Dispermic chimerism with two abnormal cell lines, 47,XY, +21 and 47,XX, +12.

Chimerism in humans appears to be a rare phenomenon that is usually discovered by accident. Here we describe a stillborn male fetus with multiple congenital anomalies which was found to have two cytogenetically abnormal cell lines, 47,XY, +21 and 47, XX, +12. The difference in sex chromosome constitution between the cell lines indicated that the fetus had dispermic chimerism. To our knowledge, this is the first report of chimerism with two abnormal cell lines.     

Eighty-fourth annual session. He Hahnemann Medical College,Philiadelphia, April 19, 20, 21, 22, 1971. Officers,abstracts, demonstrations

The mature ultimobranchial follicle of the rat consists of two or more layers of cells (U cells) surrounding a lumen containing cell debris. The ultrastructure of the outer, or basal, U cell is characterized by the presence of half desmosomes on the basal plasma membrane and pinocytotic vesicles near it, by little granular reticulum but an abundance of free ribosomes, by clusters of fibrils connected to desmosomes and possibly free in the cytoplasm. The cell ages by accumulation of clusters of fibrils and it undergoes differentiation to form more apical U cells which contain fewer ribosomes and have fibrils dispersed in the cytoplasm. The apical U cell is desquamated into the lumen and ultimately becomes a carcass containing a dense matting of fibers and vacuoles containing a reticulated material resembling that in the lumen. U cells are observed associated with typical thyroid epithelium in the thyroid of the newborn rat in relatively large follicles containing colloid and desquamated cells. They also form rods of cells in the very young rat. Mixed follicles containing both U cells and typical thyroid epithelium occur at all ages.     

Apoptosis, oncosis, and necrosis. An overview of cell death.

The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis, physiological cell death, programmed cell death, chromatolysis (the first name of apoptosis in 1914), karyorhexis, karyolysis, and cell suicide, of which there are three forms: by lysosomes, by free radicals, and by a genetic mechanism (apoptosis). Some of the typical features of apoptosis are discussed, such as budding (as opposed to blebbing and zeiosis) and the inflammatory response. For cell death not by apoptosis the most satisfactory term is accidental cell death. Necrosis is commonly used but it is not appropriate, because it does not indicate a form of cell death but refers to changes secondary to cell death by any mechanism, including apoptosis. Abundant data are available on one form of accidental cell death, namely ischemic cell death, which can be considered an entity of its own, caused by failure of the ionic pumps of the plasma membrane. Because ischemic cell death (in known models) is accompanied by swelling, the name oncosis is proposed for this condition. The term oncosis (derived from ónkos, meaning swelling) was proposed in 1910 by von Reckling-hausen precisely to mean cell death with swelling. Oncosis leads to necrosis with karyolysis and stands in contrast to apoptosis, which leads to necrosis with karyorhexis and cell shrinkage.     

Extracellular matrix, cell skeletons, and embryonic development

During embryonic development, the extracellular matrix (ECM) promotes the production of differentiated products by epithelial cells and the migration of mesenchymal cells, and probably also plays a role in epithelial-mesenchymal transformation. Here we examine the role of the cell skeleton (actin, microtubules, intermediate filaments) in mediating matrix effects on mesenchymal cell morphology, migration, and formation. The interaction of both epithelial cells and mesenchymal cells with ECM seems to involve the actin cortex, which is best developed in the base of the epithelial cell, where it attaches to underlying matrix via membrane-intercalated receptors. To interact with the matrix, the fibroblast has appropriate ECM receptors and an actin cortex around the whole cell. The actin cortex is absolutely required for assumption of bipolar shape, elongation, and movement through the matrix. Since the cortex seems to be anchored to the matrix, it is unlikely that it moves during cell migration. A new hypothesis states that the microtubule- and intermediate filament-rich endoplasm, containing the nucleus, moves past the actin cortex-receptor-matrix complex into the newly synthesized front end of the mesenchymal cell to effect forward movement. When epithelial cells transform into mesenchyme in the embryo, or when they are induced to do this in vitro, they switch from the keratin intermediate filament profile to one rich in vimentin, and the effect of cell matrix interaction on cell shape is profoundly altered. Vimentin-actin interactions with ECM may be a major factor in the ability of a cell to become mesenchymal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dispermic chimerism with two abnormal cell lines, 47,XY, +21 and 47,XX, +12

