In a medical sense biomodulation could be considered a biochemical or cellular response to a disease or therapeutic stimulus. In cancer pathophysiology, the initial oncogenic stimulus leads to cellular and biochemical changes that allow cells, tissue, and organism to accommodate and accept the oncogenic insult. In epithelial cell cancer development, the process of carcinogenesis is frequently characterized by sequential cellular and biochemical adaptations as cells transition through hyperplasia, dysplasia, atypical dysplasia, carcinoma in situ, and invasive cancer. In some cases, the adaptations may persist after the initial oncogenic stimulus is gone in a type of “hit-and-run” oncogenesis. These pathophysiological changes may interfere with cancer prevention therapies targeted solely to the initial oncogenic insult, perhaps contributing to resistance development. Characterization of these accommodating adaptations could provide insight for development of cancer preventive regimens that might more effectively biomodulate preneoplastic cells towards a more normal state.
cancer prevention; biomodulation; hit and run oncogenesis; viral oncogenesis; hormonal oncogenesis
Neurorestorative therapy targets multiple types of parenchymal cells in the intact tissue of the injured brain tissue to increase neurogenesis, angiogenesis, oligodendrogenesis, and axonal remodeling during recovery from neurological injury. In our laboratory, we tested thymosin β4 (Tβ4) as a neurorestorative agent to treat models of neurological injury. This review discusses our results demonstrating that Tβ4 improves neurological functional outcome in a rat model of embolic stroke, a mouse model of multiple sclerosis, and a rat model of traumatic brain injury. Tβ4 is a pleiotropic peptide exhibiting many actions in several different types of tissues. One mechanism associated with improvement of neurological improvement from Tβ4 treatment is oligodendrogenesis involving the differentiation of oligodendrocyte progenitor cells to mature myelin-secreting oligodendrocytes. Moreover, our preclinical data provide a basis for movement of Tβ4 into clinical trials for treatment of these devastating neurological diseases and injuries.
thymosin β4; stroke; multiple sclerosis; traumatic brain injury; rat
Obesity, a growing health problem worldwide, has been associated with the metabolic syndrome, diabetes, cardiovascular disease, hypertension, and other chronic diseases. Recently, the obesity–cancer link has received much attention. Epidemiological studies have shown that obesity is also associated with increased risk of several cancer types, including colon, breast, endometrium, liver, kidney, esophagus, gastric, pancreatic, gallbladder, and leukemia, and can also lead to poorer treatment and increased cancer-related mortality. Biological mechanisms underlying the relationship between obesity and cancer are not well understood. They include modulation of energy balance and calorie restriction, growth factors, multiple signaling pathways and inflammatory processes. Key among the signaling pathways linking obesity and cancer is the PI3K/Akt/mTOR cascade, which is a target of many of the obesity-associated factors and regulates cell proliferation and survival. Understanding the molecular and cellular mechanisms of the obesity–cancer connection is important in developing potential therapeutics. The link between obesity with cancer underscores the recommendation to maintain a healthy body weight throughout life as one of the most important ways to protect against cancer.
obesity; cancer; mechanisms; recommendations; prevention
Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity worldwide. No effective pharmacological treatments are available for TBI because all Phase II/III TBI clinical trials have failed. This highlights a compelling need to develop effective treatments for TBI. Endogenous neurorestoration occurs in the brain after TBI, including angiogenesis, neurogenesis, synaptogenesis, oligodendrogenesis and axonal remodeling, which may be associated with spontaneous functional recovery after TBI. However, the endogenous neurorestoration following TBI is limited. Treatments amplifying these neurorestorative processes may promote functional recovery after TBI. Thymosin beta4 (Tβ4) is the major G-actin-sequestering molecule in eukaryotic cells. In addition, Tβ4 has other properties including anti-apoptosis and anti-inflammation, promotion of angiogenesis, wound healing, stem/progenitor cell differentiation, and cell migration and survival, which provide the scientific foundation for the corneal, dermal, and cardiac wound repair multicenter clinical trials. Here, we describe Tβ4 as a neuroprotective and neurorestorative candidate for treatment of TBI.
thymosin beta4; traumatic brain injury; rat; neuroprotection; neurorestoration
Heart failure (HF) is a major cause of mortality and morbidity, representing a leading cause of death and hospitalization among U.S. Medicare beneficiaries. Advances in science have generated effective interventions to reduce adverse outcomes in HF, particularly in patients with reduced left ventricular ejection fraction. Unfortunately, effective therapies for heart failure are often not utilized in an effective, safe, timely, equitable, patient-centered, and efficient manner. Further, the risk of adverse outcomes for HF remains high. The last decades have witnessed the growth of efforts to measure and improve the care and outcomes of patients with HF. This paper will review the evolution of quality measurement for HF, including a brief history of quality measurement in medicine; the measures that have been employed to characterize quality in heart failure; how the measures are obtained; how measures are employed; and present and future challenges surrounding quality measurement in heart failure.
