Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability

Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (MSI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted.     

Interleukin-8 and RANTES inhibit basophil histamine release induced with monocyte chemotactic and activating factor/monocyte chemoattractant peptide-1 and histamine releasing factor.

The objective of this study was to investigate the effect of interleukin-8 (IL-8) and RANTES on basophil histamine release induced with monocyte chemoattractant peptide-1 (MCP-1) and crude histamine releasing factor (HRF). IL-8 induced low levels of histamine release (8.5 +/- 0.5%) from basophils obtained from only six of 20 donors at high concentrations (10(-6) M). RANTES induced histamine release (16 +/- 2%) from basophils of four of 15 donors at 10(-7) M concentration. However, both IL-8 and RANTES inhibited MCP-1 and HRF-induced histamine release from basophils dose-dependently at concentrations of 10(-9) to 10(-7) M. Basophils from all donors showed a significant inhibitory response (greater than 15%). The maximal inhibition of MCP-1 and HRF by IL-8 was 28 +/- 4% and 48 +/- 8%, respectively. The maximal inhibition of MCP-1 and HRF by RANTES was 26 +/- 4% and 43 +/- 6%, respectively. Peripheral blood mononuclear cell-derived HRF was purified into three distinct peaks by reverse-phase high performance liquid chromatography. Peak I contained MCP-1 as judged by binding to an immunoaffinity column that was prepared with anti-MCP-1 antibody. IL-8 inhibited histamine release induced with all three peaks of HRF. The inhibition of histamine release by IL-8 was significantly higher in normal subjects than in allergic patients (59 +/- 9% versus 31 +/- 7%, P less than 0.05). Both IL-8 and RANTES inhibited cytokine-induced histamine release only and did not affect histamine release by anti-IgE, FMLP, and C5a.(ABSTRACT TRUNCATED AT 250 WORDS)     

Innate immune responses in children and adults with Shigellosis

An array of pro- and anti-inflammatory mediators of the innate immune system was analyzed in stool, urine, and rectal mucosa samples from adults and children with shigellosis to better understand their role in recovery from and in the immunopathogenesis of the disease. Increased concentrations of lactoferrin (Lf), myeloperoxidase (MPO), prostaglandin E(2), and leukotriene B(4) (LTB(4)) in stool during acute shigellosis in both children and adults indicated that activated cells of the innate defense system at the mucosal site were secreting the mediators. Increased concentration of MPO and 8-iso-prostaglandin F(2alpha) and lower levels of superoxide dismutase (SOD) activity in stool during acute Shigella infection suggested increased formation of reactive oxygen species, free radical-catalyzed peroxidation of membrane lipids, and decreased scavenging of the reactive oxygen radicals. In children, lower expression of SOD in tissue with severe inflammation and lower levels of SOD activity in stool for longer periods compared to adults may further worsen the tissue damage and predispose the children to a lowered defense. Both adult and pediatric patients had significantly higher expression of inducible nitric oxide synthase (iNOS) in the rectum with severe inflammation, compared to that seen with mild inflammation, accompanied by persistently up-regulated iNOS mRNA, reflecting increased production of nitric oxide at the local site. However, in contrast to adults, reduced urinary nitrate levels in pediatric patients during acute shigellosis suggested lower production of nitric oxide in the renal compartment. Persistent production of Lf in pediatric patients may contribute to chronic inflammation in the rectum. In addition, increased production of proinflammatory mediators in the rectum of patients with severe histology suggested contribution of these molecules to the immunopathogenesis of severe colitis caused by shigellae.     

Epidemiology and risk factors of asthma-chronic obstructive pulmonary disease overlap in low- and middle-income countries

1. Download high-res image (220KB)
2. Download full-size image

     

The impact of duration versus extent of TCR occupancy on T cell activation: a revision of the kinetic proofreading model

The widely accepted kinetic proofreading theory proposes that rapid TCR dissociation from a peptide/MHC ligand allows for stimulation of early but not late T cell activation events, explaining why low-affinity TCR ligands are poor agonists. We identified a low-affinity TCR ligand which stimulated late T cell responses but, contrary to predictions from kinetic proofreading, inefficiently induced early activation events. Furthermore, responses induced by this ligand were kinetically delayed compared to its high-affinity counterpart. Using peptide/MHC tetramers, we showed that activation characteristics could be dissociated from TCR occupancy by the peptide/MHC ligands. Our data argue that T cell responses are triggered by a cumulative signal which is reached at different time points for different TCR ligands.     

