The Role of Calcium in the Regulation of Apoptosis

The recognition that apoptosis is regulated by an evolutionarily conserved set of polypeptides from the nematode Caenorhabditis elegans to humans suggests that a conserved set of biochemical mechanism(s) may also be involved in the response. Early evidence suggested that the endogenous endonuclease implicated in apoptosis in most model systems is Ca2+ -dependent, and subsequent work from a number of independent laboratories suggests that alterations in cytosolic Ca2+ homeostasis are one of the conserved biochemical pathways regulating the response. Molecular targets for Ca2+ are now being identified and include signal transduction intermediates, endonuclease(s) and proteases, and the enzymes involved in the maintenance of phospholipid asymmetry in the plasma membrane. Furthermore, interesting preliminary work suggests that BCL-2 suppresses apoptosis via a mechanism that is linked to intracellular Ca2+ compartmentalization, and it appears that Ca2 + alterations in some examples of apoptosis occur as the result of changes within the mitochondria. This review will summarize what is known about the role of Ca2+ in the regulation of apoptosis and discuss how Ca2+ might interact with some of the other biochemical signals implicated in cell death

The transferome of metabolic genes explored: analysis of the horizontal transfer of enzyme encoding genes in unicellular eukaryotes

Metabolic network analysis in multiple eukaryotes identifies how horizontal and endosymbiotic gene transfer of metabolic enzyme-encoding genes leads to functional gene gain during evolution

Intrinsic subtypes and bladder cancer metastasis

AbstractRecent studies demonstrated that bladder cancers can be grouped into basal and luminal molecular subtypes that possess distinct biological and clinical characteristics. Basal bladder cancers express biomarkers characteristic of cancer stem cells and epithelial-to-mesenchymal transition (EMT). Patients with basal cancers tend have more advanced stage and metastatic disease at presentation. In preclinical models basal human orthotopic xenografts are also more metastatic than luminal xenografts are, and they metastasize via an EMT-dependent mechanism. However, preclinical and clinical data suggest that basal cancers are also more sensitive to neoadjuvant chemotherapy (NAC), such that most patients with basal cancers who are aggressively managed with NAC have excellent outcomes. Importantly, luminal bladder cancers can also progress to become invasive and metastatic, but they appear to do so via mechanisms that are much less dependent on EMT and may involve help from stromal cells, particularly cancer-associated fibroblasts (CAFs). Although patients with luminal cancers do not appear to derive much clinical benefit from NAC, the luminal tumors that are infiltrated with stromal cells appear to be sensitive to anti-PDL1 antibodies and possibly other immune checkpoint inhibitors. Therefore, neoadjuvant and/or adjuvant immunotherapy may be the most effective approach in treating patients with advanced or metastatic infiltrated luminal bladder cancers

metaSHARK: a WWW platform for interactive exploration of metabolic networks

The metaSHARK (metabolic search and reconstruction kit) web server offers users an intuitive, fully interactive way to explore the KEGG metabolic network via a WWW browser. Metabolic reconstruction information for specific organisms, produced by our automated SHARKhunt tool or from other programs or genome annotations, may be uploaded to the website and overlaid on the generic network. Additional data from gene expression experiments can also be incorporated, allowing the visualization of differential gene expression in the context of the predicted metabolic network. metaSHARK is available at

Horizontal gene transfer contributed to the evolution of extracellular surface structures

The single-cell layered ectoderm of the fresh water polyp Hydra fulfills the function of an epidermis by protecting the animals from the surrounding medium. Its outer surface is covered by a fibrous structure termed the cuticle layer, with similarity to the extracellular surface coats of mammalian epithelia. In this paper we have identified molecular components of the cuticle. We show that its outermost layer contains glycoproteins and glycosaminoglycans and we have identified chondroitin and chondroitin-6-sulfate chains. In a search for proteins that could be involved in organising this structure we found PPOD proteins and several members of a protein family containing only SWT (sweet tooth) domains. Structural analyses indicate that PPODs consist of two tandem β-trefoil domains with similarity to carbohydrate-binding sites found in lectins. Experimental evidence confirmed that PPODs can bind sulfated glycans and are secreted into the cuticle layer from granules localized under the apical surface of the ectodermal epithelial cells. PPODs are taxon-specific proteins which appear to have entered the Hydra genome by horizontal gene transfer from bacteria. Their acquisition at the time Hydra evolved from a marine ancestor may have been critical for the transition to the freshwater environment

Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer

Background Selective cyclooxygenase inhibitors may retard the progression of cancer, but they have enhanced thrombotic potential. We report on cardiovascular adverse events in patients receiving rofecoxib to reduce rates of recurrence of colorectal cancer. Methods All serious adverse events that were cardiovascular thrombotic events were reviewed in 2434 patients with stage II or III colorectal cancer participating in a randomized, placebo-controlled trial of rofecoxib, 25 mg daily, started after potentially curative tumor resection and chemotherapy or radiotherapy as indicated. The trial was terminated prematurely owing to worldwide withdrawal of rofecoxib. To examine possible persistent risks, we examined cardiovascular thrombotic events reported up to 24 months after the trial was closed. Results The median duration of active treatment was 7.4 months. The 1167 patients receiving rofecoxib and the 1160 patients receiving placebo were well matched, with a median follow-up period of 33.0 months (interquartile range, 27.6 to 40.1) and 33.4 months (27.7 to 40.4), respectively. Of the 23 confirmed cardiovascular thrombotic events, 16 occurred in the rofecoxib group during or within 14 days after the treatment period, with an estimated relative risk of 2.66 (from the Cox proportional-hazards model; 95% confidence interval [CI], 1.03 to 6.86; P = 0.04). Analysis of the Antiplatelet Trialists’ Collaboration end point (the combined incidence of death from cardiovascular, hemorrhagic, and unknown causes; of nonfatal myocardial infarction; and of nonfatal ischemic and hemorrhagic stroke) gave an unadjusted relative risk of 1.60 (95% CI, 0.57 to 4.51; P = 0.37). Fourteen more cardiovascular thrombotic events, six in the rofecoxib group, were reported within the 2 years after trial closure, with an overall unadjusted relative risk of 1.50 (95% CI, 0.76 to 2.94; P = 0.24). Four patients in the rofecoxib group and two in the placebo group died from thrombotic causes during or within 14 days after the treatment period, and during the follow-up period, one patient in the rofecoxib group and five patients in the placebo group died from cardiovascular causes. Conclusions Rofecoxib therapy was associated with an increased frequency of adverse cardiovascular events among patients with a median study treatment of 7.4 months’ duration. (Current Controlled Trials number, ISRCTN98278138.

Prostaglandin E2 drives cyclooxygenase-2 expression via cyclic AMP response element activation in human pancreatic cancer cells.

Cyclooxygenase-2 (COX-2) is constitutively expressed in most human primary carcinomas and with its synthesized product, prostaglandin E2 (PGE2), appears to play important roles in tumor invasion, angiogenesis, resistance to apoptosis and suppression of host immunity. However, the molecular mechanisms that control COX-2 expression are unclear. The purpose of this study was to clarify the mechanism of basal and PGE2-mediated COX-2 expression in the highly metastatic L3.6pl human pancreatic cancer cell line. Using RNA interference to disrupt the expression of CREB and the NF-kappaB p65 subunit, we found that both are involved in maintaining basal COX-2 expression in L3.6pl cells. We also demonstrated that PGE2 increased the cyclic AMP concentration, thereby activating protein kinase A (PKA), which in turn phosphorylated the cyclic AMP response element binding protein (CREB), leading to interaction with the cyclic AMP response element in the promoter region of the COX-2 gene. Immunocytochemical analysis confirmed that PGE2 stimulated the translocation of PKA to the nucleus and increased the immuno-reactivity of phosphorylated CREB. Pretreatment with the PKA selective inhibitor H 89 and the E-prostanoid receptor 2 inhibitor AH 6809 reduced COX-2 upregulation by PGE2. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay results further suggested a role for CREB in COX-2 transcriptional control. Understanding the pathways that control COX-2 expression may lead to a better understanding of its dysregulation in pancreatic carcinomas and facilitate the development of novel therapeutic approaches

