Chase over the Nile: The Social Evolution of Riverine Landscape in Urban Egypt

Throughout its history, Cairo evolved as a regional metropolis that sprawls along the banks of the Nile accumulating narratives of evolving social landscape. Overlooking the Nile reflected a privileged social position and place for the urban elite. In spatial terms, the urban bourgeoisie tend to develop living havens in enclaves that are distant from the populace’s everyday life. Ironically, exclusive settlements only attract urban growth further in their direction. This chapter offers an analytical reading of the socio-spatial structure of Cairo following the emergence and decline of a series bourgeoisie quarters along the shores of the Nile. It reports urban narratives based on archival records, documents and investigation of historical texts and travelers’ accounts. This essay argues that cities are essentially social constructs in which hierarchy and connectivity are fundamental aspects of its economic and spatial logic. Through social ambition and desire for upgrade, middle class infiltrate into bourgeoisie havens and sometimes encircle it, seeking better living condition inscribed by social mobility and connectivity to centres of wealth and power. Being both natural barrier and cohesive spine, the Nile helped Cairo to develop successive nucleuses of highly crafted urban experiences that have left their imprints on the contemporary urban scene.

Preproendothelin-1 expression in human mesangial cells: evidence for a p38 mitogen-activated protein kinase/protein kinases- C-dependent mechanism

Endothelin-1 (ET-1) has been implicated in the pathogenesis of renal inflammation. This study investigated the mechanisms underlying the synergistic upregulation of preproET-1 gene expression in human mesangial cells after co-stimulation with thrombin and tumor necrosis factor alpha (TNFalpha). Whereas thrombin induced a moderate upregulation of preproET-1 mRNA, co-stimulation with TNFalpha resulted in a strong and protracted upregulation of this mRNA species. Thrombin+TNFalpha-induced upregulation of preproET-1 expression was found to require p38 mitogen-activated protein kinase and protein kinases C, whereas activation of extracellular signal-regulated kinase, c-Jun-N-terminal kinase, or intracellular Ca(2+) release were not required. Actinomycin D chase experiments suggested that enhanced stability of preproET-1 mRNA did not account for the increase in transcript levels. PreproET-1 promoter analysis demonstrated that the 5'-flanking region of preproET-1 encompassed positive regulatory elements engaged by thrombin. Negative modulation of thrombin-induced activation exerted by the distal 5' portion of preproET-1 promoter (-4.4 kbp to 204 bp) was overcome by co-stimulation with TNFalpha, providing a possible mechanism underlying the synergistic upregulation of preproET-1 expression by these two agonists. In conclusion, human mesangial cell expression of preproET-1 may be increased potently in the presence of two common proinflammatory mediators, thereby providing a potential mechanism for ET-1 production in inflammatory renal disease.

Phase I Study Of The Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, In Combination With Temozolomide in Patients with Advanced Solid Tumors

Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy.

Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated.

Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen.

Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.

Radical 1,4-aryl transfer in arylcarboxamides leading to phthalimides, biaryls and enantiomerically enriched beta-arylethylamines

5-exo Cyclisation of vinyl-, aryl- and alkyl-radicals onto the aryl group of arylcarboxamides is followed by beta-scission of the resulting spirocyclohexadienyl radicals with ejection of a carbamoyl radical. The fate of this radical depends on the substrate but, in the cases studied, either 5-endo cyclisation or direct reduction follows to give phthalimides, biaryls or beta-arylethylamines.

A record of rapid Holocene climate change preserved in hyrax middens from southwestern Africa

The discovery of sensitive paleoenvironmental proxies contained within fossilized rock hyrax middens from the margin of the central Namib Desert, Africa, is providing unprecedented insight into the region's environmental history. High-resolution stable carbon and nitrogen isotope records spanning 0-11,700 cal (calibrated) yr B. P. indicate phases of relatively humid conditions from 8700-7500, 6900-6700, 5600-4900, and 4200-3500 cal yr B. P., with a period of marked aridity occurring from 3500 until ca. 300 cal yr B. P. Transitions between these phases appear to have occurred very rapidly, often within <200 years. Of particular importance are: (1) the observed relationship between regional aridification and the decline in Northern Hemisphere insolation across the Holocene, and (2) the significance of suborbital scale variations in climate that covary strongly with fluctuations in solar forcing. Together, these elements call for a fundamental reexamination of the role of orbital forcing on tropical African systems, and a reconsideration of what factors drive climate change in the region. The quality and resolution of these data far surpass any other evidence available from the region, and the continued development of this unique archive promises to revolutionize paleoenvironmental studies in southern Africa.

