The present paper deals with a free boundary problem modeling the growth process of necrotic multi-layer tumors. We prove the existence of flat stationary solutions and determine the linearization of our model at such an equilibrium. Finally, we compute the solutions of the stationary linearized problem and comment on bifurcation.

The transcriptional co‐activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD‐family co‐activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP‐TEAD cooperates with the RAS‐induced AP‐1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with (...) MRTF‐SRF to promote activation of cancer‐associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2‐LATS1/2) pathway and the key upstream activators are mechanically induced Integrin‐SRC and E‐cadherin‐AJUBA/TRIP6/LIMD1, growth factor induced PI3K‐AKT, and inflammation‐induced G‐protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy. (shrink)

The aim of this article is to show how a tumor can modify energy substrates fluxes in the brain to support its own growth. To address this question we use a modeling approach to explain brain nutrient kinetics. In particular we set up a system of 17 equations for oxygen, lactate, glucose concentrations and cells number in the brain. We prove the existence and uniqueness of nonnegative solutions and give bounds on the solutions. We also provide numerical simulations.

Epithelial tissues serve as critical barriers in metazoan organisms, maintaining structural integrity and facilitating essential physiological functions. Epithelial cell polarity regulates mechanical properties, signaling, and transport, ensuring tissue organization and homeostasis. However, the barrier function is challenged by cell turnover during development and maintenance. To preserve tissue integrity while removing dying or unwanted cells, epithelial tissues employ cell extrusion. This process removes both dead and live cells from the epithelial layer, typically causing detached cells to undergo apoptosis. Transformed cells, however, (...) often resist apoptosis, leading to multilayered structures and early carcinogenesis. Malignant cells may invade neighboring tissues. Loss of cell polarity can lead to multilayer formation, cell extrusion, and invasion. Recent studies indicate that multilayer formation in epithelial cells with polarity loss involves a mixture of wild‐type and mutant cells, leading to apical or basal accumulation. The directionality of accumulation is regulated by mutations in polarity complex genes. This phenomenon, distinct from traditional apical or basal extrusion, exhibits similarities to the endophytic or exophytic growth observed in human tumors. This review explores the regulation and implications of these phenomena for tissue biology and disease pathology. (shrink)

Recent work by Fernández‐Sánchez and coworkers examining the impact of applied pressure on the malignant phenotype of murine colon tissue in vivo revealed that mechanical perturbations can drive malignant behavior in genetically normal cells. Their findings build upon an existing understanding of how the mechanical cues experienced by cells within a tissue become progressively modified as the tissue transforms. Using magnetically stimulated ultra‐magnetic liposomes to mimic tumor growth ‐induced solid stress, Fernández‐Sánchez and coworkers were able to stimulate β‐catenin (...) to promote the cancerous behavior of both a normal and genetically modified colon epithelium. In this perspective, we discuss their findings in the context of what is currently known regarding the role of the mechanical landscape in cancer progression and β‐catenin as a mechanotransducer. We review data that suggest that mechanically regulated activation of β‐catenin fosters development of a malignant phenotype in tissue and predict that mechanical cues may contribute to tumor heterogeneity. (shrink)

The tumor microenvironment (TME) plays a pivotal role in the behavior and development of solid tumors as well as shaping the immune response against them. As the tumor cells proliferate, the space they occupy and their physical interactions with the surrounding tissue increases. The growing tumor tissue becomes a complex dynamic structure, containing connective tissue, vascular structures, and extracellular matrix (ECM) that facilitates stimulation, oxygenation, and nutrition, necessary for its fast growth. Mechanical cues such as stiffness, (...) solid stress, interstitial fluid pressure (IFP), matrix density, and microarchitecture influence cellular functions and ultimately tumor progression and metastasis. In this fight, our body is equipped with T cells as its spearhead against tumors. However, the altered biochemical and mechanical environment of the tumor niche affects T cell efficacy and leads to their exhaustion. Understanding the mechanobiological properties of the TME and their effects on T cells is key for developing novel adoptive tumor immunotherapies. (shrink)

Cancer is a complex disease, necessitating research on many different levels; at the subcellular level to identify genes, proteins and signaling pathways associated with the disease; at the cellular level to identify, for example, cell-cell adhesion and communication mechanisms; at the tissue level to investigate disruption of homeostasis and interaction with the tissue of origin or settlement of metastasis; and finally at the systems level to explore its global impact, e.g. through the mechanism of cachexia. Mathematical models have been proposed (...) to identify key mechanisms that underlie dynamics and events at every scale of interest, and increasing effort is now being paid to multi-scale models that bridge the different scales. With more biological data becoming available and with increased interdisciplinary efforts, theoretical models are rendering suitable tools to predict the origin and course of the disease. The ultimate aims of cancer models, however, are to enlighten our concept of the carcinogenesis process and to assist in the designing of treatment protocols that can reduce mortality and improve patient quality of life. Conventional treatment of cancer is surgery combined with radiotherapy or chemotherapy for localized tumors or systemic treatment of advanced cancers, respectively. Although radiation is widely used as treatment, most scheduling is based on empirical knowledge and less on the predictions of sophisticated growth dynamical models of treatment response. Part of the failure to translate modeling research to the clinic may stem from language barriers, exacerbated by often esoteric model renderings with inaccessible parameterization. Here we discuss some ideas for combining tractable dynamical tumor growth models with radiation response models using biologically accessible parameters to provide a more intuitive and exploitable framework for understanding the complexity of radiotherapy treatment and failure. (shrink)

Recently, we identified myeloid‐derived growth factor (MYDGF) as a blood flow‐induced angiocrine signal that promotes human and mouse hepatocyte proliferation and survival. Here, we review literature reporting changes in blood flow after partial organ resection in the liver, lung, and kidney, and we describe the angiocrine signals released by endothelial cells (ECs) upon blood flow alterations in these organs. While hepatocyte growth factor (HGF) and MYDGF are important angiocrine signals for liver regeneration, by now, angiocrine signals have also (...) been reported to stimulate hyperplasia and/or hypertrophy during the regeneration of lungs and kidneys. In addition, angiocrine signals play a critical role in tumor growth. Understanding the mechano‐elastic properties and flow‐mediated alterations in the organ‐specific microvasculature is crucial for therapeutic approaches to maintain organ health and initiate organ renewal. (shrink)

On the basis of the evidence that tumor development is suppressed by the embryonic microenvironment, some experiments using the factors taken from Zebrafish embryo at precise stages of cell differentiation were made. These experiments demonstrated a significant growth inhibition on different tumor cell lines in vitro. The observed mechanism of tumor growth inhibition is connected with the key-role cell cycle regulation molecules, such as p53 and pRb, which are modified by transcriptional or post-translational processes. Research (...) on apoptosis and differentiation revealed that treatment with these factors induces caspase-3 with a p73 apoptotic-dependent pathway activation and a concurrent significant normalization of e-cadherin and beta-catenin ratio. Other experiments found a synergistic effect on the colon cancer proliferation curve after the concurrent treatment with these factors and 5-fluorouracil. Finally, a product prepared for human therapy demonstrated 19.8% regression and 16% stable disease in an... (shrink)

High-resolution neuroimaging modalities are used often in studies involving healthy volunteers. Subsequently, a significant increase in the incidental discovery of asymptomatic intracranial abnormalities raised the important ethical issues of when follow-up and treatment may be necessary. We examined the literature to establish a practical set of criteria for approaching incidental findings. Our objective is to develop an algorithm for when follow-up may be important and to provide recommendations that would increase the likelihood of follow-up. A systematic literature search was performed (...) using the PubMed and MEDLINE databases to identify articles describing brain tumors and intracranial aneurysms. The treatment algorithm we present suggests that incidental intracranial masses suspicious for glioma should be biopsied or resected, while other masses are to be followed with serial imaging based on the expected growth pattern. Lack of follow-up can result in adverse outcomes that can be mitigated by using technology to facilitate communication and improve follow-up care. The importance of training physicians to be good communicators is also stressed. New technology including automated telephone systems, texting and email will improve access to patients and hopefully encourage compliance and follow-up. (shrink)

Cancers have a formidable capacity to develop resistance to a large and diverse array of chemical, biologic, and physical anti‐neoplastic agents. This can be largely traced to the instability of the tumor cell genome, and the resultant ability of tumor cell populations to generate phenotypic variants rapidly. It is therefore argued that anti‐cancer strategies should be directed at eliminating those genetically stable normal diploid cells that are required for the progressive growth of tumors. Micro‐vascular endothelial cells comprising (...) the tumor vasculature represent such a normal cell target. Moreover, specificity for tumor associated vasculature by anti‐cancer agents may be achieved by virtue of the fact that many of the endothelial cells that comprise these blood vessels are in an immature, cycling, and ‘activated’ state, in contrast to the endothelial cells associated with normal tissue and organ blood vessels. (shrink)

The retinoblastoma sensitivity protein (Rb) and the p53 gene product both appear to function as negative regulators of cell division or abnormal cellular growth in some differentiated cell types. Several types of cancers have been shown to be derived from cells that have extensively mutated both alleles of one or both of these genes, resulting in a loss‐of‐function mutation. In the case of the p53 gene, this mutational process appears to occur in two steps, with the first mutation at (...) the p53 locus resulting in a trans‐dominant phenotype. The mutant p53 gene product enters into an oligomeric protein complex with the wild‐type p53 protein derived from the other normal allele and such a complex is inactive or less efficient in its negative regulation of growth control. This intermediate stage of carcinogenesis selects for the proliferation of cells with one mutant allele, enhancing the probability of obtaining a cancer cell with both alleles damaged.The DNA tumor viruses have evolved mechanisms to interact with the Rb and p53 negative regulators of cellular growth in order to enhance their own replication in growing cells. SV40 and adenovirus type 5 produce viral encoded proteins that also form oligomeric protein complexes with p53 and Rb, presumably inactivating their functions. These viral proteins are also the oncogene products of these viruses. Thus, the mechanisms by which cancer may arise in a host, via mutations or virus infections, have fundamental common pathways effecting the same cellular genes and gene products; Rb and p53. (shrink)

The role of the microenvironment in cancer development is being increasingly appreciated. This paper will review data that highlight an emerging distinction between two different entities: the microenvironment that altered/preneoplastic/neoplastic cells find in the tissue where they reside, and the peculiar microenvironment inside the focal lesion (tumor) that these cells contribute to create. While alteration in the tissue environment can contribute to the selective clonal expansion of altered cells to form focal proliferative lesions, the atypical, non‐integrated growth pattern (...) that defines such focal lesions leads to the appearance of what is correctly referred to as the tumor microenvironment. The latter represents a new and unique biological milieu, characterized by hypoxia, acidosis and other biochemical and metabolic alterations, including genetic instability, that can set the stage for tumor progression to occur. Thus, the two microenvironments act in sequence and play complementary roles in the development of overt neoplasia. This distinction has important implications for the understanding of disease pathogenesis and for the management of preneoplastic/neoplastic lesions at various stages of cancer development. BioEssays 29:738–744, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In the case of magnetic resonance imaging (MRI) imaging, image processing is crucial. In the medical industry, MRI images are commonly used to analyze and diagnose tumor growth in the body. A number of successful brain tumor identification and classification procedures have been developed by various experts. Existing approaches face a number of obstacles, including detection time, accuracy, and tumor size. Early detection of brain tumors improves options for treatment and patient survival rates. Manually segmenting brain (...) tumors from a significant number of MRI data for brain tumor diagnosis is a tough and time-consuming task. Automatic image segmentation of brain tumors is required. The objective of this study is to evaluate the degree of accuracy and simplify the medical picture segmentation procedure used to identify the type of brain tumor from MRI results. Additionally, this work suggests a novel method for identifying brain malignancies utilizing the Bagging Ensemble with K-Nearest Neighbor (BKNN) in order to raise the KNN’s accuracy and quality rate. For image segmentation, a U-Net architecture is utilized first, followed by a bagging-based k-NN prediction algorithm for classification. The goal of employing U-Net is to improve the accuracy and uniformity of parameter distribution in the layers. Each decision tree is fitted on a little different training dataset during classification, and the bagged decision trees are effective since each tree has minor differences and generates slightly different skilled predictions. The overall classification accuracy was up to 97.7 percent, confirming the efficiency of the suggested strategy for distinguishing normal and pathological tissues from brain MR images; this is greater than the methods that are already in use. (shrink)

Growth and morphogenesis in the mammary gland depend on locally derived growth factors such as those in the epidermal growth factor (EGF) superfamily. Cripto-1 (CR-1, human; Cr-1, mouse)—also known as teratocarcinoma-derived growth factor-1—is a novel EGF-related protein that induces branching morphogenesis in mammary epithelial cells both in vitro and in vivo and inhibits the expression of various milk proteins. In the mouse, Cr-1 is expressed in the growing terminal end buds in the virgin mouse mammary gland (...) and expression increases during pregnancy and lactation. Cr-1/CR-1 is overexpressed in mouse and human mammary tumors and inappropriate overexpression of Cr-1 in mouse mammary epithelial cells can lead to the clonal expansion of ductal hyperplasias. Taken together, this evidence suggests that Cr-1/CR-1 performs a role in normal mammary gland development and that it might contribute to the early stages of mouse mammary tumorigenesis and the pathobiology of human breast cancer. BioEssays 1999;21:61–70. Published 1999 John Wiley & Sons, Inc. (shrink)

