Purine nucleoside phosphorylase: A new marker for free oxygen radical injury to the endothelial cell

The effect of ischemia and reperfusion on purine nucleoside phosphorylase was studied in an isolated perfused rat liver model. This enzyme is localized primarily in the cytoplasm of the endothelial and Kupffer cells; some activity is associated with the parenchymal cells. Levels of this enzyme accurately predicted the extent of ischemia and reperfusion damage to the microvascular endothelial cell of the liver. Livers from Lewis rats were subjected to 30, 45 and 60 min of warm (37° C) no flow ischemia that was followed by a standard reperfusion period lasting 45 min. Purine nucleoside phosphorylase was measured at the end of the no flow ischemia and reperfusion periods as was superoxide generation (O2‐). Bile production was monitored throughout the no flow ischemia and reperfusion periods. Control perfusions were carried out for 120 min. A significant rise in purine nucleoside phosphorylase levels as compared with controls was observed at the end of ischemia in all the three groups. The highest level, 203.5 ± 29.2 mU/ml, was observed after 60 min of ischemia. After the reperfusion period, levels of purine nucleoside phosphorylase decreased in the 30‐ and 45‐min groups 58.17 ± 9.66 mU/ml and 67.5 ± 17.1 mU/ml, respectively. These levels were equal to control perfusions. In contrast, after 60 min of ischemia, levels of purine nucleoside phosphorylase decreased early in the reperfusion period and then rose to 127.8 ± 14.8 mU/ml by the end of reperfusion (p < 0.0001). Superoxide generation at the beginning of reperfusion was higher than in controls with similar values observed at the end of 30, 45 and 60 min of ischemia. During reperfusion, production of superoxide continued. Bile production was significantly lower at the end of 30 min (0.044 ± 0.026 μl/min/gm), 45 min (0.029 ± 0.0022 μ/min/gm) and 60 min of ischemia (0.022 ± 0.008 μ/min/gm) when compared with bile production by control livers during the corresponding time (0.680 ± 0.195, 0.562 ± 0.133 and 0.480 ± 0.100 μ/min/gm respectively; p < 0.001). During reperfusion, rates of bile production were normal after 30 and 45 min of ischemia. In contrast, significantly lower rates of bile production, 0.046 ± 0.36 μ/min/gm (p < 0.001) occurred during reperfusion after 60 min of ischemia. Control livers during the same period produced 0.330 ± 0.056 μl/min/gm of bile. The results indicate that purine nucleoside phosphorylase levels may be a good index of oxidative injury to the liver in ischemia reperfusion and reliably predict the functional state of the organ after reperfusion. Copyright © 1990 American Association for the Study of Liver Disease

Crossed product orders over valuation rings II: Tamely ramified crossed product algebras

Let V be a commutative valuation domain of arbitrary K rull-dimension, with quotient field F, let K be a finite Galois extension of F with group G, and let S be the integral closure of V in K. Suppose that one has a 2-cocycle on G that takes values in the group of units of S. Then one can form the crossed product of G over S, S * G, which is a V-order in the central simple F-algebra K * G. If S * G is assumed to be a Dubrovin valuation ring of K * G, then the main result of this paper is that, given a suitable definition of tameness for central simple algebras, K * G is tamely ramified and defectless over F if and only if K is tamely ramified and defectless over F. The residue structure of S * G is also considered in the paper, as well as its behaviour upon passage to Henselization

The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1

<p>Abstract</p> <p>Background</p> <p>Heat shock protein 90 (HSP90) inhibitors have emerged as a promising class of anti-cancer drugs in both solid and hematologic malignancies. The HSP90 family includes the cytosolic HSP90 (HSP90AA1), the ER paralogue gp96 (HSP90B1) and the mitochondrial member TRAP1 (HSP90L). We evaluated the <it>in vitro </it>anti-tumor activity and mechanism of action of PU-H71, a novel purine scaffold HSP90 inhibitor in human multiple myeloma cell lines.</p> <p>Methods</p> <p>Multiple human myeloma cell lines including cells that are resistant to corticosteroids and bortezimab were treated with PU-H71, followed by analysis of cell viability, cell cycle progression and apoptosis, by flow cytometry and caspase 3 immunoblot. Induction of unfolded protein response was studied by XBP-1 s immunoblot. The role of gp96 was further assessed by small hairpin RNA knockdown of gp96 before treatment with PU-H71.</p> <p>Results</p> <p>PU-H71 has potent <it>in vitro </it>anti-myeloma activity in both drug-sensitive and drug-resistant cell lines. PU-H71 activates the unfolded protein response and induces caspase-dependent apoptosis. The stable gp96 knockdown human myeloma cell line was found to be more resistant to PU-H71 and other HSP90 inhibitors including 17-AAG and 17-DMAG, even though these cells are more sensitive to conventional anti-myeloma drugs.</p> <p>Conclusion</p> <p>We conclude that PU-H71 is a promising drug for the treatment of myeloma. Our finding further suggests that PU-H71 and the geldanamycin analogues work in part by inhibiting the endoplasmic reticulum gp96 along with the cytosolic HSP90.</p