Chimerism in humans appears to be a rare phenomenon that is usually discovered by accident. Here we describe a stillborn male fetus with multiple congenital anomalies which was found to have two cytogenetically abnormal cell lines, 47,XY, +21 and 47, XX, +12. The difference in sex chromosome constitution between the cell lines indicated that the fetus had dispermic chimerism. To our knowledge, this is the first report of chimerism with two abnormal cell lines. © 2001 Wiley‐Liss, Inc.     

pHMA,a pH‐sensitive GFP reporter for cell engulfment,in Drosophila embryos,tissues, and cells

Engulfment of apoptotic cells by phagocytosis ensures the removal of unwanted and defective cells. We developed a genetically encoded marker for cell engulfment, pHMA, which consists of the pH‐Sensitive derivative of GFP, pHluorin, fused to the actin‐binding domain of Moesin. In healthy cells of Drosophila embryos and cultured cells, pHMA resides at the cell cortex. In dying cells, pHMA loses its cortical localization and reports a modest decrease in pH. In embryos, the dying cells lose their apical contacts, then move basally and are ultimately engulfed by neighboring cells or macrophages. The cell corpse material is strongly acidified soon after engulfment and persists in the phagocytic cell for several hours. Changes in the pHMA signal correlate well with increases or decreases in apoptosis. These data show that pHMA is a useful reporter for cell engulfment and can be used in screening for mutations that affect cell engulfment. Developmental Dynamics 239:559–573, 2010. © 2009 Wiley‐Liss, Inc.     

Redox imbalance, macrocytosis, and RBC homeostasis

The erythrocyte represents a major component of the antioxidant capacity of the blood through the enzymes contained in the cell, the glutathione system, and the low-molecular-weight antioxidants of the erythrocyte membrane. A further major red blood cell contribution is in regenerating consumed redox equivalents via the oxidative pentose phosphate pathway and glutathione reductase. Moreover, its extracellular antioxidant capacity, its mobility, and the existence of reducing equivalents far in excess of its normal requirements make erythrocytes function as an effective oxidative sink in the organism. That is why red blood cell metabolism and homeostasis strongly affect the antioxidant properties of the whole body. Conversely, the relation between macrocytosis and oxidative stress has not been fully delineated. Reviewing the mechanisms involved in red blood cell homeostasis in cases of redox imbalance is crucial in identification of factors that could potentially improve erythrocyte survival and defense against oxidant damage.     

Macrophage phenotype bioengineered by magnetic,genetic, or pharmacologic interference

In all eukaryotes, the cell shape depends on the actin filament cytoskeleton, which is regulated by the small GTPase RhoA. It is well known that the cell shape determines cell function and behavior. Inversely, any change in the cell behavior and/or function reverberates at the cell shape. In this review, we describe how mechanical/magnetic, genetic, or pharmacologic interference with the actin cytoskeleton enforces changes in cell shape and function and how such techniques can be used to control the phenotype and functions of immune cells such as macrophages and to develop novel anti-cancer and anti-rejection clinical therapies.

     

Update in cancer chemotherapy, Part IV. Lung cancer, Part 2

An update of cancer chemotherapy in 1985 that deals with the various therapies of lung cancer is described. At present, the stage of the disease and cell type are the major factors that determine the treatment. Important differences in the biological behavior and response to treatment exist between small cell and non-small cell cancers. Treatment of the small cell type, which is sensitive to many of the cancer chemotherapeutic agents, is discussed in this paper. Treatment of the non-small cell types was described in the October issue of the Journal.     