quality measurement; heart failure; outcomes
Climate change is expected to lead to latitudinal and altitudinal temperature increases. High elevation regions such as the highlands of Africa, and those that have temperate climate are most likely to be affected. The highlands of Africa generally exhibit low ambient temperatures. This restricts the distribution of Anopheles mosquitoes, the vectors of malaria, filariasis and O’nyong’nyong fever. The development and survival of larval and adult mosquitoes are temperature dependent, as are mosquito biting frequency and pathogen development rate. Given that various Anopheles species are adapted to different climatic conditions, changes in the climate could lead to changes in species composition in an area which may change the dynamics of mosquito-borne disease transmission. It is important to consider the effect of climate change on rainfall which is critical to the formation and persistence of mosquito breeding sites. In addition, environmental changes such as deforestation could increase local temperatures in the highlands; this could enhance the vectorial capacity of the Anopheles. This experimental data will be invaluable in facilitating the understanding of the impact of climate change on Anopheles.
Hemorrhagic transformation (HT) associated with recombinant tissue plasminogen activator (rt-PA) complicates and limits its use in stroke. Here, we provide a focused review on the involvement of matrix metalloproteinase 9 (MMP-9) in rt-PA–associated HT in cerebral ischemia, and we review emerging evidence that the selective inhibitor of the sulfonylurea receptor 1 (Sur1), glibenclamide (U.S. adopted name, glyburide), may provide protection against rt-PA–associated HT in cerebral ischemia. Glyburide inhibits activation of MMP-9, ameliorates edema formation, swelling, and symptomatic hemorrhagic transformation, and improves preclinical outcomes in several clinically relevant models of stroke, both without and with rt-PA treatment. A retrospective clinical study comparing outcomes in diabetic patients with stroke treated with rt-PA showed that those who were previously on and were maintained on a sulfonylurea fared significantly better than those whose diabetes was managed without sulfonylureas. Inhibition of Sur1 with injectable glyburide holds promise for ameliorating rt-PA–associated HT in stroke.
rt-PA; Sur1; glyburide; MMP-9; cerebral ischemia; stroke
Certain chromosomal regions called common fragile sites are prone to difficulty during replication. Many tumors have been shown to contain alterations at fragile sites. Several models have been proposed to explain why these sites are unstable. Here we describe work to investigate models of fragile site instability using a yeast artificial chromosome carrying human DNA from a common fragile site region. In addition, we describe a yeast system to investigate whether repair of breaks at a naturally-occurring fragile site in yeast, FS2, involves mitotic recombination between homologous chromosomes, leading to loss of heterozygosity (LOH). Our initial evidence is that repair of yeast fragile site breaks does lead to LOH, suggesting that human fragile site breaks may similarly contribute to LOH in cancer. This work is focused on gaining understanding that may enable us to predict and prevent the situations and environments that promote genetic changes that contribute to tumor progression.
fragile site; FRA3B; flexibility peak; mitotic crossover; loss of heterozygosity; cancer
Gross chromosomal rearrangements (GCRs), or changes in chromosome structure, play central roles in evolution and are central to cancer formation and progression. GCRs underlie copy number variation (CNV), and therefore genomic disorders that stem from CNV. We study amplification in Escherichia coli as a model system to understand mechanisms and circumstances of GCR formation. Here, we summarize observations that led us to postulate that GCR occurs by a replicative mechanism as part of activated stress responses. We report that we do not find RecA to be downregulated by stress on a population basis and that constitutive expression of RecA does not inhibit amplification as would be expected if downregulation of RecA made cells permissive for nonhomologous recombination. Strains deleted for the genes for three proteins that inhibit RecA activity, psiB, dinI, and recX, all show unaltered amplification, suggesting that if they do downregulate RecA indirectly, it does not promote amplification.
nonhomologous recombination; amplification; stress; copy number variation
Immunoglobulin (Ig) class switch recombination (CSR) is responsible for diversification of antibody effector function during an immune response. This region specific recombination event, between repetitive switch (S) DNA elements, is unique to B lymphocytes and is induced by activation induced deaminase (AID). CSR is critically dependent on transcription of noncoding RNAs across S regions. However, mechanistic insight regarding this process remained unclear. New studies indicate that long range intra-chromosomal interactions among Igh transcriptional elements organize the formation of the S/S synaptosome, as prerequisite for CSR. This three dimensional chromatin architecture simultaneously brings promoters and enhancers into close proximity to facilitate transcription. Here, we recount how transcription across S DNA promotes accumulation of RNA polymerase II leading to the introduction of activating chromatin modifications and hyperaccessible chromatin that is amenable to AID activity.
