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PubMed2006

Actual number of tumor budding as a new tool for the individualization of treatment of T1 colorectal carcinomas.

BACKGROUND AND AIM: Treatment of T1 colorectal carcinomas, either local excision including endoscopic polypectomy or radical surgery, has always been problematic in everyday practice. Although previous studies have revealed that tumor budding at the invasive margin can be a marker for the malignant potential of T1 colorectal carcinomas, the evaluation of tumor budding has not been standardized as yet. In the present study, we attempted to apply the actual number of tumor budding units for the individualization of treatment in T1 colorectal carcinomas. METHODS: In 76 T1 colorectal carcinomas, associations between lymph node metastasis and clinicopathological parameters were examined statistically. A mathematical formula for predicting the risk of lymph node metastasis was constructed and decision analysis was attempted to determine individually the indication for additional surgery after endoscopic mucosal resection of T1 colorectal carcinomas. RESULTS: Of the clinicopathological parameters examined, multivariate analysis showed that the actual number of tumor budding units alone was significantly associated with lymph node metastasis. The probability of lymph node metastasis was calculated as Z = 0.07 x (budding counts) - 3.726, probability = 1/1 + e(-Z). The more the budding counts, the higher the probability of lymph node metastasis. This formula was able to accurately predict lymph node metastasis in successive cases. The actual number of tumor budding units can be applied to decision analysis in determining an indication for additional surgery after endoscopic mucosal resection of T1 colorectal carcinomas. CONCLUSIONS: The actual number of tumor budding units may be useful in the decision making for patient-oriented treatment of T1 colorectal carcinomas.

Adult↗

PubMed2004

Tumor budding as a useful prognostic marker in esophageal squamous cell carcinoma.

We examined the prognostic significance of tumor budding in patients with esophageal squamous cell carcinoma, particularly in comparison to other routine pathological findings. Fifty-six cases who underwent an esophagectomy were reviewed. We defined tumor budding as an isolated single cancer cell or a cluster composed of fewer than five cancer cells and divided these into two grades; low-grade (< 5 budding foci) and high-grade (> or = 5 budding foci) within a microscopic field of x 200. There were 22 (39.3%) and 34 (60.7%) cases with low- and high-grade budding, respectively. There were significant differences in the patients with low- and high-grade budding in relation to tumor size, pT stage, lymphovascular invasion, perineural invasion, circumferential resection margin involvement, and AJCC stage (P < 0.05). The 3-year survival rates of the patients with low- and high-grade budding were 72.3% and 30.7%, respectively (P = 0.04). We propose that tumor budding may be a pathological marker suggesting high malignancy potential and decreased postoperative survival in patients with esophageal squamous cell carcinoma.

Adult↗

PubMed2006

Below-ground bud banks increase along a precipitation gradient of the North American Great Plains: a test of the meristem limitation hypothesis.

In perennial grasslands, the below-ground population of meristems (bud bank) plays a fundamental role in plant population dynamics. Here, we tested the 'meristem limitation hypothesis' prediction - that bud banks increase along an increasing precipitation/productivity gradient in North American grasslands - and assessed the seasonal dynamics of bud banks. We sampled bud and stem populations quarterly at six sites across a 1100 km gradient in central North America. Bud banks increased with average annual precipitation, which explained 80% of the variability between the sites. In addition, seasonal changes in grass bud banks were surprisingly similar across a 2.5-fold range in precipitation and a 4-fold range of productivity: densities peaked in March, decreased in June and increased slightly in September. Increasing meristem limitation may constrain vegetation responses to inter-annual changes in resources. An important consequence of this is that biomes with large bud banks may be the most responsive to environmental change. If meristem limitation represents an important constraint on productivity responses to environmental variability, then bud banks must be considered in developing predictive models for grassland responses to environmental change.

Acclimatization↗

PubMed2001

Bud emergence is gradually delayed from S to G2 with progression of growth phase in Cryptococcus neoformans.

