Two Sides of the Same Coin: The Role of Developmental pathways and pluripotency factors in normal mammary stem cells and breast cancer metastasis.

Breast cancer initiation and progression are often observed as the result of dysregulation of normal developmental processes and pathways. Studies focused on normal mammary stem/progenitor cell activity have led to an understanding of how breast cancer cells acquire stemness-associated properties including tumor initiation, survival and multi-lineage differentiation into heterogeneous tumors that become difficult to target therapeutically. Importantly, more recent investigations have provided valuable insight into how key developmental regulators can impact multiple phases of metastasis, where they are repurposed to not only promote metastatic phenotypes such as migration, invasion and EMT at the primary site, but also to regulate the survival, initiation and maintenance of metastatic lesions at secondary organs. Herein, we discuss findings that have led to a better understanding of how embryonic and pluripotency factors contribute not only to normal mammary development, but also to metastatic progression. We further examine the therapeutic potential of targeting these developmental pathways, and discuss how a better understanding of compensatory mechanisms, crosstalk between pathways, and novel experimental models could provide critical insight into how we might exploit embryonic and pluripotency regulators to inhibit tumor progression and metastasis.

The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L.

Tumor-initiating cells (TIC) represent a subset of tumor cells with increased self-renewal capability. TICs display resistance to frontline cancer treatment and retain the ability to repopulate a tumor after therapy, leading to cancer relapse. NOTCH signaling has been identified as an important driver of the TIC population, yet mechanisms governing regulation of this pathway in cancer remain to be fully elucidated. Here we identify a novel mechanism of NOTCH regulation and TIC induction in breast cancer via the miR-106b-25 miRNA cluster. We show that the miR-106b-25 cluster upregulates NOTCH1 in multiple breast cancer cell lines, representing both estrogen receptor (ER+) and triple negative breast cancer (TNBC) through direct repression of the E3 ubiquitin ligase, NEDD4L. We further show that upregulation of NOTCH1 is necessary for TIC induction downstream of miR-106b-25 in both ER + and TNBC breast cancer cells, and that re-expression of NEDD4L is sufficient to reverse miR106b-25-mediated NOTCH1 upregulation and TIC induction. Importantly, we demonstrate a significant positive correlation between miR-106b-25 and NOTCH1 protein, yet a significant inverse correlation between miR-106b-25 and NEDD4L mRNA in human breast cancer, suggesting a critical role for the miR106b-25/NEDD4L/NOTCH1 axis in the disease. Further, we show for the first time that NEDD4L expression alone is significantly associated with a better relapse-free prognosis for breast cancer patients. These data expand our knowledge of the mechanisms underlying NOTCH activation and TIC induction in breast cancer, and may provide new avenues for the development of therapies targeting this resistant subset of tumor cells.

Chronic pneumonitis of infancy. A unique form of interstitial lung disease occurring in early childhood.

We describe nine infants with a rare form of interstitial lung disease that is characterized by marked alveolar septal thickening, striking alveolar pneumocyte hyperplasia, and an alveolar exudate containing numerous macrophages and foci of eosinophilic debris. Primitive mesenchymal cells predominate within the widened alveolar septa; inflammatory cells are scant. This entity occurs exclusively in infants and very young children and differs from other types of interstitial pneumonia occurring in either children or adults. The histologic findings suggest that it may reflect slowly resolving or recurrent pneumonia superimposed on immature or abnormally developed lungs. The term chronic pneumonitis of infancy was chosen to reflect the unique occurrence of this lesion in young children and to emphasize its distinction from adult forms of interstitial pneumonia.

Solitary hepatic cyst and benign bile duct polyp: a heretofore unheralded association.

