Targeting the FGFR Pathway in Urothelial Carcinoma: the Future Is Now.

OPINION STATEMENT: As we come to better understand cancer genomics, we are increasingly shifting towards precision medicine. FGFR has been elucidated as one of the oncogenic driver pathways in urothelial carcinoma, leading to exciting targeted drug development. Although many agents are being investigated, erdafitinib is the only FGFR inhibitor currently approved by the FDA for treating platinum-refractory metastatic urothelial carcinoma harboring susceptible FGFR2/3 alterations, with seemingly higher response rates than second-line chemotherapy or immunotherapy. In this review, we summarize the clinical data supporting FGFR inhibition, ways to optimize its use in routine clinical practice including FGFR testing, dosing, and toxicity management. We also highlight ongoing efforts evaluating combination strategies and testing in earlier treatment settings to further expand this targeted therapeutic approach in urothelial carcinoma.

Uncovering cynicism in medical training: a qualitative analysis of medical online discussion forums.

OBJECTIVE: The development of cynicism in medicine, defined as a decline in empathy and emotional neutralisation during medical training, is a significant concern for medical educators. We sought to use online medical student discussion groups to provide insight into how cynicism in medicine is perceived, the consequences of cynicism on medical trainee development and potential links between the hidden curriculum and cynicism. SETTING: Online analysis of discussion topics in Premed101 (Canadian) and Student Doctor Network (American) forums. PARTICIPANTS: 511 posts from seven discussion topics were analysed using NVivo 11. Participants in the forums included medical students, residents and practising physicians. METHODS: Inductive content analysis was used to develop a data-driven coding scheme that evolved throughout the analysis. Measures were taken to ensure the trustworthiness of findings, including duplicate independent coding of a sub-sample of posts and the maintenance of an audit trail. RESULTS: Medical students, residents and practising physicians participating in the discussion forums engaged in discourse about cynicism and highlighted themes of the hidden curriculum resulting in cynicism. These included the progression of cynicism over the course of medical training as a coping mechanism; the development of challenging work environments due to factors such as limited support, hierarchical demands and long work hours; and the challenge of initiating change due to the tolerance of unprofessionalism and the highly stressful nature of medicine. CONCLUSION: Our unique study of North American medical discussion posts demonstrates that cynicism develops progressively and is compounded by conflicts between the hidden and formal curriculum. Online discussion groups are a novel resource to provide insight into the culture of medical training.

Postnatal dilatation of umbilical cord vessels and its impact on wall integrity: Prerequisite for the artificial placenta.

INTRODUCTION: A lung assist device, which acts as an artificial placenta, can provide additional gas exchange for preterm and term newborns with respiratory failure. The concept of the lung assist device requires a large bore access via umbilical vessels to allow pumpless extracorporeal blood flow rates up to 30 mL/kg/min. After birth, constricted umbilical vessels need to be reopened for vascular access. The objective is to study the impact of umbilical vessel expansion on vessel integrity for achieving large bore access. METHODS: Umbilical cords from healthy term deliveries were cannulated and dilatated with percutaneous transluminal angioplasty catheters in 1 mm increments from 4 to 8 mm for umbilical artery and from 4 to 15 mm for umbilical vein, n = 6 per expansion diameter. Paraffin-embedded transverse sections of dilated and control samples were HE & Van Gieson stained. Effects of dilatation, shown by splitting, were measured. RESULTS: Umbilical vessel expansion led to concentric splitting, shown by areas devoid of extracellular matrix and nuclei in the tunica intima and media. No radial splitting was observed. Results suggest an expansion threshold of umbilical artery at 6 mm and umbilical vein at 7 mm, while maximal splitting was observed above this threshold (3.6 ± 0.8%, p = 0.043 for umbilical artery 7 mm and 6.3 ± 1.8%, p = 0.048 for umbilical vein 8 mm). Endothelial cell sloughing was present in all dilated samples but not in the control samples. CONCLUSION: The suggested thresholds for safe expansions are similar to in utero umbilical vessel diameters and demonstrate a proof of concept for attaining large bore access for the lung assist device.

Time Dependent Distribution of MicroRNA 144 after Intravenous Delivery.