Transforming growth factor‐β (TGF‐β) and its related proteins regulate broad aspects of body development, including cell proliferation, differentiation, apoptosis and gene expression, in various organisms. Deregulated TGF‐β function has been causally implicated in the generation of human fibrotic disorders and in tumor progression. Nevertheless, the molecular mechanisms of TGF‐β action remained essentially unknown until recently. Here, we discuss recent progress in our understanding of the mechanism of TGF‐β signal transduction with respect to the regulation of gene expression, the (...) control of cell phenotype and the potential usage TGF‐β for the treatment of human diseases. (shrink)

Human neoplasms develop following the progressive accumulation of genetic and epigenetic alterations to oncogenes and tumor suppressor genes. These alterations confer a growth advantage to the cancer cell, leading to its clonal proliferation, invasion into surrounding tissues, and spread to distant organs. Genes that are altered in neoplasia affect three major biologic pathways that normally regulate cell growth and tissue homeostasis: the cell cycle, apoptosis, and differentiation. While each of these pathways can be defined by a unique (...) set of molecular events, they are not biologically separate. Rather, they function more as an integrated molecular network, and perturbations in one pathway can have profound consequences on another. Insights into what distinguishes the regulation of growth and differentiation in a normal cell versus a cancer cell have led to the development of novel anticancer therapies. BioEssays 24:83–90, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Proteolytic cleavage of extracellular matrix (ECM) is a critical regulator of many physiological and pathological events. It affects fundamental processes such as cell growth, differentiation, apoptosis and migration. Most proteases are produced as inactive proenzymes that undergo proteolytic cleavage for activation. Proteolytic activity is additionally modified by endogenous inhibitors. Mechanisms that localize and concentrate protease activity in the pericellular microenvironment of cells are prerequisites for processes like angiogenesis, bone development, inflammation and tumor cell invasion. Methods that enable real‐time, (...) high‐resolution imaging and precise quantification of local proteolytic activity in vitro and in vivo remain major challenges. These methods will play an important role in the understanding of basic principles e.g. in cancer cell invasion, the identification of new therapeutical targets and hence drug design. This review highlights mechanisms and functions of local proteolytic activity with special emphasis on tumor cell invasion and metastasis, and focuses on techniques for the investigation of this process. BioEssays 27:1181–1191, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The immune surveillance theory postulates that spontaneous tumors are normally rejected by the immune system and appear only when they override host‐immune recognition and rejection mechanisms. The present mini‐review describes a spontaneous tumor system, the reticulum cell sarcomas (RCS) in SJL/J mice, that is dependent on host tumor‐specific immune lymphocytes for growth. This continuous tumor‐specific response results in tumor progression and death of the host. This tumor system contradicts the basic concept of immune surveillance. (...) We propose as an explanation that some highly antigenic tumors, like the RCS, may have evolved in a non‐autonomous fashion but, nevertheless, have lost regulatory controls of cell proliferation. In the RCS system, the tumor expresses Class II MHC I‐E like specificities that are not expressed on the host cells and which selectively stimulate a subpopulation of I‐E specific T cells, the Vβ17a+ clonotype, leading to their expansion and continuous nurturing of the tumor via secreted lymphokines. This neoantigenic stimulation bypasses the tumor regulatory response that might have resulted if the tumor had not expressed neo‐antigens. Furthermore, passive administration of anti‐clonotypic antibody to tumor‐bearing mice results in tumor regression and long‐term survival through removal of the tumor reactive T cells. Thus, in this tumor system, immunosuppressive treatments are the prescription for tumor rejection. (shrink)

Analysing cylindromatosis and the associated defects in the CYLD gene is providing novel insights into the molecular principles of epithelial growth control and carcinogenesis in, and beyond, the skin. In this review, we summarize the histopathology and histogenesis of cylindromas, and the available genetic information on patients with these skin appendage tumors. Focusing on recent data concerning the normal functions and signaling interactions of the CYLD gene product, we explain how CYLD interferes with TNF‐α or TLR‐mediated signaling as well (...) as with JNK or NF‐κB‐dependent p65/50 signaling to limit inflammation. In addition, we delineate how CYLD interferes with activation of the proto‐oncogene Bcl3 and with cyclin D1 expression to limit tumorigenesis, and chart how tumor growth‐promoting agents or UV light and inflammatory mediators can activate CYLD. We argue that these recent insights into CYLD function and cylindroma pathogenesis may lead to the development of novel molecular strategies for cancer prevention and treatment. BioEssays 29:1203–1214, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. These tumors may therefore be (...) susceptible to disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity. -/- . (shrink)

In lieu of an abstract, here is a brief excerpt of the content:A Bittersweet Score:A Father’s Account of His Family’s 20-Year Journey After a Pediatric Brain Tumor DiagnosisChristopher RileyI hadn’t seen him for 20 years, not since the day he drilled a hole in Peter’s head and left the stainless steel drill and bloody bit on the bedside table. He figured prominently in the story I often told of that day when he, a doctor in training, [End Page 3] (...) informed my wife Kathy and me that, “Wow,” our five-year-old son had “an impressive tumor” in his brain. He announced it with the admiration I reserve for a touchdown pass or stunning sunset. Since that day, he had become a venerable physician. Back then he was the resident who met us in the ER after our pediatrician told us that the MRI of Peter’s brain was “not normal,” that “there might be a growth.” As if there might not be. I imagined that Peter’s brain might simply have an unusual shape, or that the scan revealed some undiscovered fracture and the authorities only wanted to lock me up and all with my son would be well. The thrilled young doctor slew those hopes with an ice pick: “Wow, that’s an impressive tumor.” I said, “That’s the first time anyone has used the word tumor.” The doctor appeared mortified and started over.Now 20 years later we found ourselves at the same party and I felt a compulsion to introduce myself, remind him we’d met that day in 1993, and tell him what had become of Peter and his family in the decades since he’d made that mortifying mistake, one I hoped had become for him a defining moment. To my disappointment, he didn’t seem to remember.Peter was my red-haired boy. Fearless and whip smart, he told a stream of knock-knock jokes and performed dance routines choreographed by his 8-year-old sister Rachel. Six months of headaches, vomiting and clumsy falls led to discovery of the tumor. When I phoned my parents with the news, I couldn’t speak the words, words that felt as if they spelled my boy’s doom. My body refused to pronounce them.The war for Peter’s life began with surgery. I sat with Kathy in the surgical waiting area, fearing every minute that I would see the surgeon approaching with his shoulders slumped in mortal defeat. I learned during those hours that fear of your child’s death is a physical pain, a constriction in the chest, a suffocation. At the end of that wait, the surgeon told us the tumor was out and Peter had survived. The pathology indicated the tumor was a medulloblastoma. Without additional treatment, including radiation, it was certain to come back. Kathy’s knees buckled. Having just endured one life-and-death battle, we were plunged into another. To complicate matters, Peter wasn’t waking from surgery. Even after the anesthesia wore off, Peter remained groggy, unable to move or focus his eyes.Through the following days, Peter failed to rouse or speak. Sores formed at the back of his neck where his unswallowed saliva pooled. Neurologists doubted he knew us. His doctors hoped Peter would recover but it was possible he would remain as he was indefinitely. As I sat holding his useless hand, watching his useless body, I thought I’d never loved him as much as I did now.Peter’s doctors presented two treatment options. The first consisted of relatively high doses of daily radiation, the most effective known method for preventing the return of the cancer. But radiation wasn’t good for young brains. It “shaved IQ points,” they said in wild understatement. So they offered a second, experimental option, one that reduced radiation by a third and added months of chemotherapy. The doctors hoped this new regimen would be as effective as the old but cause less cognitive damage. They asked us to choose. It seemed impossible. We gathered the scant available data. We weighed the risks. We prayed. We took a leap. Without asking him, we made a decision for Peter we knew... (shrink)