Solitary hepatic cysts are uncommon lesions that can produce jaundice by extrinsic compression on the extrahepatic biliary tree. In two recent cases of solitary hepatic cyst with jaundice, an intraluminal polypoid adenoma that obstructed the common hepatic duct was discovered. Concurrence of these two unusual lesions suggests that they may be associated. The importance of recognizing this association is illustrated by two case reports. In case 1, extrinsic compression by the cyst on the common hepatic duct was identified as the cause of jaundice at the initial operation. In case 2, choledocholithiasis was the initial explanation for the jaundice. In both cases, palpation and exploration of the proximal bile ducts with probes and catheters failed to discover the polyp. However, jaundice persisted postoperatively in both cases, and subsequent contrast radiography revealed an intraluminal filling defect in the common hepatic duct. In both cases, reoperation was required, and a benign bile duct polyp was discovered and excised. Thus, the presence of jaundice in a patient with a cystic hepatic mass should suggest the possibility of a concurrent bile duct polyp. Awareness of this possibility should permit recognition of such a polyp at initial operation.

Coarctation of the midaortic arch presenting with monoparesis.

A 6 1/2-month-old infant was seen with right-arm monoparesis, right upper extremity hypertension, and findings of a coarctation located in the midaortic arch between the innominate and left common carotid arteries. Associated left cerebral atrophy (Dyke-Davidoff syndrome) was documented by computed tomography. Excision of the coarctation segment with primary repair of the arch and reanastomosis of the left carotid to the innominate artery was accomplished.

Demyelinating and gliotic cerebellar lesions in Langerhans cell histiocytosis.

PURPOSE: To describe the involvement of the cerebellum by a gliotic and demyelinating process in Langerhans cell histiocytosis. METHODS: A retrospective analysis of all (N = 30) cases of Langerhans cell histiocytosis followed at our institution since 1975 yielded four patients with CT and/or MR evidence of cerebellar abnormalities. RESULTS: Four patients manifested strikingly similar findings of symmetric nonenhancing hypodensities in the dentate nuclei region of the cerebellum, which were hypointense on short-repetition-time/short-echo-time MR and hyperintense on long-repetition-time/long-echo-time MR. Biopsy in one patient yielded areas of demyelination, cell loss, and gliosis without histiocytic infiltration. CONCLUSION: Langerhans cell histiocytosis involves the cerebellum in a specific and poorly understood manner. Lesions on imaging may precede clinical findings by years. Lesions may occur in patients who have never experienced radiation therapy and may act as a marker for eventual central nervous system deterioration.

Fetal central nervous system abnormalities.

The advances in the sonographic imaging of the fetus have made the detailed examination of the fetal central nervous system (CNS) a routine part of the prenatal sonogram. A logical sonographic approach to the diagnosis of fetal CNS abnormalities is presented, based on the normal sonographic anatomy and the understanding of CNS pathology. This approach results in a classification of CNS abnormalities derived from ultrasound findings. The main categories are (1) hydrocephalus, (2) entities that mimic hydrocephalus, and (3) neural tube defects. Once a disorder is classified and all ultrasound abnormalities identified, a differential diagnosis can be developed.

The dilemma of Saussurean communication.

A Saussurean communication system exists when an entire communicating population uses a single 'language' that maps states unambiguously onto symbols and then back into the original states. This paper describes a number of simulations performed with a genetic algorithm to investigate the conditions necessary for such communication systems to evolve. The first simulation shows that Saussurean communication evolves in the simple case where direct selective pressure is placed on individuals to be both good transmitters and good receivers. The second simulation demonstrates that, in the more realistic case where selective pressure is only placed on doing well as a receiver, Saussurean communication fails to evolve. Two methods, inspired by research on the Prisoner's Dilemma, are used to attempt to solve this problem. The third simulation shows that, even in the absence of selective pressure on transmission, Saussurean communication can evolve if individuals interact multiple times with the same communication partner and are given the ability to respond differentially based on past interaction. In the fourth simulation, spatially organized populations are used, and it is shown that this allows Saussurean communication to evolve through kin selection.

Nontuberculous Mycobacteria subcarinal lymphadenitis and severe airway obstruction.

This report has emphasized the importance of a careful evaluation of the chest roentgenogram for lymphadenopathy in children with wheezing, cough, or other symptoms of lower airway disease. This patient report also illustrates that intrathoracic lymphadenitis caused by nontuberculous mycobacteria should be considered in children with unexplained airway obstruction.

