Biology of childhood hepatoblastoma and the search for novel treatments.

Our research laboratory has a longstanding interest in developmental disorders and embryonic tumors, and recent efforts have focused on the pathogenesis of pediatric liver tumors. This review focuses on hepatoblastoma (HB), the most common pediatric liver malignancy. Despite advances in treatment, patients with metastatic HB have a poor prognosis, and survivors often have permanent side effects attributable to chemotherapy.

Deep learning quantification reveals a fundamental prognostic role for ductular reaction in biliary atresia.

Background: We aimed to quantify ductular reaction (DR) in biliary atresia using a neural network in relation to underlying pathophysiology and prognosis.

Methods: Image-processing neural network model was applied to 259 cytokeratin-7-stained native liver biopsies of patients with biliary atresia and 43 controls. The model quantified total proportional DR (DR%) composed of portal biliary epithelium (BE%) and parenchymal intermediate hepatocytes (PIH%).

Bacterial translocation markers and toll-like receptors in biliary atresia following successful portoenterostomy.

Aim: The gut-liver axis may contribute to pathophysiology of cholestatic liver disorders like biliary atresia (BA) by bacterial translocation (BT). Toll-like receptors (TLR) are pattern recognition receptors known to activate innate immunity and secretion of inflammatory cytokines. Herein, we examined BT-associated biomarkers and TLRs in relation to liver injury after successful portoenterostomy (SPE) in BA.

expression is elevated in hepatoblastoma and correlates with inferior patient survival.

Hepatoblastoma (HB) is the most common malignant liver tumor among children. To gain insight into the pathobiology of HB, we performed RNA sequence analysis on 5 patient-derived xenograft lines (HB-243, HB-279, HB-282, HB-284, HB-295) and 1 immortalized cell line (HUH6). Using cultured hepatocytes as a control, we found 2,868 genes that were differentially expressed in all of the HB lines on mRNA level.

SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration.

Background: In response to hypoxia, tumor cells undergo transcriptional reprogramming including upregulation of carbonic anhydrase (CA) IX, a metalloenzyme that maintains acid-base balance. CAIX overexpression has been shown to correlate with poor prognosis in various cancers, but the role of this CA isoform in hepatoblastoma (HB) has not been examined.

Methods: We surveyed the expression of CAIX in HB specimens and assessed the impact of SLC-0111, a CAIX inhibitor, on cultured HB cells in normoxic and hypoxic conditions.

Serum FGF19 predicts outcomes of Kasai portoenterostomy in biliary atresia.

Background And Aims: Outcomes after Kasai portoenterostomy (KPE) for biliary atresia remain highly variable for unclear reasons. As reliable early biomarkers predicting KPE outcomes are lacking, we studied the prognostic value of FGF19.

Approach And Results: Serum and liver specimens, obtained from biliary atresia patients (N=87) at KPE or age-matched cholestatic controls (N=26) were included.

Analysis of Non-Relapsed and Relapsed Adult Type Granulosa Cell Tumors Suggests Stable Transcriptomes during Tumor Progression.

Adult-type granulosa cell tumor (AGCT) is a rare ovarian malignancy characterized by slow growth and hormonal activity. The prognosis of AGCT is generally favorable, but one-third of patients with low-stage disease experience a late relapse, and over half of them die of AGCT. To identify markers that would distinguish patients at risk for relapse, we performed Lexogen QuantSeq 3' mRNA sequencing on formalin-fixed paraffin-embedded, archival AGCT tissue samples tested positive for the pathognomonic Forkhead Box L2 () mutation.

Liver secretin receptor predicts portoenterostomy outcomes and liver injury in biliary atresia.

Biliary atresia (BA) is a chronic neonatal cholangiopathy characterized by fibroinflammatory bile duct damage. Reliable biomarkers for predicting native liver survival (NLS) following portoenterostomy (PE) surgery are lacking. Herein we explore the utility of 22 preidentified profibrotic molecules closely connected to ductular reaction (DR) and prevailing after successful PE (SPE), in predicting PE outcomes and liver injury.