Gliomas are diffuse and invasive brain tumors with the nefarious ability to evade even seemingly draconian treatment measures. Here we introduce a simple mathematical model for drug delivery of chemotherapeutic agents to treat such a tumor. The model predicts that heterogeneity in drug delivery related to variability in vascular density throughout the brain results in an apparent tumor reduction based on imaging studies despite continual spread beyond the resolution of the imaging modality. We discuss a clinical example for (...) which the model-predicted scenario is relevant. The analysis and results suggest an explanation for the clinical problem of the long-standing confounding observation of shrinkage of the lesion in certain areas of the brain with continued growth in other areas. (shrink)

Global Stomach Cancer Treatment Market Size research report offers in-depth assessment of revenue growth, market definition, segmentation, industry potential, influential trends for understanding the future outlook and current prospects for the market. -/- Stomach cancer is the fifth most common cancer in the world. According to Cancer Research U.K., 6,697 gastric carcinoma cases are diagnosed each year. Stomach cancers are classified into three types. Gastric Adenocarcinoma is the most common type of stomach cancer and accounts for 90%-95% of stomach (...) cancer cases. Gastrointestinal Stromal Tumor (GIST) and Gastric Neuroendocrine Tumors (gNET) are rare in nature. Rising incidence of cancer cases and limited drugs as first-line treatment are the major factors that have encouraged many pharmaceutical giants to conduct research for the development of novel drugs. -/- Drivers & Restraints -/- The global stomach cancer treatment market size stood at USD 2.61 Billion in 2018 and is projected to reach USD 8.20 Billion by 2026, exhibiting at a CAGR of 15.3% in the forecast period -/- This study provides information about the sales and revenue during the historic and forecasted period of (2024 to 2030). Understanding the segments helps in identifying the importance of different factors that aid market growth. Estimations about the CAGR value for specific forecast period, market drivers, market restraints, and competitive strategies are assessed in this Stomach Cancer Treatment Market report. -/- This report focuses on Stomach Cancer Treatment Market volume and value at the global level, regional level and company level. From a global perspective, this report represents overall Stomach Cancer Treatment Market market size by analysing historical data and future prospect. Regionally, this report focuses on several key regions: North America, Europe, Asia-Pacific, Latin America and Middle East and Africa. -/- Competitive Strategic Window: -/- The Competitive Strategic Window analyses the competitive landscape in terms of markets, applications, and geographies to help the vendor define an alignment or fit between their capabilities and opportunities for future growth prospects. It describes the optimal or favorable fit for the vendors to adopt successive merger and acquisition strategies, geography expansion, research & development, and new product introduction strategies to execute further business expansion and growth during a forecast period. -/- . (shrink)

Alterations in the expression of certain genes or in their products can render benign tumor cells metastatic. Experimentally this has been quickly performed by transferring dominantly acting oncogenes such as c‐H‐rasEJ into susceptible cells, but in vivo such a rapid qualitative change in a dominantly acting oncogene occurs only rarely, and progression to highly metastatic phenotypes is thought to occur through a slow stepwise process. Such slow changes can be reversible and need not involve known dominantly acting oncogenes, consistent (...) with clinical observations. An important element of the natural progression of tumors to malignancy may be their ability to circumvent microenvironmental controls that regulate growth and cellular diversity and to evolve into heterogeneous phenotypes, a process that appears to involve mainly quantitative changes in gene expression but which can be rapidly stimulated in cell culture by the introduction of a dominantly acting oncogene. It is proposed that the highly malignant cells that have slowly evolved in vivo with only a few qualitative gene changes have undergone extensive cycles of diversification and accumulation of quantitative changes in the expression of genes that encode products that are related to malignancy and metastasis. Thus, highly malignant cellular phenotypes can arise quickly through specific qualitative changes in critical controlling genes or more slowly by less critical qualitative genetic changes, coupled with cellular diversification and accumulation of quantitative changes in gene expression. (shrink)

Sigmoid functions have been applied in many areas to model self limited population growth. The most popular functions; General Logistic (GL), General von Bertalanffy (GV), and Gompertz (G), comprise a family of functions called Theta Logistic ( $$ \Uptheta $$ L ). Previously, we introduced a simple model of tumor cell population dynamics which provided a unifying foundation for these functions. In the model the total population ( N ) is divided into reproducing ( P ) and non-reproducing/quiescent (...) ( Q ) sub-populations. The modes of the rate of change of ratio P / N was shown to produce GL, GV or G growth. We now generalize the population dynamics model and extend the possible modes of the P / N rate of change. We produce a new family of sigmoid growth functions, Trans-General Logistic (TGL), Trans-General von Bertalanffy (TGV) and Trans-Gompertz (TG)), which as a group we have named Trans-Theta Logistic ( T $$ \Uptheta $$ L ) since they exist when the $$ \Uptheta $$ L are translated from a two parameter into a three parameter phase space. Additionally, the model produces a new trigonometric based sigmoid ( TS ). The $$ \Uptheta $$ L sigmoids have an inflection point size fixed by a single parameter and an inflection age fixed by both of the defining parameters. T $$ \Uptheta $$ L and TS sigmoids have an inflection point size defined by two parameters in bounding relationships and inflection point age defined by three parameters (two bounded). While the Theta Logistic sigmoids provided flexibility in defining the inflection point size, the Trans-Theta Logistic sigmoids provide flexibility in defining the inflection point size and age. By matching the slopes at the inflection points we compare the range of values of inflection point age for T $$ \Uptheta $$ L versus $$ \Uptheta $$ L for model growth curves. (shrink)