Palpable spongy mass over the clavicle, an underutilized sign of clavicular fracture in the newborn.

This prospective study emphasizes the importance of an early physical finding of neonatal clavicular fracture, termed "the palpable spongy mass sign." Of the 1,661 term neonates examined at our tertiary center over a 20-month period, 24 had clinical signs of a clavicular fracture. In 22 of the 24 neonates, the fractures were documented by positive radiographs or callus formation. None of the fractures was recognized because of an asymmetric Moro reflex, visible swelling, or bruising. The palpable spongy mass was present in 18 of the 22 fractures (82%), crepitus in 10 (45%), angulation deformity in two (9%), and localized tenderness in one (5%). Any combination of crepitus, deformity, and localized tenderness was detected in 11 of the 22 (50%) fractures. When the palpable spongy mass sign was added to these three signs, all but one fracture was clinically detected (95%), emphasizing the importance of using all physical findings. We conclude that "the clavicular spongy mass sign" is highly sensitive and predictive of neonatal clavicular fractures.

Hemophilia-like arthropathy of the knee associated with cutaneous and synovial hemangiomas. Report of 3 cases and review of the literature.

Three patients with cutaneous and/or synovial hemangiomas demonstrated roentgenographic alterations in the knees, simulating hemophilic arthropathy. In 2 cases, unilateral synovial hemangiomas appeared to be present; in the third patient, who had bilateral abnormalities, the Kasabach-Merritt syndrome was evident, resulting in a consumption coagulopathy and hemorrhagic tendency. The pathogenesis of this unusual arthropathy is discussed.

A spectrum of renal tubular ectasia and hepatic fibrosis.

Renal tubular cystic disease and hepatic fibrosis exhibit a specific genetic pattern and pathological findings. The renal collecting tubules are dilated and the liver shows fibrosis with proliferation and dilatation of the bile ducts. The findings fall into a spectrum with marked renal disease and mild liver involvement at one end and mild renal involvement with severe liver disease at the other. Between these extremes lies an intermediate form which is genetically and pathologically similar, but exhibits a wide range of clinical and radiological findings due to the variability of renal and liver involvement.

Computed tomography of the subperitoneal space: demonstration of direct spread of intraabdominal disease.

The direct spread of intraabdominal disease via peritoneal folds is clearly demonstrated with computed tomography (CT). This extensive network of peritoneal folds can be conceptualized as the subperitoneal space. These subperitoneal communications within the abdomen are described and demonstrated by CT scans and a schematic drawing. Direct spread of disease within and between abdominal compartments is illustrated with selected clinical cases stressing the CT imaging method.

Mechanism of direct spread of abdominal neuroblastoma: CT demonstration and clinical implications.

Neuroblastoma, a malignant tumor of neural crest origin, is the most common extracranial solid tumor in children. In 1971 Evans et al. introduced a clinical staging for neuroblastoma. Over sixty percent of patients present with neuroblastoma beyond stage I. Despite more aggressive therapy there has been only minimal improvement in survival. Since 1978, all patients with neuroblastoma have had CT scanning as part of their initial evaluation at our institution. Children with abdominal neuroblastoma beyond stage I form the basis of this report. Selected cases illustrating the permeative nature of neuroblastoma and the mechanism of direct abdominal spread by CT scanning are presented. The tumor originates in the retroperitoneum and spreads to the abdominal aorta where it gains access to the subperitoneal space via the celiac axis and superior mesenteric artery. These vessels course from the aorta to their ultimate destination within their peritoneal folds. These folds form the interconnecting space (subperitoneal space) between the retroperitoneum and the peritoneal organs. Such scanning is extremely sensitive in detecting neuroblastoma with early infiltration into adjacent tissues and contiguous spread through abdominal spaces. The clinical implications of the permeative nature of neuroblastoma and the mechanism of contiguous abdominal spread are discussed.