bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase I Dose-Escalating and Pharmacokinetic Study of Docetaxel and Vinorelbine as First-Line Chemotherapy for Metastatic Breast Cancer
Authors: Delord Jean Pierre , Dalenc Florence , Pinguet Frédéric , Nguyen Laurent , Lochon Isabelle , Poublanc Muriel , Chatelut Etienne , Roche Henri
Published: January 2008

Docetaxel and vinorelbine are both active drugs as single agents in the treatment of metastatic breast cancer. We performed a phase I dose-escalating and pharmacokinetic study to assess the safety profile of a new combination regimen and the pharmacokinetic interaction of vinorelbine and docetaxel. Patients with metastatic breast cancer received first-line treatment with both drugs on days 1–5. Treatment was restarted on day 21 of each cycle. We had to stop the escalation at the first step of the study (vinorelbine 20 mg/m2 followed by docetaxel 30 mg/m2 on days 1 and 5) because of hematological toxicity. In 4 additional patients who received G-CSF supplementation, no major leukopenia occurred, suggesting that the toxicity profile of this combination is very homogenous and focused on neutrophils. We found no pharmacokinetic interaction between the two drugs. These results suggest that a pharmacodynamic interaction was the cause of the hematological toxicity and that sequential regimens should be preferably further explored.
Is Whole-Brain Radiotherapy Effective and Safe in Elderly Patients with Brain Metastases?
Authors: Nieder Carsten , Thamm Reinhard , Astner Sabrina T. , Geinitz Hans , Molls Michael
Published: January 2008

Objective: The outcome of whole-brain radiotherapy in elderly patients with brain metastases is not well documented. As the number of such patients is expected to increase, we evaluated our results. Methods: Seventeen patients aged 75–82 years were identified for this retrospective analysis. The majority received 30 Gy in 10 fractions plus steroids (without other local or systemic measures). The median Karnofsky performance score (KPS) was 70. Results: Symptomatic improvement was observed in 53%. Median survival of the responding patients was 4.5 months. However, median survival of the non-responding patients was 1.4 months only. All patients that survived for more than 4 months had a KPS ≧70 and metachronous brain metastases. None of the patients with KPS <70 survived for more than 2.2 months. None of the patients developed severe acute toxicity. One patient developed severe late neurotoxicity. Conclusions: Most elderly patients with brain metastases have an unfavourable prognosis. However, as in other populations, assessment of KPS and few other factors might guide the choice of treatment. Radiation therapy might lead to symptomatic responses in approximately half of the patients, but long-term survivors appear at risk of neurotoxicity. As promising results were published from a retrospective radiosurgery series, prospective trials appear warranted.
Dose-Finding Phase I and Pharmacokinetic Study of Capecitabine (Xeloda) in Combination with Epirubicin and Cyclophosphamide (CEX) in Patients with Inoperable or Metastatic Breast Cancer
Authors: Saji Shigehira , Toi Masakazu , Morita Satoshi , Iwata Hiroji , Ito Yoshinori , Ohno Shinji , Kobayashi Tadashi , Hozumi Yasuo , Sakamoto Junichi
Published: January 2008

Objective: The present study aimed to identify the recommended dose (RD) of capecitabine, epirubicin and cyclophosphamide (CEX) combination treatment for inoperable or metastatic breast cancer and to assess response rate, tolerability and pharmacokinetics in Japanese patients. Methods: Patients received 3-week cycles of fixed-dose intravenous cyclophosphamide (600 mg/m2, day 1), intravenous epirubicin (75–100 mg/m2, day 1) and oral capecitabine (628–900 mg/m2 twice daily, days 1–14). Dose escalation/deescalation decisions for consecutive cohorts were made using the continual reassessment method (CRM). RD was defined as dose level closest to that causing dose-limiting toxicity (DLT) in 33% of patients. Results: Among the 17 patients enrolled, 3 experienced DLT (hand-foot syndrome, anorexia, mucositis; all grade 3) and 3 (18%) febrile neutropenia. Based on CRM calculation, mean DLT occurrence probabilities (90% confidence intervals in parentheses) for levels 2, 3 and 4 were 21% (8–42%), 35% (17–56%) and 56% (38–71%), respectively. Level 3 was thus chosen as the RD. Combination treatment did not affect pharmacokinetic parameters of capecitabine, epirubicin or their metabolites. Objective responses were achieved by 7 patients (41%), including partial responses in 4 of 6 patients (67%) receiving the RD. Conclusion: CEX represents a well-tolerated regimen, and RD for Japanese patients was determined to be capecitabine 900 mg/m2 twice daily in combination with epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 using the CRM.
Expression of PINCH Protein in Gliomas and Its Clinicopathological Significance
Authors: Wang Ming-Wei , Gu Ping , Zhang Zhi-Yong , Zhu Zhen-Long , Li Yan-Min , Zhao Hui-Xin , Sun Xiao-Feng
Published: January 2008

Objectives: Particularly interesting new cysteine-histidine-rich protein (PINCH), as a LIM domain adapter protein, functions in the integrin and growth factor signal transduction pathway, and is upregulated in tumor-associated stroma in several types of cancers. However, no study of PINCH has been carried out in gliomas, therefore we examined PINCH expression in gliomas and its clinicopathological significance. Methods: PINCH expression was immunohistochemically examined in 82 gliomas, along with 26 matched adjacent normal brain samples and 10 recurred gliomas. Results: PINCH was strongly expressed in the primary (35%, p = 0.0001) or recurred tumors (40%, p = 0.004) and weak in normal brain tissue. PINCH expression was significantly increased in high-grade gliomas (55 vs. 24%, high- vs. low-grade gliomas, p = 0.004). There was no association of PINCH expression with gender, age, tumor number, size, histological type and tumor location (p > 0.05). Conclusions: PINCH expression may be involved in glioma development and differentiation.
Ischemia/Reperfusion Induce Renal Tubule Apoptosis by Inositol 1,4,5-Trisphosphate Receptor and L-Type Ca2+ Channel Opening
Authors: Wu Di , Chen Xiangmei , Ding Rui , Qiao Xi , Shi Suozhu , Xie Yuansheng , Hong Quan , Feng Zhe
Published: January 2008

Recent studies suggest that besides the L-type calcium channel, two calcium channels on the endoplasmic reticulum (ER), the inositol 1,4,5-trisphosphate receptor (InsP3R) and ryanodine receptor (RyR), may play a role in the apoptotic process of renal tubular cells induced by ischemia/reperfusion (I/R) injury. We used antimycin A to induce cell I/R injury in vitro and found an elevation of the cytosolic calcium concentration and consequently apoptosis. Blocking either the L-type calcium channel with nicardipine or the InsP3R with TMB-8 can inhibit cytochrome c release, activate caspase 3 and decrease the apoptotic cell number. However, blocking the RyR with dantrolene had no effect. We further found that Ca2+ influx through the L-type channel is needed for the opening of the InsP3R which activates a cascade of Ca2+ release from the ER store. To test these blockers in vivo, in a rat renal I/R model, pretreatment with nicardipine and TMB-8, but not dantrolene, can protect renal function. Taken together, our results suggest that after I/R injury, Ca2+ influx through the L-type calcium channel triggers the Ca2+ release from the InsP3R and finally induces apoptosis. The InsP3R could be a new target for the treatment of renal I/R injury.
Epigenetic and Genetic Alterations of the EDNRB Gene in Nasopharyngeal Carcinoma
Authors: Zhou Liang , Feng Xiangling , Shan Wenjiao , Zhou Wen , Liu Weidong , Wang Lei , Zhu Bin , Yi Hongmei , Yao Kaitai , Ren Caiping
Published: January 2008

Background: Loss of heterozygosity (LOH) at 13q22 is a common event in nasopharyngeal carcinoma (NPC). EDNRB gene located at 13q22 has been demonstrated to be hypermethylated in some kinds of tumors. In the current study, we focused on the epigenetic and genetic alterations of EDNRB in NPC. Methods: The mRNA expression of EDNRB was detected by semiquantitative RT-PCR and real-time quantitative PCR in 49 NPC and 12 chronic nasopharyngitis biopsies. The methylation and LOH status of EDNRB were examined by methylation-specific polymerase chain reaction, microsatellite PCR and sequencing. We also examined the mRNA expression of EDNRB in four NPC cell lines after 5-aza-2′-deoxycytidine treatment. Results:EDNRB was downregulated in primary NPC tissues and NPC cell lines, and a relatively higher methylation level of EDNRB was found in NPC biopsies (84%) compared to that in chronic nasopharyngitis biopsies (42%). Treatment of NPC cell lines with 5-aza-2′-deoxycytidine activated EDNRB expression. LOH of EDNRB gene was also found at two microsatellite sites with ratios of 6.25 and 16.67% in NPC. Conclusion: Our results suggested that EDNRB expression may be affected by aberrant promoter methylation and gene deletion and may play a role in the development of NPC.
Expression of Platelet-Activating Factor Receptor: A Novel Prognosticator in Patients with Hepatocellular Carcinoma following Hepatectomy
Authors: Kitagawa Dai , Taketomi Akinobu , Kayashima Hiroto , Kuroda Yosuke , Itoh Shinji , Yamashita Yo-ichi , Maehara Yoshihiko
Published: January 2008

Backgrounds and Aims: Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a phospholipid mediator and acts by binding to a specific G-protein-coupled receptor. Though various functions of PAF have been associated with tumor activities, the mechanism of PAF-PAF receptor signaling in the development of hepatocellular carcinoma (HCC) remains to be elucidated. Methods: In this study, PAF receptor (PAFR) expression was examined in hepatoma cell lines (Huh7, PLC/PRF/5 and HepG2) and clinical samples of HCC (n = 60) using immunohistochemical staining. The relationships between the expression of PAFR and clinicopathological parameters were also investigated. Results: An immunohistochemical study showed that 24 HCC cases (40%) showed a lower PAFR expression than non-cancerous hepatocytes. The patients were divided into two groups according to the degree of PAFR expression: the high (n = 36) and low PAFR groups (n = 24). Lower expression of PAFR was correlated with poor differentiation, portal vein invasion, high levels of serum α-fetoprotein and poor prognosis after surgery. In the low PAFR group, multiple recurrences and distant metastases were more often observed than in the high PAFR group. Multivariate analysis revealed that lower PAFR expression in addition to portal vein invasion is significantly related to survival after hepatectomy. Conclusions: A lower expression of PAFR correlated with poor differentiation and a poor prognosis, and may therefore be used as a prognostic marker in HCC after hepatectomy.
Relationship between Clinical Response to Therapy and Health-Related Quality of Life Outcomes in Patients with Moderate to Severe Plaque Psoriasis
Authors: Revicki Dennis A. , Willian Mary K. , Menter Alan , Saurat Jean-Hilaire , Harnam Neesha , Kaul Martin
Published: January 2008