Cell,membrane, and diffusion—an essay in bio-theory

The Cell Theory is criticised and an alternative version proposed. It is suggested that the notion of a sponge-like, spongioform, cell (7) might be preferable to the classical notion of a membrane-bound cell. This would allow consideration of the probability that cells behave like sponges and procure their material and metabolite requirements entrained in a convected flow of water past their internal membrane systems. I shall consider some deductive consequences of this alternative in a companion article (1). The Cell Theory, however, formulated on the basis of a membrane-bound cell, specifically excludes the possibility of convective flow in and out of cells. For that reason, the metaphysical and historical foundations of Cell Theory are re-examined, the cases for the physicochemical viewpoint as against the teleological viewpoint further discussed, and the relationship of them to the notions of ‘cell’, ‘membrane’, and ‘diffusion’ looked into all over again.It is concluded that there is more evidence, from light and electron microscopy, for a spongioform cell than for a balloon cell.     

Malignant gastrointestinal neuroectodermal tumor: Cytologic,histologic, immunohistochemical,and molecular pitfalls

Malignant gastrointestinal neuroectodermal tumor (GNET) is a rare malignant primary gastrointestinal mesenchymal tumor which can be diagnosed via fine-needle aspiration (FNA) cytology. In the context of FNA, the diagnosis requires a cell block and the use of significant resources including immunohistochemical stains and molecular testing. The differential diagnosis of GNET includes clear cell sarcoma (CCS), gastrointestinal stromal tumor (GIST), gastric schwannoma, metastatic melanoma, malignant perivascular epithelioid cell tumor (PEComa) and granular cell tumor, among others. Here we describe a case which was initially diagnosed as malignant granular cell tumor by FNA which was later revised to GNET following the finding of an EWSR1-ATF1 fusion gene rearrangement.     

Small cell carcinoma of the urinary bladder--histogenesis, genetics, diagnosis, biomarkers, treatment, and prognosis.

Small cell carcinoma of the urinary bladder is a rare but highly aggressive malignancy with a dismal prognosis. Most patients present with advanced disease at the time of diagnosis. Hematuria is the most frequent presenting symptom. Histologically, small cell carcinoma of the urinary bladder is indistinguishable from its pulmonary counterpart. Coexistence with other types of carcinoma is common. Histogenesis is uncertain; there are several competing theories, including origin from stem cells, from urothelial cells, and from neuroendocrine cells in normal or metaplastic urothelium. The molecular pathogenesis remains unclear. Immunohistochemical staining can be extremely helpful in establishing the diagnosis, and in investigating the use of potential therapeutic strategies. Currently, combinations of surgical resection, chemotherapy, and radiation therapy represent the main treatment options. The recent observation of c-kit and epidermal growth factor receptor expression in more than 25% of patients with urinary bladder small cell carcinoma opens new avenues for further investigation. Improvement in survival may depend upon the identification of new molecular markers to facilitate earlier diagnosis and the development of novel targeted therapies. In this paper, we review general aspects of small cell carcinoma of the urinary bladder, focusing on the ways in which our understanding of this entity has been positively influenced by studies of the histopathologic and immunohistochemical findings, and by investigations of genetic alterations in this disease.     

Update in cancer chemotherapy, Part III: Lung cancer, Part 1

An update in cancer chemotherapy that deals with the various therapies of lung cancer is described. At present, the stage of the disease and cell type are the major factors that determine the treatment. Important differences in the biological behavior and response to treatment exist between small cell and non-small cell cancers. The small cell type is sensitive to many chemotherapeutic agents. Differences in response to chemotherapy and survival have been less among the non-small cell types.     

Autoimmunity, immunologic tolerance, and gene therapy

Research in our laboratory focuses on three major themes:

1. Costimulation and cell death in autoimmunity.
2. Molecular mechanisms of immunologie tolerance.
3. Gene therapy of autoimmune diseases.

We have performed a large series of experiments using T cell receptor (TCR) transgenic mice examining mechanisms of autoimmunity and peripheral T cell tolerance. A major focus of our current research is to understand the roles of costimulation and cell death in T cell tolerance and T cell-mediated autoimmune diseases. This involves studies of the TCR, the costimulatory molecules, and the cytokines. We are also exploring novel strategies for the treatment of autoimmune diseases by gene transfer.     

Novocell, Inc

Novocell, Inc. is a stem cell engineering company creating, delivering and commercializing cell and drug therapies for diabetes and other chronic diseases. The use of human embryonic stem cells provides a scalable source of any differentiated lineage that has potential for cell replacement therapy, as well as tools for drug discovery to create regenerative medicines.     

