Pediatric Tumors as Disorders of Development: The Case for In Vitro Modeling Based on Human Stem Cells.

Despite improvements in patient outcomes, pediatric cancer remains a leading cause of non-accidental death in children. Recent genetic analysis of patients with pediatric cancers indicates an important role for both germline genetic predisposition and cancer-specific somatic driver mutations. Increasingly, evidence demonstrates that the developmental timepoint at which the cancer cell-of-origin transforms is critical to tumor identity and therapeutic response.

Consensus and controversy in the management of paediatric and adult patients with ovarian immature teratoma: the Malignant Germ Cell International Consortium perspective.

Ovarian immature teratoma (IT) is a rare neoplasm comprising ∼3% of ovarian cancers, occurring primarily in young females. Management presents several challenges, including those with elevated serum alpha-fetoprotein, potential confusion regarding pathology interpretation, and paucity of data to support decision-making. MaGIC (https://magicconsortium.

Comparison of intraocular lens tilt after capsular sutured scleral fixation with capsular segments versus uneventful cataract surgery.

Purpose: To evaluate and compare intraocular lens (IOL) tilt between uneventful phacoemulsification with in-the-bag IOL implantation and sutured scleral fixation (SSF) of the lens bag with a capsular tension segment (type 6 D / Morcher) using a Sheimpflug camera.

Setting: Clinical Practice, Hospital. Barcelona and A Coruña, Spain.

Maintenance of Human Primordial Germ Cell-Like Cells in a Long-Term Culture System.

Primordial germ cells (PGCs) are the earliest form of mammalian germ lineage. In humans, PGCs are present during a very early and limited window in development, limiting the ability to study fundamental developmental steps in human reproductive biology. However, recent advancements in generating in-vitro models of gametogenesis have allowed the field to generate human primordial germ cell-like cells (hPGCLCs).

Children's Oncology Group's 2023 blueprint for research: Germ cell tumors.

Extracranial germ cell tumors (GCT) are a biologically diverse group of tumors occurring in children, adolescents, and young adults. The majority of patients have excellent outcomes, but treatment-related toxicities impact their quality of survivorship. A subset of patients succumbs to the disease.

Characterization of expression and prognostic implications of GD2 and GD3 synthase in canine histiocytic sarcoma.

GD2 and GD3 are disialoganglioside oncofetal antigens important in oncogenesis. GD2 synthase (GD2S) and GD3 synthase (GD3S) are needed for GD2 and GD3 production. The objectives of this study are to validate the use of RNA in situ hybridization (RNAscope®) in the detection of GD2S and GD3S in canine histiocytic sarcoma (HS) in vitro and optimize this technique in canine formalin-fixed paraffin-embedded (FFPE) tissues.

Characterization of expression and prognostic implications of transforming growth factor beta, programmed death-ligand 1, and T regulatory cells in canine histiocytic sarcoma.

Histiocytic sarcoma (HS) is an aggressive malignant neoplasm in dogs. Expression and prognostic significance of transforming growth factor beta (TGF-β), programmed death-ligand 1 (PD-L1), and T regulatory cells (Tregs) in HS is unknown. The goal of this study was to investigate the expression and prognostic significance of TGF-β, PD-L1, and FoxP3/CD25 in canine HS utilizing RNA in situ hybridization (RNAscope®).

Early experience with targeted therapy as a first-line adjuvant treatment for pediatric low-grade glioma.

Objective: Pediatric low-grade gliomas (pLGGs) frequently exhibit dysregulation of the mitogen-activated protein kinase (MAPK) pathway. Targeted therapies, including mutant BRAF inhibitors (dabrafenib) and MEK inhibitors (trametinib), have shown promise in patients in whom conventional chemotherapy has failed. However, few studies have investigated the use of targeted therapy as a first-line treatment for pLGG.

Advancing clinical and translational research in germ cell tumours (GCT): recommendations from the Malignant Germ Cell International Consortium.

