Positive Growth Signals Research Articles

Evaluation of Factors that may Cause False Positive Growth Signals in Blood Cultures-As the Word 'Factors' will Include Both Microbial and Patients as well as Others

Background: In the present study, it was aimed to identify the microorganism and the factors due to the patients which may cause false positive results in automated blood culture systems, and to evaluate the parameters to be used in interpreting the results correctly. Materials and methods: The study was carried out between 2016-2017. Fully automated Bact/Alert 3D (BioMerieux, France) system was used as the blood culture method. Blood cell counting was evaluated by fluorescence flow cytometry method. When the signal was received from the blood culture system, the presence of microorganism was first investigated using Gram staining. In spite of the presence of a growth signal, the absence of microorganisms in the acridine oranges, gram preparations and the absence of growth in the inoculated plates was accepted as false positivity. These bottles were also subcultured onto a chocolate agar and a Sabouraud Dextrose Agar media, and were incubated for 14 days. Mann Whitney U test and Chi-Square test were used for statistical analysis. Permission was taken with the number 10.03.20707. Results: A total of 9216 aerobic blood cultures were included in the study, 1839 (19.9%) of those indicated a positive growth signal. False positivity was detected in 69 (0.75%) of the blood culture bottles. The mean incubation time for positive growth signal was 20 hours in the bottles giving true positive growth signal, whereas the mean incubation time for positive growth signal was 3 hours in the bottles giving false positive growth signal (p

CtBP represses Dpp-dependent Mad activation during Drosophila eye development

Complex networks of signaling pathways maintain the correct balance between positive and negative growth signals, ensuring that tissues achieve proper sizes and differentiation pattern during development. In Drosophila, Dpp, a member of the TGFβ family, plays two main roles during larval eye development. In the early eye primordium, Dpp promotes growth and cell survival, but later on, it switches its function to induce a developmentally-regulated cell cycle arrest in the G1 phase and neuronal photoreceptor differentiation. To advance in the identification and characterization of regulators and targets of Dpp signaling required for retinal development, we carried out an in vivo eye-targeted double-RNAi screen to identify punt (Type II TGFβ receptor) interactors. Using a set of 251 genes associated with eye development, we identified CtBP, Dad, Ago and Brk as punt genetic interactors. Here, we show that downregulation of Ago, or conditions causing increased tissue growth including overexpression of Myc or CyclinD-Cdk4 are sufficient to partially rescue punt-dependent growth and photoreceptor differentiation. Interestingly, we show a novel role for the transcriptional co-repressor CtBP in inhibiting Dpp-dependent Mad activation by phosphorylation, downstream or in parallel to Dad, the inhibitory Smad. Furthermore, CtBP downregulation activates JNK signaling pathway, implying a complex regulation of signaling pathways by CtBP during eye development.

Do Analystss Capital Expenditure Forecasts Affect Corporate Investment Efficiency?

We examine whether the information conveyed in a relatively new analyst research output — capital expenditure (capex) forecasts — affects corporate investment efficiency. We find that firms with analyst capex forecasts exhibit higher investment efficiency. This effect is stronger when the forecasts are issued by analysts with higher ability or greater industry knowledge. Moreover, the effect of capex forecasts on investment efficiency varies with the signals they convey about future growth opportunities — positive-growth signals are more effective in reducing underinvestment, while negative-growth signals are more effective in reducing overinvestment. Cross-sectional tests suggest that these effects operate at least in part through both a financing channel and a monitoring channel. Taken together, our results suggest that analysts’ capex forecasts convey useful information about firms’ growth opportunities to managers and investors, which can facilitate efficient investment.

HOXB13-mediated suppression of p21WAF1/CIP1 regulates JNK/c-Jun signaling in prostate cancer cells.

