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PubMed1984

Better prognosis of many cancers in female: a phenomenon not explained by study of steroid receptors.

Experimental evidence indicates that specific sex hormonal imbalance, deficiency, and excess may be causes of tumors or at least contribute in some way to their development. Clinical observations show that the prognoses of patients with various malignancies differ among males and females, and some cancers can be alleviated and partially controlled by altering the accustomed hormonal environment. Although beneficial effects usually are only temporary, there is no doubt that some cancers are hormone-dependent to a degree. A significant number of prostatic carcinoma in males and breast carcinoma in both sexes have been treated with various additive or ablative endocrine manipulations. The detection and quantitation of specific steroid binding proteins in hormone-sensitive tumors have enhanced our understanding of the mechanism of endocrinal therapy. Excluding carcinoma of the breast and of the sex organs (ovary and uterus in females, testis and prostate in males), many other solid tumors have been tested for the presence of estrogen and other steroid receptors. A fair number of solid cancers contains estrogen and progesterone receptors (ER, PR), even those from male patients. Thus, the better prognosis of females with sarcoma, melanoma, liver, colorectal and other cancers cannot simply be explained by the presence or absence of estrogen or progesterone receptors. This review attempts to summarize clinical reports of this interesting phenomenon, including therapeutic results with estrogenic, antiestrogenic, and other hormonal approaches.

Adolescent↗

PubMed2004

A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease.

Hyposmia is one of the most prevalent symptoms of Parkinson's disease. It may occur even before the motor symptoms start. To determine whether the olfactory dysfunctions, like the motor symptoms, are associated with a loss of dopamine, the number of dopaminergic cells in the olfactory bulb of Parkinson's disease patients was studied using tyrosine hydroxylase immunohistochemistry. The quantitative analysis reveals that the total number of tyrosine hydroxylase-immunoreactive neurons in the olfactory bulb is twice as high in Parkinson patients compared to age and gender-matched controls. Because dopamine is known to inhibit olfactory transmission in the olfactory glomeruli, we suggest that the increase of dopaminergic neurons in the olfactory bulb is responsible for the hyposmia in Parkinson patients. The increase of dopamine in the olfactory bulb explains why olfaction does not improve with levodopa therapy.

Aged↗

PubMed1984

A hypothesis to explain the enigmatic natural history of neuroblastoma.

A hypothesis is developed for neuroblastoma that attempts to explain the enigmatic natural history of this tumor and the variation in success of therapy as a function of the age of the child at diagnosis. It is postulated that neuroblastoma arising in the young patient has a relative paucity of clonogenically viable stem cells, whereas tumors arising in the older children have a substantial number of such clonogenic cells, as in most human tumors.

Age Factors↗

PubMed2003

Differences in the vascular patterns of basal and squamous cell skin carcinomas explain their differences in clinical behaviour.

Tumour angiogenesis is essential for tumour growth and appears to play an important role both at the transition from hyperplasia to invasive growth and at a late stage in the dissemination process. Basal cell carcinomas (BCCs) and trichoepitheliomas (TEs) are related tumours that share the properties of invasive growth but without the capacity to metastasize. Squamous cell carcinomas (SCCs) of the skin are derived from a similar cell type and they have both invasive and metastatic potential. The aim of this study was to investigate whether the behaviour of these tumours could be explained by differences in their microvasculature. The study looked both qualitatively and quantitatively at the microvasculature of BCCs (n=50) and TEs (n=33) and compared them with normal skin (n=6) and with SCCs of the skin (n=22). Vessel counts were performed using a standard graticule count method after immunohistochemical staining for CD31. Counts were made of blood vessels in the stroma surrounding the tumour and also for vessels in the body of the tumour. The stromal counts for all the tumour groups differed significantly from normal skin. The SCC counts differed significantly from the counts for the BCCs and TEs. There was no significant difference between the counts for different subtypes of BCC or TE groups. While vessels could be found in the body of the SCCs, none was seen in the nodular BCC or the TE groups. There was no correlation between the vascular density and the depth of invasion. Overall, invasive growth correlated with an angiogenic response in the stroma, while metastatic potential correlated with microvessels being present in the body of the tumour.

Adult↗

PubMed1998

Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.

Collagenases↗

PubMed2006

Conformational flexibility may explain multiple cellular roles of PEST motifs.

