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Apoptosis, inflammation, and wound healing are critical pathophysiological events associated with various liver diseases. Currently, there is a lack of in vivo approaches to study hepatocyte apoptosis-induced liver injury and repair. To address this critical knowledge gap, we developed a unique genetically modified mouse model, namely, 3-Transgene (Tg) with inducible Hepatocyte-Specific Apoptosis Phenotype (3xTg-iHAP) in this study. The 3xTg-iHAP mice possess three transgenes including Alb-Cre, Rosa26-rtTA, and tetO-Fasl on a B6 background. These mice are phenotypically normal, viable, and fertile. After subcutaneous administration of a single dose of doxycycline (5 mg/kg, Dox) to 3xTg-iHAP mice, we observed a complete histological spectrum of sterile liver wound-healing responses: asymptomatic hepatocyte apoptosis at 8 h, necrotic liver injury and sterile inflammation at 48 h, followed by hepatocyte mitosis and regeneration within 7 days. During the injury phase, the mice exhibited an increase in the biomarkers of alanine aminotransferase (ALT), chemokine (C-X-C motif) ligand 1 (CXCL1), and IL-6 in peripheral blood, as well as α-smooth muscle actin (α-SMA) protein in liver tissues. Conversely, the mice displayed a decrease in these markers in the recovery phase. Remarkably, this model shows that the sterile liver injury following elevated hepatocyte apoptosis is associated with an increase in myeloid cells in the liver. Within 7 days post-Dox administration, the liver of Dox-treated 3xTg-iHAP mice displays a normal histological structure, indicating the completion of wound healing. Together, we established a novel mouse model of injury and regeneration induced by hepatocyte apoptosis. This tool provides a robust in vivo platform for studying the pathophysiology of sterile liver inflammation, regeneration, and new therapeutic interventions for liver diseases. NEW & NOTEWORTHY: Bu et al. present a triple-transgenic mouse model, namely, 3xTg-iHAP mice that are engineered to explore hepatocyte apoptosis-triggered sterile liver injury and regeneration. This model demonstrates a full spectrum of liver wound-healing responses from asymptomatic apoptosis to injury, myeloid cell-dominant sterile inflammation, and repair after induction of hepatocyte-specific apoptosis. The robust nature of this model makes it an invaluable in vivo tool for studying sterile liver inflammation, regeneration, and new therapeutic strategies. [ABSTRACT FROM AUTHOR]

* Context.--Melanotic schwannoma (MS) is a nerve sheath tumor with a uniform composition of variably melanin-producing Schwann cells and metastatic potential. The MS is an uncommon neoplasm, accounting for less than 1% of all nerve sheath tumors, with a predilection for spinal nerve involvement. Microscopically, the tumors are characterized by spindle and epithelioid cells arranged in interlacing fascicles, with marked accumulation of melanin in neoplastic cells and associated melanophages. The MSs are frequently associated with Carney complex, showing features of psammoma bodies and adipose-like cells. Strict criteria of malignancy in MS are not well developed, although a combination of worrisome histologic features (large, vesicular nuclei, with macronucleoli, brisk mitotic activity, and necrosis) raises concern for aggressive behavior.Objective.--To review the current status of the MS literature, discussing putative etiology, histopathology, current genetics, and differential diagnoses, including overlap with other pigmented tumors.Data Sources.--Search of PubMed (National Center for Biotechnology Information, Bethesda, Maryland) and the authors' own experiences.Conclusions.--The occurrence of MS at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its high tendency to recur locally and to metastasize, which highlights the importance of diagnostic recognition, ancillary molecular genetic testing, and close clinical follow-up of patients with MS.(Arch Pathol Lab Med. 2018;142:1517-1523; doi: 10.5858/arpa.2017-0162-RA), Melanotic schwannoma (MS) is a nerve sheath tumor with a uniform composition of variably melaninproducing Schwann cells and metastatic potential. (1-44) MS is an uncommon neoplasm, accounting for less than [...]