Regulation of human B-cell activation,proliferation, and differentiation by soluble factors

This review describes a series of studies performed in our laboratory which have focused on the activation and subsequent proliferation and differentiation of human B lymphocytes. Utilizing polyclonal signals which activate B cells by interacting with their surface membrane Ig, we have examined the events in the transition of a resting B lymphocyte to an Ig-secreting cell. A major theme in these studies is the role of soluble factors in B cell proliferation and B cell differentiation. Specific B cell growth and differentiation factors are described. Data on their sources, biochemical characterization, and methods of assay are included. Additionally, the potential role of interleukin 2 in human B cell function is discussed. The recognition that B cells exist in a variety of activation states and that transition between different states is dependent upon different signals was the impetus for a series of studies which more precisely delineated these states and the signals involved. These findings and the observations from other investigators led to a proposed model of the sequential steps in a factor-dependent B cell differentiation pathway. This model is discussed and related to the mechanisms of T cell activation and growth. Finally, the effects of two pharmacologic agents, glucocorticoids and cyclosporin A, on human B cell function are described and discussed in the context of this model.     

Metastatic renal cell carcinoma,clear cell type,of the parotid gland

Renal cell carcinoma (RCC), clear cell type, is a commonly encountered metastatic tumor that can present at unusual anatomic sites many years after the primary tumor resection. Noncutaneous metastasis to the parotid gland is unusual; however, a number of cases of parotid RCC metastasis have been reported. Fine‐needle aspiration biopsy (FNAB) is regularly utilized during the evaluation of salivary gland lesions, where it has a high sensitivity, specificity, and accuracy; however, the identification and definitive diagnosis of primary and metastatic clear cell neoplasms is a potential diagnostic pitfall for salivary gland FNAB. Here, we describe a case of RCC, clear cell type, metastatic to the parotid gland that was diagnosed entirely from FNAB cell block material, which is the first such reported case to our knowledge. We review the literature for cases of parotid RCC metastasis and focus on the utility of FNAB for synchronous versus metachronous presentations. Finally, we evaluate the differential diagnosis of clear cell parotid lesions, including ancillary histologic studies, and propose an algorithmic approach to clear cell neoplasms of the salivary gland. Diagn. Cytopathol. 2014;42:974–983. © 2014 Wiley Periodicals, Inc.     

Expression patterns and cell cycle profiles of PCNA, MCM6, cyclin D1, cyclin A2, cyclin B1, and phosphorylated histone H3 in the developing mouse retina

A challenge in studying organogenesis is the ability to identify progenitor cell populations. To address this problem, we characterized the expression patterns of cell cycle proteins during mouse retinal development and used flow cytometry to determine the expression profiles in the cell cycle. We found that MCM6 and PCNA are expressed in essentially all retinal progenitor cells throughout the proliferative period and these proteins are readily detectable in all cell cycle phases. Furthermore, their expression levels are downregulated as cells exit the cell cycle and differentiate. We also analyzed the expression of Cyclins D1, A2, and B1, and phosphorylated Histone H3 and found unexpected expression patterns and cell cycle profiles. The combined utilization of the markers tested and the use of flow cytometry should further facilitate the study of stem and progenitor cell behavior during development and in adult tissues.     

Muscle stem cells in development, regeneration, and disease

Somatic stem cell populations participate in the development and regeneration of their host tissues. Skeletal muscle is capable of complete regeneration due to stem cells that reside in skeletal muscle and nonmuscle stem cell populations. However, in severe myopathic diseases such as Duchenne Muscular Dystrophy, this regenerative capacity is exhausted. In the present review, studies will be examined that focus on the origin, gene expression, and coordinated regulation of stem cell populations to highlight the regenerative capacity of skeletal muscle and emphasize the challenges for this field. Intense interest has focused on cell-based therapies for chronic, debilitating myopathic diseases. Future studies that enhance our understanding of stem cell biology and repair mechanisms will provide a platform for therapeutic applications directed toward these chronic, life-threatening diseases.