PEST sequences are one of the major motifs that serve as signal for the protein degradation and are also involved in various cellular processes such as phosphorylation and protein-protein interaction. In our earlier study, we found that these motifs contribute largely to eukaryotic protein disorder. This observation led us to evaluate their conformational variability in the nonredundant Protein Data Bank (PDB) structures. For this purpose, crystallographic temperature factors, structural alignment of multiple NMR models, and dihedral angle order parameters have been used in this study. The study has revealed the hypermobility of PEST motifs as compared to other regions of the protein. Conformational flexibility may allow them to participate in number of molecular interactions under different conditions. This analysis may explain the role of protein backbone flexibility in bringing about multiple cellular roles of PEST motifs.

Amino Acid Motifs↗

PubMed2005

A molecular model to explain paclitaxel and docetaxel sensitivity changes through adduct formation with primary amines in electrospray ionization mass spectrometry.

The objective of this study was to adopt a molecular modeling approach to understand changes in signal intensity due to adduct formation with short-chain alkylamines for two anticancer agents, paclitaxel and docetaxel, during electrospray mass spectrometric analysis. We describe a simple and intuitive modeling procedure using a comparison of hydropathic interaction (HINT) scores to explain differences in responses of amine adducts formed with the two analytes. The responses of paclitaxel and docetaxel were generally enhanced considerably (up to approximately 500% in some instances) on adding the amines. However, for the docetaxel adduct formed with added decylamine in the mobile phase, the response dropped by 32%. A mechanistic understanding for this behavior is proposed, and binding scores calculated from corresponding molecular models were found to be consistent with the trend obtained from mass spectrometric data.

Amines↗

PubMed2003

Measuring explained variation in linear mixed effects models.

We generalize the well-known R(2) measure for linear regression to linear mixed effects models. Our work was motivated by a cluster-randomized study conducted by the Eastern Cooperative Oncology Group, to compare two different versions of informed consent document. We quantify the variation in the response that is explained by the covariates under the linear mixed model, and study three types of measures to estimate such quantities. The first type of measures make direct use of the estimated variances; the second type of measures use residual sums of squares in analogy to the linear regression; the third type of measures are based on the Kullback-Leibler information gain. All the measures can be easily obtained from software programs that fit linear mixed models. We study the performance of the measures through Monte Carlo simulations, and illustrate the usefulness of the measures on data sets.

Antipsychotic Agents↗

PubMed2003

Proportion of treatment effect (PTE) explained by a surrogate marker.

In time-varying covariate analysis of clinical survival data, it is often of interest to estimate the proportion of treatment effect (PTE), along with its confidence intervals, explained by a surrogate marker. The conventional procedure for such an analysis fits data into two working models separately to estimate the treatment effects before and after adjustment of the covariate. The construction of confidence intervals for the PTE under the conventional procedure lacks support by standard statistical software such as SAS, and could be very computationally demanding even after the support is available in the future. To overcome this problem, we propose a new procedure to simplify the computation. Under the new procedure, the treatment effects before and after adjustment of the covariate are simultaneously estimated from a single model. More important than saving computational effort, the new procedure can also be effectively applied to multiple-covariate models for the decomposition of overall treatment effect and for the comparison of PTE among several surrogate markers. The new procedure is applied to the motivating data example from the LIFE study, and demonstrates flexibility that the conventional procedure currently lacks.

Antihypertensive Agents↗

PubMed1990

Measures of explained variation for survival data.

The predictive power of a set of prognostic variables in a survival time model is a concept distinct from the statistical significance of the variables or the adequacy of the model fit. In this paper we discuss the importance of quantifying the predictive power of a prognostic model, and suggest measures of explained variation as a possible quantification. The important features of our approach are that (1) the measures are completely model-based; (2) a specification of the time range of interest is easily incorporated; and (3) the null models used for comparison are derived as mixtures of the predicted distributions.

Analysis of Variance↗

PubMed2001

A method to assess the proportion of treatment effect explained by a surrogate endpoint.

Randomized clinical trials are the standard for evaluating new drugs, devices and procedures. Traditional clinical trials entail not only considerable expense, but require considerable time to complete. The use of surrogate endpoints constitutes an effort to control cost and completion time for clinical trials. We propose a method to quantify the proportion of treatment effect explained by a surrogate endpoint based on a general model setting which includes the commonly used linear, logistic and Cox regression models. The interpretation of this quantitative measure is facilitated by graphical displays. To reduce the variability associated with the estimate, a meta-analytic approach is proposed based on random effects models. An example using real clinical trial data is given to illustrate the proposed procedures.