Background: Health-related quality of life (HRQOL) outcomes are associated with clinical response to treatment in psoriasis. However, the association between HRQOL outcomes and more substantial degrees of Psoriasis Area and Severity Index (PASI) response and physician and patient global ratings remains ill defined. Objective: This study examined the relationship between achieving a 75% or ≧90% improvement in PASI and HRQOL outcome measures. Methods: Secondary analyses were completed using data for 1,469 patients with moderate to severe plaque psoriasis from two adalimumab clinical trials. HRQOL was measured via the Dermatology Life Quality Index (DLQI) and the Short Form 36 (SF 36) Health Survey. Clinical response was assessed by the PASI, physician’s global assessment and patient’s global assessment status scores. Clinical response was categorized into 6 groups based on PASI response: <25% (n = 332); 25 to <50% (n = 137); 50 to <75% (n = 170); 75 to <90% (n = 288); 90 to <100% (n = 255), and 100% (n = 192). Analysis of covariance models compared baseline measures and 16-week changes in HRQOL scores. Results: Statistically significant differences were observed between PASI response groups in DLQI total scores and in SF 36 summary and scale scores (p < 0.0001). The PASI 100 and PASI 90 to <100 groups demonstrated a >10-point decrease in DLQI total scores. Moreover, these changes were statistically significantly greater than those observed for the PASI 75 to <90 group (p < 0.001) and the other PASI response groups (p < 0.001). For the SF 36, the greatest changes were observed in the PASI 75 to <90, PASI 90 to <100 and PASI 100 groups, which all had improvements of >4 points in the Mental Component and Physical Component Summary (MCS and PCS) scores. Statistically significantly greater differences in DLQI total and SF 36 summary and scale scores were also observed between patient’s global assessment categories (p < 0.0001) and between physician’s global assessment categories (p < 0.0001). Conclusion: Improvement in PASI response of >75% corresponded to improvements in HRQOL outcome measures for patients with moderate to severe psoriasis. PASI 90 or 100 responders had greater improvements in DLQI total score than PASI 75 responders.
Alternative Splicing of Vasohibin-1 Generates an Inhibitor of Endothelial Cell Proliferation, Migration, and Capillary Tube Formation
Authors: Kern Johann , Bauer Monika , Rychli Kathrin , Wojta Johann , Ritsch Andreas , Gastl Günther , Gunsilius Eberhard , Untergasser Gerold
Published: January 2008

Objective—

In this study, the alternative splicing product of vasohibin 1 (VASH1B) was analyzed in direct comparison to the major isoform (VASH1A) for antiangiogenic effects on endothelial colony forming cells (ECFCs) from peripheral blood and on human umbilical vein endothelial cells (HUVECs).

Methods and Results—

Expression studies in primary human endothelial cells revealed that both vasohibin proteins, hVASH1A and hVASH1B, localized in the nucleus and cytoplasm. Adenoviruses carrying the cDNA for VASH1A/B and purified recombinant proteins were used to study the function of both molecules in ECFCs and HUVECs. Recombinant VASH1A protein did not inhibit cell proliferation, tube formation, or vessel growth in vivo in the chick chorioallantoic membrane (CAM) assay, but promoted endothelial cell migration in vitro. The VASH1B protein had an inhibitory effect on cell proliferation, migration, tube formation, and inhibited blood vessel formation in the CAM assay. Adenoviral overexpression of VASH1B, but not of VASH1A, resulted in inhibition of endothelial cell growth, migration, and capillary formation. Interestingly, overexpression of VASH1A and B induced apoptosis in proliferating human fibroblasts, but did not affect cell growth of keratinocytes.

Conclusion—

Our data point out that alternative splicing of the VASH1 pre-mRNA transcript generates a potent antiangiogenic protein.
Functional MRI of Delayed Chronic Lithium Treatment in Rat Focal Cerebral Ischemia
Authors: Kim Young R. , van Meer Maurits P.A. , Tejima Emiri , Murata Yoshi , Mandeville Joseph B. , Dai George , Chuang De-Maw , Rosen Bruce R. , Lo Eng H.
Published: January 2008

Background and Purpose—

The use of lithium as a neuroprotective agent has been demonstrated using various models in which improvements in infarct size, DNA damage, and neurological function were reported. We further investigated neurohemodynamic aspects of the treatment-associated recovery by assessing the therapeutic efficacy of delayed chronic lithium treatment using functional MRI.

Methods—

Ipsilesional functional MRI activations in the somatosensory cortex, acquired 2 weeks after the 90-minute transient middle cerebral artery occlusion, were compared between lithium- and saline-treated rats. Specifically, MRI signal changes based on blood oxygenation level dependence and functional cerebral blood volume responses were examined using electrical stimulation of forelimbs. Additional immunohistochemical assays were performed.