Chromatin; class switch recombination; transcription; long range interactions
Hyperglycemia is associated with enhanced cortical toxicity and larger infarct volumes following focal cerebral ischemia. Initial blood glucose in acute ischemic stroke patients may also contribute to a differential response to thrombolysis (tPA) and affect risk of symptomatic intracerebral hemorrhage (sICH). The Stroke Hyperglycemia Insulin Network Effort (SHINE) study is a phase III single-blinded, randomized control trial comparing an intensive level of glucose control to standard of care glucose control in hyperglycemic stroke patients. In stratifying randomization by treatment with intravenous tPA, the SHINE trial offers a unique opportunity to evaluate an association between euglycemic control and outcomes from stroke thrombolysis in a prospective, comparative study. We hypothesize that normalization of blood glucose in the acute stroke setting may reduce risk of thrombolysis-induced sICH. With enrollment recently underway, the stratified results from the SHINE trial could substantially influence future treatment decisions for hyperglycemic stroke patients.
stroke; hyperglycemia; glucose; thrombolysis; tPA; hemorrhage
An impressive biodiversity (>10,000 species) of marine snails (suborder Toxoglossa or superfamily Conoidea) have complex venoms, containing ca. 100 biologically active, disulfide-rich peptides. In the genus Conus, the most intensively investigated toxoglossan lineage (~500 species), a small set of venom gene superfamilies undergo rapid sequence hyperdiversification within their mature toxin regions. Each major lineage of Toxoglossa has its own distinct set of venom gene superfamilies. Two recently identified venom gene superfamilies are expressed in the large Turridae clade, but not in Conus. Thus, as major venomous molluscan clades expand, a small set of lineage specific venom gene superfamilies undergo accelerated evolution. The juxtaposition of extremely conserved signal sequences with hypervariable mature peptide regions is unprecedented and raises the possibility that in these gene superfamilies, the signal sequences are conserved as a result of an essential role they play in enabling rapid sequence evolution of the region of the gene that encodes the active toxin.
venom peptides; accelerated evolution; Conidae; Turridae
Within less than 10 years after the realization of the double helix of DNA, the ability of aminoglycosides to influence the misreading or readthrough of premature termination codons was discovered. It took another three decades to clone and sequence disease genes and appreciate the similarity of mutation spectra for most inborn errors. Nonsense mutations once again have become the target of readthrough compounds. In this brief review, we trace the development in our laboratory of the next generation of readthrough agents, small molecule readthrough (SMRT) drug-like chemicals, and assays for comparing their in vitro activity. Possible mechanisms of action and potential clinical applications are also considered.
SMRT compounds; nonsense mutation; primary immunodeficiency; DNA
Semi-conservative replication ensures that the DNA sequence of sister chromatids is identical except for replication errors and variation in the length of telomere repeats resulting from replicative losses and variable end processing. What happens with the various epigenetic marks during DNA replication is less clear. Many chromatin marks are likely to be copied onto both sister chromatids in conjunction with DNA replication, whereas others could be distributed randomly between sister chromatids. Epigenetic differences between sister chromatids could also emerge in a more predictable manner for example following processes that are associated with lagging strand DNA replication. The resulting epigenetic differences between sister chromatids could result in different gene expression patterns in daughter cells. This possibility has been difficult to test because techniques to distinguish between parental sister chromatids require analysis of single cells and are not obvious. Here we briefly review the topic of sister chromatid epigenetics and discuss how the identification of sister chromatids in cells could change the way we think about asymmetric cell divisions and “stochastic’ variation in gene expression between cells in general and paired daughter cells in particular.
DNA replication; chromatin; epigenetic marks; sister chromatids
Cardiovascular disease (CVD) is now the leading cause of mortality worldwide. Particularly in Low and Middle Income Countries, rapid urbanization and secondary factors such as increasing obesity, poor diet and lack of exercise have combined to propel CVD into this position. Given the enormous scope of this problem and the complex cultural, societal and political issues that are involved, and equally sophisticated and multipronged approach is required to combat CVD at the global level. In this review we outline the basic, clinical and population level challenges that we face in defending ourselves against this disease.