Simulation-based design study for the passive shielding of the COSINUS dark matter experiment.

The COSINUS (Cryogenic Observatory for SIgnatures seen in Next-generation Underground Searches) experiment aims at the detection of dark matter-induced recoils in sodium iodide (NaI) crystals operated as scintillating cryogenic calorimeters. The detection of both scintillation light and phonons allows performing an event-by-event signal to background discrimination, thus enhancing the sensitivity of the experiment. The choice of using NaI crystals is motivated by the goal of probing the long-standing DAMA/LIBRA results using the same target material.

Neutrophil gelatinase-associated lipocalin does not originate from the kidney during reperfusion in clinical renal transplantation.

Background: Acute Kidney Injury (AKI) is a common clinical complication. Plasma/serum neutrophil gelatinase-associated lipocalin (NGAL) has been proposed as a rapid marker of AKI. However, NGAL is not kidney-specific.

FOXL2 in adult-type granulosa cell tumour of the ovary: oncogene or tumour suppressor gene?

A recurrent mutation in FOXL2 (c.402C>G; p.C134W) is present in over 95% of adult-type granulosa cell tumours (AGCTs).

Neuropilin-2 Is Associated With Increased Hepatoblastoma Cell Viability and Motility.

The neuropilins NRP1 and NRP2 are multifunctional glycoproteins that have been implicated in several cancer-related processes including cell survival, migration, and invasion in various tumor types. Here, we examine the role of neuropilins in hepatoblastoma (HB), the most common pediatric liver malignancy. Using a combination of immunohistochemistry, RNA analysis and western blotting, we observed high level expression of and in 19 of 20 HB specimens and in a majority of human HB cell lines (HUH6 and five cell lines established from patient-derived xenografts) studied but not in normal hepatocytes.

Prognostic and Pathophysiologic Significance of IL-8 (CXCL8) in Biliary Atresia.

Interleukin (IL)-8 (CXCL8), a chemokine involved in neutrophil recruitment, has been implicated in ductular reaction and liver fibrogenesis. We studied liver and serum IL-8 expression in a large biliary atresia (BA) cohort and explored its prognostic and pathophysiological potential. IL-8 expression was assessed in liver utilizing quantitative polymerase chain reaction (qPCR), immunohistochemistry and in situ hybridization and in serum using an enzyme-linked immunosorbent assay, among 115 BA patients, 10 disease controls and 68 normal controls.

Evolving Up-regulation of Biliary Fibrosis-Related Extracellular Matrix Molecules After Successful Portoenterostomy.

Successful portoenterostomy (SPE) improves the short-term outcome of patients with biliary atresia (BA) by relieving cholestasis and extending survival with native liver. Despite SPE, hepatic fibrosis progresses in most patients, leading to cirrhosis and a deterioration of liver function. The goal of this study was to characterize the effects of SPE on the BA liver transcriptome.

Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Patient Granulosa Cell Tumor Cells In Vitro.

Granulosa cell tumors (GCT) constitute only ~5% of ovarian neoplasms yet have significant consequences, as up to 80% of women with recurrent GCT will die of the disease. This study investigated the effectiveness of procaspase-activating compound 1 (PAC-1), an activator of procaspase-3, in treating adult GCT (AGCT) in combination with selected apoptosis-inducing agents. Sensitivity of the AGCT cell line KGN to these drugs, alone or in combination with PAC-1, was tested using a viability assay.

Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage.

During late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development.

GATA6 modulates the ductular reaction to bile duct ligation.

Background: GATA6, a transcription factor expressed in cholangiocytes, has been implicated in the response to liver injury. In biliary atresia, a disease characterized by extrahepatic bile duct obstruction, liver expression of GATA6 increases with pathological bile duct expansion and decreases after successful Kasai portoenterostomy. The aim of this study was to garner genetic evidence that GATA6 is involved in ductular formation/expansion.