Many prostate cancer (PCa) patients die of recurrent disease due to the emergence of hormone-independent cancer cells of which the mechanism is not fully understood. Our previous studies demonstrated that most castration- resistant prostate cancers (CRPC) overexpress the HOXB13 transcription factor to confer positive growth signals. Since HOXB13 also suppresses p21WAF1/CIP1 (p21) expression, we studied the correlation between HOXB13 and p21 in selected samples of PCa. While there was no statistically significant correlation between expression of HOXB13 and p21, HOXB13-deficient tumors had three times higher odds for expressing p21 than HOXB13-positive tumors. Moreover, CRPC showed more negative correlation than hormone-dependent PCa (HDPC). Further in vitro proliferation assay demonstrated that androgen did not affect the growth-suppressive function of p21 in androgen-dependent PCa cells, suggesting that p21 seems to override the growth-promoting function of androgen and suppression of p21 expression by HOXB13 is an important step in PCa cell survival under no androgen influence. HOXB13 also inhibited AP-1 signals via suppressed expression of JNK/c-Jun. While HOXB13 suppressed p21 expression via regulation of JNK signals, alteration of p21 expression also affected c-Jun and AP-1 activity. Taken together, overexpression of HOXB13 in CRPC is an important step in avoiding the growth-suppressive effect of p21 in a harsh condition such as an androgen-deprived environment.

Pure Graphene Oxide Doped Conducting Polymer Nanocomposite for Bio-interfacing.

Advanced materials that are highly biocompatible and easily modifiable with biomolecules are of great importance for bio-interfacing and the development of biodevices. Here, a biocompatible conducting polymer based nanocomposite was electrochemically synthesized through the electropolymerization of poly(3, 4-ethylene dioxythiophene) (PEDOT) in the presence of graphene oxide (GO) as the only dopant. GO contains many negatively charged carboxyl functional groups and is highly dispersible in aqueous solutions, enabling its facile incorporation and even distribution throughout the conducting polymer. PEDOT/GO films exhibited minimal cytotoxicity after 24 h and supported neuron growth with significantly longer neurites than a control PEDOT/PSS film, indicating that the PEDOT/GO film provides a positive growth signal to developing neurons. While some of the negatively charged functional carboxyl groups of GO "dope" the PEDOT, others are exposed freely on the surface of the nanocomposite allowing easy functionalization of the PEDOT/GO composite with biomolecules. Functional laminin peptide, RNIAEIIKDI (p20), was covalently bound to the surface of the PEDOT/GO film and maintained its bioactivity, as evidenced by an increased neurite outgrowth from neurons cultured on the functionalized composite surface. The ease of biomolecule functionalization of the PEDOT/GO nanocomposite, along with its low electrochemical impedance, minimal toxicity and permissiveness to neuron growth, underlines its potential as a material for widespread biosensing, neural interfacing and tissue engineering applications.

English

A three day old baby delivered at B. S. Medical College Hospital, Bankura developed features of neonatal septicaemia two days after normal delivery. Patient’s blood culture sample was processed in BacT/Alert 3D Automated blood culture system. Positive growth signal was obtained at 48 hrs. Subculture on solid non-selective and selective media, morphological studies including typical motilities and standard recommended bio-chemical tests revealed the isolate to be Listeria monocytogenes. Antibiogram studies further corroborated the identity of the isolate. This case report underlines the importance of Automated blood culture detection system in the identification of fastidious but clinically dangerous pathogens. This is most probably the first report of neonatal septicemia due to Listeria monocytogenes from eastern India.