Germ cell tumours (GCTs) are a heterogeneous group of rare neoplasms that present in different anatomical sites and across a wide spectrum of patient ages from birth through to adulthood. Once these strata are applied, cohort numbers become modest, hindering inferences regarding management and therapeutic advances. Moreover, patients with GCTs are treated by different medical professionals including paediatric oncologists, neuro-oncologists, medical oncologists, neurosurgeons, gynaecological oncologists, surgeons, and urologists.

Implementing Optimal Care Pathways for Aboriginal and Torres Strait Islander People With Cancer: A Survey of Rural Health Professionals' Self-Rated Learning Needs.

Objective: In 2018, the Optimal Care Pathway (OCP) for Aboriginal and Torres Strait Islander people with cancer was developed in Australia to improve the cancer care experiences and outcomes of Aboriginal and Torres Strait Islander people.

Methods: Our study examined health professionals' learning needs to meet the clinical practice requirements of the new OCP. An electronic questionnaire was distributed to 120 health professionals providing oncology care in two rural areas in Victoria, Australia.

Expanding homogeneous culture of human primordial germ cell-like cells maintaining germline features without serum or feeder layers.

In vitro expansion of human primordial germ cell-like cells (hPGCLCs), a pluripotent stem cell-derived PGC model, has proved challenging due to rapid loss of primordial germ cell (PGC)-like identity and limited cell survival/proliferation. Here, we describe long-term culture hPGCLCs (LTC-hPGCLCs), which actively proliferate in a serum-free, feeder-free condition without apparent limit as highly homogeneous diploid cell populations maintaining transcriptomic and epigenomic characteristics of hPGCLCs. Histone proteomics confirmed reduced H3K9me2 and increased H3K27me3 marks in LTC-hPGCLCs compared with induced pluripotent stem cells (iPSCs).

Divergent roles for KLF4 and TFCP2L1 in naive ground state pluripotency and human primordial germ cell development.

During embryo development, human primordial germ cells (hPGCs) express a naive gene expression program with similarities to pre-implantation naive epiblast (EPI) cells and naive human embryonic stem cells (hESCs). Previous studies have shown that TFAP2C is required for establishing naive gene expression in these cell types, however the role of additional naive transcription factors in hPGC biology is not known. Here, we show that unlike TFAP2C, the naive transcription factors KLF4 and TFCP2L1 are not required for induction of hPGC-like cells (hPGCLCs) from hESCs, and they have no role in establishing and maintaining a naive-like gene expression program in hPGCLCs with extended time in culture.

An Extended Culture System that Supports Human Primordial Germ Cell-like Cell Survival and Initiation of DNA Methylation Erasure.

The development of an in vitro system in which human primordial germ cell-like cells (hPGCLCs) are generated from human pluripotent stem cells (hPSCs) has been invaluable to further our understanding of human primordial germ cell (hPGC) specification. However, the means to evaluate the next fundamental steps in germ cell development have not been well established. In this study we describe a two dimensional extended culture system that promotes proliferation of specified hPGCLCs, without reversion to a pluripotent state.

Generation of three human induced pluripotent stem cell sublines (MZT04D, MZT04J, MZT04C) for reproductive science research.

We generated three human induced pluripotent stem cell (hiPSC) sublines from human dermal fibroblasts (HDFs) (MZT04) generated from a skin biopsy donated from a previously fertile woman. The skin biopsy was broadly consented for generating hiPSC lines for biomedical research, including unique consent specifically for studying human fertility, infertility and germ cells. hiPSCs were reprogrammed using Sendai virus vectors and were subsequently positive for markers of self-renewal including OCT4, NANOG, TRA-1-81 and SSEA-4.

The TFAP2C-Regulated OCT4 Naive Enhancer Is Involved in Human Germline Formation.