Exposure to commensal and pathogenic organisms strongly influences our immune system. Exposure to helminths was frequent before humans constructed their current highly hygienic environment. Today, in highly industrialized countries, contact between humans and helminths is rare. Congruent with the decline in helminth infections is an increase in the prevalence of autoimmune and inflammatory disease. It is possible that exclusion of helminths from the environment has permitted the emergence of immune-mediated disease. We review the protective effects of helminths on expression of inflammatory bowel disease, multiple sclerosis, and animal models of these and other inflammatory diseases. We also review the immune pathways altered by helminths that may afford protection from these illnesses. Helminth exposure tends to inhibit IFN-γ and IL-17 production, promote IL-4, IL-10, and TGF-β release, induce CD4+ T cell Foxp3 expression, and generate regulatory macrophages, dendritic cells, and B cells. Helminths enable protective pathways that may vary by specific species and disease model. Helminths or their products likely have therapeutic potential to control or prevent immune-mediated illness.
helminths; dendritic cells; IBD; Treg; macrophage; autoimmunity
Claudins are tight junction integral membrane proteins that are key regulators of the paracellular pathway. The paracellular pathways in the inner ear and in the kidney are predominant routes for transepithelial cation transport. Mutations in claudin-14 cause nonsyndromic recessive deafness DFNB29. A recent genome-wide association study (GWAS) has identified claudin-14 as a major risk gene of hypercalciuric nephrolithiasis. In vitro analyses show claudin-14 functions as a cation barrier in epithelial cells. The barrier function of claudin-14 is crucial for generating the K+ gradient between perilymph and endolymph in the inner ear. However, neither homozygous individuals with DFNB29 mutations nor claudin-14 knockout mice show any renal dysfunction. In this review, I have discussed several possible mechanisms to integrate the physiological function of claudin-14 in the inner ear and the kidney.
tight junction; ion channel; kidney; inner ear
Leptin, an adipocyte-derived cytokine, crosses the blood-brain barrier to act on many regions of the CNS. It participates in the regulation of energy balance, inflammatory processes, immune regulation, synaptic formation, memory condensation, and neurotrophic activities. This review focuses on the newly identified actions of leptin on astrocytes. We first summarize the distribution of leptin receptors in the brain, with a focus on the hypothalamus where the leptin receptor is known to mediate essential feeding suppression activities, and on the hippocampus, where leptin facilitates memory, reduces neurodegeneration, and plays a dual role in seizures. We will then discuss regulation of the non-neuronal leptin system in obesity. Its relationship with neuronal leptin signaling is illustrated by in vitro assays in primary astrocyte culture and by in vivo studies on mice after pretreatment with a glial metabolic inhibitor or after cell-specific deletion of intracellular signaling leptin receptors. Overall, the glial leptin system shows robust regulation and plays an essential role in obesity. Strategies to manipulate this non-neuronal leptin signaling may have major clinical impact.
leptin; CNS; obesity; astrocytes; blood–brain barrier
Overweight sedentary individuals are at increased risk for cardiovascular disease, diabetes and some neurological disorders. Beneficial effects of dietary energy restriction (DER) and exercise on brain structural plasticity and behaviors have been demonstrated in animal models of aging and acute (stroke and trauma) and chronic (Alzheimer’s and Parkinson’s diseases) neurological disorders. The findings described below, and evolutionary considerations, suggest brain-derived neurotrophic factor (BDNF) plays a critical role in the integration and optimization of behavioral and metabolic responses to environments with limited energy resources and intense competition. In particular, BDNF signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and DER. In the hypothalamus, BDNF inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise- and DER-induced improvements in cognitive function and neuroprotection. DER improves cardiovascular stress adaptation by a mechanism involving enhancement of brainstem cholinergic activity. Collectively, findings reviewed in this article provide a rationale for targeting BDNF signaling for novel therapeutic interventions in a range of metabolic and neurological disorders.
autonomic nervous system; brain-derived neurotrophic factor; cognition; diabetes; exercise; neurogenesis; synaptic plasticity
In the last 50 years, the average self-reported sleep duration in the United States has decreased by 1.5 to 2 hours in parallel with an increasing prevalence of obesity and diabetes. Epidemiological studies and meta-analyses report a strong relationship between short or disturbed sleep, obesity and abnormalities in glucose metabolism. This relationship is likely to be bidirectional and causal in nature, but many aspects remain to be elucidated. Sleep and the internal circadian clock influence a host of endocrine parameters. Sleep curtailment in humans alters multiple metabolic pathways leading to more insulin resistance, possibly decreased energy expenditure, increased appetite and immunological changes. On the other hand, psychological, endocrine and anatomical abnormalities in individuals with obesity and/or diabetes can interfere with sleep duration and quality, thus creating a vicious cycle. In this review, we address mechanisms linking sleep with metabolism, highlight the need for studies conducted in real life settings, and explore therapeutic interventions to improve sleep with a potential beneficial effect on obesity and its comorbidities.