T cell state transition produces an emergent change detector

We model the stages of a T cell response from initial activation to T cell expansion and contraction using a system of ordinary differential equations. Results of this modeling suggest that state transitions enable the T cell population to detect change and respond effectively to changes in antigen stimulation levels, rather than simply the presence or absence of antigen. A key component of the system that gives rise to this emergent change detector is initial activation of naïve T cells. The activation step creates a barrier that separates the long-term, slow dynamics of naïve T cells from the short-term, fast dynamics of effector T cells. This separation allows the T cell population to compare current, up-to-date changes in antigen levels to long-term, steady state levels. As a result, the T cell population responds very effectively to sudden shifts in antigen levels, even if the antigen were already present prior to the change. This feature provides a mechanism for T cells to react to rapidly expanding sources of antigen stimulation, such as viruses, while maintaining tolerance to constant or slowly fluctuating sources of stimulation, such as healthy tissue during growth. In addition to modeling T cell activation, we also formulate a model of the proliferation of effector T cells in response to the consumption of positive growth signal, secreted throughout the T cell response. We discuss how the interaction between T cells and growth signal generates an emergent threshold detector that responds preferentially to large changes in antigen stimulation while ignoring small ones. As a final step, we discuss how the de novo generation of adaptive regulatory T cells during the latter phase of the T cell response creates a negative feedback loop that controls the duration and magnitude of the T cell response. Hence, the immune network continually adjusts to a shifting baseline of (self and non-self) antigens, and responds primarily to abrupt changes in these antigens rather than merely their presence or absence.

Paucity of mycobacteria in mucosal bowel biopsies from adults and children with early inflammatory bowel disease

BackgroundThe presence of Mycobacterium avium subspecies paratuberculosis (MAP) has previously been inferred in the genesis of Crohn's disease (CD), and a higher incidence of MAP PCR positivity has been demonstrated in the gut and peripheral blood of CD patients than in healthy individuals. The objective of this prospective study was to assess the potential etiological role of MAP in the pathogenesis of CD. MethodsThe presence of mycobacteria was assessed in bowel biopsies from newly diagnosed, treatment naïve Norwegian patients with IBD, including CD and ulcerative colitis (UC), as compared to a hospital-based cohort of CD and UC patients. Biopsies were collected from the small and large bowel in 354 individuals with suspected IBD. Detection of mycobacteria was performed by long-term cultivation in combination with direct detection by MAP IS900-specific PCR. ResultsAmong the specimens included from the patients with early IBD, samples from only two of the patients with CD (2.7%) and two of the non-IBD controls (1.5%) exhibited a positive growth signal. None of the CD patients and only one of the non-IBD controls was MAP PCR positive. Only the single PCR positive non-IBD control was also mycobacterial culture positive with Mycobacterium avium subsp. hominissuis. In the referral patients with long-term IBD, the prevalence of growth signal and MAP PCR positivity was higher (52 and 9%, respectively). ConclusionsThese findings demonstrate the paucity of MAP in the gut of treatment naïve CD patients. This study does not provide evidence for a role of MAP in early IBD.

Molecular constitution of breast but not other reproductive tissues is rich in growth promoting molecules: A possible link to highest incidence of tumor growths

In the current study we tested if highest incidence of benign as well as cancer growths in breast tissue is due to constitutive molecular composition of this tissue. To delineate the molecular basis, we compared the expression of nine functional gene modules (total 578 genes) that regulate major positive growth and negative inhibitory signals in normal breast with two other reproductive tissues, ovary and uterus. We present data to demonstrate that breast tissues constitutively have very highly elevated levels of several growth promoting molecules and diminished levels of inhibitory molecules which may, in part, contribute for highest incidence of tumor growths in this tissue.

Temporal and spatial expression pattern of the myostatin gene during larval and juvenile stages of the Chilean flounder ( Paralichthys adspersus)

The full length cDNA sequence of the myostatin gene was cloned from a teleostean fish, the Chilean flounder ( Paralichthys adspersus) through RT-PCR amplification coupled with the RACE approach to complete the 5′- and 3′-region. The deduced amino acid sequence encodes a protein of 377 amino acid residues, including the structural domains responsible for its biological activity. Amino acid sequence comparison revealed high sequence conservation, and confirmed that the isolated sequence corresponds to the MSTN1 gene. Gene expression analysis showed that cfMSTN mRNA is present in a wide variety of tissues in juvenile fish. In addition, we assessed the spatial expression pattern of the MSTN mRNA during embryos and larval stages through whole mount in situ hybridization. No expression was observed in embryos, whereas in larvae of 8 and 9 days post fertilization, the notochord, somites, intestine and some discrete territories in the head, such as brain and eye, were positive for MSTN mRNA. Our results contribute to the knowledge of the MSTN system in larval and juvenile stages; in particular the strong expression observed in the notochord suggests that MSTN, in synchronization with positive growth signals, may play an important role in the control of the development of larvae somites.

