Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinicopathological-Associated Regulatory Network of Deregulated circRNAs in Hepatocellular Carcinoma

Simple Summary Here, we present a novel strategy to identify key signatures of clinically-relevant co-expressed circRNA-mRNA networks in pertinent cancer-pathways that modulate the prognosis of HCC patients, by integrating clinicopathological features, circRNA and mRNA expression profiles. Five master circRNAs were identified and experimentally demonstrated to upregulate proliferate and promote transformation. Through further integration with miRNA-expression profiles, clinically-relevant competing-endogenous-RNA (ceRNA) networks of circRNA-miRNA-mRNAs were constructed. The most up-regulated nodal-circRNA, circGPC3 was experimentally demonstrated to up-regulate cell-cycle, migration and invasion. circGPC3 was found to act as a sponge of miR-378a-3p to regulate ASPM expression and modulate cell transformation. These 5 nodal circRNAs has potential to be good prognostic biomarkers with good prognostic performance. circGPC3 has great potential to be a promising non-invasive prognostic biomarker for early HCC. We have thus demonstrated the robustness of bioinformatically-predicted master circRNAs in clinically-relevant, circRNA-mRNA networks, underscoring the important roles that these identified deregulated key/master circRNAs play in HCC. Abstract Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Here, we present a novel strategy to identify key circRNA signatures of clinically relevant co-expressed circRNA-mRNA networks in pertinent cancer-pathways that modulate prognosis of HCC patients, by integrating clinic-pathological features, circRNA and mRNA expression profiles. Through further integration with miRNA expression profiles, clinically relevant competing-endogenous-RNA (ceRNA) networks of circRNA-miRNA-mRNAs were constructed. At least five clinically relevant nodal-circRNAs, co-expressed with numerous genes, were identified from the circRNA-mRNA networks. These nodal circRNAs upregulated proliferation (except circRaly) and transformation in cells. The most upregulated nodal-circRNA, circGPC3, associated with higher-grade tumors and co-expressed with 33 genes, competes with 11 mRNAs for two shared miRNAs. circGPC3 was experimentally demonstrated to upregulate cell-cycle and migration/invasion in both transformed and non-transformed liver cell-lines. circGPC3 was further shown to act as a sponge of miR-378a-3p to regulate APSM (Abnormal spindle-like microcephaly associated) expression and modulate cell transformation. This study identifies 5 key nodal master circRNAs in a clinically relevant circRNA-centric network that are significantly associated with poorer prognosis of HCC patients and promotes tumorigenesis in cell-lines. The identification and characterization of these key circRNAs in clinically relevant circRNA-mRNA and ceRNA networks may facilitate the design of novel strategies targeting these important regulators for better HCC prognosis.
CC Chemokine Ligand 7 Derived from Cancer-Stimulated Macrophages Promotes Ovarian Cancer Cell Invasion

Simple Summary Ovarian cancer is the most lethal of gynecological malignancies. Although metastasis leads to a bleak prognosis and high mortality, the molecular and cellular processes of ovarian cancer metastasis remain largely unclear. Non-malignant cells including macrophages constitute a unique microenvironment that can completely change the nature of malignant cells at various levels. In this study, we found that the expression of chemokine (C-C motif) ligand 7 (CCL7), a soluble inflammatory factor, was enhanced in macrophages stimulated by human ovarian cancer cells as well as peritoneal macrophages from patients with ovarian cancer; CCL7 promoted the invasion of ovarian cancer cells. Our study elucidates the crosstalk between macrophages and ovarian cancer cells that contributes to ovarian cancer metastasis. Abstract In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.
Role and Perspective of Molecular Simulation-Based Investigation of RNA–Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding

Aberrant RNA–protein complexes are formed in a variety of diseases. Identifying the ligands that interfere with their formation is a valuable therapeutic strategy. Molecular simulation, validated against experimental data, has recently emerged as a powerful tool to predict both the pose and energetics of such ligands. Thus, the use of molecular simulation may provide insight into aberrant molecular interactions in diseases and, from a drug design perspective, may allow for the employment of less wet lab resources than traditional in vitro compound screening approaches. With regard to basic research questions, molecular simulation can support the understanding of the exact molecular interaction and binding mode. Here, we focus on examples targeting RNA–protein complexes in neurodegenerative diseases and viral infections. These examples illustrate that the strategy is rather general and could be applied to different pharmacologically relevant approaches. We close this study by outlining one of these approaches, namely the light-controllable association of small molecules with RNA, as an emerging approach in RNA-targeting therapy.
The Risk of Hospitalization in COVID-19 Patients Can Be Predicted by Lung Ultrasound in Primary Care