Results—

The ratio of ipsilesional to contralesional blood oxygenation level dependence response magnitudes significantly improved with lithium treatments. In contrast, the increase of the functional cerebral blood volume response magnitude ratio was not statistically significant. Nonetheless, the lithium treatment induced significant enhancements of total functional MRI activation (defined as a product of activation volume and response magnitude) for both blood oxygenation level dependence and functional cerebral blood volume methods. Increased cerebral blood volume in periinfarct tissues suggests a possible stroke-induced vascular transformation in both saline- and lithium-treated rats; however, other MRI-derived vascular parameters (vascular size index and microvascular volume) and immunohistochemical staining (CD31, glia fibrillary-associated protein, and matrix metalloproteinase-9) may imply that the neoformation of vasculature was differently affected by the lithium treatment.

Conclusions—

The delayed chronic lithium treatment enhanced the blood oxygenation level dependence functional MRI response magnitude in the absence of neurological improvement and influenced vascular formation in poststroke animal models.
Picturing Persian Victory: The Painted Battle Scene on the Munich Wood
Authors: Summerer Lâtife
Published: January 2008

The present article analyses the battle scene on the painted beam in Munich, which originally belonged to the ensemble of an extensively painted tomb chamber near Tatarlı, and reviews its interpretation as an historical depiction that was proposed by the first editor Peter Calmeyer. The author concludes that this battle scene bears no clear indications to connect it with a specific historical event; rather, it seems to depict an exemplary Persian victory over enemies, who are conveyed as a unified ethnic group by their uniform costumes and pointed caps.The article analyses the evidence of the iconography in detail with particular regard to the forms of narration and the context, and in the light of this review attempts to show alternative ways how this painted Persian victory may be viewed and interpreted.
An Achaemenid « Palace » at Qarajamirli (Azerbaijan) Preliminary Report on the Excavations in 2006
Authors: Gagoshidze Iulon , Knauß Florian , Babaev Ilyas
Published: January 2008

Excavations on a small mound near the village Qarajamirli in western Azerbaijan provided remains of a monumental building, as well as quite a number of fragments of limestone column bases. The symmetrical ground plan of the building, the architectural sculpture and the pottery found on the floor closely follow Persian models from the Achaemenid era. Similar structures are known from Sary Tepe (Azerbaijan) and Gumbati (Georgia). These, as well as the building in Qarajamirli, can be interpreted as the residences of Persian officials, who left this area when the Achaemenid Empire collapsed. The painted pottery from the following period, when some peasants or herdsmen occasionally lived there, so far finds parallels only in Eastern Georgia.
Oriental Innovations in Samtskhe (Southern Georgia) in the 1st Millenium BC
Authors: Licheli Vakhtang
Published: January 2008

The only archaeological monument of the 1st Millennium BC in Southern Georgia (Samtskhe), which is systematically explored, is a multi-layer settlement and necropolis in Atskuri. The assemblages of the 6th-2nd centuries BC from Atskuri testify to the close relation with the Greek world on one side and with the Achaemenian cultural area on the other. Rich burials excavated in Atskuri in the last years contain numerous objects of Achaemenian type, which are mostly local imitations of Achaemenian objects. This material also shows that Achaemenian traditions continued to exist in Southern Georgia into the post-Achaemenian era.
Wall Painting from Dahaneh-ye Gholaman (Sistan)
Authors: Sajjadi S. Mansur Seyyed
Published: January 2008

The site of Dahaneh-ye Gholaman (Sistan, in the southeastern part of the Iranian Plateau) was discovered in the early 1960s by Umberto Scerrato of IsMEO (now IsIAO). It was a major urban center of the 6th to the 5th centuries BC. New excavations at Dahaneh-ye Gholaman started in October 2000. During the third campaign of excavations, traces of wall paintings and incised images have been identified in room 25. The most important scene shows a standing man, chariot rider, with a bow in his hand, shooting an animal, most probably a wild boar. In the same room and among a great variety of painted designs, which are only partly distinguishable, there are also remains of an image of a Bactrian camel.
Thermal Properties of Heat Conductive Silicone Rubber Filled with Hybrid Fillers
Authors: Wenying Zhou  , Caifeng Wang  , Qunli An  , Haiyan Ou
Published: January 2008