Nervous Wreck Interacts with Thickveins and the Endocytic Machinery to Attenuate Retrograde BMP Signaling during Synaptic Growth

Regulation of synaptic growth is fundamental to the formation and plasticity of neural circuits. Here, we demonstrate that Nervous wreck (Nwk), a negative regulator of synaptic growth at Drosophila NMJs, interacts functionally and physically with components of the endocytic machinery, including dynamin and Dap160/intersectin, and negatively regulates retrograde BMP growth signaling through a direct interaction with the BMP receptor, thickveins. Synaptic overgrowth in nwk is sensitive to BMP signaling levels, and loss of Nwk facilitates BMP-induced overgrowth. Conversely, Nwk overexpression suppresses BMP-induced synaptic overgrowth. We observe analogous genetic interactions between dap160 and the BMP pathway, confirming that endocytosis regulates BMP signaling at NMJs. Finally, we demonstrate a correlation between synaptic growth and pMAD levels and show that Nwk regulates these levels. We propose that Nwk functions at the interface of endocytosis and BMP signaling to ensure proper synaptic growth by negatively regulating Tkv to set limits on this positive growth signal.

Signaling via LTβR & HVEM‐BTLA Pathways Control Dendritic Cell Homeostasis In Vivo

Proliferation of dendritic cells (DC) in the spleen is regulated by positive growth signals through the Lymphotoxin (LT)‐β receptor, however the countering inhibitory signals that achieve homeostatic control are unresolved. Mice deficient in LTβR and the ligands, LTα or LTβ, but not LIGHT as well as in NF‐κB inducing kinase (NIK) show a specific loss of CD8α‐ DC subsets. In contrast, the CD8α‐ DC subsets were overpopulated in mice deficient in the herpesvirus entry mediator (HVEM) or B and T lymphocyte attenuator (BTLA). HVEM and BTLA DC subsets displayed a specific growth advantage in repopulating the spleen in competitive replacement bone marrow chimeric mice. Expression of HVEM and BTLA was required in DC and in the surrounding microenvironment, although DC expression of LTβR was necessary to maintain homeostasis. Moreover, enforced activation of LTβR with an agonist antibody drove expansion of CD8α‐ DC subsets overriding the HVEM‐BTLA checkpoint. These results indicate the HVEM‐BTLA pathway provides an inhibitory checkpoint regulating DC homeostasis in lymphoid tissue. Together, the LTβR and HVEM‐BTLA pathways form an integrated signaling network regulating DC homeostasis.

The Inhibitory HVEM-BTLA Pathway Counter Regulates Lymphotoxin β Receptor Signaling to Achieve Homeostasis of Dendritic Cells

Proliferation of dendritic cells (DC) in the spleen is regulated by positive growth signals through the lymphotoxin (LT)-beta receptor; however, the countering inhibitory signals that achieve homeostatic control are unresolved. Mice deficient in LTalpha, LTbeta, LTbetaR, and the NFkappaB inducing kinase show a specific loss of CD8- DC subsets. In contrast, the CD8alpha- DC subsets were overpopulated in mice deficient in the herpesvirus entry mediator (HVEM) or B and T lymphocyte attenuator (BTLA). HVEM- and BTLA-deficient DC subsets displayed a specific growth advantage in repopulating the spleen in competitive replacement bone marrow chimeric mice. Expression of HVEM and BTLA were required in DC and in the surrounding microenvironment, although DC expression of LTbetaR was necessary to maintain homeostasis. Moreover, enforced activation of the LTbetaR with an agonist Ab drove expansion of CD8alpha- DC subsets, overriding regulation by the HVEM-BTLA pathway. These results indicate the HVEM-BTLA pathway provides an inhibitory checkpoint for DC homeostasis in lymphoid tissue. Together, the LTbetaR and HVEM-BTLA pathways form an integrated signaling network regulating DC homeostasis.