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

A polycystic variant of a primary intracranial leptomeningeal astrocytoma: case report and literature review

<p>Abstract</p> <p>Background</p> <p>Primary leptomeningeal astrocytomas are rare intracranial tumors. These tumors are believed to originate from cellular nests which migrate by means of aberration, ultimately settling in the leptomeningeal structure. They may occur in both solitary and diffuse forms. The literature reports only fifteen cases of solitary primary intracranial leptomeningeal astrocytomas.</p> <p>Case presentation</p> <p>The authors report the case of a seventy-eight year-old woman with a polycystic variant of a solitary primary intracranial leptomeningeal astrocytoma. The first neurological signs were seizures and aphasia. CT and MRI scans demonstrated a fronto-parietal polycystic tumor adherent to the sub arachnoid space. A left fronto-temporo-parietal craniotomy revealed a tight coalescence between the tumor and the arachnoid layer which appeared to wrap the mass entirely. Removal of the deeper solid part of the tumor resulted difficult due to the presence of both a high vascularity and a tight adherence between the tumor and the ventricular wall.</p> <p>Conclusion</p> <p>A new case of a solitary primitive intracranial leptomeningeal astrocytoma of a rare polycystic variant is reported. Clinical, surgical, pathologic and therapeutic aspects of this tumor are discussed.</p

African ancestry of New World, Bemisia tabaci-whitefly species

Bemisia tabaci whitefly species are some of the world’s most devastating agricultural pests and plant-virus disease vectors. Elucidation of the phylogenetic relationships in the group is the basis for understanding their evolution, biogeography, gene-functions and development of novel control technologies. We report here the discovery of five new Sub-Saharan Africa (SSA) B. tabaci putative species, using the partial mitochondrial cytochrome oxidase 1 gene: SSA9, SSA10, SSA11, SSA12 and SSA13. Two of them, SSA10 and SSA11 clustered with the New World species and shared 84.8‒86.5% sequence identities. SSA10 and SSA11 provide new evidence for a close evolutionary link between the Old and New World species. Re-analysis of the evolutionary history of B. tabaci species group indicates that the new African species (SSA10 and SSA11) diverged from the New World clade c. 25 million years ago. The new putative species enable us to: (i) re-evaluate current models of B. tabaci evolution, (ii) recognise increased diversity within this cryptic species group and (iii) re-estimate divergence dates in evolutionary time

Carbon monoxide-Releasing Molecule-2 (CORM-2) attenuates acute hepatic ischemia reperfusion injury in rats

<p>Abstract</p> <p>Background</p> <p>Hepatic ischemia-reperfusion injury (I/Ri) is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO) by application of so-called CO-releasing molecules (CORMs). Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model.</p> <p>Methods</p> <p>Forty male Wistar rats were randomly assigned into four groups (n = 10). Sham group underwent a sham operation and received saline. I/R group underwent hepatic I/R procedure by partial clamping of portal structures to the left and median lobes with a microvascular clip for 60 minutes, yielding ~70% hepatic ischemia and subsequently received saline. CORM-2 group underwent the same procedure and received 8 mg/kg of CORM-2 at time of reperfusion. iCORM-2 group underwent the same procedure and received iCORM-2 (8 mg/kg), which does not release CO. Therapeutic effects of CORM-2 on hepatic I/Ri was assessed by measuring serum damage markers AST and ALT, liver histology score, TUNEL-scoring of apoptotic cells, NFkB-activity in nuclear liver extracts, serum levels of pro-inflammatory cytokines TNF-α and IL-6, and hepatic neutrophil infiltration.</p> <p>Results</p> <p>A single systemic infusion with CORM-2 protected the liver from I/Ri as evidenced by a reduction in serum AST/ALT levels and an improved liver histology score. Treatment with CORM-2 also up-regulated expression of the anti-apoptotic protein Bcl-2, down-regulated caspase-3 activation, and significantly reduced the levels of apoptosis after I/Ri. Furthermore, treatment with CORM-2 significantly inhibited the activity of the pro-inflammatory transcription factor NF-κB as measured in nuclear extracts of liver homogenates. Moreover, CORM-2 treatment resulted in reduced serum levels of pro-inflammatory cytokines TNF-α and IL-6 and down-regulation of the adhesion molecule ICAM-1 in the endothelial cells of liver. In line with these findings, CORM-2 treatment reduced the accumulation of neutrophils in the liver upon I/Ri. Similar treatment with an inactive variant of CORM-2 (iCORM-2) did not have any beneficial effect on the extent of liver I/Ri.</p> <p>Conclusions</p> <p>CORM-2 treatment at the time of reperfusion had several distinct beneficial effects on severity of hepatic I/Ri that may be of therapeutic value for the prevention of tissue damage as a result of I/Ri during hepatic surgery.</p