Compromised duodenal mucosal integrity in children with short bowel syndrome after adaptation to enteral autonomy.

Background: Intestinal adaptation has been extensively studied experimentally, but very limited data is available on human subjects. In this study we assessed intestinal adaption in humans with short bowel syndrome (SBS).

Methods: We comparatively evaluated mucosal hyperplasia, inflammation, barrier function and nutrient transport using histology, immunohistochemistry and qPCR for selected 52 key genes in duodenal biopsies obtained from children with SBS after weaning off parenteral nutrition (n = 33), and matched controls without intestinal pathology (n = 12).

Type 1 tyrosinemia in Finland: a nationwide study.

Background: Introduction of nitisinone and newborn screening (NBS) have transformed the treatment of type 1 tyrosinemia, but the effects of these changes on the long-term outcomes remain obscure. Also, the predictors for later complications, the significance of drug levels and the normalization of laboratory and imaging findings are poorly known. We investigated these issues in a nationwide study.

Chloroquine Triggers Cell Death and Inhibits PARPs in Cell Models of Aggressive Hepatoblastoma.

Hepatoblastoma (HB) is the most common pediatric liver malignancy. Despite advances in chemotherapeutic regimens and surgical techniques, the survival of patients with advanced HB remains poor, underscoring the need for new therapeutic approaches. Chloroquine (CQ), a drug used to treat malaria and rheumatologic diseases, has been shown to inhibit the growth and survival of various cancer types.

Germline Sequencing Identifies Rare Variants in Finnish Subjects with Familial Germ Cell Tumors.

Purpose: Pediatric germ cell tumors are rare, representing about 3% of childhood malignancies in children less than 15 years of age, presenting in neonates or adolescents with a greater incidence noted in older adolescents. Aberrations in primordial germ cell proliferation/differentiation can lead to a variety of neoplasms, including teratomas, embryonal carcinoma, choriocarcinoma, and yolk sac tumors.

Patients And Methods: Three Finnish families with varying familial germ cell tumors were identified, and whole-genome sequencing was performed using an Illumina sequencing platform.

Functional Profiling of FSH and Estradiol in Ovarian Granulosa Cell Tumors.

Adult-type granulosa cell tumors (AGCTs) are sex-cord derived neoplasms with a propensity for late relapse. Hormonal modulators have been used empirically in the treatment of recurrent AGCT, albeit with limited success. To provide a more rigorous foundation for hormonal therapy in AGCT, we used a multimodal approach to characterize the expressions of key hormone biomarkers in 175 tumor specimens and 51 serum samples using RNA sequencing, immunohistochemistry, RNA hybridization, quantitative PCR, and circulating biomarker analysis, and correlated these results with clinical data.

Parenteral Nutrition-Dependent Children With Short-Bowel Syndrome Lack Duodenal-Adaptive Hyperplasia but Show Molecular Signs of Altered Mucosal Function.

Background: Although adaptive mucosal growth of the remaining small intestine is an essential compensatory mechanism to bowel resection in experimental short-bowel syndrome (SBS), only scarce clinical data are available. We studied structural and molecular mechanisms of intestinal adaptation in children with SBS.

Methods: Fourteen patients, who had been dependent on parenteral nutrition (PN) since neonatal period for a median (interquartile range)1.

Incidence and long-term outcomes of surgically treated childhood hepatic malignancies in Finland.

Aim: To analyse incidence, treatment and outcomes of paediatric liver malignancies in Finland during 1987-2017.

Methods: Medical records and national cancer registry data of 47 children with liver malignancies were reviewed. Survival was calculated with the Kaplan-Meier method.

GnRH-agonist deslorelin implant alters the progesterone release pattern during early pregnancy in gilts.

The aim of this study was to investigate the relationship of progesterone (P) and luteinizing hormone (LH) during recognition and establishment of pregnancy in the gilt. Therefore, the effects of eliminating episodic LH pulses on P patterns were determined during early pregnancy. To this end, a slow-release GnRH implant deslorelin was used for GnRH down-regulation.