Exploiting the TRIP-Br family of cell cycle regulatory proteins as chemotherapeutic drug targets in human cancer

TRIP-Br1 and TRIP-Br2 are potent cell growth promoting factors that function as components of the E2F1/DP1 transcription complex to integrate positive growth signals provided by PHD zinc finger- and/or bromodomain-containing transcription factors. TRIP-Br1 has been demonstrated to be an oncogene. We recently reported that antagonism of the TRIP-Br integrator function by synthetic decoy peptides that compete with TRIP-Br for binding to PHD zinc finger- and/or bromodomain-containing proteins elicit an anti-proliferative effect and induces caspase-3-independent sub-diploidization in cancer cells in vitro. We now demonstrate the chemotherapeutic potential of TRIP-Br decoy peptides for the treatment of cutaneous and intracavitary lesions in vitro as well as in vivo in representative human nasopharyngeal cancer (CNE2), cervical cancer (Ca Ski) and melanoma (MeWo) cancer cell lines. In vitro, BrdU incorporation, colony formation assays and cell cycle analysis confirmed that TRIP-Br decoy peptides possess strong anti-proliferative effects and induce nuclear sub-diploidization in cancer cells. In vivo, NPC2, Ca Ski and MeWo-derived chick embryo chorioallantoic membrane (CAM) tumor xenografts were used to evaluate the effect of topically applied TRIP-Br peptides. Confocal microscopy and flow cytometric analysis demonstrated that cells comprising the tumor xenografts efficiently internalized topically applied FITC-labeled peptides. Fifty µM of TRIP-Br1 decoy peptide significantly suppressed the growth of NPC2-derived human nasopharyngeal tumors, while 50 µM of TRIP-Br2 decoy peptide significantly inhibited tumor growth in all three CAM tumor xenograft models. Two hundred µM of TRIP-Br1 decoy peptide significantly inhibited MeWo-derived tumors. These results suggest that the TRIP-Br integrator function may represent a novel chemotherapeutic target for the treatment of human cutaneous and intracavitary proliferative lesions.

Surface membrane antigen expression changes induced in vitro by exogenous growth factors in chronic lymphocytic leukemia cells.

The factors determining the growth and survival of cells in B chronic lymphocytic leukemia (CLL) have remained poorly understood. We investigated the effects of optimal mitogen combinations (OMCs) on the expression of 26 surface membrane antigens among 33 CLL patients. The seven OMCs used were selected after pre-testing 14 combinations of (1) S. aureus Cowan I (SAC), (2) interleukin-2 (IL-2), (3) tumor necrosis factor alpha (TNF-alpha) and (4) 12-O-tetradecanoylphorbol 13-acetate (TPA; also known as phorbol 12-myristate 13-acetate or PMA). In flow cytometry we revealed that OMCs induced statistically highly significant upregulation of the expression of CD5, CD11c, CD19, CD22, CD23, CD25, CD38, CD40, CD45, CD45RO, CD95, CD126, CD130 and FMC7, and downregulation of CD20 and CD124 expression. Interestingly, the expression of CD27, CD45RA, CD79b, CD80, CD122 and that of the immunoglobulin gene superfamily members CD21, Ig-kappa, Ig-lambda, Ig-delta and Ig-micro were not significantly affected under similar conditions. The expression of several antigens was co-regulated, suggesting common regulatory pathways. These antigens include CD11c/CD5, CD11c/CD22, CD11c/CD126, CD11c/FMC7 as well as CD27/CD45, CD27/CD45RA and CD27/CD79b. Upregulation of surface antigen expression, induced by OMCs, should be applicable in antibody therapy in vitro and in vivo, and in negative stem cell selection for autotransplantation. Furthermore, the current strategy to enhance cell surface antigen expression may be a versatile tool to raise humoral and cell-mediated host defense against CLL cells. Upregulation of proteins mediating positive growth signals (eg CD25, CD40) and negative signals or apoptosis (eg CD95) may be used to sensitize cells to chemotherapy and programmed cell death.