Biometry↗

PubMed1996

The effect of sulfite on the ATP hydrolysis and synthesis activities in chloroplasts and cyanobacterial membrane vesicles can be explained by competition with phosphate.

The effect of sulfite on ATP synthesis and hydrolysis activities is investigated in spinach chloroplasts and in membrane vesicles from the cyanobacterium Synechococcus 6716. Sulfite inhibits phenazine methosulfate-mediated cyclic photophosphorylation both in thiol-modulated chloroplasts and in cyanobacterial membranes with HSO3- (bisulfite) as the active ionic species. The observed inhibition is not due to inhibition of electron transfer or to uncoupling by sulfite. ATP synthesis in cyanobacterial membranes is more sensitive to sulfite when the inorganic phosphate concentration is decreased. This indicates competition between sulfite and phosphate for the same binding site on the ATP synthase. In cyanobacterial membranes sulfite can replace a proton gradient as activator of ATP hydrolysis in the same way as in reduced chloroplasts. By modeling, competition between sulfite and phosphate can fully explain the findings concerning both inhibition and activation.

Adenosine Triphosphate↗

PubMed1998

Modelling migration: the clock-and-compass model can explain the distribution of ringing recoveries.

The aim of the present study was to test whether the directional distributions found in ringing recoveries could be explained if night-migrating passerines use only a simple clock-and-compass strategy during autumn migration. I developed a mathematical model that predicts the expected directional distributions as a function of distance covered by birds using a clock-and-compass strategy. The predictions were compared with data from natural migration: all ringing recoveries of pied flycatchers, Ficedula hypoleuca, ringed in Scandinavia and recovered elsewhere in Europe and North Africa within the same autumn. The predictions of the model correlated strongly with the distribution of ringing recoveries. This suggests that at least young pied flycatchers, and perhaps night-migrating passerines in general, use a simple clock-and-compass strategy to reach their wintering area. If so, all the prerequisites (a compass and an internal clock) that they need to orient during migration seem to be known at present, at least at the behavioural level, and navigational abilities or any elusive map-sense are not needed for migration. Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗

PubMed2002

Heme oxygenase-1 induction may explain the antioxidant profile of pentaerythrityl trinitrate.

The organic nitrate pentaerythrityl tetranitrate (PETN) is known to exert long-term antioxidant and antiatherogenic effects by as yet unidentified mechanisms. In cultured endothelial cells derived from human umbilical vein, the active PETN metabolite PETriN (0.01-1 mM) increased heme oxygenase (HO)-1 mRNA and protein levels in a concentration-dependent fashion. HO-1 induction was accompanied by a marked increase in catalytic activity of the enzyme as reflected by enhanced formation of carbon monoxide and bilirubin. Pretreatment with PETriN or bilirubin at low micromolar concentrations protected endothelial cells from hydrogen peroxide-mediated toxicity. HO-1 induction and endothelial protection by PETriN were not mimicked by isosorbide dinitrate, another long-acting nitrate. The present study demonstrates that PETriN stimulates mRNA and protein expression as well as enzymatic activity of the antioxidant defense protein HO-1 in endothelial cells. Increased HO-1 expression and ensuing formation of cytoprotective bilirubin may contribute to and explain the specific antioxidant and antiatherogenic actions of PETN.

Animals↗

PubMed2001

Enhanced efficacy of anti-D immunoglobulin for treating ITP is not explained by higher immunoglobulin polymer content.

Several reports have suggested that low dose anti-D immunoglobulin is superior to high dose immunoglobulin for treatment of idiopathic thrombocytopenia purpura (ITP). However, some findings suggest that it is not the anti-D activity per se that is responsible for efficacy for treatment of ITP with anti-D immunoglobulin. Amongst alternative explanations for the mechanism of action is a relatively higher immunoglobulin polymer content of anti-D compared to other immunoglobulin products, which is more efficient in causing reticuloendothelial Fc receptor blockade. In order to investigate this we have evaluated the polymeric IgG content of anti-D and other immunoglobulin products. Different products showed considerable variation in immunoglobulin polymer content. There was no clear correlation between aggregate or dimer content and product type and anti-D as a class of product did not contain higher amounts of either dimer or aggregate compared to other products. Some manufacturers' products increased in polymer content on storage, but others did not show this effect. Therefore, higher immunoglobulin dimer and/or aggregate content cannot explain the increased efficacy of anti-D immunoglobulin for treatment of ITP. The role of polymeric Ig in efficacy for treatment of ITP is unclear.