The extracellular domains of several integral membrane proteins are released from the cell surface by a group of enzymes known as “sheddases” through a process called “ectodomain shedding”. Because many transmembrane growth and differentiation factors, including members of the epidermal growth factor (EGF) family that play a crucial role in development, require ectodomain shedding for proper action in vivo, proteolysis is now viewed as a regulatory mechanism in the developing embryos. Two recent reports by Zhao et al. provide (...) evidence for the role of cell surface proteolysis by an ADAM (a disintegrin and metalloprotease) in the development of murine lung.(1,2) Inhibition of tumor necrosis factor‐α converting enzyme (TACE, ADAM17) by the hydroxamic acid‐based metalloprotease inhibitor (TAPI), (1) or a targeted mutation in Zn2+‐binding domain of TACE, (2) disrupts two essential epithelial functions in lung development: branching morphogenesis and cytodifferentiation. Evidence for the role of ADAMs as sheddases in development and growth factor signaling is discussed. BioEssays 24:8–12, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Cancer stem cells (CSC) represent malignant cell subsets in hierarchically organized tumors, which are selectively capable of tumor initiation and self‐renewal and give rise to bulk populations of non‐tumorigenic cancer cell progeny through differentiation. Robust evidence for the existence of prospectively identifiable CSC among cancer bulk populations has been generated using marker‐specific genetic lineage tracking of molecularly defined cancer subpopulations in competitive tumor development models. Moreover, novel mechanisms and relationships have been discovered that link CSC to cancer therapeutic (...) resistance and clinical tumor progression. Importantly, proof‐of‐principle for the potential therapeutic utility of the CSC concept has recently been provided by demonstrating that selective killing of CSC through a prospective molecular marker can inhibit tumor growth. Herein, we review these novel and translationally relevant research developments and discuss potential strategies for CSC‐targeted therapy in the context of resistance mechanisms and molecular pathways preferentially operative in CSC. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:The 12–Minute JourneyHeather A. CarlsonI met Jack for the first time when he was in the intensive care unit as he was just waking up from his emergent tracheostomy surgery. As I walked into his room he opened his eyes in panic and he struggled to take in a deep breath, fighting the ventilator that was trying to deliver slow steady breaths for him. His face was flooded with (...) fear and the ventilator alarms were blaring. He was surrounded by nurses and respiratory technicians all trying to calm him down, while adjusting the settings on the machine. “Just try and breathe slowly,” they instructed him, though this seemed to be impossible for him as he continued to try and suck in as much air as possible through the new hole in his throat. As his arm flailed out I grabbed his hand and while holding it in mine I just tried to emulate tranquility for him. I thought to myself this is exactly how I would react if I woke up in this condition and could imagine the fear that he was now feeling. While nurses rushed around with suction equipment and the respiratory technicians made adjustments and monitored the results I stood there holding his hand silently praying that he become calm. With all of our support he did eventually relax and find the ability to sync his breathing with the ventilator settings.I am a palliative care nurse practitioner and had been asked to see Jack to help with symptom management and establishing his goals of care as he had recently been diagnosed with head and neck cancer. He had presented to the hospital with complaints of difficulty breathing and it didn’t take long for the emergency room physician to determine that his airway was almost completely occluded by tumor. Jack had actually been diagnosed with this cancer the month before, and had met with a radiation oncologist who planned to start radiation as soon as possible to avoid tumor growth that could impair his breathing. Unfortunately Jack was so anxious and scared about this treatment plan that he never went back to the cancer center. Instead, he stayed in his room in the boarding house that he lived in, smoking cigarettes to calm his nerves. Jack was a recovering alcoholic who had previously been homeless and out on the streets for many years before becoming sober and finding shelter at the boarding house where he now lived. He was a heavy smoker and found that it was one thing that helped to ease his anxiety. The thought of being strapped down to a table with a tight mask over his head while radiation zapped the cancer in his neck had terrified him. His anxiety and claustrophobia had prevented him from following through with his cancer treatment.My initial visits with Jack were spent trying to treat his anxiety as well as the pain he experienced in his neck and head.Because he had undergone a tracheostomy and was now on a ventilator he was unable to speak. To communicate he pointed to a picture board that had common sayings on it, like “I have pain” and “I have to go to the bathroom”. He also used a clipboard with paper and pen and could write what he wanted to say, but this was a time consuming endeavor. Despite this, he was a very animated gentleman who had a lot to say and he wasn’t going to let the loss of his voice impair him. I found myself enjoying my visits with him each day, as he would tell me more about himself. I quickly discovered that he was a very spiritual man and his faith was his inspiration. He wrote on his clipboard “this cancer is actually a gift” and went on to explain that he had been on a fast track toward self destruction, but now feels as though he has been given another chance at life. He spent his time in the hospital reflecting on his life’s journey and how he would be able to help others in similar circumstances. He wrote on his [End Page 192] clipboard multiple... (shrink)

Angiogenesis, the generation of new blood vessels from pre‐existing vessels, is an integral component of wound healing, responses to inflammation and other physiologic processes. It is also an essential part of tumor growth; in the absence of new vessel formation, tumors cannot expand beyond a small volume. Although much is known about angiogenesis and its regulation, there is no overall theory that describes or explains this process. It is here suggested that the intracrine hypothesis, which ascribes to certain (...) extracellular signaling peptides (whether hormones, growth factors, DNA‐binding proteins or enzymes) a role in both intracellular biology and extracellular signaling, can contribute to a more general understanding of angiogenesis. Intracrine factors participate in angiogenesis in the following ways: (1) they can act within the cells that synthesized them (type I intracrine action), (2) they can be secreted and then taken up by their cell of synthesis to act intracellularly (type II intracrine action ), or (3) they can be secreted and internalized by a distant target cell (type III intracrine action). The parallels between the intracrine growth factor mechanisms cancer cells employ in stimulating their own growth and the mechanisms operative in endothelial cell proliferation during angiogenesis (“intracrine reciprocity”) are discussed. Collectively, these explorations lead to testable hypotheses regarding the regulation of normal and pathological angiogenesis, and point to similarities between tumor‐induced angiogenesis and tissue differentiation. BioEssays 28: 943–953, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Telomeres, the ends of chromosomes, shorten with each cell division. To expand their replicative potential, various cell types use the ribonucleoprotein telomerase, which lengthens telomeres by its reverse transcriptase activity. Because of its ability to immortalize cancer cells, telomerase also plays a significant role in tumor growth. However, in recent years, a wide variety of non‐canonical effects of telomerase that are independent of telomere lengthening have been discovered, and even the notion that telomerase is restricted to very few (...) cell types has been questioned. These effects also seem to be important in carcinogenesis and might explain the tumor‐promoting effects of telomerase independently of telomere elongation. Here, the current understanding of the extratelomeric roles of telomerase and their physiological and pathological significance is reviewed. BioEssays 30:728–732, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