Background: The usefulness of Lung Ultrasound (LUS) for the diagnosis of interstitial syndrome caused by COVID-19 has been broadly described. The aim of this study was to evaluate if LUS may predict the complications (hospital admission) of COVID-19 pneumonia in primary care patients. Methods: This observational study collects data from a cohort of 279 patients with clinical symptoms of COVID-19 pneumonia who attended the Balaguer Primary Health Care Area between 16 March 2020 and 30 September 2020. We collected the results of LUS scans reported by one general practitioner. We created a database and analysed the absolute and relative frequencies of LUS findings and their association with hospital admission. We found that different LUS patterns (diffuse, attenuated diffuse, and predominantly unilateral) were risk factors for hospital admission (p < 0.05). Additionally, an evolutionary pattern during the acute phase represented a risk factor (p = 0.0019). On the contrary, a normal ultrasound pattern was a protective factor (p = 0.0037). Finally, the presence of focal interstitial pattern was not associated with hospital admission (p = 0.4918). Conclusion: The lung ultrasound was useful to predict complications in COVID-19 pneumonia and to diagnose other lung diseases such as cancer, tuberculosis, pulmonary embolism, chronic interstitial pneumopathy, pleuropericarditis, pneumonia or heart failure.
Early Survival Prediction Framework in CD19-Specific CAR-T Cell Immunotherapy Using a Quantitative Systems Pharmacology Model

Simple Summary Treatment with chimeric antigen receptor (CAR)-T cells has improved the prognosis of patients with non-Hodgkin lymphoma (NHL) substantially. Yet, as up to 60% of patients eventually relapse, insights into factors determining treatment response are highly warranted. We used mathematical modeling to characterize typical and individual concentration–time profiles of four different CAR-T cell subtypes and tumor burden in 19 NHL patients and investigated patient-/therapy-related factors associated with poor survival. A low CAR-T cell maximum expansion capacity and no previous autologous stem cell transplantation were associated with a poor prognosis. We next translated our most important model parameter into a clinical composite score, which leverages but does not require the use of the model. Based on our clinical data, we propose a clinical composite score cut-off value for early survival prediction. Additional data will be needed to update and refine the developed model and the proposed clinical composite score cut-off value. Abstract Chimeric antigen receptor (CAR)-T cell therapy has revolutionized treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). However, since 36–60% of patients relapse, early response prediction is crucial. We present a novel population quantitative systems pharmacology model, integrating literature knowledge on physiology, immunology, and adoptive cell therapy together with 133 CAR-T cell phenotype, 1943 cytokine, and 48 metabolic tumor measurements. The model well described post-infusion concentrations of four CAR-T cell phenotypes and CD19+ metabolic tumor volume over 3 months after CAR-T cell infusion. Leveraging the model, we identified a low expansion subpopulation with significantly lower CAR-T cell expansion capacities amongst 19 NHL patients. Together with two patient-/therapy-related factors (autologous stem cell transplantation, CD4+/CD8+ T cells), the low expansion subpopulation explained 2/3 of the interindividual variability in the CAR-T cell expansion capacities. Moreover, the low expansion subpopulation had poor prognosis as only 1/4 of the low expansion subpopulation compared to 2/3 of the reference population were still alive after 24 months. We translated the expansion capacities into a clinical composite score (CCS) of ‘Maximum naïve CAR-T cell concentrations/Baseline tumor burden’ ratio and propose a CCSTN-value > 0.00136 (cells·µL−1·mL−1 as predictor for survival. Once validated in a larger cohort, the model will foster refining survival prediction and solutions to enhance NHL CAR-T cell therapy response.
Monitoring of Changes in Masticatory Muscle Stiffness after Gum Chewing Using Shear Wave Elastography

This study aimed to investigate if intensive exercise affects the stiffness of the masticatory muscles measured with shear-wave elastography. The study included a cohort of healthy adults (n = 40) aged 40 ± 11 years. In each individual, the stiffness of both the masseter and temporalis muscle was examined three times: at baseline, after 10 min of intensive exercise (chewing gum), and after 10 min of relaxation. Stiffness values (median (IQR)) of both the masseter and temporalis muscle were the lowest at the baseline (11.35 (9.7–12.65) and 10.1 (9.1–10.95)), increased significantly after the exercise (12.5 (11.1–13.25) and 10.3 (10.2–10.52)) and then dropped significantly after 10 min of relaxing (11.75 (9.95–12.6) and 10.2 (9.65–11.9)). The stiffness of the temporalis muscle was significantly lower than that of the masseter muscle. The values of the stiffness of the masseters correlated significantly with the values of the stiffness of the temporalis muscles. Shear wave elastography proved to be a sensitive method for showing changes in the stiffness of the muscles involved in the mastication occurring as a response to the effort, which increased the muscle stiffness. Further research is needed to broaden knowledge on the impact of eating habits and the occurrence of parafunctions on the development of temporomandibular disorders and the condition of masticatory muscles.
Incidence, Risk, and Visual Outcomes after Repositioning of Acute Non-Traumatic Flap Dislocations Following Femtosecond-Assisted LASIK

