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Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLCs potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.

Background: Establishing an efficient multidisciplinary team for transferred postpartum haemorrhage (PPH) cases is challenging due to limited clinical exposure. We hypothesised that leveraging trauma team experience could effectively facilitate the development of such a team within a short timeframe. Methods: In September 2019, a multidisciplinary team was established at our tertiary care centre to provide rapid management of critical PPH cases transferred from the obstetric clinic, prioritising immediate resuscitation and haemostatic interventions. This historical cohort study (2017–2022) compared outcomes before (2017–2018, before group [BG]) and after (2019–2022, after group [AG]) team establishment. Outcomes included process-related quality indicators, clinical measures such as length of hospital stay, intensive care unit (ICU) days, presence of the lethal triad, and hysterectomy rate. Results: Of the 71 PPH patients transferred during the study period, 24 were in the BG and 47 in the AG. The AG demonstrated higher use of tranexamic acid (33.33% vs. 74.47%, P = 0.002), shorter time to the first blood transfusion (11 vs. 8 min, P = 0.029), and increased rates of arrival in the operating room within 60 min (25% vs. 80%, P = 0.014). Clinical outcomes showed reduced rates of cardiopulmonary resuscitation (16.67% vs. 0%, P = 0.011) and shorter ICU stays (4 vs. 1 day, P = 0.005) in the AG. Conclusions: Leveraging trauma team expertise is an effective strategy for establishing a multidisciplinary PPH team, significantly improving outcomes for critically ill PPH patients transferred from obstetric clinics. [ABSTRACT FROM AUTHOR]

Objectives: We aim to study the relative viral load using salivary polymerase chain reaction among pregnant women treated with Paxlovid. Methods: Pregnant women with coronavirus disease 2019 were allocated to two groups: those receiving Paxlovid and those receiving no antiviral agents. We compared the nasopharyngeal and salivary relative viral loads and their changes in saliva specimens. Results: Among the thirty-seven pregnant women, seventeen received Paxlovid, and twenty received no antiviral agents. The viral cycle threshold value of saliva was significantly higher than that from nasopharynx, with a median ± interquartile range of 26.44 ± 7.68 versus 17.6 ± 9.6 in the Paxlovid group (p = 0.005). Following treatment, the median salivary viral load decreased by 13.40 cycle threshold values in the Paxlovid group (from a median of [Day 0 Ct] to [Day 4/5 Ct]), compared to a change of −1.59 cycle threshold values in the no-antiviral group (from a median of [Day 0 Ct] to [Day 4/5 Ct]) (p = 0.021). The detection rate of coronavirus disease 2019 using salivary polymerase chain reaction was 83.8% (31/37). Conclusions: This study showed that saliva is a useful diagnostic tool for coronavirus disease 2019 in pregnant women, and a significant decrease in the relative viral load of saliva was observed in those treated with Paxlovid. [ABSTRACT FROM AUTHOR]

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease. Schematic was created with BioRender.com. Author summary: Fibrolamellar carcinoma (FLC) is a lethal liver cancer that is characterized by the DNAJB1-PRKACA (DP fusion) oncogene. This disease is particularly challenging to treat as it lacks non-invasive diagnostic biomarkers, known risk factors, and effective therapeutic options. Patients with FLC have a median age of 22 years and the prognosis is poor. In this study, we examined FLC tumors from independent patient cohorts and multiple disease models and found consistently elevated levels of a primate-specific long noncoding RNA named LINC00473. By leveraging single-cell analysis on patient tumors, we found that LINC00473 is enriched in tumor epithelial cells. Using multiple FLC models, we show that the DP fusion drives LINC00473 expression and that LINC00473 promotes FLC growth by mitigating cell death. We also show that LINC00473 modulates FLC energetics by increasing glycolysis and altering mitochondrial fitness. Together, this study unveils an important mechanism downstream of the signature DP fusion oncogene in FLC pathogenesis. [ABSTRACT FROM AUTHOR]