We describe the first cases of pediatric melanoma with ALK fusion gene arising within giant congenital melanocytic nevi. Two newborn boys presented with large pigmented nodular plaques and numerous smaller satellite nevi. Additional expansile nodules developed within both nevi and invasive melanomas were diagnosed before 10 months of age in both boys. Oncogenic driver mutations in NRAS and BRAF were absent in both cases. Instead, oncogenic ZEB2::ALK fusion genes were identified in both the nevus and melanoma developing within the nevus. In both cases, tumors were noted by ultrasound in utero, demonstrated significant nodularity at birth, and progressed to melanoma in the first year of life suggesting that congenital nevi with ALK fusion genes may behave more aggressively than those with other mutations. As ALK kinase inhibitors are effective against a range of tumors with similar ALK fusion kinases, identifying ALK fusion genes in congenital melanocytic nevi may provide an opportunity for targeted therapy. [ABSTRACT FROM AUTHOR]

Cathepsin L is a lysosomal enzyme thought to play a key role in malignant transformation. Recent work from our laboratory has demonstrated that this enzyme may also regulate cancer cell resistance to chemotherapy. The present study was undertaken to define the relevance of targeting cathepsin L in the suppression of drug resistance in vitro and in vivo and also to understand the mechanism(s) of its action. In vitro experiments indicated that cancer cell adaptation to increased amounts of doxorubicin over time was prevented in the presence of a cathepsin L inhibitor, suggesting that inhibition of this enzyme not only reverses but also prevents the development of drug resistance. The combination of the cathepsin L inhibitor with doxorubicin also strongly suppressed the proliferation of drug-resistant tumors in nude mice. An investigation of the underlying mechanism(s) led to the finding that the active form of this enzyme shuttles between the cytoplasm and nucleus. As a result, its inhibition stabilizes and enhances the availability of cytoplasmic and nuclear protein drug targets including estrogen receptor-[alpha], Bcr-Abl, topoisomerase-II[alpha], histone deacetylase 1, and the androgen receptor. In support of this, the cellular response to doxorubicin, tamoxifen, imatinib, trichostatin A, and flutamide increased in the presence of the cathepsin L inhibitor. Together, these findings provided evidence for the potential role of cathepsin L as a target to suppress cancer resistance to chemotherapy and uncovered a novel mechanism by which protease inhibition-mediated drug target stabilization may enhance cellular visibility and, thus, susceptibility to anticancer agents. drug resistance; topoisomerase; histone deacetylase 1; estrogen receptor

Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB. [ABSTRACT FROM AUTHOR]

