Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion.

Molecular diameter, lipophilicity and hydrophilicity exclusion affinity limits exist for small molecule carrier-mediated diffusion or transport through channel pores or interaction with the cell surface glycocalyx. The molecular structure lipophilicity limit for non-specific carrier-mediated transmembrane diffusion through polarity-selective transport channels of the cell membrane is Lexternal structure ∙ Hpolar group-1 of ≥ 1.07.

Horizontal alignment of 5' -> 3' intergene distance segment tropy with respect to the gene as the conserved basis for DNA transcription.

Aim: To study the conserved basis for gene expression in comparative cell types at opposite ends of the cell pressuromodulation spectrum, the lymphatic endothelial cell and the blood microvascular capillary endothelial cell.

Methods: The mechanism for gene expression is studied in terms of the 5' -> 3' direction paired point tropy quotients (s) and the final 5' -> 3' direction episodic sub-episode block sums split-integrated weighted average-averaged gene overexpression tropy quotient ().

Results: The final 5' -> 3' classifies an lymphatic endothelial cell overexpressed gene as a supra-pressuromodulated gene ( ≥ 0.

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells.

For proper determination of the apoptotic potential of chemoxenobiotics in synergism, it is important to understand the modes, levels and character of interactions of chemoxenobiotics with cells in the context of predicted conserved biophysical properties. Chemoxenobiotic structures are studied with respect to atom distribution over molecular space, the predicted overall octanol-to-water partition coefficient (Log OWPC; unitless) and molecular size viz a viz van der Waals diameter (vdWD). The Log OWPC-to-vdWD ( ) parameter is determined, and where applicable, hydrophilic interacting moiety/core-to-vdWD ( ) and lipophilic incorporating hydrophobic moiety/core-to-vdWD ( ) parameters of their part-structures are determined.

Permeation thresholds for hydrophilic small biomolecules across microvascular and epithelial barriers are predictable on basis of conserved biophysical properties.

Purpose: Neutral small hydrophiles are permeable to varying degrees, across the aqueous pores of phospholipid bilayer protein channels, with their potential for permeation into cells being predictable, on the basis of hydrophilicity and size. Here, it is hypothesized that permeation thresholds for small hydrophiles, across capillary zona occludens tight junction and inter-epithelial junction pore complexes are predictable, on the basis of predicted hydrophilicity in context of predicted molecular size and charge distribution, as are those of cations and anions, on the basis of predicted ionization in context of predicted atomic size.

Methods: Small hydrophiles are categorized by charge distribution.

Pressuromodulation at the cell membrane as the basis for small molecule hormone and peptide regulation of cellular and nuclear function.

Building on recent knowledge that the specificity of the biological interactions of small molecule hydrophiles and lipophiles across microvascular and epithelial barriers, and with cells, can be predicted on the basis of their conserved biophysical properties, and the knowledge that biological peptides are cell membrane impermeant, it has been further discussed herein that cellular, and thus, nuclear function, are primarily regulated by small molecule hormone and peptide/factor interactions at the cell membrane (CM) receptors. The means of regulating cellular, and thus, nuclear function, are the various forms of CM Pressuromodulation that exist, which include Direct CM Receptor-Mediated Stabilizing Pressuromodulation, sub-classified as Direct CM Receptor-Mediated Stabilizing Shift Pressuromodulation (Single, Dual or Tri) or Direct CM Receptor-Mediated Stabilizing Shift Pressuromodulation (Single, Dual or Tri) cum External Cationomodulation (≥3+ → 1+); which are with respect to acute CM receptor-stabilizing effects of small biomolecule hormones, growth factors or cytokines, and also include Indirect CM- or CM Receptor-Mediated Pressuromodulation, sub-classified as Indirect 1ary CM-Mediated Shift Pressuromodulation (Perturbomodulation), Indirect 2ary CM Receptor-Mediated Shift Pressuromodulation (Tri or Quad Receptor Internal Pseudo-Cationomodulation: SS 1+), Indirect 3ary CM Receptor-Mediated Shift Pressuromodulation (Single or Dual Receptor Endocytic External Cationomodulation: 2+) or Indirect (Pseudo) 3ary CM Receptor-Mediated Shift Pressuromodulation (Receptor Endocytic Hydroxylocarbonyloetheroylomodulation: 0), which are with respect to sub-acute CM receptor-stabilizing effects of small biomolecules, growth factors or cytokines. As a generalization, all forms of CM pressuromodulation decrease CM and nuclear membrane (NM) compliance (whole cell compliance), due to pressuromodulation of the intracellular microtubule network and increases the exocytosis of pre-synthesized vesicular endogolgi peptides and small molecules as well as nuclear-to-rough endoplasmic reticulum membrane proteins to the CM, with the potential to simultaneously increase the NM-associated chromatin DNA transcription of higher molecular weight protein forms, secretory and CM-destined, mitochondrial and nuclear, including the highest molecular weight nuclear proteins, Ki67 (359 kDa) and Separase (230 kDa), with the latter leading to mitogenesis and cell division; while, in the case of growth factors or cytokines with external cationomodulation capability, CM Receptor External Cationomodulation of CM receptors (≥3+ → 1+) results in cationic extracellular interaction (≥3+) with extracellular matrix heparan sulfates (≥3+ → 1+) concomitant with lamellopodesis and cell migration.