Changes in viral load and HBsAg and HBeAg status with age in HBV chronic carriers in The Gambia

<p>Abstract</p> <p>Background</p> <p>Little is known about changes in hepatitis B viral load (HBV DNA) in relation to age in Africa. The aim of this study is to determine the natural course of HBV chronic infection, particularly in relation to sequential changes in serum HBV DNA levels and hepatitis B surface (HBsAg) antigen/hepatitis e antigen (HBeAg) status by age.</p> <p>Methods</p> <p>The study was conducted on 190 HBV chronic carriers, aged 1–19 years who were followed for 19 years. 160, 99 and 123 were traced at 5, 9 and 19 years later. All available samples were tested for HBsAg and HBeAg, whilst 170, 61, 63 and 81 were tested for HBV DNA at the baseline, and at 5, 9 and 19 years following recruitment.</p> <p>Results</p> <p>In general HBeAg which correlated with high levels of HBV DNA was lost at a much faster rate than HBsAg. 86% of the carriers who were recruited at the age of 1–4 yrs lost HBeAg by the age of 19 years compared to 30% who lost HBsAg. HBeAg negative carriers had serum HBV DNA levels of < 10⁵copies per mL, HBV DNA positivity declined from 100% in 1–4 yrs old carriers at recruitment to 62.5%,60% and 88% at 5, 9 and 19 years respectively following recruitment.</p> <p>Conclusion</p> <p>After 19 years of follow up, the majority of HBV surface antigen carriers had lost HBeAg positivity and had low levels of viral replication. However small proportions (10–20%) retained HBeAg and continue to have high levels of viral replication.</p

Modular Evolution and the Origins of Symmetry: Reconstruction of a Three-Fold Symmetric Globular Protein

SummaryThe high frequency of internal structural symmetry in common protein folds is presumed to reflect their evolutionary origins from the repetition and fusion of ancient peptide modules, but little is known about the primary sequence and physical determinants of this process. Unexpectedly, a sequence and structural analysis of symmetric subdomain modules within an abundant and ancient globular fold, the β-trefoil, reveals that modular evolution is not simply a relic of the ancient past, but is an ongoing and recurring mechanism for regenerating symmetry, having occurred independently in numerous existing β-trefoil proteins. We performed a computational reconstruction of a β-trefoil subdomain module and repeated it to form a newly three-fold symmetric globular protein, ThreeFoil. In addition to its near perfect structural identity between symmetric modules, ThreeFoil is highly soluble, performs multivalent carbohydrate binding, and has remarkably high thermal stability. These findings have far-reaching implications for understanding the evolution and design of proteins via subdomain modules

Prospectus, May 6, 1974

KAREN COLEMAN ELECTED NEW STU-GO PRES; Gallup Explains Effect Of Polls; Parkland Debate Team Ends Year At Nationals; All Races Close Despite Poor Voter Turnout; Enthusiam Abounds At IOC Spring Carnival; IE Team Winds-Up Season With Good National Showing; Parkland College Foundation Officers Selected At Meeting; Cruisin\u27 \u2774; Letter To The Editor; The Short Circuit; Let\u27s Go To The Bars; IVC New Service Officer, Menaugh; Vet\u27s Corner; Monday\u27s Coach; Cobras Win One, Lose Three In Double-Header; Parkland Athlete Randy Williams Looks Over Schools; I/M Tryouts Now For And Tennis Track, Golf; Amana Commune, A Lifestyle From A Dream; Pulitzer Prize Poet To Appear At Parkland; Library Hours During Exam Week; A Column By and For Women; National Women\u27s Music Festival; Crosswords; Student Raffle; President\u27s Report; Registration Info For Fall, 1974 Available To Students Now; Happy Birthday; Classified Ads; Parkland Players To Present Play; Recycle Paper; Wainwright Captures Audience With Real Life Situations; American Odyssey; Parkland Events; Final Exam Schedule - Spring Quarter, 1973-1974; Sangamon State Representative; Krannert Art Schedulehttps://spark.parkland.edu/prospectus_1974/1013/thumbnail.jp