The G2 index of the yeast Cryptococcus neoformans determined by laser scanning cytometer was 2-3 times higher than the budding index during transition to the stationary phase of the culture, indicating that buds emerged in the G2 phase of the cell cycle. To clarify whether buds also emerge in G2 during exponential growth of the culture, DNA content for each cell was measured with a fluorescence microscope equipped with a photomultiplier. The DNA content of cells having tiny buds varied rather widely, depending on growth phases and strains used. Typically, buds of C. neoformans emerged soon after initiation of DNA synthesis in the early exponential phase. However, bud emergence was delayed to G2 during transition to the stationary phase, and in the early stationary phase budding scarcely occurred, although roughly half of the cells completed DNA synthesis. Thus, the timing of budding in C. neoformans was actually shifted to later cell cycle points with progression of the growth phase of the culture.

Cryptococcus neoformans↗

PubMed1973

Electron Micrography of Bud Formation in Metschnikowia krissii.

The fine structure of bud formation of Metschnikowia krissii was studied by means of ultramicrotomy and transmission electron microscopy. Bud protrusion and development were observed by scanning electron microscopy. Bud formation in this yeast takes place by an extension of a small localized area of the existing parent wall. The parent cell and its bud are initially separated by the plasmalemma, creating an intercellular site within which the generation of new cell wall (bud and birth scar areas) occurs centripetally. When the dividing wall is complete and new cell wall material is formed, a narrow cleavage plane becomes increasingly defined. This cleavage plane apparently proceeds laterally toward the direction of the existing outer walls which rupture, resulting in the separation of the bud from the parent cell. The bud scar is prominently convex in shape; the birth scar is less conspicuous and initially concave in shape. Comparison of bud formation in M. krissii is made with that observed in Saccharomyces cerevisiae and Rhodotorula glutinis.

Journal Article↗

PubMed2001

CAP1, an adenylate cyclase-associated protein gene, regulates bud-hypha transitions, filamentous growth, and cyclic AMP levels and is required for virulence of Candida albicans.

In response to a wide variety of environmental stimuli, the opportunistic fungal pathogen Candida albicans exits the budding cycle, producing germ tubes and hyphae concomitant with expression of virulence genes, such as that encoding hyphal wall protein 1 (HWP1). Biochemical studies implicate cyclic AMP (cAMP) increases in promoting bud-hypha transitions, but genetic evidence relating genes that control cAMP levels to bud-hypha transitions has not been reported. Adenylate cyclase-associated proteins (CAPs) of nonpathogenic fungi interact with Ras and adenylate cyclase to increase cAMP levels under specific environmental conditions. To initiate studies on the relationship between cAMP signaling and bud-hypha transitions in C. albicans, we identified, cloned, characterized, and disrupted the C. albicans CAP1 gene. C. albicans strains with inactivated CAP1 budded in conditions that led to germ tube formation in isogenic strains with CAP1. The addition of 10 mM cAMP and dibutyryl cAMP promoted bud-hypha transitions and filamentous growth in the cap1/cap1 mutant in liquid and solid media, respectively, showing clearly that cAMP promotes hypha formation in C. albicans. Increases in cytoplasmic cAMP preceding germ tube emergence in strains having CAP1 were markedly diminished in the budding cap1/cap1 mutant. C. albicans strains with deletions of both alleles of CAP1 were avirulent in a mouse model of systemic candidiasis. The avirulence of a germ tube-deficient cap1/cap1 mutant coupled with the role of Cap1 in regulating cAMP levels shows that the Cap1-mediated cAMP signaling pathway is required for bud-hypha transitions, filamentous growth, and the pathogenesis of candidiasis.

Amino Acid Sequence↗

PubMed2006

The YLDL sequence within Sendai virus M protein is critical for budding of virus-like particles and interacts with Alix/AIP1 independently of C protein.