We formulate a dynamic model of vascular tumor growth, in which the interdependence of vascular dynamics with tumor volume is considered. The model describes the angiogenic switch; thus the inhibition of the vascularization process by antiangiogenic drugs may be taken into account explicitly. We validate the model against volume measurement data originating from experiments on mice and analyze the model behavior assuming different inputs corresponding to different therapies. Furthermore, we show that a simple extension of the model (...) is capable of considering cytotoxic and antiangiogenic drugs as inputs simultaneously in qualitatively different ways. (shrink)

Angiogenesis plays an essential role in tumor growth, invasion and metastasis. After initial pessimism about the usefulness of the antiangiogenic therapeutic approach for cancer, interest has increased in the development of antiangiogenic compounds after the first clinical approval of an antiangiogenic therapy. The anti‐vascular endothelial growth factor (VEGF) antibody bevacizumab has recently been approved for use in combination with chemotherapy for the treatment of metastatic colorectal and non‐small cell lung cancer patients. However, no survival benefit has been (...) demonstrated in anti‐VEGF monotherapy trials, probably due to the high complexity of tumor angiogenesis regulation. Experimental and clinical data, including the approval of the multitargeted drugs sunitinib and sorafenib, indicate that exciting results, including tumor regression, can be expected from the combined targeting of different pathways in the tumor angiogenesis scenario. Several obstacles, including the high cost of new molecular targeted drugs make this therapeutic approach difficult. BioEssays 29:1159–1168, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Consenting for Novel and Dangerous Surgical Procedures with Minimal Supporting EvidenceMichelle J. ClarkeFrank1 was a 19–year–old man referred to me after a workup for back pain led to the discovery of a large, aggressive tumor in his sacrum. The tumor wrapped around the nerves controlling bowel, bladder, and leg function. We performed a needle biopsy and learned that the tumor was an angiosarcoma, an extremely aggressive (...) and usually deadly form of cancer. However, the tumor was unique in that it theoretically could be cured if removed in one piece. But, to do so would necessitate sacrificing the nerves, leaving the patient irreversibly incontinent, lacking sexual function, and confined to a wheelchair.Once we knew the diagnosis, Frank came to the office with his family to discuss treatment options. He appeared terrified and was almost silent through the appointment, deferring most questions to his parents. Due to the speed of tumor growth, we discussed palliative therapy, conventional treatment, and the one–piece or “en bloc” surgery, which was new and unproven for his disease. Based on the remarkable tumor growth we noted during the work–up, with palliative treatment the patient would likely survive for less than six months. Conventional treatment, in which surgery is done to remove part of the tumor while sparing the nerves to bowel and bladder function, was known to have a high rate of recurrence and death. Further, this tumor didn’t respond well to radiation and chemotherapy, so chance of survival was limited, although his life might have been extended for a short period. Thus our conversation turned to the novel “en bloc” procedure.The en bloc procedure offered a hope of long–term survival unlike the other options. However, this came with an enormous cost. The surgery itself would be planned to occur over three days with five separate surgical teams and a very real chance of major complications or death. Nerves to bowel and bladder would be cut, irreversibly leaving the patient without sexual function, and completely incontinent with a urinary catheter and colostomy. Walking was expected to be disrupted or potentially impossible due to the nerve resection. We went to great lengths over the course of many visits to describe the impact of the surgery on the patient’s function, and the impact on his quality of life. To make matters more challenging, as this procedure was so new and the tumor so rare, research did not yet exist to quantify his likelihood of long–term survival.Personally I was very uncomfortable with the situation. From a medical standpoint, the surgery offered was the best distillation of research and professional experience. En bloc surgery offered the best—if not the only—chance for survival in [End Page 5] this young man. Additionally, having treated many spine–injured patients I was aware that many patients with similar deficits led happy and productive lives following an emotional and physical adjustment period. However the surgery was also extreme. I worried that we would not be able to accomplish the goal of a one–piece resection and would accidentally spill some of the tumor, creating all of the deficits but no survival benefit. Frankly, I thought there was a 25% chance that would happen, which was explained to the family preoperatively. Were we overreaching our abilities and making a dying patient’s life worse by proceeding?Second, I was uneasy about the social situation. The patient’s family was very supportive, traveling with him to all appointments and assisting with his care. The patient himself usually deferred all scheduling to his mother, which wasn’t entirely unusual for such a young man. However it was difficult to grasp how much the patient understood of his disease or supported the plan. We attempted to delve more deeply into his thoughts, including without his parents present, but got only short answers, which revealed little. While the family appeared to have accepted the diagnosis and wanted to get to the business of treatment, the patient seemed to me to still carry the shock of his recent cancer diagnosis. Pushed by the rapid tumor growth, we were limited in how long we could wait for... (shrink)

Mutations in growth factor receptor signaling pathways are common in cancer cells, including the highly lethal brain tumor glioblastoma (GBM) where they drive tumor growth through mechanisms including altering the uptake and utilization of nutrients. However, the impact of changes in micro‐environmental nutrient levels on oncogenic signaling, tumor growth, and drug resistance is not well understood. We recently tested the hypothesis that external nutrients promote GBM growth and treatment resistance by maintaining the activity (...) of mechanistic target of rapamycin complex 2 (mTORC2), a critical intermediate of growth factor receptor signaling, suggesting that altered cellular metabolism is not only a consequence of oncogenic signaling, but also potentially an important determinant of its activity. Here, we describe the studies that corroborate the hypothesis and propose others that derive from them. Notably, this line of reasoning raises the possibility that systemic metabolism may contribute to responsiveness to targeted cancer therapies. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Prepping for the Day You Hope Never Arrives:Facing RecurrenceTerra TrevorMy 14–year–old son was eight years past diagnosis of a brain tumor. Gone were the pristine sick days when his white hooded sweatshirt stayed spotlessly clean for weeks at a time. Each time he left a muddy footprint on the kitchen floor I rejoiced; it felt so good to have a healthy kid again. However, my son was a (...) survivor of an anaplastic ependymoma, grade IV, brain tumor, and although I wanted to be out of the woods, I knew we were not. I’d climbed out of the space where medical problems were fi led in my mind, yet I kept the door open because statics showed that the type of brain tumor he had, frequently recurred.Still, I was determined to keep our lives as ordinary as possible. But for a brain tumor family this meant staying connected to sources of support. Parent programs, patient and sibling support groups [End Page 27] and camps, and we remained connected to hospital resources. Most of all we needed to have fun as a family, and we attended the cancer survivor picnics and parties our hospital hosted, where the doctors served as volunteers, grilling hamburgers and dishing up ice cream for the guest of honor patients.My husband and I felt confident that as long as we worked as a team with our doctors and stayed connected to resources offered, we would find a way to meet any challenges that might surface.In the end ultimately what saved us was this mosaic of support provided to us over the years from a multitude of good people and organizations offering help when we needed it most. And I had the opportunity to learn to accept help, which it turns out, is far harder than offering to help.Shortly after my son Jay celebrated his 8th year as a brain tumor survivor, I watched him open the medicine cabinet and reach for the bottle of Advil, for the second time in a row that day. “Do you have a headache again?” I asked. He shrugged his shoulders, then hiccupped hard, and ducked his head in the toilet and threw up. Tears welled in his eyes. I sank into the deep, silent panic that made me calm.Our primary care physician called in an authorization for an MRI. Jay hid his fear behind a mask of quiet strength. It was ten days before his fifteenth birthday.While we waited for the MRI appointment, that week Jay was elected student of the month, and he got a lead part in the school play. My idyll of family hood continued until the MRI confirmed my worst fear—the tumor was back, and this time its fingers spread into the brainstem.We had to decide on a plan of treatment. Surgery was scheduled. When Jay was admitted to the hospital and I requested that he be placed in the pediatric ward, an environment he was familiar with, they agreed. Although Jay was a teenager, the recurrence caused him to revert emotionally back to a younger age. It was as if he was seven–years–old again, reliving his first brain tumor experience, and he kept his childhood security item—a small teddy bear with him, tucked under the hospital covers, like he had with the first diagnosis.Luck held. With surgery most of the tumor was resected and symptoms disappeared. Three days later, on Thanksgiving, he was feeling well enough to be excited about the Thanksgiving dinner our hospital provided us. A table and chairs were brought in, along with a feast of good food. The nurses gave Jay lavish attention, they laughed at the corny jokes he told, and made us feel like special company.Within a week Jay was out of the hospital, recovering well. But what to do about the remaining brain tumor slivers that were inoperable? He had already received his lifetime dose of whole brain radiation, and chemotherapy available offered little hope of curing a recurrent tumor. But there was a small chance that stereotactic radiation might stall tumor growth. We set up a consultation.We had... (shrink)