Human primordial germ cells (hPGCs) are the first embryonic progenitors in the germ cell lineage, yet the molecular mechanisms required for hPGC formation are not well characterized. To identify regulatory regions in hPGC development, we used the assay for transposase-accessible chromatin using sequencing (ATAC-seq) to systematically characterize regions of open chromatin in hPGCs and hPGC-like cells (hPGCLCs) differentiated from human embryonic stem cells (hESCs). We discovered regions of open chromatin unique to hPGCs and hPGCLCs that significantly overlap with TFAP2C-bound enhancers identified in the naive ground state of pluripotency.

Restoring Fertility with Human Induced Pluripotent Stem Cells: Are We There Yet?

Overcoming infertility with assisted reproduction requires high-quality eggs and sperm. For those young women who no longer make functional eggs, the hope of conceiving a biological child just got one step closer with a recent publication in Science from Yamashiro et al. (2018).

PRDM14 is expressed in germ cell tumors with constitutive overexpression altering human germline differentiation and proliferation.

Germ cell tumors (GCTs) are a heterogeneous group of tumors occurring in gonadal and extragonadal locations. GCTs are hypothesized to arise from primordial germ cells (PGCs), which fail to differentiate. One recently identified susceptibility loci for human GCT is PR (PRDI-BF1 and RIZ) domain proteins 14 (PRDM14).

Modeling human infertility with pluripotent stem cells.

Human fertility is dependent upon the correct establishment and differentiation of the germline. This is because no other cell type in the body is capable of passing a genome and epigenome from parent to child. Terminally differentiated germline cells in the adult testis and ovary are called gametes.

Novel association of familial testicular germ cell tumor and autosomal dominant polycystic kidney disease with PKD1 mutation.

Adolescent brothers were diagnosed with testicular germ cell tumors within the same month. Both were found to have multiple renal cysts on pretreatment imaging done for staging. The proband, his brother, and their mother, were all found to have a novel splice variant in intron 8 of the PKD1 gene by clinical exome sequencing.

Microarray expression profiling in adhesion and normal peritoneal tissues.

Objective: To identify molecular markers associated with adhesion and normal peritoneal tissue using microarray expression profiling.

Design: Comparative study.

Setting: University hospital.

Secondary amenorrhea attributed to occlusion of microperforate transverse vaginal septum.

Objective: To present a case of secondary amenorrhea after occlusion of microperforate transverse vaginal septum.

Design: Case report.

Setting: Academic teaching hospital.

Case of sisters with complete androgen insensitivity syndrome and discordant Müllerian remnants.

Objective: Presentation of complete androgen insensitivity in two members of the same family with differing residual Müllerian tissue.

Design: Case report.

Setting: Rural hospital setting.

Airway epithelial NF-kappaB activation modulates asbestos-induced inflammation and mucin production in vivo.

To investigate the role of bronchiolar epithelial NF-kappaB activity in the development of inflammation and fibrogenesis in a murine model of asbestos inhalation, we used transgenic (Tg) mice expressing an IkappaBalpha mutant (IkappaBalphasr) resistant to phosphorylation-induced degradation and targeted to bronchial epithelium using the CC10 promoter. Sham and chrysotile asbestos-exposed CC10-IkappaBalphasr Tg(+) and Tg(-) mice were examined for altered epithelial cell proliferation and differentiation, cytokine profiles, lung inflammation, and fibrogenesis at 3, 9, and 40 days. KC, IL-6 and IL-1beta were increased (p < or = 0.

Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-delta knockout mice.

The signaling pathways leading to the development of asbestos-associated diseases are poorly understood. Here we used normal and protein kinase C (PKC)-delta knockout (PKCdelta-/-) mice to demonstrate multiple roles of PKC-delta in the development of cell proliferation and inflammation after inhalation of chrysotile asbestos. At 3 days, asbestos-induced peribronchiolar cell proliferation in wild-type mice was attenuated in PKCdelta-/- mice.