The thermal conductivities of vinyl endblocked polymethylsiloxane reinforced with silicone nitride (Si3N4) particles alone or in combination with silicone carbide whisker (SiCw) were investigated in this article. The results indicate that the silicone rubber incorporating of 50 vol% hybrid Si3N4 particles of different sizes at an optimal weight ratio exhibited the highest thermal conductivity of 1.48 W/m K compared to each single particle size filler used only; moreover, the combined use of hybrid Si3N4 and SiCw with the weight ratio of 9:1 provided the composites with higher thermal conductivity due to the structuring filler in hybrid fillers, improved thermal stability and reduced coefficient of thermal expansion (CTE) for comparison with the hybrid Si3N4 particles used alone. In addition, the surface treatment of the hybrid fillers with 3-methacryloyloxy-propyltrimethoxysilane enhanced the thermal conductivity and reduced CTE of the composites.
Acamprosate supports abstinence, Naltrexone prevents excessive drinking: evidence from a meta-analysis with unreported outcomes
Authors: Rösner Susanne , Leucht Stefan , Lehert Philippe , Soyka Michael
Published: January 2008

Two pharmacological agents have repeatedly been shown to be efficacious for relapse prevention in alcohol dependence: The putative glutamate-antagonist acamprosate and the opioid-antagonist naltrexone. Clinical evidence for both drugs is based on various outcome criteria. Whereas for acamprosate primarily abstinence maintenance has been demonstrated, studies with naltrexone have mostly emphasised the prevention of heavy drinking. The remaining effects of both drugs are not always reported; accordingly the corresponding database is fragmentary. Thus, the primary objective of the present meta-analysis was to complete the efficacy profiles for acamprosate and naltrexone and to compare them with each other. Unreported results, requested from the study investigators and the drug manufacturers, were integrated in the computation of effect sizes. For the meta-analysis, emphasis was placed on the conceptual distinction between having a first drink and returning to heavy drinking. Naltrexone was found to have a significant effect on the maintenance of abstinence as well as the prevention of heavy drinking. Acamprosate was shown only to support abstinence; it did not influence alcohol consumption after the first drink. When the efficacy profiles of the two drugs were compared, acamprosate was found to be more effective in preventing a lapse, whereas naltrexone was better in preventing a lapse from becoming a relapse. The superiority of either one drug or over the other one cannot be determined as a general rule, it rather depends on the therapeutic target. Benefits in the treatment of alcohol dependence might be optimized by matching the efficacy profiles of specific antidipsotropics with the motivational status of alcohol-dependent patients.
The `metaphorical annihilation' of the Second Lebanon War (2006) from the Israeli political discourse
Authors: Gavriely-Nuri Dalia
Published: January 2008

Combining discourse analysis with gender theories and the discipline of political studies, this article focuses on two discursive phenomena: first, it demonstrates the flexibility and efficiency of exclusion mechanisms beyond the realm of minority relations to abstract concepts but especially political events; second, it demonstrates the power of metaphor for neutralizing the negative cargo of controversial political situations for the purpose of transforming them into consensual events. The case study explored is the Israeli political discourse during the 33 days of the Second Lebanon War (2006). By intensive use of `war-normalizing metaphors', the political discourse `annihilated' the war: these metaphorical constructions framed the war as a `normal' event, an integral part of Israeli daily life, despite the 3970 katyusha rockets that fell within the borders of Israel and the massive Israel Defense Forces bombing of southern Lebanon.
The Ethics of Conviction Versus the Ethics of Responsibility
Authors: Enderle Georges
Published: January 2008