Gliolectin-mediated carbohydrate binding at the Drosophila midline ensures the fidelity of axon pathfinding.

Gliolectin is a carbohydrate-binding protein (lectin) that mediates cell adhesion in vitro and is expressed by midline glial cells in the Drosophila melanogaster embryo. Gliolectin expression is maximal during early pathfinding of commissural axons across the midline (stages 12-13), a process that requires extensive signaling and cell-cell interactions between the midline glia and extending axons. Deletion of the gliolectin locus disrupts the formation of commissural pathways and also delays the completion of longitudinal pathfinding. The disruption in commissure formation is accompanied by reduced axon-glial contact, such that extending axons grow on other axons and form a tightly fasciculated bundle that arches over the midline. By contrast, pioneering commissural axons normally cross the midline as a distributed array of fibers that interdigitate among the midline glia, maximizing contact and, therefor, communication between axon and glia. Restoration of Gliolectin protein expression in the midline glia rescues the observed pathfinding defects of null mutants in a dose-dependent manner. Hypomorphic alleles generated by ethylmethanesulfonate mutagenesis exhibit a similar phenotype in combination with a deletion and these defects are also rescued by transgenic expression of Gliolectin protein. The observed phenotypes indicate that carbohydrate-lectin interactions at the Drosophila midline provide the necessary surface contact to capture extending axons, thereby ensuring that combinatorial codes of positive and negative growth signals are interpreted appropriately.

Transport and accumulation rates of abscisic acid and aldehyde oxidase activity in Pisum sativum L. in response to suboptimal growth conditions

Pea plants (Pisum sativum L.) grown initially in nutrient solutions with adequate nitrogen supply (4 mM NO3-) were transferred to solutions containing salt (50 or 100 mM NaCl), ammonium (4 mM) or a low nitrogen supply (0.4 mM NO3-). No changes of abscisic acid (ABA) content were found in roots of stressed pea plants 9 d after the beginning of the treatments; however, accumulation of ABA in the leaves was observed. Old leaves accumulated ABA to a higher extent than young leaves. Accumulation of ABA in leaves of ammonium-fed plants and plants grown under low nitrogen supply occurred in the absence of both increased ABA xylem loading rate and enhanced aldehyde oxidase (AO, EC 1.2.3.1) activity in roots. Enhanced leaf AO activity was observed in all treatments, with the highest increase in old leaves. Among the three AO isoforms (AO-1, AO-2 and AO-3) detected in extracts of pea leaves, the lowest one AO-3 (highest mobility in the gel) correlated with ABA production and showed the highest increment in response to the treatments. The increase of AO activity detected in leaves after 2 weeks of stress application was less prominent than after 9 d, suggesting a transient enhancement of ABA production following the onset of stress. An increase of ABA xylem loading rate as well as AO root activity 4 d and 9 d after application of the treatments was observed only in salt-treated plants followed by a decrease after 14 d in 100 mM NaCl. Decreased cytokinin (trans-zeatin riboside) delivery rate into the xylem sap was observed in all treatments. The role of abscisic acid and cytokinins as positive and negative growth signals, as well as the involvement of root-generated ABA on ABA accumulation in leaves is discussed.