Notch signaling plays an essential role in the processes of embryogenesis and cellular differentiation, and it is believed that the oncogenic effects of dysregulated Notch signaling are an anomalous reflection of the normal functions of this cascade. Nonetheless, the cellular events associated with oncogenic Notch signaling have thus far remained elusive. In a recent report, Ferres‐Marco et al.1 described how they used the Drosphila eye as a model system and found that elevated Notch signaling in combination with activation of components (...) of the Polycomb complex of transcriptional repressors led to metastatic growth of tumors through epigenetic silencing of the Rbf gene. Rbf is the Drosophila homologue of the retinoblastoma tumor‐suppressor gene (Rb), thus it represents a novel link between Notch signaling, tumor growth and metastasis. BioEssays 28: 692–695, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

High‐molecular‐weight hyaluronan acts as a ligand of the tumor‐suppressive Hippo signal, whereas degradation of hyaluronan from a high‐molecular‐weight form to a low‐molecular‐weight forms by hyaluronidase 2 inhibits Hippo signal activation and thereby activates the pro‐oncogenic transcriptional coactivator yes‐associated protein (YAP), which creates a cancer‐predisposing microenvironment and drives neoplastic transformation of cells through both cell‐autonomous and non‐cell‐autonomous mechanisms. In fact, accumulation of low‐molecular‐weight hyaluronan in tissue stroma is observed in many types of cancers. Since inhibition of YAP activity suppresses (...) class='Hi'>tumor growth in vivo, pharmacological intervention of the Hippo‐YAP signal is an attractive approach for future drug development. In this review, pharmacological intervention of excessive hyaluronan degradation as a novel approach for inhibition of the Hippo‐YAP signal is also discussed. Development of hyaluronidase inhibitors may provide novel therapeutic strategies for human malignant tumors. (shrink)

Melatonin, the chief hormone of the pineal gland, is produced and secreted into the blood in a circadian manner with maximal production always occurring during the dark phase of the light dark cycle. Whereas the 24h rhythm of melatonin production is very robust in young animals including humans, the cycle deteriorates during ageing. The rhythm of melatonin can be substantially preserved during ageing by restricting the food intake of experimental animals; this same treatment increases the life span of the animals. (...) The exogenous administration of melatonin to non‐food restricted animals also reportedly increases their survival. Moreover, melatonin has been shown to have immunoenhancing effects and oncostatic properties. The implication of these studies is that melatonin may have both direct and indirect beneficial effects in delaying ageing processes or it may retard the development of processes (e.g., immunodeficiency and tumor growth) which contribute to a reduced life span. (shrink)

Alpha‐fetoprotein (AFP)AFP, alpha‐fetoprotein; T3R, thyroid hormone (triiodothyronine) receptor; RAR, retionic acid receptor; erbA, putative thyroid hormone receptor proto‐oncogene products; VDR, vitamin D receptor; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; HRE, hormone response element on DNA; RXR, retionic‐X‐receptor; RAP, receptor auxiliary (accessory) proteins; E, estrogen. is a tumor‐associated fetal marker, associated both with tumor growth and with birth defects. AFP, whose precise function is unknown, has been classified as belonging to a protein (...) superfamily together with albumin and vitamin D‐binding (Gc) protein. AFP has been shown to bind various ligands in vitro including fatty acids, estrogens, thyroid hormones and retinoic acids. The steroid/thyroid nuclear receptor superfamily of proteins has recently become a major focus of biomedical investigation regarding regulation of gene expression. These receptors are thought to bind to DNA‐hormone response elements (HRE) that affect growth, development, differentiation, reproduction and homeostasis. The HREs are known to share DNA sequences with the various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine‐zipper dimerization (heptad) motif in the carboxy‐terminal third domain of both rodent and human AFP is postulated. The presence of nine such hydrophobic repeats in the third domain of the AFP molecule mimics the heptad dimerization repeats found in the retinoic acid, thyroid, e‐erbA and other members of the nuclear receptor superfamily. Computer analysis revealed that the most conservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40–60% homology with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth‐regulatory properties (both inhibition and enhancement) that have been ascribed to AFP in the last decade. (shrink)

Melanomas arise from transformed melanocytes, positioned at the dermal‐epidermal junction in the basal layer of the epidermis. Melanocytes are completely surrounded by keratinocyte neighbors, with which they communicate through direct contact and paracrine signaling to maintain normal growth control and homeostasis. UV radiation from sunlight reshapes this communication network to drive a protective tanning response. However, repeated rounds of sun exposure result in accumulation of mutations in melanocytes that have been considered as primary drivers of melanoma initiation and progression. (...) It is now clear that mutations in melanocytes are not sufficient to drive tumor formation—the tumor environment plays a critical role. This review focuses on changes in melanocyte‐keratinocyte communication that contribute to melanoma initiation and progression, with a particular focus on recent mechanistic insights that lay a foundation for developing new ways to intercept melanoma development. (shrink)