Inhibition of Secretion of Interleukin (IL)-12/IL-23 Family Cytokines by 4-Trifluoromethyl-celecoxib Is Coupled to Degradation via the Endoplasmic Reticulum Stress Protein HERP

Interleukin-12 (IL-12), p80, and IL-23 are structurally related cytokines sharing a p40 subunit. We have recently demonstrated that celecoxib and its COX-2-independent analogue 4-trifluoromethyl-celecoxib (TFM-C) inhibit secretion but not transcription of IL-12 (p35/p40) and p80 (p40/p40). This is associated with a mechanism involving altered cytokine-chaperone interaction in the endoplasmic reticulum (ER). In the present study, we found that celecoxib and TFM-C also block secretion of IL-23 (p40/p19 heterodimers). Given the putative ER-centric mode of these compounds, we performed a comprehensive RTPCR analysis of 23 ER-resident chaperones/foldases and associated co-factors. This revealed that TFM-C induced 1.5-3-fold transcriptional up-regulation of calreticulin, GRP78, GRP94, GRP170, ERp72, ERp57, ERdj4, and ERp29. However, more significantly, a 7-fold up-regulation of homocysteine-inducible ER protein (HERP) was observed. HERP is part of a high molecular mass protein complex involved in ER-associated protein degradation (ERAD). Using co-immunoprecipitation assays, we show that TFM-C induces protein interaction of p80 and IL-23 with HERP. Both HERP siRNA knockdown and HERP overexpression coupled to cycloheximide chase assays revealed that HERP is necessary for degradation of intracellularly retained p80 by TFM-C. Thus, our data suggest that targeting cytokine folding in the ER by small molecule drugs could be therapeutically exploited to alleviate in appropriate inflammation in autoimmune conditions.

Evidence for progressive Holocene aridification in southern Africa recorded in Namibian hyrax middens: Implications for African Monsoon dynamics and the

Presented here are stable nitrogen isotope data from a rock hyrax (Procavia capensis) middens from northwestern Namibia that record a series of rapid aridification events beginning at ca. 3800 cal yr BP, and which mark a progressive decrease in regional humidity across the Holocene. Strong correlations exist between this record and other terrestrial and marine archives from southern Africa, indicating that the observed pattern of climate change is regionally coherent. Combined, these data indicate hemispheric synchrony in tropical African climate change during the Holocene, with similar trends characterising the termination of the 'African Humid Period' (AHP) in both the northern and southern tropics. These findings run counter to the widely accepted model of direct low-latitude insolation forcing, which requires an antiphase relationship to exist between the hemispheres. The combined dataset highlights: 1) the importance of forcing mechanisms influencing the high northern latitudes in effecting low-latitude climate change in Africa, and 2) the potential importance of solar forcing and variations in the Earth's geomagnetic shield in determining both long-term and rapid centennial-scale climate changes, identifying a possible mechanism for the variations marking the AHP termination in both the southern and northern tropics. (C) 2010 University of Washington. Published by Elsevier Inc. All rights reserved.

Isolation of monocytes from human peripheral blood using immuno-affinity expanded-bed adsorption

A novel technique for the separation of monocytes from human peripheral blood preparations has been developed. The technique is based on the use of expanded-bed adsorption and a solid perfluorocarbon derivatized with avidin or streptavidin for the indirect positive or negative capture of cells labeled with biotinylated monoclonal antibodies. The perfluorocarbon support was prepared and characterized and the contactor design and operating conditions, that enable cells to be selectively isolated, were investigated. Experiments consisted of applying an immunolabeled pulse of 1 x 10(8) peripheral blood mononuclear cells (PBMCs), isolated by density gradient centrifugation, directly onto a refrigerated expanded bed. The major cell types remaining were T-lymphocytes, B-lymphocytes, and monocytes. Monocytes could be positively adsorbed, following labeling with anti-CD14 mAb, with a clearance of up to 89% and a depletion factor of 7.6. They could also be

A Phase I Clinical Study of Cisplatin-Incorporated Polymeric Micelles (NC-6004) in Patients with Solid Tumors

BACKGROUND: On the basis of preclinical studies of NC-6004, a cisplatin-incorporated micellar formulation, we hypothesised that NC-6004 could show lower toxicity than cisplatin and show greater anti-tumour activity in phase I study. METHODS: A total of 17 patients were recruited in a range of advanced solid tumour types. NC-6004 was administered intravenously (i.v.) every 3 weeks. The dose escalation started at 10?mg?m(-2) and was increased up to 120?mg?m(-2) according to the accelerated titration method and modified Fibonacci method. RESULTS: One dose-limiting toxicity (DLT) occurred in a patient who was given 90?mg?m(-2) of NC-6004, otherwise any significant cisplatin-related toxicity was not observed or generally mild toxicity was observed. Despite the implementation of post-hydration and pre-medication regimen, renal impairment and hypersensitivity reactions still developed at 120?mg?m(-2), which led to the conclusion that the maximum tolerated dose was 120?mg?m(-2), and the recommended dose was 90?mg?m(-2), although DLT was not defined as per protocol. Stable disease was observed in seven patients. The maximum concentration and area under the concentration-time curve of ultrafilterable platinum at 120?mg?m(-2) NC-6004 were 34-fold smaller and 8.5-fold larger, respectively, than those for cisplatin. CONCLUSION: The delayed and sustained release of cisplatin after i.v. administration contributes to the low toxicity of NC-6004.