Although the use of femtosecond lasers instead of mechanical devices has decreased the incidence of flap complications following laser-assisted in situ keratomileusis (LASIK), dislocations and striae still occur. Flap repositioning is an effective intervention to improve visual outcomes after acute flap complications in both microkeratome-assisted and femtosecond-assisted LASIK. This retrospective case series included patients undergoing flap repositioning secondary to acute flap dislocation and/or visually significant striae within the first two weeks following femtosecond LASIK (FS-LASIK) from 2015 to 2020 at a single institution. Preoperative, intraoperative, and postoperative de-identified data were analyzed for incidence, risk factors, and visual acuity outcomes. The incidence of flap repositioning was 0.35% in 21,536 eyes (n = 70). Indications for repositioning included acute flap dislocation (35.7%) and visually significant striae (64.3%). High myopia (OR = 3.04, p = 0.001) and patient age over 50 years (OR = 3.69, p = 0.001) were the strongest risk factors for these complications. Prior to flap repositioning, uncorrected distance visual acuity (UDVA) of 20/20 or better and 20/40 or better occurred in 19% and 57% of eyes, respectively. After repositioning, a final UDVA of 20/20 or better and 20/40 or better occurred in 78% and 98% of eyes, respectively. After repositioning, one line of UDVA was lost in two eyes (2.8%) and two lines were lost in one eye (1.4%). Risk factors for acute flap dislocation included high myopia and age over 50 years. Flap repositioning was effective in salvaging visual outcomes.
Trends and Age-Period-Cohort Effects on the Prevalence, Incidence and Mortality of Hepatocellular Carcinoma from 2008 to 2017 in Tianjin, China

Objectives: China is the country most afflicted by hepatocellular carcinoma in the world. However, little is known about the epidemiology of hepatocellular carcinoma in China. This study aimed to examine the trends of the prevalence, incidence, and mortality of hepatocellular carcinoma in China, and to investigate the effects of age, period, and birth cohort on the epidemiological trend. Methods: The data were obtained from the Urban Employee Basic Medical Insurance claims database (2003–2017) in Tianjin, China, which covers 5.95 million individuals. The average annual percentage change of the prevalence, incidence, and mortality were accessed using joinpoint regression. Age-period-cohort models were produced to quantify the effects of age, period, and cohort. Results: The hepatocellular carcinoma prevalence rate increased by 5.13% annually from 20.12/100,000 in 2008 to 30.49/100,000 in 2017, and the incidence rate was almost unchanged, from 13.91/100,000 in 2008 to 14.09/100,000 in 2017, but mortality decreased by 1.80% annually from 8.18/100,000 in 2008 to 7.34/100,000 in 2017. The age-period-cohort analysis revealed that the prevalence rate was remarkably increased from age 25, peaked in age 60, and decreased at age 70 and over. In the period index, the prevalence rate increased gradually from 2008 to 2016, and decreased a little in 2017. In the cohort index, the prevalence rate decreased approximately linearly from the 1925 cohort to the 1990 cohort. The result for the incidence was similar to the prevalence. The mortality rate increased approximately linearly from age 45 to 85, decreased from the 1925 cohort to the 1990 cohort, but it changed a little with the change of period. Conclusions: The findings of this study could inform the necessity of conducting earlier screening for high-risk individuals and improving the treatment of hepatocellular carcinoma, which may also help to predict future changes in hepatocellular carcinoma epidemiology.
Gemcitabine/Nab-Paclitaxel versus FOLFIRINOX in Locally Advanced Pancreatic Cancer: A European Multicenter Study

Simple Summary Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line therapies for metastatic pancreatic cancer (PC) but have rarely been compared, especially in patients with locally advanced PC (LAPC). By carefully selecting patients, it is likely these two regimens lead to similar survival outcomes. Through a multicenter European study, biases regarding practice habits are reduced. Hence, we observed no difference between GN and FFX as first-line treatments in patients with LAPC in terms of either survival, tumor response or tumor resection rate. Further trials are needed to confirm these data. Abstract Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line therapies for metastatic pancreatic cancer (PC) but have rarely been compared, especially in patients with locally advanced PC (LAPC). Methods: This is a retrospective European multicenter study including patients with LAPC treated with either GN or FFX as the first-line therapy between 2010 and 2019. Coprimary objectives were progression-free survival (PFS) and overall survival (OS), both estimated using the Kaplan–Meier method. Results: A total of 147 patients (GN: n = 60; FFX: n = 87) were included. Tumor resection rates were similar between the two groups (16.7% vs. 16.1%; p = 1), with similar R0 resection rates (88.9%). Median PFS rates were not statistically different: 9 months (95% CI: 8–13.5) vs. 12.1 months (95% CI: 10.1–14.6; p = 0.8), respectively. Median OS rates were 15.7 months (95% CI: 12.6–20.2) and 16.7 months (95% CI: 14.8–20.4; p = 0.7), respectively. Abdominal pain at the baseline (HR = 2.03, p = 0.03), tumors located in the tail of the pancreas (HR = 4.35, p = 0.01), CA19-9 > 200 UI/L (HR = 2.03, p = 0.004) and tumor resection (HR = 0.37, p = 0.007) were independent prognostic factors for PFS, similarly to OS. CA19-9 ≤ 200 UI/L (OR = 2.6, p = 0.047) was predictive of the tumor response. Consolidation chemoradiotherapy, more often used in the FFX group (11.7% vs. 50.6%; p < 0.001), was not predictive. Conclusion: This retrospective study did not show any difference between GN and FFX as the first-line treatment in patients with LAPC.
Ideal Cardiovascular Health in Former Smokers

