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.

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.

The subserous thoracoabdominal continuum: embryologic basis and diagnostic imaging of disease spread.

This report establishes and details the clinical concept of the subperitoneal space and the subpleural space as components of the continuum formed by the subserous space. The subserous space is an anatomic plane formed in the embryo that persists during development into the adult. This is the basis of the thoracoabdominal continuum. The embryologic development is presented from the viewpoint not of the contents and their relationships within the developing coelomic cavity but rather that of a continuous space deep to the lining serous membrane. Clinical material is presented that illustrates different disease processes that can directly spread in either direction within this continuum. This unifying concept provides an understanding of the pathogenesis of direct spread of disease processes within and between the thorax and abdomen.

Renal oncocytomatosis.

Renal oncocytoma is an uncommon benign renal neoplasm of unknown etiology. Bilateral, multicentric renal oncocytomas are rare and diffuse renal oncocytomas are even rarer. We report a patient with incidentally detected marked bilateral nephromegaly due to innumerable oncocytomas. The term "oncocytomatosis" should be strictly applied to cases in which oncocytomas diffusely infiltrate the kidneys.

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.

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.

Direct spread of subperitoneal disease into solid organs: radiologic diagnosis.

The subperitoneal space is the continuous space interconnecting the peritoneum and retroperitoneum and the abdominal organs. This report expands the concept of direct spread of disease via the subperitoneal space to include direct extension into the solid abdominal viscera (i.e., liver, kidneys, and spleen). Discussion of the anatomy, case presentations, and imaging with computed tomography, ultrasound, and magnetic resonance are presented. This unifying concept provides an understanding for direct spread of disease presenting clinically or being imaged within a solid abdominal organ.

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.

Inflammatory myofibroblastic tumor in children.

The authors presented the cases of two children with inflammatory myofibroblastic (IMF) tumor and reviewed the literature to facilitate the preoperative recognition, delineate the clinical features, and describe the natural history of this entity. The first child had IMF tumor arising from the mesentery of the small intestine. He presented with an abdominal mass associated with severe inflammatory response manifested by fever, impaired growth, thrombocytosis, and microcytic, hypochromic anemia. After surgical resection, his fever resolved and his growth rate and the laboratory abnormalities normalized. Five months after initial diagnosis, the fever, anemia, and thrombocytosis recurred along with two tumors arising from the omentum and the abdominal soft tissue. After the second surgery, he remains free of recurrent disease for 30 months. The second child presented with a lung mass that was radiologically indistinguishable from pulmonary sequestration. After surgical resection, she remains free of recurrent disease for 18 months. IMF tumor should be considered in any solid tumor that occurs in association with a chronic inflammatory response. IMF tumor should also be considered in the differential diagnosis of pulmonary sequestration.

Spread of disease via the subperitoneal space: the small bowel mesentery.

The designation of the subperitoneal space emphasizes the continuum of the potential space of extraperitoneal and intraperitoneal areolar tissue traversed by blood vessels, lymphatics, and nerves. Across its root, the subserous connective tissue of the small bowel mesentery is anatomically continuous with that deep to the posterior parietal peritoneum. There is thereby provided an avenue of spread from multiple sites to and from the small bowel mesentery and its relationships. These include perforated lesions of the bowel, pancreatitis, lymphoma, neuroblastoma, leiomyosarcoma of small bowel, and hemorrhage of retroperitoneal and pelvic origin.

Bidirectional spread of disease via the subperitoneal space: the lower abdomen and left pelvis.

In early fetal life a persistent interconnection between the peritoneum and retroperitoneum of the abdomen and pelvis is formed--the subperitoneal space (SS). This paper serves to complete the description of the specific anatomical nuances of the SS as they relate to the bidirectional direct spread of disease in the left lower abdomen and pelvis. Described are the two avenues of communication (central and lateral pathways) within this portion of the SS. Selected cases illustrating the bidirectional spread of disease processes within this portion of the SS are reported.

Zinc-induced copper deficiency in an infant.

OBJECTIVE: To describe the case of a 13-month-old girl who developed copper deficiency as a result of excessive zinc gluconate ingestion. SETTING: Tertiary care hospital in Syracuse, NY. INTERVENTIONS: Cessation of zinc ingestion followed by intravenous and oral copper chloride therapy. MEASUREMENTS/MAIN RESULTS: Ingestion of zinc gluconate, 120 mg/d for 6 months, and thereafter 180 mg/d for 1 month, preceded the clinical presentation of listlessness, anemia, neutropenia, poor weight gain, abnormal sparse hair, and scorbuticlike bone changes. Findings on a bone marrow examination included ring sideroblasts and suggested copper deficiency. Plasma zinc level was 36.7 mumol/L, serum ceruloplasmin level was 20 mg/L, and serum copper level was undetectable. Clinical and laboratory abnormalities resolved shortly after initiation of copper therapy. CONCLUSIONS: This case demonstrates the reciprocal relationship of copper and zinc metabolism and exemplifies the important interrelationships of dietary trace minerals.

Prenatal sonographic evaluation of short-limbed dwarfism: an algorithmic approach.

Prenatal sonographic evaluation of short-limbed dwarfism is initiated when a significantly shortened femur is found or by referral of a patient with a family history of skeletal dysplasia. If a short femur is demonstrated, all the long bones are measured and evaluated for bowing, fractures, and mineralization. The bone dysplasia is categorized according to whether it is mesomelic, rhizomelic, or micromelic and whether bowing or fractures are present. The fetal spine, head, thorax, hands, and feet are carefully evaluated to differentiate the type of bone dysplasia and to determine whether it is lethal. Serial examinations may be necessary. This approach will provide sufficient information to counsel the family, manage the pregnancy, and direct the postnatal evaluation.