On the future development of optimally-sized lipid-insoluble systemic therapies for CNS solid tumors and other neuropathologies.

It remains a challenge to deliver effective concentrations of therapeutics into CNS pathologies, which is primarily due to the fact that current and investigational CNS therapeutics are suboptimally-sized to accumulate to effective concentrations in individual diseased CNS tissue cells. The blood-CNS barrier of blood capillary microvasculature within neuropathologic tissues is known to be permeable to lipid-insoluble macromolecules in a wide-spectrum of neuropathologies. In the case of CNS solid tumor tissue blood capillaries, the physiological upper limit of pore size to the transcapillary passage of spherical lipid-insoluble macromolecules is approximately 12 nanometers, and systemically administered imageable dendrimer nanoparticles within the 7 to 10 nanometer size range accumulate to therapeutic concentrations in solid tumors since this size range of particles maintain peak blood concentrations for several hours.

Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability.

Background: Much of our current understanding of microvascular permeability is based on the findings of classic experimental studies of blood capillary permeability to various-sized lipid-insoluble endogenous and non-endogenous macromolecules. According to the classic small pore theory of microvascular permeability, which was formulated on the basis of the findings of studies on the transcapillary flow rates of various-sized systemically or regionally perfused endogenous macromolecules, transcapillary exchange across the capillary wall takes place through a single population of small pores that are approximately 6 nm in diameter; whereas, according to the dual pore theory of microvascular permeability, which was formulated on the basis of the findings of studies on the accumulation of various-sized systemically or regionally perfused non-endogenous macromolecules in the locoregional tissue lymphatic drainages, transcapillary exchange across the capillary wall also takes place through a separate population of large pores, or capillary leaks, that are between 24 and 60 nm in diameter. The classification of blood capillary types on the basis of differences in the physiologic upper limits of pore size to transvascular flow highlights the differences in the transcapillary exchange routes for the transvascular transport of endogenous and non-endogenous macromolecules across the capillary walls of different blood capillary types.

Overcoming the challenges in the effective delivery of chemotherapies to CNS solid tumors.

Locoregional therapies, such as surgery and intratumoral chemotherapy, do not effectively treat infiltrative primary CNS solid tumors and multifocal metastatic solid tumor disease of the CNS. It also remains a challenge to treat such CNS malignant solid tumor disease with systemic chemotherapies, although these lipid-soluble small-molecule drugs demonstrate potent cytotoxicity in vitro. Even in the setting of a 'normalized' tumor microenvironment, small-molecule drugs do not accumulate to effective concentrations in the vast majority of tumor cells, which is due to the fact that small-molecule drugs have short blood half-lives.

Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors.

Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers.

Physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumors.

Background: The existence of large pores in the blood-tumor barrier (BTB) of malignant solid tumor microvasculature makes the blood-tumor barrier more permeable to macromolecules than the endothelial barrier of most normal tissue microvasculature. The BTB of malignant solid tumors growing outside the brain, in peripheral tissues, is more permeable than that of similar tumors growing inside the brain. This has been previously attributed to the larger anatomic sizes of the pores within the BTB of peripheral tumors.

Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half-life.

Background: The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure.

Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells.

Background: Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation.

Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography in the RG2 rat brain tumor model.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is widely used to evaluate tumor permeability, yet measurements have not been directly validated in brain tumors. Our purpose was to compare estimates of forward leakage K(trans) derived from DCE-MRI to the estimates K obtained using [(14)C]aminoisobutyric acid quantitative autoradiography ([(14)C]AIB QAR), an established method of evaluating blood-tumor barrier permeability. Both DCE-MRI and [(14)C]AIB QAR were performed in five rats 9 to 11 days following tumor implantation.

Variations in structural protein expression and endothelial cell proliferation in relation to clinical manifestations of cerebral cavernous malformations.

Objective: Cerebral cavernous malformations (CCMs) are associated with hemorrhagic proliferation of endothelial-lined vascular caverns, resulting in hemorrhagic stroke, epilepsy, and other neurological manifestations. We hypothesize that structural protein expression and endothelial cell proliferation markers within CCM lesions are different in the setting of various clinical manifestations.

Methods: The percentage of immunohistochemically stained caverns positive for collagen IV, fibronectin, laminin, alpha-smooth muscle actin, myosin, and smoothelin and the percentage of dividing endothelial cells within caverns were determined in 36 excised CCM surgical specimens.

Pathobiology of human cerebrovascular malformations: basic mechanisms and clinical relevance.

Cerebrovascular malformations affect more than 3% of the population, exposing them to a lifetime risk of hemorrhagic stroke, seizures, and focal neurological deficits. Cerebral cavernous malformations (CCMs) exhibit an immature vessel wall, a brittle hemorrhagic tendency, and epileptogenesis, whereas arteriovenous malformations (AVMs) lack capillary beds and manifest apoplectic bleeding under high-flow conditions. There are also more benign venous anomalies, capillary malformations, and lesions with mixed and transitional features.