In his famous lecture on ‘Politics as a Vocation’, Max Weber coined and elaborated on the antithesis between the ethics of conviction and the ethics of responsibility, which has had a far-reaching impact on the ethics discussions, particularly in German-speaking countries. The article explores what Weber himself meant with this distinction and what implications result from it. As an interesting historical observation, Weber's interpretation of ‘Do not resist an evildoer’ in the (Christian) New Testament is contrasted with Mahatma Gandhi's diametrically opposed interpretation. After criticizing Weber's position, the article outlines how today's business ethics can be based on a new and different foundation that overcomes the ‘profound antithesis’ between the ethics of conviction and the ethics of responsibility without disregarding the tensions between internal attitudes and external action results.
Whose Responsibility? Swedish Local Decision Makers and the Scale of Climate Change Abatement
Authors: Lundqvist Lennart J. , von Borgstede Chris
Published: January 2008

This article uses a framework combining the discourse of scalar politics with a social dilemma perspective. The aim is to find answers to why political interests advocate a specific scalar arrangement. Analyzing informant interviews with top politicians and administrators in four municipal governments in the Gothenburg region of southwestern Sweden, we find that although all recognize the social dilemma, the size and capacity of their local government lead to different scalar arguments about responsibility for climate change. Regardless of municipal size and capacity, however, actors' recommendations finally converge in a pattern of path dependence. Already well-entrenched structures of intermunicipal urban cooperation are seen as the scalarly most appropriate vehicle for addressing the social dilemma and for allocating responsibility for climate-related regional action. This opens up for comparative urban research on how new and existing transboundary urban structures handle climate issues in terms of legitimacy and efficiency.
Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5
Authors: Carter Bing Z. , Mak Duncan H. , Schober Wendy D. , Dietrich Martin F. , Pinilla Clemencia , Vassilev Lyubomir T. , Reed John C. , Andreeff Michael
Published: January 2008

Acute myeloid leukemia (AML) cells are relatively resistant to tumor necrosis factor α–related apoptosis-inducing ligand (TRAIL). We previously reported that triptolide, a potent anticancer agent from a Chinese herb, decreases XIAP in leukemic cells. We evaluated the combination of triptolide and TRAIL and found synergistic promotion of apoptosis in AML cells. XIAP-overexpressing U937 cells (U937XIAP) were more resistant to TRAIL than U937neo cells, and inhibition of XIAP with the small-molecule inhibitor 1396-11 enhanced TRAIL-induced apoptosis, implying XIAP as a resistance factor in AML. Furthermore, triptolide increased DR5 levels in OCI-AML3, while the DR5 increase was blunted in p53-knockdown OCI-AML3 and p53-mutated U937 cells, confirming a role for p53 in the regulation of DR5. In support of this finding, disruption of MDM2-p53 binding with subsequent increase in p53 levels by nutlin3a increased DR5 levels and sensitized OCI-AML3 cells to TRAIL. The combination of 1396-11 plus nutlin3a plus TRAIL was more effective than either the 1396-11 and TRAIL or nutlin3a and TRAIL combinations in OCI-AML3 cells, further supporting the role of triptolide as a sensitizer to TRAILinduced apoptosis in part by independent modulation of XIAP expression and p53 signaling. Thus, the combination of triptolide and TRAIL may provide a novel strategy for treating AML by overcoming critical mechanisms of apoptosis resistance.
Evidence-based diagnosis of type 1 von Willebrand disease: a Bayes theorem approach
Authors: Tosetto Alberto , Castaman Giancarlo , Rodeghiero Francesco
Published: January 2008

The diagnosis of type 1 von Willebrand disease (VWD) is based on the presence of bleeding symptoms, reduced von Willebrand factor (VWF) levels, and autosomal inheritance of the phenotype. To better appreciate the contribution of clinical and laboratory data to the final diagnosis of VWD, we computed the likelihoods of having VWD as a function of the bleeding score (LRscore), of VWF level (LRVWF), and of number of first-degree family members with reduced VWF levels (LRfamily). The 3 likelihoods were therefore combined using the Bayes theorem, giving the final probability (odds) of having VWD. LRfamily and LRVWF were the 2 factors mostly influencing the final probability of having VWD. Data from the present study provide an evidence-based description of the minimal criteria for the diagnosis of type 1 VWD. As an example, presence of VWF levels lower than 40 IU/dL in at least 2 family members (including the proband) and a bleeding score of at least 1 were found to be required for a final odd of VWD higher than 2.0 (false-positive rate less than one-half). Validation of this approach and of its clinical utility is, however, required by analysis in other cohorts of well-characterized type 1 VWD patients.
Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy
Authors: Carlino Claudia , Stabile Helena , Morrone Stefania , Bulla Roberta , Soriani Alessandra , Agostinis Chiara , Bossi Fleur , Mocci Carlo , Sarazani Filippo , Tedesco Francesco , Santoni Angela , Gismondi Angela
Published: January 2008

