Cancer and Radiation Therapy: Current Advances and Future Directions

In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. However with its increasing incidence, the clinical management of cancer continues to be a challenge for the 21st century. Treatment modalities comprise of radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Radiation therapy remains an important component of cancer treatment with approximately 50% of all cancer patients receiving radiation therapy during their course of illness; it contributes towards 40% of curative treatment for cancer. The main goal of radiation therapy is to deprive cancer cells of their multiplication (cell division) potential. Celebrating a century of advances since Marie Curie won her second Nobel Prize for her research into radium, 2011 has been designated the Year of Radiation therapy in the UK. Over the last 100 years, ongoing advances in the techniques of radiation treatment and progress made in understanding the biology of cancer cell responses to radiation will endeavor to increase the survival and reduce treatment side effects for cancer patients. In this review, principles, application and advances in radiation therapy with their biological end points are discussed

Intrastrain and interstrain genetic variation within a paralogous gene family in Chlamydia pneumoniae

BACKGROUND: Chlamydia pneumoniae causes human respiratory diseases and has recently been associated with atherosclerosis. Analysis of the three recently published C. pneumoniae genomes has led to the identification of a new gene family (the Cpn 1054 family) that consists of 11 predicted genes and gene fragments. Each member encodes a polypeptide with a hydrophobic domain characteristic of proteins localized to the inclusion membrane. RESULTS: Comparative analysis of this gene family within the published genome sequences provided evidence that multiple levels of genetic variation are evident within this single collection of paralogous genes. Frameshift mutations are found that result in both truncated gene products and pseudogenes that vary among isolates. Several genes in this family contain polycytosine (polyC) tracts either upstream or within the terminal 5' end of the predicted coding sequence. The length of the polyC stretch varies between paralogous genes and within single genes in the three genomes. Sequence analysis of genomic DNA from a collection of 12 C. pneumoniae clinical isolates was used to determine the extent of the variation in the Cpn 1054 gene family. CONCLUSIONS: These studies demonstrate that sequence variability is present both among strains and within strains at several of the loci. In particular, changes in the length of the polyC tract associated with the different Cpn 1054 gene family members are common within each tested C. pneumoniae isolate. The variability identified within this newly described gene family may modulate either phase or antigenic variation and subsequent physiologic diversity within a C. pneumoniae population

Amphiphysin IIm Is Required for Survival of Chlamydia pneumoniae in Macrophages

Macrophages play a critical role in both innate and acquired immunity because of their unique ability to internalize, kill, and degrade bacterial pathogens through the process of phagocytosis. The adaptor protein, amphiphysin IIm, participates in phagocytosis and is transiently associated with early phagosomes. Certain pathogens, including Chlamydia pneumoniae, have evolved mechanisms to subvert macrophage phagosome maturation and, thus, are able to survive within these cells. We report here that, although amphiphysin IIm is usually only transiently associated with the phagosome, it is indefinitely retained on vacuoles containing C. pneumoniae. Under these wild-type conditions, C. pneumoniae do not elicit significant nitric oxide (NO) production and are not killed. Abrogation of amphiphysin IIm function results in C. pneumoniae–induced NO production and in the sterilization of the vacuole. The data suggest that C. pneumoniae retains amphiphysin IIm on the vacuole to survive within the macrophage

Different Renal Function Equations and Dosing of Direct Oral Anticoagulants in Atrial Fibrillation

BACKGROUND: Randomized trials of direct oral anticoagulants (DOACs) adopted the Cockcroft-Gault (CG) formula to calculate estimated glomerular filtration rate (eGFR) to determine the dosages of DOACs. OBJECTIVES: The authors aimed to investigate the agreements/disagreements of eGFRs calculated using different equations (CG, Modified Diet in Renal Disease [MDRD], and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formulas), and their impacts on the dosages of DOACs and clinical outcomes. METHODS: Medical data from a multicenter health care provider in Taiwan including 39,239 patients with atrial fibrillation were used. Among these patients, there were 11,185 and 2,323 patients treated with DOACs and warfarin, respectively. RESULTS: At the cutoff values of eGFR of 50 mL/min, the agreements were 78% between MDRD and CG and 81% between CKD-EPI and CG. The disagreements among the different equations were largely due to overestimations, especially for patients aged >75 years and with a body weight of <50 kg (58.8% for MDRD and 50.9% for CKD-EPI). Among patients receiving DOACs whose dosages were defined as “on label” based on MDRD or CKD-EPI, only those whose dosages were “truly on label” based on CG were associated with a lower risk of major bleeding (adjusted HR: 0.34; 95% CI: 0.26-0.45) compared to warfarin. CONCLUSIONS: The adoptions of MDRD or CKD-EPI rather than CG would result in inappropriate dosing of DOACs (mainly overdosing), which would attenuate the advantages of DOACs compared to warfarin. The CG equation should be used as the gold standard to calculate eGFRs and guide the DOAC dosages

LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast cancer

Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We show here that LARG, from 11q23, has functional characteristics of a tumor suppressor. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, utilizing both loss of heterozygosity (LOH) analysis and microarray comparative genomic hybridization (CGH). LARG (also called ARHGEF12), identified from the analyzed region, was underexpressed in 34% of primary breast carcinomas and 80% of breast cancer cell lines including the MCF-7 line. Multiplex ligation-dependent probe amplification on 30 primary breast cancers and six breast cancer cell lines showed that LARG had the highest frequency of deletion compared to the BCSC-1 and TSLC1 genes, two known candidate tumor suppressor genes from 11q. In vitro analysis of breast cancer cell lines that underexpress LARG showed that LARG could be reactivated by trichostatin A, a histone deacetylase inhibitor, but not by 5-Aza-2{prime}-deoxycytidine, a demethylating agent. Bisulfite sequencing and quantitative high-throughput analysis of DNA methylation confirmed the lack of CpG island methylation in LARG in breast cancer. Restoration of LARG expression in MCF-7 cells by stable transfection resulted in reduced proliferation and colony formation, suggesting that LARG has functional characteristics of a tumor suppressor gene

Predictors of survival for younger patients less than 50 years of age with non-small cell lung cancer (NSCLC): A California Cancer Registry analysis

BackgroundNon-small cell lung cancer (NSCLC) is uncommonly diagnosed in patients younger than 50 years of age. We analyzed the California Cancer Registry (CCR) to describe epidemiologic characteristics and outcomes in this patient subset and to identify factors prognostic for cause-specific survival (CSS).MethodsPatients diagnosed with NSCLC between 1/1/98 through 12/31/09 and reported to the (CCR) as of October 2011 were included. The primary outcome measure was CSS. Cox regression models were used to evaluate predictors of CSS in young patients with NSCLC, adjusted for potential confounders. Interaction analysis was performed between age groups (&lt;50 vs. ≥50) and specific demographic and tumor covariates.ResultsWe identified 132,671 lung cancer cases, of which 114,451 (86.3%) had NSCLC. Of these, 6389 (5.6%) were&lt;50 years of age (median, 46 years). The most common histology was adenocarcinoma (3697, 57.9%). Most patients had stage III (1522, 23.8%) or IV (3655, 57.2%) disease. Fewer young patients were diagnosed in recent years (n, % of total NSCLC population of that era): 1998-2001 (2355, 6.0), 2002-2005 (2182, 5.7), and 2006-2009 (1852, 5.0), P&lt;0.001. Multivariate analysis showed that age &lt;50 years was an independent predictor of improved CSS (HR 0.827, P&lt;0.001). Significant predictors of better CSS in patients &lt;50 years included female sex, Asian or Hispanic ethnicity, lower stage, later year of diagnosis, and higher socioeconomic status, among others. Adenocarcinoma histology was not associated with improved CSS in this patient subset (HR 0.987, P=0.78). Interaction analysis revealed that Hispanic race and bronchioloalveolar histology had differential CSS outcomes dependent on age group.ConclusionsThis large registry study found that age &lt;50 years is an independent predictor of improved CSS. Variables prognostic for CSS differed somewhat from those in older patients

Galectin-3 contributes to pathogenesis of IgA nephropathy.

IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous "grouped" ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease

Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c

Cortico-basal ganglia circuits are critical for speech and language and are implicated in autism spectrum disorder, in which language function can be severely affected. We demonstrate that in the mouse striatum, the gene Foxp2 negatively interacts with the synapse suppressor gene Mef2c. We present causal evidence that Mef2c inhibition by Foxp2 in neonatal mouse striatum controls synaptogenesis of corticostriatal inputs and vocalization in neonates. Mef2c suppresses corticostriatal synapse formation and striatal spinogenesis, but can itself be repressed by Foxp2 through direct DNA binding. Foxp2 deletion de-represses Mef2c, and both intrastriatal and global decrease of Mef2c rescue vocalization and striatal spinogenesis defects of Foxp2-deletion mutants. These findings suggest that Foxp2-Mef2C signaling is critical to corticostriatal circuit formation. If found in humans, such signaling defects could contribute to a range of neurologic and neuropsychiatric disorders.National Institutes of Health (U.S.) (Grant R37 HD028341)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Award R37 HD028341

Phosphorylation of Nicastrin by SGK1 Leads to Its Degradation through Lysosomal and Proteasomal Pathways

The gamma-secretase complex is involved in the intramembranous proteolysis of a variety of substrates, including the amyloid precursor protein and the Notch receptor. Nicastrin (NCT) is an essential component of the gamma-secretase complex and functions as a receptor for gamma-secretase substrates. In this study, we determined that serum- and glucocorticoid-induced protein kinase 1 (SGK1) markedly reduced the protein stability of NCT. The SGK1 kinase activity was decisive for NCT degradation and endogenous SGK1 inhibited gamma-secretase activity. SGK1 downregulates NCT protein levels via proteasomal and lysosomal pathways. Furthermore, SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation. Collectively, our findings indicate that SGK1 is a gamma-secretase regulator presumably effective through phosphorylation and degradation of NCT