Background: The clinical management of children post-pyeloplasty with persistent hydronephrosis (HN) by ultrasonography(US) or prolonged t 1/2 drainage by Well Tempered Renography (WTR) is not well structured. Reasons for unresolved hydronephrosis include irreversible pathologic changes in the proximal collecting system, transient obstruction due to edema at the site of repair, and persistent obstruction due to failed pyeloplasty. To help in the differentiation of these possibilities, this study correlated various histopathologic features of the excised renal pelvic specimen to radiologic outcome following pyeloplasty. Methods: Of 220 children that underwent pyeloplasty between 1988-1996 for isolated ureteropelvic junction (UPJ) obstruction, 41 children (42 kidneys) on retrospective review had adequate postoperative radiographic studies (US and/or WTR), and histologic specimens. Prenatal hydronephrosis was the diagnosis in 36/41 patients. The median age at time of pyeloplasty was 3.3 months. Median follow-up was 19.7 months (range 3 months to 7 yrs) with intervals at 3, 6, 9, 12 months and 2 years. Radiologic improvement in HN was defined as a decrease in [is greater than or equal to] 1 grade (Society for Fetal Urology grading system). Improvement in a WTR was defined as a decrease in drainage time (t 1/2 [is greater than] 5 min or 20%) or non-obstructed curve. Histologic features of the muscularis propria (MP) in the renal pelvic specimen ([micro]m thickness, % surface area collagen and elastin content / distribution) were correlated with the radiographic time line. Results: Post Pyeloplasty Radiologic Improvement follow-up based on US based on WTR 3 months 8/26 (31%) 9/15 (60%) 6 months 17/30 (57%) 14/18 (78%) 9 months 22/26 (80%) 22/26 (85%) 12 months 26/27 (96%) 25/28 (89%) 2 years 29/30 (97%) 25/27 (93%) Radiologic Improvement via MP Thickness follow-up 250 um p value 3 months 9/9 (100%) 6/21 (29%) Of the various histologic measures, only MP thickness significantly correlated with radiologic improvement (n=39). At 3 months, 15/30 (50%) patients with radiologic improvement had a mean MP thickness of 240[micro]m [+ or -] 33.0 (mean [+ or -] S.E.M.) while the remaining 15 patients without improve had a mean MP thickness of 377[micro]m [+ or -] 16.3 (p [is less than] .001). At 6 months, 22/34 (64.7%) patients with radiologic improvement had a mean MP thickness of 255[micro]m [+ or -] 25.7 while the remaining 12 patients without improve had a mean MP thickness of 376[micro]m [+ or -] 18.7 (p [is less than] .001). Two patients that did not have radiologic improvement and underwent reoperation at 9 months and 20 months (MP thickness were 397 [micro]m and 416 [micro]m respectively). Average MP thickness of the age matched control was 97 [micro]m (n=9). Both % collagen and elastin did not correlate with improvement of hydronephrosis and/or drainage time at any study time point. Conclusions: MP thickness of the renal pelvis was found to correlate significantly with the radiographic improvement during clinical follow-up i.e. specimens with MP thickness [is less than] 250 [micro]m show faster improvement in US and/or WTR than thicker specimens. Additionally, we have shown a time line to expect radiologic improvement in post-pyeloplasty children. These findings can be clinically used post-pyeloplasty to guide pediatric urologists to differentiate children with non improved radiologic studies with ultimate good outcome from those requiring intervention for persistent obstructive hydronephrosis. Peter D. Furness III, MD; Sang Won Han, MD; Max Maizels, MD FAAP; Pauline M. Chou, MD; Sandra K. Fernbach MD; and Earl Y. Cheng, MD. Department of Urology, Yonsei University College of Medicine, Seoul, Korea; Departments of Pathology, Radiology and Urology, Children&apos;s Memorial Hospital, Chicago, IL.3, Peter D. Furness III, MD; Sang Won Han, MD; Max Maizels, MD FAAP; Pauline M. Chou, MD; Sandra K. Fernbach MD; and Earl Y. Cheng, MD. Department of Urology, Yonsei [...]

Aims. Malignant ectomesenchymoma is a rare pediatric neoplasm with dual mesenchymal and neuroectodermal elements. Mesenchymal component is usually rhabdomyosarcoma, particularly embryonal subtype, whereas neuroectodermal derivatives are frequently a neuroblastic tumor. Ectomesenchymoma manifests in various sites given the wide migration of neural crest cells during development, though the pelvis/perineum is most often involved. Moreover, no unique unifying molecular abnormality has been determined. Methods. We conducted a retrospective study to analyze the spectrum of ectomesenchymal tumors encountered in our pediatric population. Six patients were identified and data pertaining to patients' demographic, tumor size and site, histologic components with immunophenotypic profile, molecular alterations, treatment and outcome were collected. Results. Mesenchymal elements, represented by rhabdomyosarcoma in all instances, were the dominant component in the majority of cases (5/6). Embryonal and alveolar morphology had similar distribution (3/6) and all patients with alveolar subtype harbored the characteristic translocations of this entity. The neuroectodermal component was most often a neuroblastic-like neoplasm (4/6); however, 2/6 cases demonstrated primitive neuroectodermal tumor-like morphology. No unifying alterations were found on molecular studies. Conclusions. Our analysis extends the histologic and molecular spectrum of these tumors and highlights their heterogeneity. The percentage of cases with alveolar rhabdomyosarcoma or primitive neuroectodermal-like tumor components suggests that these types of elements might be underreported. This study is also the first to demonstrate FOXO1 gene rearrangements in malignant ectomesenchymoma with alveolar rhabdomyosarcoma subtype. [ABSTRACT FROM AUTHOR]