BACKGROUND: miR-144 has potential benefits in protecting against myocardial ischemia and suppression of tumor growth. We have previously shown that a single intravenous injection of miR-144 provides potent cardioprotection, but its kinetics and distribution are not known. METHODS: Single stranded mature miR-144 or Cy3-labelled-miR-144 was delivered into C57/B6 mice by tail vein injection. RESULTS: After intravenous injection, the signal of Cy3-labelled-miR-144 in the kidney, brain, heart and liver peaks at 60 minutes, and is predominantly localised to the endothelium at that stage. In the kidney and heart, Cy3-labelled-miR-144 signal is detectable within the parenchymal tissues for at least 3 days, after which it starts to decrease, but brain Cy3-miR-144 signal rapidly decreases after 1 hour, and is lost at day 1, with no parenchymal uptake detected. Cy3-miR-144 signal can be detected until day 28 in the liver. Stem loop RTPCR confirmed the temporal pattern shown by miR-144 in kidney, brain and heart, but in liver there was a continuous rise following the initial injection until day 28 with no signs of decrease, suggesting de-novo synthesis. CONCLUSION: There is early endothelial uptake of injected miR-144 followed by organ-specific distribution and kinetics. In the liver, there appears to be a positive feedback process that leads to continued accumulation of miR-144 that persists for at least 28 days. These observations should be taken into account when designing experiments utilizing parenteral miR-144 and assessing the biology of its actions.

Pulmonary vascular changes 22 years after single lung transplantation for pulmonary arterial hypertension: a case report with molecular and pathological analysis.

This study was undertaken to characterize the molecular and pathological mechanisms of pulmonary vascular remodeling in a patient who developed chronic lung allograft dysfunction and recurrent pulmonary hypertension (PH) 22 years after undergoing a right single lung transplantation for pulmonary arterial hypertension (PAH). Histopathologic examination of the explanted lungs at the time of retransplantation showed characteristics of diffuse vascular remodeling combined with features of acute and chronic thromboemboli and evidence of bronchiolitis obliterans in the right lung allograft. In contrast, the native left lung demonstrated pulmonary arterial changes in keeping with PAH associated with disseminated pulmonary ossification. Real-time polymerase chain reaction and Western blot-performed on the first lung allograft, the native lung, and the new donor lung-demonstrated increased expression of apoptotic-related gene and protein levels in the lung allograft compared with the native PAH lung and the donor lung. Localization of cell apoptosis determined by triple immunostaining for caspase 3, CD31, and smooth muscle actin was positive in the pulmonary endothelial cells but not the smooth muscle cells of the lung allograft, while no positive staining was detected for cell death in the native PAH lung. The presence of PH in the lung allograft 22 years after transplantation was associated with upregulation of apoptotic markers and evidence of apoptotic endothelial cell death compared with the native lung and donor lung.

A Biochemical Approach to Understand the Pathogenesis of Advanced Pulmonary Arterial Hypertension: Metabolomic Profiles of Arginine, Sphingosine-1-Phosphate, and Heme of Human Lung.

Pulmonary arterial hypertension (PAH) is a vascular disease characterized by persistent precapillary pulmonary hypertension (PH), leading to progressive right heart failure and premature death. The pathological mechanisms underlying this condition remain elusive. Analysis of global metabolomics from lung tissue of patients with PAH (n = 8) and control lung tissue (n = 8) leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted arginine pathways with increased Nitric oxide (NO) and decreased arginine. Our results also showed specific metabolic pathways and genetic profiles with increased Sphingosine-1-phosphate (S1P) metabolites as well as increased Heme metabolites with altered oxidative pathways in the advanced stage of the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to the vascular remodeling in severe pulmonary hypertension. Profiling metabolomic alterations of the PAH lung has provided a new understanding of the pathogenic mechanisms of PAH, which benefits therapeutic targeting to specific metabolic pathways involved in the progression of PAH.

De novo synthesize of bile acids in pulmonary arterial hypertension lung.

Although multiple, complex molecular studies have been done for understanding the development and progression of pulmonary hypertension (PAH), little is known about the metabolic heterogeneity of PAH. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we found bile acid metabolites, which are normally product derivatives of the liver and gallbladder, were highly increased in the PAH lung. Microarray showed that the gene encoding cytochrome P450 7B1 (CYP7B1), an isozyme for bile acid synthesis, was highly expressed in the PAH lung compared with the control. CYP7B1 protein was found to be primarily localized on pulmonary vascular endothelial cells suggesting de novo bile acid synthesis may be involved in the development of PAH. Here, by profiling the metabolomic heterogeneity of the PAH lung, we reveal a newly discovered pathogenesis mechanism of PAH.

Metabolomic heterogeneity of pulmonary arterial hypertension.

Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH.