Radiation damage to biological systems is determined by the type of radiation, the total dosage of exposure, the dose rate, and the region of the body exposed. Three modes of cell death-necrosis, ...apoptosis, and autophagy-as well as accelerated senescence have been demonstrated to occur in vitro and in vivo in response to radiation in cancer cells as well as in normal cells. The basis for cellular selection for each mode depends on various factors including the specific cell type involved, the dose of radiation absorbed by the cell, and whether it is proliferating and/or transformed. Here we review the signaling mechanisms activated by radiation for the induction of toxicity in transformed and normal cells. Understanding the molecular mechanisms of radiation toxicity is critical for the development of radiation countermeasures as well as for the improvement of clinical radiation in cancer treatment.
The microbial etiology of urinary infections has been regarded as well established and reasonably consistent.
Escherichia coli remains the predominant uropathogen (80%) isolated in acute ...community-acquired uncomplicated infections, followed by
Staphylococcus saprophyticus (10% to 15%).
Klebsiella,
Enterobacter, and
Proteus species, and enterococci infrequently cause uncomplicated cystitis and pyelonephritis.
The pathogens traditionally associated with UTI are changing many of their features, particularly because of antimicrobial resistance. The etiology of UTI is also affected by underlying host factors that complicate UTI, such as age, diabetes, spinal cord injury, or catheterization. Consequently, complicated UTI has a more diverse etiology than uncomplicated UTI, and organisms that rarely cause disease in healthy patients can cause significant disease in hosts with anatomic, metabolic, or immunologic underlying disease. The majority of community-acquired symptomatic UTIs in elderly women are caused by
E coli. However, gram-positive organisms are common, and polymicrobial infections account for up to 1 in 3 infections in the elderly. In comparison, the most common organisms isolated in children with uncomplicated UTI are
Enterobacteriaceae. Etiologic pathogens associated with UTI among patients with diabetes include
Klebsiella spp., Group B streptococci, and
Enterococcus spp., as well as
E coli. Patients with spinal cord injuries commonly have
E coli infections. Other common uropathogens include
Pseudomonas and
Proteus mirabilis.
Recent advances in molecular biology may facilitate the identification of new etiologic agents for UTI. The need for accurate and updated population surveillance data is apparent, particularly in light of concerns regarding antimicrobial resistance. This information will directly affect selection of empiric therapy for UTI.
Clinical and epidemiologic studies have shown that obesity is associated with asthma and that these associations differ by asthma subtype. Little is known about the shared genetic components between ...obesity and asthma.
We sought to identify shared genetic associations between obesity-related traits and asthma subtypes in adults.
A cross-trait genome-wide association study (GWAS) was performed using 457,822 subjects of European ancestry from the UK Biobank. Experimental evidence to support the role of genes significantly associated with both obesity-related traits and asthma through a GWAS was sought by using results from obese versus lean mouse RNA sequencing and RT-PCR experiments.
We found a substantial positive genetic correlation between body mass index and later-onset asthma defined by asthma age of onset at 16 years or greater (Rg = 0.25, P = 9.56 × 10−22). Mendelian randomization analysis provided strong evidence in support of body mass index causally increasing asthma risk. Cross-trait meta-analysis identified 34 shared loci among 3 obesity-related traits and 2 asthma subtypes. GWAS functional analyses identified potential causal relationships between the shared loci and Genotype-Tissue Expression (GTEx) quantitative trait loci and shared immune- and cell differentiation–related pathways between obesity and asthma. Finally, RNA sequencing data from lungs of obese versus control mice found that 2 genes (acyl-coenzyme A oxidase-like ACOXL and myosin light chain 6 MYL6) from the cross-trait meta-analysis were differentially expressed, and these findings were validated by using RT-PCR in an independent set of mice.
Our work identified shared genetic components between obesity-related traits and specific asthma subtypes, reinforcing the hypothesis that obesity causally increases the risk of asthma and identifying molecular pathways that might underlie both obesity and asthma.
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Accelerated senescence is a primary response to cellular stresses including DNA damaging agents (e.g., ionizing radiation) and is widely believed to be caused by continuous proliferative signaling in ...the presence of cell cycle arrest. Studies of signal transduction pathways leading to accelerated senescence have revealed that inhibition of mammalian target of rapamycin (mTOR) by rapamycin rescues cells from senescence. However, the molecular mechanisms upstream of mTOR following ionizing radiation (IR) are not well defined. We investigated signal transduction leading to IR-induced accelerated senescence in human pulmonary artery endothelial cells (HPAEC). Exposure of HPAEC to X-rays (10 Gy, 2.4 Gy/min) upregulated senescence markers including p53, p21/waf1, and senescence-associated beta galactosidase (SA-β-gal). Ly294002 (a phosphatidylinositol-3-kinase PI3K inhibitor) or rapamycin (an mTOR inhibitor) blocked the induction of cellular senescence markers suggesting roles for PI3K and mTOR. Pathway-directed microarrays revealed increased transcription of insulin-like growth factor I (IGF-1), a modulator of cell growth and proliferation upstream of mTOR. qRT-PCR confirmed that both IGF-1 and IGF-2 mRNA were increased in response to X-rays, and ELISA showed increased secretion of IGF-1 protein into the medium of irradiated HPAEC. Consistent with upregulation of these ligands, we found that X-ray exposure led to hyperphosphorylation of IGF-1R, the receptor for IGF-1 and -2. Treatment with AG1024, an IGF-1R inhibitor, suppressed IR-induced upregulation of p53, p21/waf1, and SA-β-gal. Together these findings suggest that IGF-1R is a key regulator of IR-induced accelerated senescence in a pathway that requires intact mTOR activity upstream of both p53 and p21/waf1.
Background. Cryptococcal meningitis (CM) is the proximate cause of death in 20%–30% of persons with acquired immunodeficiency syndrome in Africa. Methods. Two prospective, observational cohorts ...enrolled human immunodeficiency virus (HIV)—infected, antiretroviral-naive persons with CM in Kampala, Uganda. The first cohort was enrolled in 2001–2002 (n=92), prior to the availability of highly active antiretroviral therapy (HAART), and the second was enrolled in 2006–2007 (n=44), when HAART was available. Results. Ugandans presented with prolonged CM symptoms (median duration, 14 days; interquartile range, 7–21 days). The 14-day survival rates were 49% in 2001–2002 and 80% in 2006 (P<.001). HAART was started 35±13 days after CM diagnosis and does not explain the improved 14-day survival rate in 2006. In 2006–2007, the survival rate continued to decrease after hospitalization, with only 55% surviving to initiate HAART as an outpatient. Probable cryptococcal-related immune reconstitution inflammatory syndrome occurred in 42% of patients, with 4 deaths. At 6 months after CM diagnosis, 18 persons (41%) were alive and receiving HAART in 2007. The median cerebral spinal fluid (CSF) opening pressure was 330 mm H2O; 81% of patients had elevated pressure (>200 mm H2O). Only 5 patients consented to therapeutic lumbar puncture. There was a trend for higher mortality for pressures >250 mm H2O (odds ratio OR, 2.1; 95% confidence interval CI, 0.9–5.2; P=.09). Initial CSF WBC counts of <5 cells/mL were associated with failure of CSF sterilization (OR, 17.3; 95% CI, 3.1–94.3; P<.001), and protein levels <35 mg/dL were associated with higher mortality (OR, 2.0; 95% CI, 1.2–3.3; P=.007). Conclusions. Significant CM-associated mortality persists, despite the administration of amphotericin B and HIV therapy, because of the high mortality rate before receipt of HAART and because of immune reconstitution inflammatory syndrome—related complications after HAART initiation. Approaches to increase acceptance of therapeutic lumbar punctures are needed.
Abstract
Purpose: The use of clinical radiation for cancer treatment is limited by damage to underlying normal tissue including to the vascular endothelium. We investigated the mechanisms of ...X-ray-induced cell damage to endothelial cells.
Methods: We evaluated necrosis, apoptosis, cellular senescence, and the contribution of endoplasmic reticulum (ER) stress in pulmonary artery endothelial cells (PAEC) irradiated with X-rays (2-50 Gray Gy).
Results: Clonogenic assays showed that 10 Gy induced ∼99.9% loss of cell viability. No necrosis was detected using lactate dehydrogenase assays, but a low population underwent extrinsic and intrinsic apoptosis, as indicated by the activation of caspases 3, 8, and 9 as well as by neutral comet assay. A majority of PAEC underwent accelerated senescence, as indicated by morphological changes, increased 21 kD cyclin-dependent kinase inhibitor (p21/waf1), decreased sirtuin 1 (SIRT1), and elevated senescence-associated β-galactosidase (SA-β-gal). ER stress was detected by assays for glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and growth arrest and DNA damage-inducible protein 34 (GADD34) mRNA, and transient phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). The ER stress inhibitor salubrinal blocked ∼50% of apoptosis with no effect on senescence.
Conclusions: X-rays primarily induced cellular senescence with limited levels of apoptosis in endothelial cells. ER stress contributed to apoptosis but not to senescence.
Providing health care in sub-Saharan Africa is a complex problem. Recent reports call for more resources to assist in the prevention and treatment of infectious diseases that affect this population, ...but policy makers, clinicians, and the public frequently fail to understand that diagnosis is essential to the prevention and treatment of disease. Access to reliable diagnostic testing is severely limited in this region, and misdiagnosis commonly occurs. Understandably, allocation of resources to diagnostic laboratory testing has not been a priority for resource-limited health care systems, but unreliable and inaccurate laboratory diagnostic testing leads to unnecessary expenditures in a region already plagued by resource shortages, promotes the perception that laboratory testing is unhelpful, and compromises patient care. We explore the barriers to implementing consistent testing within this region and illustrate the need for a more comprehensive approach to the diagnosis of infectious diseases, with an emphasis on making laboratory testing a higher priority.
Obesity increases asthma prevalence and severity. However, the underlying mechanisms are poorly understood, and consequently, therapeutic options for asthma patients with obesity remain limited. Here ...we report that cholecystokinin-a metabolic hormone best known for its role in signaling satiation and fat metabolism-is increased in the lungs of obese mice and that pharmacological blockade of cholecystokinin A receptor signaling reduces obesity-associated airway hyperresponsiveness. Activation of cholecystokinin A receptor by the hormone induces contraction of airway smooth muscle cells. In vivo, cholecystokinin level is elevated in the lungs of both genetically and diet-induced obese mice. Importantly, intranasal administration of cholecystokinin A receptor antagonists (proglumide and devazepide) suppresses the airway hyperresponsiveness in the obese mice. Together, our results reveal an unexpected role for cholecystokinin in the lung and support the repurposing of cholecystokinin A receptor antagonists as a potential therapy for asthma patients with obesity.
The microbial etiology of urinary infections has been regarded as well established and reasonably consistent. Escherichia coli remains the predominant uropathogen (80%) isolated in acute ...community-acquired uncomplicated infections, followed by Staphylococcus saprophyticus (10% to 15%). Klebsiella, Enterobacter, and Proteus species, and enterococci infrequently cause uncomplicated cystitis and pyelonephritis. The pathogens traditionally associated with UTI are changing many of their features, particularly because of antimicrobial resistance. The etiology of UTI is also affected by underlying host factors that complicate UTI, such as age, diabetes, spinal cord injury, or catheterization. Consequently, complicated UTI has a more diverse etiology than uncomplicated UTI, and organisms that rarely cause disease in healthy patients can cause significant disease in hosts with anatomic, metabolic, or immunologic underlying disease. The majority of community-acquired symptomatic UTIs in elderly women are caused by E coli. However, gram-positive organisms are common, and polymicrobial infections account for up to 1 in 3 infections in the elderly. In comparison, the most common organisms isolated in children with uncomplicated UTI are Enterobacteriaceae. Etiologic pathogens associated with UTI among patients with diabetes include Klebsiella spp., Group B streptococci, and Enterococcus spp., as well as E coli. Patients with spinal cord injuries commonly have E coli infections. Other common uropathogens include Pseudomonas and Proteus mirabilis.Recent advances in molecular biology may facilitate the identification of new etiologic agents for UTI. The need for accurate and updated population surveillance data is apparent, particularly in light of concerns regarding antimicrobial resistance. This information will directly affect selection of empiric therapy for UTI.
Abstract
Human immunodeficiency virus 1 (HIV-1) exposed seronegative (HESN) individuals may have unique characteristics that alter susceptibility to HIV-1 infection. However, identifying truly ...exposed HESN is challenging. We utilized stored data and biospecimens from HIV-1 serodifferent couple cohorts, in which couples’ HIV-1 exposures were quantified based on unprotected sex frequency and viral load of the partner with HIV-1. We compared peripheral blood gene expression between 15 HESN and 18 seroconverters prior to infection. We found PTPRC (encoding CD45 antigen) and interferon-response pathways had significantly higher expression among individuals who went on to become seropositive and thus may be a signature for increased acquisition risk.
We analyzed transcriptional signatures associated with HIV acquisition in an African cohort with quantified HIV exposure. PTPRC (CD45 antigen) and interferon-response pathways, both markers of immune activation, had significantly higher expression among individuals who went on to acquire HIV.
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