The assessment of hormones in saliva has gained wide acceptance in clinical endocrinology. To date, there is no hypothesis as to why some hormones can be found in saliva, while others cannot, and whether there is a physiological consequence of this fact. A number of carefully performed studies give examples of important physiological hormonal activity in saliva. Steroids, such as androgens, act as pheromones in olfactory communication of various mammalian species, such as facilitating mating behavior in swine or serving as (...) odor cues for rodent nestlings. Salivary peptide hormones, such as epidermal growth factor (EGF) and transforming growth factor‐α (TGF‐α), and amines such as melatonin, are involved in the regulation of inflammatory processes and in the promotion of cell proliferation, and contribute to a rapid wound healing in the oropharyngeal epithelia. Current data provide evidence of the involvement of salivary cytokines, such as interleukin‐8 and leptin, in tumorgenesis in the oral cavity and the salivary glands. The tumor tissues express and release significantly more of these cytokines than healthy glands. Consequently, the assessment of salivary hormone profiles may provide promising targets for diagnostic tumor markers. (shrink)

Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non‐endosteal perisinusoidal niche. Single‐cell molecular profiling and in vivo cell lineage analyses play key roles (...) in discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor‐making cells when deleterious mutations occur in tumor suppressor genes. The emerging hypothesis is that osteoblast‐chondrocyte transitional identities confer a special subset of endosteal stromal cells with stem cell‐like properties, which may make them susceptible for tumorigenic transformation. Endosteal stem cells are likely to represent an important therapeutic target of bone diseases caused by aberrant bone formation. (shrink)

Metastatic spread of tumor cells is one of the most common causes of death in cancer patients. Therefore, elucidation of the molecular mechanisms that underlie the formation of metastatic colonies has been one of the major objectives of cancer research during the last two decades. In this review we will mainly discuss the mechanisms that cause a malignant cell to grow at a given site rather than at other possible sites, taking into account experimental and clinical evidence published on (...) the subject. As a whole this evidence tends to confirm the hypothesis that organ‐specific colonization by malignant cells often follows very specific and close interactions between the cancer cell and the target organ, either in terms of specific cellular adhesion or growth promotion. In this paper we would like to underscore the fact that cellular adhesion, either specific or unspecific, is a necessary but, by itself, insufficient condition for the development of metastases. It is the ability of the tumor cells to grow at the site where they arrested that ultimately determines whether a metastatic colony develops or fails to develop at that site. (shrink)

A brain tumor is an abnormal mass or growth of a cell that leads to certain death, and this is still a challenging task in clinical practice. Early and correct diagnosis of this type of cancer is very important for the treatment process. For this reason, this study aimed to develop computer-aided systems for the diagnosis of brain tumors. In this research, we proposed three different end-to-end deep learning approaches for analyzing effects of local and deep features for (...) brain MRI images anomaly detection. The first proposed system is Directional Bit-Planes Deep Autoencoder which extracts and learns local and direction features. The DBP-DAE by decomposition of a local binary pattern into eight bit-planes extracts are directional and inherent local-structure features from the input image and learns robust feature for classification purposes. The second one is a Dilated Separable Residual Convolutional Network which extracts high and low-level features. The main advantage of this approach is that it is robust and shows stable results regardless to size of image database and to solve overfitting problems. To explore the effects of mixture of local and deep extracted feature on accuracy of classification of brain anomaly, a multibranch convolutional neural network approach is proposed. This approach is designed according to combination of DBP-DAE and DSRCN in an end-to-end manner. Extensive experiments conducted based on brain tumor in MRI image public access databases and achieves significant results compared to state-of-the-art algorithms. In addition, we discussed the effectiveness and applicability of CNNs with a variety of different features and architectures for brain abnormalities such as Alzheimer’s. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Ice Cream for BreakfastMichelle MethvenIn June of 2011, on a warm sunny day in Toronto, Canada, my partner and I brought our daughter Stella into the local hospital emergency room for what we believed would be a routine check–up. She had been exhibiting worsening clumsiness and limping for the previous two weeks and we thought it would be easier just to get her seen and have whatever it was (...) dealt with rather than wait two months to see a specialist. My partner and I believed it was likely a severe ear infection, or maybe Lyme disease from a recent camping trip. We each called our workplaces and said we would be an hour or so late. Nothing could have prepared us for the news 22 hours after arriving at the hospital, that Stella had a cancerous mass in her brain. After a biopsy three days later to confirm the diagnosis, Stella was diagnosed with Diffuse Intrinsic Pontine Glioma (DIPG), and given less than a year to live.Parents most often describe DIPG as “a monster.” The tumour saturates the pons and shuts down nerve pathways one at a time. In no particular order, and in no particular time, sufferers (most often young children) lose the ability to walk, sit up, hold up their head, speak and see. The pons is also responsible for breathing, swallowing and regulating the heartbeat, so death can come in many forms at any given time. Though it destroys the brain’s ability to command, the person continues to think and understand as the main part of the brain is untouched. Different from most cancers, chemotherapy and radiation have almost no effect on DIPG; even trials with the most toxic chemotherapies do not slow its progress.My partner and I were shaken to the core at this diagnosis. Looking at our energetic, redheaded [End Page 31] mop–topped little imp, it was impossible to fathom that she had just been given a fatal diagnosis. Yet we knew the doctors at the hospital were among the best and most sought–after in the world, so denial was never a part of our mantra.A week after Stella was diagnosed, we met with a neuro–oncologist to discuss our plans. The only treatment that is slightly effective for DIPG is focal radiation, which can stall the tumor’s growth, granting what is known as a “honeymoon period” of no new symptoms. The honeymoon lasts approximately six months, but there are no guarantees. Twenty percent of children get no honeymoon whatsoever after radiation, and others get only weeks. The doctor we met with confirmed radiation would not be curative, but would “buy time”. He explained that radiation involved six weeks of treatment, seven days a week. Following the six weeks of treatment, there would be a period of anywhere from one to six months in which Stella would likely be asymptomatic. However, at some point, the symptoms generally return and when they do, children deteriorate relatively quickly. Sometimes it takes a month or two, but on occasion there is as little as two weeks between progression and death.As Stella’s parents, we were not convinced that the prescribed radiation was something we wanted to subject Stella to. Because she was only two, and a very spirited and energetic child, it would have been virtually impossible to have her lie quietly on the table in hospital each day for six weeks while radiation was put behind her ear. The neuro–oncologists’ solution was that Stella be sedated for each daily radiation treatment, which would make her groggy for a big part of the day and necessitate needles and IV. As parents, we were presented with an impossible gamble. Do we risk taking away six weeks of her still somewhat symptom–free life for a possible extra three to six months later? And the timing was difficult as well. It was late June. If we chose to radiate it would mean spending the entire summer shuttling her between hospital and home with no weeks at the cottage, and much less time to attend neighbourhood BBQ’s, parties, trips to the park, the library, science centre and zoo... (shrink)