families. [Extracted from the article]

Infants with perinatal asphyxia and moderate-to-severe hypoxic ischemic encephalopathy (HIE) are currently treated with therapeutic hypothermia (TH) as part of a brain protective strategy. However, perinatal asphyxia is a risk factor for development of persistent pulmonary hypertension (PPHN). As such, the aim of this study was to quantify the risk of PPHN in infants undergoing TH and assess short-term outcomes in infants developing PPHN. All N = 59 infants undergoing TH for moderate-to-severe HIE over a period of 3 years (January 2020-December 2022) at a single center were included. PPHN was diagnosed in N = 10 (17%), with this deemed to have been exacerbated by TH in n = 6 (10%). Only 50% (5/10) with PPHN required inhaled nitric oxide, and none of the infants received extracorporeal membrane oxygenation. PPHN was not found to be significantly associated with short-term outcomes, including the extent of HIE on brain magnetic resonance imagings, in-hospital mortality or requirement for nasogastric feeding at discharge. In conclusion, TH appears to be a safe and effective treatment for moderate-to-severe HIE with or without PPHN.

Competing Interests: Competing interests: None declared.

Cerebral vasospasm (CV) is a significant complication following aneurysmal subarachnoid hemorrhage (aSAH), and lacks a comprehensive molecular understanding. Given the temporal trajectory of intracranial aneurysm (IA) formation, its rupture, and development of CV, altered gene expression might be a molecular substrate that runs through these clinical events, influencing both disease inception and progression. Utilizing RNA-Seq, we analyzed tissue samples from ruptured IAs with and without vasospasm to identify the dysregulated genes. In addition, temporal gene expression analysis was conducted. We identified seven dysregulated genes in patients with ruptured IA with vasospasm when compared with those without vasospasm. We found 192 common genes when the samples of each clinical subset of patients with IA, that is, unruptured aneurysm, ruptured aneurysm without vasospasm, and ruptured aneurysm with vasospasm, were compared with control samples. Among these common genes, TNFSF13B , PLAUR , OSM , and LAMB3 displayed temporal expression (progressive increase) with the pathological progression of disease that is formation of aneurysm, its rupture, and consequently the development of vasospasm. We validated the temporal gene expression pattern of OSM at both the transcript and protein levels and OSM emerges as a crucial gene implicated in the pathological progression of disease. In addition, RSAD2 and ATP1A2 appear to be pivotal genes for CV development. To the best of our knowledge, this is the first study to compare the transcriptome of aneurysmal tissue samples of aSAH patients with and without CV. The findings collectively provide new insights on the molecular basis of IA and CV and new leads for translational research.

Immunotherapy harnesses neoantigens encoded within the human genome, but their therapeutic potential is hampered by low expression, which may be controlled by the nonsense-mediated mRNA decay (NMD) pathway. This study investigates the impact of UPF1-knockdown on the expression of non-canonical/mutant proteins, employing proteogenomic to explore UPF1 role within the NMD pathway. Additionally, we conducted a comprehensive pan-cancer analysis of UPF1 expression and evaluated UPF1 expression in Triple-Negative Breast Cancer (TNBC) tissue in-vivo. Our findings reveal that UPF1-knockdown leads to increased translation of non-canonical/mutant proteins, particularly those originating from retained-introns, pseudogenes, long non-coding RNAs, and unannotated transcript biotypes. Moreover, our analysis demonstrates elevated UPF1 expression in various cancer types, with notably heightened protein levels in patient-derived TNBC tumors compared to adjacent tissues. This study elucidates UPF1 role in mitigating transcriptional noise by degrading transcripts encoding non-canonical/mutant proteins. Targeting this mechanism may reveal a new spectrum of neoantigens accessible to the antigen presentation pathway. Our novel findings provide a strong foundation for the development of therapeutic strategies aimed at targeting UPF1 or modulating the NMD pathway., (© 2024 Wiley-VCH GmbH.)

Background: Breast cancer is one of the leading causes of cancer deaths in women. Early diagnosis offers the best hope for a cure. Ductal carcinoma in situ is considered a precursor of invasive ductal carcinoma of the breast. In this study, we carried out microRNA sequencing from 7 ductal carcinoma in situ (DCIS), 6 infiltrating ductal carcinomas (IDC Stage IIA) with paired normal, and 5 unpaired normal breast tissue samples., Methods: We have deployed miRge for microRNA analysis, DESeq for differential expression analysis, and Cytoscape for competing endogenous RNA network investigation., Results: Here, we identified 76 miRNAs that were differentially expressed in DCIS and IDC. Additionally, we provide preliminary evidence of miR-365b-3p and miR-7-1-3p being overexpressed, and miR-6507-5p, miR-487b-3p, and miR-654-3p being downregulated in DCIS relative to normal breast tissue. We also identified a miRNA miR-766-3p that was overexpressed in earlystage IDCs. The overexpression of miR-301a-3p in DCIS and IDC was confirmed in 32 independent breast cancer tissue samples., Conclusion: Higher expression of miR-301a-3p is associated with poor overall survival in The Cancer Genome Atlas Breast Cancer (TCGA-BRCA) dataset, indicating that it may be associated with DCIS at high risk of progressing to IDC and warrants deeper investigation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)