Biopolymers↗

PubMed1994

Increased calcium absorption in nephrolithiasis explained by uptake studies in ileal brush border membrane vesicles.

We previously showed that recurrent calcium renal stone formers have enhanced urinary excretions of calcium and oxalate resulting from malabsorption of citrate. In the present investigation, the mechanism of the citrate-induced increased calcium uptake was studied using guinea pig ileal brush border membrane vesicles. In this model, calcium is absorbed in a concentration dependent, single mechanism uptake with a Km of 275 +/- 30 umol/liter (SD) and a Vmax of 4.0 +/- 0.5 nmol/min.mg protein. Under conditions of maximal calcium uptake, both citrate and phosphate inhibited calcium absorption into brush border membrane vesicles (BBMVs). In contrast, when phosphate and citrate were added together, calcium absorption normalized. Citrate inhibition of calcium absorption appeared to be due to free citrate ions, and phosphate ions overcame this inhibition. Phosphate inhibition was mostly due to decreased concentrations of ionized calcium and partly to precipitation of insoluble calcium phosphate. These studies confirm that the effects of citrate in humans in enhancing calcium absorption occur in the lumen of the gut and are not related to further biochemical conversions of citrate by the gut cells, to effects of citrate on calcium-related hormones, or to the renal handling of calcium. Also, the effects of citrate on increasing calcium absorption should be increased or attenuated in patients who malabsorb citrate, and this explains the increased urinary calcium and oxalate excretions reported for recurrent calcium stone formers.

Animals↗

PubMed2001

The simultaneous activation hypothesis: explaining recovery from deep to phonological dyslexia.

Deep dyslexia evolved into phonological dyslexia in one patient. Semantic errors resolved while phonological and derivational errors persisted in reading. Nonword reading improved but remained inferior to word reading. Despite a residual semantic deficit naming improved. The Simultaneous Activation Hypothesis explains recovery from deep to phonological dyslexia and the continued dissociation between reading and naming errors. Partial recovery to all three reading routes increased constraints for word selection at the phonological output lexicon (POL) improving word reading. With recovery, the POL receives additional supportive information from the partially recovered direct oral reading route and grapheme-to-phoneme conversion (GPC) eliminating semantic errors in oral reading. Nonword reading also improved because of partial recovery to all three routes. Semantic errors in naming persisted because additional constraints were unavailable at the POL to activate a phonological entry. Phonological and derivational errors were more frequent in reading than in naming the result of incomplete GPC recovery. Residual nonword reading deficits resulted from incomplete GPC recovery, indicated by the persistence of neologisms in nonwords. The Simultaneous Activation Hypothesis readily accounts for the evolution from deep to phonological dyslexia.

Adult↗

PubMed1996

A novel hypothesis to explain the hemorrhagic and connective tissue manifestations of Ebola virus infection.

The hemorrhagic and connective tissue complications of infection with Ebola virus are poorly understood. While searching for homologies and motifs of the aortic aneurysm-associated autoantigenic protein 40 kDa (AAAP-40), we have noted some short sequences (possibly shared epitopes) that occur in the envelope glycoprotein (40 kDa) of the Ebola virus. As a first step toward determining whether molecular mimicry of human matrix proteins by the Ebola virus protein might explain some of the severe connective tissue manifestations of infection, we have tested whether immunoglobulin (IgG) purified from the sera of patients with abdominal aortic aneurysm (AAA) are immunoreactive with the 40-kDa protein of the Ebola virus. Immunoblots of soluble Ebola proteins (strain Mayinga/Zaire) were probed with IgG's purified from the sera of eight patients with AAA and two healthy young control volunteers. The proteins were also probed with IgG extracted from the walls of two surgical aneurysm specimens. Serum IgG from eight consecutively studied AAA patients was immunoreactive with an Ebola virus protein of 40 kDa, consistent with the envelope glycoprotein. IgG's extracted from the walls of two AAAs were also reactive. The control sera were not reactive. In addition to the Ebola sequences in AAAP-40, an Ebola sequence also occurs in the microfibril-associated glycoprotein-4 (MAGP-4), which is distributed ubiquitously throughout connective tissue with elastin. We hypothesize that the catastrophic hemorrhagic and connective tissue complications of Ebola virus infection may be the result of these shared epitopes.

Aged↗