Xenogeneic patch closure of the small intestine: a novel approach to fistula management

Previous work from our laboratory demonstrated the feasibility of utilizing placental-derived collagen tissue matrix (CTM) as a bowel wall substitute. We reasoned that this technique would also be suitable in managing intestinal fistulae. To test this hypothesis, we created a chronic cecal fistula in rats and randomly managed some with primary repair and others with CTM replacement. Leak rates, mortality, bursting pressures and histologic scores were similar, suggesting that a chronic fistula can be successfully managed with either a CTM or primary repair.     

Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey

BACKGROUND: The treatment of patients with asymptomatic primary hyperparathyroidism remains controversial despite a National Institutes of Health consensus statement. This statement also recommended a randomized clinical trial because none exists to address this issue. METHODS: Informed consent was obtained from 53 asymptomatic patients with confirmed asymptomatic primary hyperparathyroidism who participated in this randomized trial of parathyroidectomy versus observation. Patients completed the SF-36 Health Survey, an instrument that measures wellness, every 6 months for 2 years. Average annual changes were compared. RESULTS: Fifty-three patients (42 female, 11 male) with asymptomatic, mild (serum calcium level, 10.1-11.5 mg/dL) asymptomatic primary hyperparathyroidism who agreed to participate were randomized into either a surgical group or an observation group. The mean calcium level was 10.31 mg/dL. The only demographic difference between groups was age, with the operative group being older (66.7 vs 62.6 years; P <.03). The scores on 2 of the 9 domains of the SF-36 were significantly different (P <.007 and <.012, respectively); both favored the operative group. CONCLUSIONS: Improved function is seen after parathyroidectomy when compared with patients who did not undergo operation. This study supports surgical management of mild primary hyperparathyroidism at the time of diagnosis because many patients have reversible nonclassic symptoms of the disease.     

Stacking effects in van der Waals heterostructures of blueP and Janus XYO (X = Ti,Zr, Hf: Y = S,Se) monolayers

Using first-principles calculations, the geometry, electronic structure, optical and photocatalytic performance of blueP and XYO (X = Ti, Zr, Hf; Y = S, Se) monolayers and their corresponding van der Waal heterostructures in three possible stacking patterns, are investigated. BlueP and XYO (X = Ti, Zr, Hf; Y = S, Se) monolayers are indirect bandgap semiconductors. A tensile strain of 8(10)% leads to TiSeO(ZrSeO) monolayers transitioning to a direct bandgap of 1.30(1.61) eV. The calculated binding energy and AIMD simulation show that unstrained(strained) blueP and XYO (X = Ti, Zr, Hf; Y = S, Se) monolayers and their heterostructures are thermodynamically stable. Similar to the corresponding monolayers, blueP-XYO (X = Ti, Zr, Hf: Y = S, Se) vdW heterostructures in three possible stacking patterns are indirect bandgap semiconductors with staggered band alignment, except blueP-TiSeO vdW heterostructure, which signifies straddling band alignment. Absorption spectra show that optical transitions are dominated by excitons for blueP and XYO (X = Ti, Zr, Hf; Y = S, Se) monolayers and the corresponding vdW heterostructures. Both E_VB and E_CB in TiSO, ZrSO, ZrSeO and HfSO monolayers achieve energetically favorable positions, and therefore, are suitable for water splitting at pH = 0, while TiSeO and HfSeO monolayers showed good response for reduction and fail to oxidise water. All studied vdW heterostructures also show good response to any produced O₂, while specific stacking reduces H⁺ to H₂.

Using first-principles calculations, the geometry, electronic structure, optical and photocatalytic performance of blueP and XYO (X = Ti, Zr, Hf; Y = S, Se) monolayers and their corresponding van der Waal heterostructures in three possible stacking patterns, are investigated.