sleep; obesity; insulin resistance; diabetes; appetite
Cord blood (CB) transplantation has been used over the last 24 years to treat patients with malignant and non-malignant disorders. CB has its advantages and disadvantages compared to other sources of hematopoietic stem (HSCs) and progenitor (HPCs) cells for transplantation. More knowledge of the cytokines, and intracellular signaling molecules regulating HSCs and HPCs could be used to modulate these regulators for clinical benefit. This review provides brief information on the field of CB transplantation and studies from the author’s laboratory that focus on regulation of HSCs and HPCs by CD26/DPPIV, SDF-1/CXCL12, the Rheb2-mTOR pathway, SIRT1, DEK, cyclin dependent kinase inhibitors, and cytokines/growth factors. It also briefly discusses cryopreservation of CB HSCs and HPCs.
Cord blood; stem and progenitor cells; intracellular signals; cytokines
Research on deep brain stimulation (DBS) for treatment-resistant depression appears promising, but concerns have been raised about the decisional capacity of severely depressed patients and their potential misconceptions about the research. We assessed 31 DBS research participants with the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), a well-validated capacity measure, and with a scale to measure therapeutic misconception, which occurs when subjects do not recognize key differences between treatment and clinical research. Correlations with baseline depressive symptoms were explored. Subjects’ performance on the MacCAT-CR was excellent, but therapeutic misconception was still apparent. A trend toward significance was found in the correlation between baseline depression ratings and total therapeutic misconception score. Responses to open-ended prompts revealed both reassuring and concerning statements related to expectations of risk, benefit, and individualization. Even severely depressed patients did not manifest impairments in their capacity to consent to DBS research. Therapeutic misconception, however, remained prevalent.
research ethics; deep brain stimulation; decisional capacity; therapeutic misconception
Population distribution estimates by age and race/ethnicity from the U.S. Census Bureau for the years 2010 and 2050 were combined with estimates of stroke incidence from population-based surveillance studies to forecast the distribution of incident stroke cases for the years 2010 and 2050. Over these 40 years, the number of incident strokes will more than double, with the majority of the increase among the elderly (age 75+) and minority groups (particularly Hispanics). These increases are likely to present major logistical, scientific, and ethnical issues in the near future.
stroke; incidence; aging; race; projections
Female mosquitoes gorge on vertebrate blood, a rich nutrient source for developing eggs. But gorging meals increase the risk of predation. Mosquitoes are quick to reduce the flight payload with a potent diuresis. Diuretic peptides of the insect kinin family induce a tenfold-reduction in the paracellular resistance of Malpighian tubules and increase the paracellular permeation of Cl−, the counterion of the transepithelial secretion of Na+ and K+. As a result, the transepithelial secretion of NaCl and KCl and water increases. Insect kinins signal to the opening of the paracellular pathway via G protein-coupled receptors and the elevation of intracellular [Ca2+], which leads to the reorganization of the cytoskeleton associated with the septate junction. The reorganization may affect the septate junctional proteins that control the barrier and permselectivity properties of the paracellular pathway. The proteins involved in the embryonic formation of the septate junction and in epithelial polarization are largely known for ectodermal epithelia, but the proteins that form and mediate the dynamic functions of the septate junction in Malpighian tubules remain to be determined.
septate junction; paracellular permeability; paracellular chloride transport; leucokinin; aedeskinin; insect kinins; septa; integral membrane proteins; scaffolding proteins; actin; adducin; actin depolymerizing factor; cytoskeleton
Recent studies indicate that beside digestion and absorption of nutrients and water and electrolytes homeostasis, another key function of the intestine is to regulate the trafficking of environmental antigens across the host mucosal barrier. Intestinal tight junctions (TJ) create gradients for the optimal absorption and transport of nutrients and control the balance between tolerance and immunity to non-self antigens. To meet diverse physiological challenges, intestinal epithelial TJ must be modified rapidly and in a coordinated fashion by regulatory systems that orchestrate the state of assembly of the TJ multi-protein network. While considerable knowledge exists about TJ ultrastructure, relatively little is known about their physiological and pathophysiological regulation. Our discovery of zonulin, the only known physiologic modulator of intercellular TJ described so far, increased understanding of the intricate mechanisms that regulate the intestinal epithelial paracellular pathway and led us appreciate that its up-regulation in genetically susceptible individuals leads to autoimmune diseases.