Former smokers remain at increased risk for cardiovascular diseases compared to never smokers, but have lower risk than current smokers. We therefore hypothesized that former smokers would have an ideal cardiovascular health phenotype that was intermediate between current and never smokers. Differences in ideal cardiovascular health between never (n = 1025), former (n = 428), and current (n = 108) smokers were evaluated in the My Research Legacy study, which collected cardiovascular health data from the Life’s Simple 7 survey and digital health devices. Former smokers had a higher burden of prevalent cardiovascular disease, hypertension, diabetes mellitus, and hypercholesterolemia compared to current and never smokers (all p < 0.01). Former smokers’ Life’s Simple 7 Health Scores, a measure of ideal cardiovascular health, were intermediate between current and never smokers (4.9 ± 1.3 vs. 6.3 ± 1.5 vs. 7.0 ± 1.4, p < 0.01). As former smokers shared similarities with both current and never smokers, we performed a cluster analysis, which identified two phenogroups of former smokers. The phenogroups differed significantly across all 7 cardiovascular health and behavior categories (all p < 0.01). These findings suggest that former smokers are a heterogeneous group and increased attention to cardiovascular health factors and behaviors is warranted to achieve ideal cardiovascular health.
Vitamin K2 as a New Modulator of the Ceramide De Novo Synthesis Pathway

The aim of the study was to evaluate the influence of vitamin K2 (VK2) supplementation on the sphingolipid metabolism pathway in palmitate-induced insulin resistant hepatocytes. The study was carried out on human hepatocellular carcinoma cells (HepG2) incubated with VK2 and/or palmitic acid (PA). The concentrations of sphingolipids were measured by high-performance liquid chromatography. The expression of enzymes from the sphingolipid pathway was assessed by Western blotting. The same technique was used in order to determine changes in the expression of the proteins from the insulin signaling pathway in the cells. Simultaneous incubation of HepG2 cells with palmitate and VK2 elevated accumulation of sphinganine and ceramide with increased expression of enzymes from the ceramide de novo synthesis pathway. HepG2 treatment with palmitate and VK2 significantly decreased the insulin-stimulated expression ratio of insulin signaling proteins. Moreover, we observed that the presence of PA w VK2 increased fatty acid transport protein 2 expression. Our study showed that VK2 activated the ceramide de novo synthesis pathway, which was confirmed by the increase in enzymes expression. VK2 also intensified fatty acid uptake, ensuring substrates for sphingolipid synthesis through the de novo pathway. Furthermore, increased concentration of sphingolipids, mainly sphinganine, inhibited insulin pathway proteins phosphorylation, increasing insulin resistance development.
Cortactin Is Required for Efficient FAK, Src and Abl Tyrosine Kinase Activation and Phosphorylation of Helicobacter pylori CagA

Cortactin is a well-known regulatory protein of the host actin cytoskeleton and represents an attractive target of microbial pathogens like Helicobacter pylori. H. pylori manipulates cortactin’s phosphorylation status by type-IV secretion-dependent injection of its virulence protein CagA. Multiple host tyrosine kinases, like FAK, Src, and Abl, are activated during infection, but the pathway(s) involved is (are) not yet fully established. Among them, Src and Abl target CagA and stimulate tyrosine phosphorylation of the latter at its EPIYA-motifs. To investigate the role of cortactin in more detail, we generated a CRISPR/Cas9 knockout of cortactin in AGS gastric epithelial cells. Surprisingly, we found that FAK, Src, and Abl kinase activities were dramatically downregulated associated with widely diminished CagA phosphorylation in cortactin knockout cells compared to the parental control. Together, we report here a yet unrecognized cortactin-dependent signaling pathway involving FAK, Src, and Abl activation, and controlling efficient phosphorylation of injected CagA during infection. Thus, the cortactin status could serve as a potential new biomarker of gastric cancer development.