For many enveloped viruses, cellular multivesicular body (MVB) sorting machinery has been reported to be utilized for efficient viral budding. Matrix and Gag proteins have been shown to contain one or two L-domain motifs (PPxY, PT/SAP, YPDL, and FPIV), some of which interact specifically with host cellular proteins involved in MVB sorting, which are recruited to the viral budding site. However, for many enveloped viruses, L-domain motifs have not yet been identified and the involvement of MVB sorting machinery in viral budding is still unknown. Here we show that both Sendai virus (SeV) matrix protein M and accessory protein C contribute to virus budding by physically interacting with Alix/AIP1. A YLDL sequence within the M protein showed L-domain activity, and its specific interaction with the N terminus of Alix/AIP1(1-211) was important for the budding of virus-like particles (VLPs) of M protein. In addition, M-VLP budding was inhibited by the overexpression of some deletion mutant forms of Alix/AIP1 and depletion of endogenous Alix/AIP1 with specific small interfering RNAs. The YLDL sequence was not replaceable by other L-domain motifs, such as PPxY and PT/SAP, and even YPxL. C protein was also able to physically interact with the N terminus of Alix/AIP1(212-357) and enhanced M-VLP budding independently of M-Alix/AIP1 interaction, although it was not released from the transfected cells itself. Our results suggest that the interaction of multiple viral proteins with Alix/AIP1 may enhance the efficiency of the utilization of cellular MVB sorting machinery for efficient SeV budding.

Amino Acid Motifs↗

PubMed1998

Virus maturation by budding.

Enveloped viruses mature by budding at cellular membranes. It has been generally thought that this process is driven by interactions between the viral transmembrane proteins and the internal virion components (core, capsid, or nucleocapsid). This model was particularly applicable to alphaviruses, which require both spike proteins and a nucleocapsid for budding. However, genetic studies have clearly shown that the retrovirus core protein, i.e., the Gag protein, is able to form enveloped particles by itself. Also, budding of negative-strand RNA viruses (rhabdoviruses, orthomyxoviruses, and paramyxoviruses) seems to be accomplished mainly by internal components, most probably the matrix protein, since the spike proteins are not absolutely required for budding of these viruses either. In contrast, budding of coronavirus particles can occur in the absence of the nucleocapsid and appears to require two membrane proteins only. Biochemical and structural data suggest that the proteins, which play a key role in budding, drive this process by forming a three-dimensional (cage-like) protein lattice at the surface of or within the membrane. Similarly, recent electron microscopic studies revealed that the alphavirus spike proteins are also engaged in extensive lateral interactions, forming a dense protein shell at the outer surface of the viral envelope. On the basis of these data, we propose that the budding of enveloped viruses in general is governed by lateral interactions between peripheral or integral membrane proteins. This new concept also provides answers to the question of how viral and cellular membrane proteins are sorted during budding. In addition, it has implications for the mechanism by which the virion is uncoated during virus entry.

Gene Expression Regulation, Viral↗

PubMed2005

Key stages in mammary gland development: the mammary end bud as a motile organ.

In the rodent, epithelial end buds define the tips of elongating mammary ducts. These highly motile structures undergo repeated dichotomous branching as they aggressively advance through fatty stroma and, turning to avoid other ducts, they finally cease growth leaving behind the open, tree-like framework on which secretory alveoli develop during pregnancy. This review identifies the motility of end buds as a unique developmental marker that represents the successful integration of systemic and local mammotrophic influences, and covers relevant advances in ductal growth regulation, extracellular matrix (ECM) remodeling, and cell adhesion in the inner end bud. An unexpected growth-promoting synergy between insulin-like growth factor-1 and progesterone, in which ducts elongate without forming new end buds, is described as well as evidence strongly supporting self-inhibition of ductal elongation by end-bud-secreted transforming growth factor-beta acting on stromal targets. The influence of the matrix metalloproteinase ECM-remodeling enzymes, notably matrix metalloproteinase-2, on end bud growth is discussed in the broader context of enzymes that regulate the polysaccharide-rich glycosaminoglycan elements of the ECM. Finally, a critical, motility-enabling role for the cellular architecture of the end bud is identified and the contribution of cadherins, the netrin/neogenin system, and ErbB2 to the structure and motility of end buds is discussed.

Animals↗

PubMed2004

Signalling by the FGFR-like tyrosine kinase, Kringelchen, is essential for bud detachment in Hydra vulgaris.

Signalling through fibroblast growth factors (FGFR) is essential for proper morphogenesis in higher evolved triploblastic organisms. By screening for genes induced during morphogenesis in the diploblastic Hydra, we identified a receptor tyrosine kinase (kringelchen) with high similarity to FGFR tyrosine kinases. The gene is dynamically upregulated during budding, the asexual propagation of Hydra. Activation occurs in body regions, in which the intrinsic positional value changes. During tissue displacement in the early bud, kringelchen RNA is transiently present ubiquitously. A few hours later - coincident with the acquisition of organiser properties by the bud tip - a few cells in the apical tip express the gene strongly. About 20 hours after the onset of evagination, expression is switched on in a ring of cells surrounding the bud base, and shortly thereafter vanishes from the apical expression zone. The basal ring persists in the parent during tissue contraction and foot formation in the young polyp, until several hours after bud detachment. Inhibition of bud detachment by head regeneration results in severe distortion, disruption or even complete loss of the well-defined ring-like expression zone. Inhibition of FGFR signalling by SU5402 or, alternatively, inhibition of translation by phosphorothioate antisense oligonucleotides inhibited detachment of buds, indicating that, despite the dynamic expression pattern, the crucial phase for FGFR signalling in Hydra morphogenesis lies in bud detachment. Although Kringelchen groups with the FGFR family, it is not known whether this protein is able to bind FGFs, which have not been isolated from Hydra so far.

Amino Acid Sequence↗

PubMed1988

Initial limb budding is independent of apical ectodermal ridge activity; evidence from a limbless mutant.

Outgrowth of normal chick limb bud mesoderm is dependent on the presence of a specialized epithelium called the apical ectodermal ridge. This ectodermal ridge is induced by the mesoderm at about the time of limb bud formation. The limbless mutation in the chick affects apical ectodermal ridge formation in the limb buds of homozygotes. The initial formation of the limb bud appears to be unaffected by the mutation but no ridge develops and further outgrowth, which is normally dependent on the ridge, does not take place. As a result, limbless chicks develop without limbs. In the present study, which utilized a pre-limb-bud recombinant technique, limbless mesoderm induced an apical ectodermal ridge in grafted normal flank ectoderm. However, at stages when normal flank ectoderm is capable of responding to ridge induction, limbless flank ectoderm did not form a ridge or promote outgrowth of a limb in response to normal presumptive wing bud mesoderm. We conclude from this that the limbless mutation affects the ability of the ectoderm to form a ridge. In addition, because the limbless ectoderm has no morphological ridge and no apparent ridge activity (i.e. it does not stabilize limb elements in stage-18 limb bud mesoderm), the limbless mutant demonstrates that the initial formation of the limb bud is independent of apical ectodermal ridge activity.

Animals↗

PubMed1991

Budding-specific lectin induced in epithelial cells is an extracellular matrix component for stem cell aggregation in tunicates.

We have examined immunocytochemically the expression, localization and in vivo function of a calcium-dependent and galactose-binding 14 x 10(3) Mr lectin purified from the budding tunicate, Polyandrocarpa misakiensis. Lectin granules first appeared in the inner epithelium of a double-walled bud vesicle. Soon after the bud entered the developmental phase, the granules were secreted into the mesenchymal space, where the lectin-positive extracellular matrix (ECM) developed. The lectin was also produced and secreted by granular leucocytes during budding. Hemoblasts, pluripotent stem cells in the blood, were often found in association with the ECM and they aggregated with epithelial cells to form organ rudiments. The lectin showed a high binding affinity for hemoblast precursors. The blockage of epithelial transformation of stem cells by galactose in in vivo bioassy was ineffective in the presence of the lectin. Polyclonal anti-lectin antibody prevented the hemoblasts spreading on the ECM and moving toward the epithelium, but it did not block the cell-cell adhesion of hemoblasts. By three days of bud development, lectin granules and ECM have almost disappeared from the developing bud together with a cessation of hemoblast aggregation. These results show that Polyandrocarpa lectin is a component of the ECM induced specifically in budding and suggest strongly that it plays a role in bud morphogenesis by directing the migration of pluripotent stem cells to the epithelium.

Animals↗

PubMed1992

Role of the chicken homeobox-containing genes GHox-4.6 and GHox-8 in the specification of positional identities during the development of normal and polydactylous chick limb buds.

During early stages of normal chick limb development, the homeobox-containing (HOX) gene GHox-4.6 is expressed throughout the posterior mesoderm of the wing bud from which most of the skeletal elements including the digits will develop, whereas GHox-8 is expressed in the anterior limb bud mesoderm which will not give rise to skeletal elements. In the present study, we have examined the expression of GHox-4.6 and GHox-8 in the wing buds of two polydactylous mutant chick embryos, diplopodia-5 and talpid2, from which supernumerary digits develop from anterior limb mesoderm, and have also examined the expression of these genes in response to polarizing zone grafts and retinoic acid-coated bead implants which induce the formation of supernumerary digits from anterior limb mesoderm. We have found that the formation of supernumerary digits from the anterior mesoderm in mutant and experimentally induced polydactylous limb buds is preceded by the ectopic expression of GHox-4.6 in the anterior mesoderm and the coincident suppression of GHox-8 expression in the anterior mesoderm. These observations suggest that the anterior mesoderm of the polydactylous limb buds is "posteriorized" and support the suggestion that GHox-8 and GHox-4.6, respectively, are involved in specifying the anterior non-skeletal and posterior digit-forming regions of the limb bud. Although the anterior mesodermal domain of GHox-8 expression is severely impaired in the mutant and experimentally induced polydactylous limb buds, this gene is expressed by the prolonged, thickened apical ectodermal ridges of the polydactylous limb buds that extend along the distal anterior as well as the distal posterior mesoderm.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development.

The c-ret gene encodes a receptor tyrosine kinase that is expressed in the Wolffian duct and ureteric bud of the developing excretory system. Newborn mice homozygous for a mutation in c-ret displayed renal agenesis or severe hypodysplasia, suggesting a critical role for this gene in metanephric kidney development. To investigate the embryological basis of these defects, we characterized the early development of the excretory system in mutant homozygotes, and observed a range of defects in the formation, growth and branching of the ureteric bud, which account for the spectrum of renal defects seen at birth. Co-culture of isolated ureteric buds and metanephric mesenchyme show that the primary defect is intrinsic to the ureteric bud. While the mutant bud failed to respond to induction by wild-type mesenchyme, mutant mesenchyme was competent to induce the growth and branching of the wild-type bud. Furthermore, the mutant metanephric mesenchyme displayed a normal capacity to differentiate into nephric tubules when co-cultured with embryonic spinal cord. These findings suggest a model in which c-ret encodes the receptor for a (yet to be identified) factor produced by the metanephric mesenchyme, which mediates the inductive effects of this tissue upon the ureteric bud. This factor appears to stimulate the initial evagination of the ureteric bud from the Wolffian duct, as well as its subsequent growth and branching.

Animals↗

PubMed1999

beta-catenin signaling can initiate feather bud development.

Intercellular signaling by a subset of Wnts is mediated by stabilization of cytoplasmic beta-catenin and its translocation to the nucleus. Immunolocalization of beta-catenin in developing chick skin reveals that this signaling pathway is active in a dynamic pattern from the earliest stages of feather bud development. Forced activation of this pathway by expression of a stabilized beta-catenin in the ectoderm results in the ectopic formation of feather buds. This construct is sufficient to induce bud formation since it does so both within presumptive feather tracts and in normally featherless regions where tract-specific signals are absent. It is also insensitive to the lateral inhibition that mediates the normal spacing of buds and can induce ectopic buds in interfollicular skin. However, additional patterning signals cooperate with this pathway to regulate gene expression within domains of stabilized beta-catenin expression. Localized activation of this pathway within the bud as it develops is required for normal morphogenesis and ectopic activation of the pathway leads to abnormally oriented buds and growths on the feather filaments. These results suggest that activation of the beta-catenin pathway initiates follicle development in embryonic skin and plays important roles in the subsequent morphogenesis of the bud.

Animals↗

PubMed2001

Identification of pleiotrophin as a mesenchymal factor involved in ureteric bud branching morphogenesis.

Branching morphogenesis is central to epithelial organogenesis. In the developing kidney, the epithelial ureteric bud invades the metanephric mesenchyme, which directs the ureteric bud to undergo repeated branching. A soluble factor(s) in the conditioned medium of a metanephric mesenchyme cell line is essential for multiple branching morphogenesis of the isolated ureteric bud. The identity of this factor had proved elusive, but it appeared distinct from factors such as HGF and EGF receptor ligands that have been previously implicated in branching morphogenesis of mature epithelial cell lines. Using sequential column chromatography, we have now purified to apparent homogeneity an 18 kDa protein, pleiotrophin, from the conditioned medium of a metanephric mesenchyme cell line that induces isolated ureteric bud branching morphogenesis in the presence of glial cell-derived neurotrophic factor. Pleiotrophin alone was also found to induce the formation of branching tubules in an immortalized ureteric bud cell line cultured three-dimensionally in an extracellular matrix gel. Consistent with an important role in ureteric bud morphogenesis during kidney development, pleiotrophin was found to localize to the basement membrane of the developing ureteric bud in the embryonic kidney. We suggest that pleiotrophin could act as a key mesenchymally derived factor regulating branching morphogenesis of the ureteric bud and perhaps other embryonic epithelial structures.