Late glacial interhemispheric climate dynamics revealed in South African hyrax middens

Our ability to identify the timing and extent of past major climate fluctuations is central to understanding changes in the global climate system. Of the events that have occurred in recent geological time, the Younger Dryas (YD, 13-11.5 ka), an abrupt return to near-glacial conditions during the last glacial-interglacial transition (ca. 18-11.5 ka), is one of the most widely reported. While this event is apparent throughout the Northern Hemisphere (Peteet, 1995), evidence for its occurrence in the Southern Hemisphere remains equivocal due to a lack of well-dated terrestrial records. Here we report high-resolution stable carbon and nitrogen isotope records obtained from a rock hyrax midden, revealing the first unequivocal terrestrial manifestation of the YD from the southern African subtropics. These results provide key evidence for the relative influence of the YD, and suggest that a subtropical-temperate transition zone existed along the oceanic Subtropical Front (similar to 41 degrees S) across the Southern Hemisphere, with the Northern Hemisphere exerting a strong influence on all but the higher latitudes of the Southern Hemisphere after the Heinrich Stadial 1 (15 ka).

Patient selection for oncology phase I trials: a multi-institutional study of prognostic factors.

PURPOSE The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials. PATIENTS AND METHODS Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis. Results The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical tumor growth rate, lymphocytes, and WBC. Two different models of prognostic scores for 90-day mortality were generated by using these factors, including or excluding PS; both achieved specificities of more than 85% and sensitivities of approximately 50% when using a score cutoff of 5 or higher. These models were not superior to the previously published Royal Marsden Hospital score in their ability to predict 90-day mortality. CONCLUSION Patient selection using any of these prognostic scores will reduce non-drug-related 90-day mortality among patients enrolled in phase I trials by 50%. However, this can be achieved only by an overall reduction in recruitment to phase I studies of 20%, more than half of whom would in fact have survived beyond 90 days.

Rock hyrax middens: A palaeoenvironmental archive for southern African drylands

Like many of the world's subtropical regions, southern Africa is highly sensitive to changes in the earth's climate system, but a dearth of reliable palaeoenvironmental records means that relatively little is known about how regional environments have been affected over centennial to multi-millennial timescales. To a large extent this sensitivity is a function of the position of these regions at the interface between temperate and tropical circulation systems. The resulting seasonality and irregularity of rainfall have limited the development of suitable archives, such as lakes and wetlands, for the preservation of palaeoenvironmental proxies.

This paper reviews and evaluates the value of rock hyrax middens as novel palaeoenvironmental archives in southern Africa. Considered are (1) the contemporary taxonomy, distribution and ecology of hyraxes, (2) the mechanisms of hyrax midden development, their physical and chemical structure, rates of accumulation and age; and (3) the palaeoenvironmental proxies preserved within hyrax middens, including fossil pollen, stable isotopes and biomarkers. The interpretive constraints and opportunities offered by these various midden characteristics are assessed with a view to demonstrating the potential of these deposits, widespread as they are through arid and semi-arid southern Africa, in providing a more detailed and chronologically resolved view of late Quaternary palaeoenvironments across the subcontinent. (C) 2012 Elsevier Ltd. All rights reserved.

Clinicopathological features of homologous recombination-deficient epithelial ovarian cancers: Sensitivity to PARP inhibitors, platinum, and survival

Up to 50% of epithelial ovarian cancers (EOC) display defects in the homologous recombination (HR) pathway. We sought to determine the ramifications of the homologous recombination-deficient (HRD) status on the clinicopathologic features, chemotherapy response, and survival outcomes of patients with EOCs. HR status was determined in primary cultures from ascitic fluid in 50 chemotherapy-naïve patients by a functional RAD51 immunofluorescence assay and correlated with in vitro sensitivity to the PARP inhibitor (PARPi), rucaparib. All patients went on to receive platinum-based chemotherapy; platinum sensitivity, tumor progression, and overall survival were compared prospectively in HR-competent versus HRD patients. Compared with HR-competent patients, the HRD group was predominantly serous with a higher median CA125 at presentation. HRD was associated with higher ex vivo PARPi sensitivity and clinical platinum sensitivity. Median follow-up duration was 14 months; patients in the HRD group had lower tumor progression rates at 6 months, lower overall/disease-specific death rates at 12 months, and higher median survival. We therefore suggest that HRD as predicted by a functional RAD51 assay correlates with in vitro PARPi sensitivity, clinical platinum sensitivity, and improved survival outcome.