Transport and accumulation rates of abscisic acid and aldehyde oxidase activity in Pisum sativum L. in response to suboptimal growth conditions

Pea plants ( Pisum sativum L.) grown initially in nutrient solutions with adequate nitrogen supply (4 mM NO 3− ) were transferred to solutions containing salt (50 or 100 mM NaCl), ammonium (4 mM) or a low nitrogen supply (0.4 mM NO 3− ). No changes of abscisic acid (ABA) content were found in roots of stressed pea plants 9 d after the beginning of the treatments; however, accumulation of ABA in the leaves was observed. Old leaves accumulated ABA to a higher extent than young leaves. Accumulation of ABA in leaves of ammonium‐fed plants and plants grown under low nitrogen supply occurred in the absence of both increased ABA xylem loading rate and enhanced aldehyde oxidase (AO, EC 1.2.3.1) activity in roots. Enhanced leaf AO activity was observed in all treatments, with the highest increase in old leaves. Among the three AO isoforms (AO‐1, AO‐2 and AO‐3) detected in extracts of pea leaves, the lowest one AO‐3 (highest mobility in the gel) correlated with ABA production and showed the highest increment in response to the treatments. The increase of AO activity detected in leaves after 2 weeks of stress application was less prominent than after 9 d, suggesting a transient enhancement of ABA production following the onset of stress. An increase of ABA xylem loading rate as well as AO root activity 4 d and 9 d after application of the treatments was observed only in salt‐treated plants followed by a decrease after 14 d in 100 mM NaCl. Decreased cytokinin ( trans‐ zeatin riboside) delivery rate into the xylem sap was observed in all treatments. The role of abscisic acid and cytokinins as positive and negative growth signals, as well as the involvement of root‐generated ABA on ABA accumulation in leaves is discussed.

Cell cycle control as a basis for cancer drug development (Review).

Normal cell cycle progression relies on the cell's ability to translate extracellular signals such as mitogenic stimuli and intact extracellular matrices in order to efficiently replicate DNA and divide. Cyclin dependent kinases (cdks) respond to these signals and are largely responsible for positively pushing cells through the cell cycle. Due to their pivotal role in cell division, nature has evolved elaborate mechanisms to regulate the kinase activity of cdks. Cyclins are cdk binding partners which are required for kinase activity and their protein levels are intimately linked to the cell cycle stage. A variety of other cdk regulators such as phosphorylation events, natural inhibitors and complex stability are discussed. Phosphorylation of various cdk substrates results in diverse outcomes such as changes in gene expression, formation of prereplicative complexes and breakdown of the nuclear envelope. Cancer cells evolve in part by over-riding normal cell cycle regulation. Abnormal cdk activity is accomplished by cyclin amplification, cdk or substrate mutation as well as inactivation of inhibitors. The selective growth advantage of cancer cells also stems from amplification of positive growth signals, mutation of checkpoint and surveillance genes as well as deregulation of programmed cell death or apoptosis. The full potential of cancer therapies, such as small molecule inhibitors and gene therapy among others, focusing on our knowledge of cell cycle regulation has yet to be reached.

Estrogen responsiveness and control of normal human breast proliferation.

Our understanding of the hormonal control of the proliferation of normal human breast epithelium is still surprisingly meager. However, the results of a number of recent studies have confirmed that estrogen is the major steroid mitogen for the luminal epithelial cell population (the usual targets for neoplastic transformation). Estrogen seemingly exerts its effects on cell division indirectly as there is complete dissociation between the population of luminal epithelial cells expressing the estrogen receptor (ER)4 and those that proliferate. We suggest that the ER-negative proliferating cells represent a precursor or stem cell population that differentiates to ER-containing, nonproliferative cells. In turn, these ER-positive cells act as 'estrogen sensors' and transmit positive or negative paracrine growth signals to the precursor cells depending on the prevailing hormonal environment. As yet there is no direct evidence supporting this hypothesis but we suggest ways in which it may be obtained. The implication of these studies is that inhibition of luminal epithelial proliferation with tamoxifen or pure antiestrogens or by preventing ovarian steroid secretion should be an effective strategy for the prevention of breast cancer. In addition, we may be able to predict the risk of breast cancer in an individual by measuring the intrinsic estrogen sensitivity of her breast epithelium. Finally, study of the paracrine mechanisms of growth control in the normal human breast may provide new, more specific, therapeutic targets for breast cancer prevention.