Animals↗

PubMedDate not supplied

Efficiency of the polymer bur SmartPrep compared with conventional tungsten carbide bud bur in dentin caries excavation.

SmartPrep is a rotating instrument for dentin caries excavation made from a special polymer. The manufacturer's product information stated that SmartPrep removes carious dentin selectively. This in vitro study compared the efficiency of SmartPrep with conventional tungsten carbide bud burs. Fifty extracted teeth were split in the center of a carious lesion. The 100 specimens were randomly divided into five groups. Five dentists were asked to excavate 10 teeth each: one half with SmartPrep and the corresponding half with conventional bud burs. The time needed for the caries excavation was measured. Subsequently, histological specimens were produced from all cavities and analyzed by light-microscope after Mallory-Azan-staining. The thickness of the remaining caries was measured (< 1 mm or > 1 mm). The time expended was analyzed using the paired t-test. The results were analyzed for the remaining caries and thickness of the carious layer for every tooth, using the non-parametric Wilcoxon test for combined random samples. A binary logistical regression was performed to determine the influence of the three variables (tooth, sections or bur) on the criteria "caries" or "carious layer thickness (> 1 mm)." The average time to excavate a cavity with SmartPrep was 208.1 seconds, and it was 228.32 seconds with conventional bud burs. The difference between the recorded times was not statistically significant (p > 0.05). In 37 of 50 teeth, the number of carious sections was higher in the SmartPrep group than in the bud bur group. In nine teeth, the quantity of carious sections was higher in the bud bur group than in the SmartPrep group. Four teeth showed no difference in the number of carious sections. The results were statistically significantly different (p < 0.001). In 30 teeth, the number of carious sections with a carious layer thicker than 1 mm was higher in the SmartPrep group compared with the bud bur group. In nine teeth, the number of carious sections was higher in the bud bur group than in the SmartPrep group. Eleven teeth showed no difference in thickness of the carious dentin layer. These results were statistically significantly different (p = 0.003). Binary logistical regression showed that only the variable "bur" (bud bur or SmartPrep) influenced the results concerning the criterion "caries" (p < 0.001).

Dental Caries↗

PubMedDate not supplied

Tumour 'budding' and its relationship to p53 and Bcl-2 expression in colorectal cancer.

The formation of poorly-differentiated clusters of cancer cells in the tumour growth zone, defined as "tumour budding", is a likely factor determining the biological malignancy of colorectal cancer (CRC). The aim of the study was to evaluate tumour budding in the CRC growth zone and to analyse its relationship to chosen anatomoclinical parameters, and to p53 and Bcl-2 protein expression in the tumour budding and in the main tumour mass. Fifty-seven colorectal cancers, classified as pT3 and G2, were used for analysis. Immunohistochemical investigations were performed using the anti-human p53 and Bcl-2 protein monoclonal antibodies (Dako/p53, No M7001 and Dako/Bcl-2, No M 0887, respectively). It has been found that p53 overexpression in the primary tumour and the presence of lymph node metastases correlate with strongly-positive tumour budding (p < 0.04 and p < 0.000001). However, low expression of p53 protein in the primary tumour and lack of lymph node metastases was statistically significantly correlated with the absence of tumour budding. A statistically significant correlation was shown between p53 protein expression in the tumour budding and expression of p53 in the primary tumour and lymph node metastases (p < 0.05). We also observed a statistically significant correlation between Bcl-2 protein expression in the tumour budding and its expression in the primary tumour and lymph node metastases (p < 0.05). These data suggest that tumour budding of cancer, in combination with other markers, may provide more information about the biological behaviour of colorectal cancer.

Cell Division↗