During early pregnancy, uterine mucosa decidualization is accompanied by a drastic enrichment of CD56highCD16− natural killer (NK) cells. Decidual NK (dNK) cells differ from peripheral blood NK (pbNK) cells in several ways, but their origin is still unclear. Our results demonstrate that chemokines present in the uterus can support pbNK cell migration through human endothelial and stromal decidual cells. Notably, we observed that pregnant women's pbNK cells are endowed with higher migratory ability compared with nonpregnant women's or male donors' pbNK cells. Moreover, NK cell migration through decidual stromal cells was increased when progesterone-cultured stromal cells were used as substrate, and this correlated with the ability of progesterone to up-regulate stromal cell chemokine expression. Furthermore, we demonstrate that dNK cells migrate through stromal cells using a distinct pattern of chemokines. Finally, we found that pbNK cells acquire a chemokine receptor pattern similar to that of dNK cells when they contact decidual stromal cells. Collectively these results strongly suggest that pbNK cell recruitment to the uterus contributes to the accumulation of NK cells during early pregnancy; that progesterone plays a crucial role in this event; and that pbNK cells undergo reprogramming of their chemokine receptor profile once exposed to uterine microenvironment.
Halibut mitochondrial genomes contain extensive heteroplasmic tandem repeat arrays involved in DNA recombination
Authors: Mjelle Kenneth A , Karlsen Bård O , Jørgensen Tor E , Moum Truls , Johansen Steinar D
Published: January 2008

Background

Halibuts are commercially important flatfish species confined to the North Pacific and North Atlantic Oceans. We have determined the complete mitochondrial genome sequences of four specimens each of Atlantic halibut (Hippoglossus hippoglossus), Pacific halibut (Hippoglossus stenolepis) and Greenland halibut (Reinhardtius hippoglossoides), and assessed the nucleotide variability within and between species.

Results

About 100 variable positions were identified within the four specimens in each halibut species, with the control regions as the most variable parts of the genomes (10 times that of the mitochondrial ribosomal DNA). Due to tandem repeat arrays, the control regions have unusually large sizes compared to most vertebrate mtDNAs. The arrays are highly heteroplasmic in size and consist mainly of different variants of a 61-bp motif. Halibut mitochondrial genomes lacking arrays were also detected.

Conclusion

The complexity, distribution, and biological role of the heteroplasmic tandem repeat arrays in halibut mitochondrial control regions are discussed. We conclude that the most plausible explanation for array maintenance includes both the slipped-strand mispairing and DNA recombination mechanisms.
Profiling expression changes caused by a segmental aneuploid in maize
Authors: Makarevitch Irina , Phillips Ronald L , Springer Nathan M
Published: January 2008

Background

While changes in chromosome number that result in aneuploidy are associated with phenotypic consequences such as Down syndrome and cancer, the molecular causes of specific phenotypes and genome-wide expression changes that occur in aneuploids are still being elucidated.

Results

We employed a segmental aneuploid condition in maize to study phenotypic and gene expression changes associated with aneuploidy. Maize plants that are trisomic for 90% of the short arm of chromosome 5 and monosomic for a small distal portion of the short arm of chromosome 6 exhibited a phenotypic syndrome that includes reduced stature, tassel morphology changes and the presence of knots on the leaves. The knotted-like homeobox gene knox10, which is located on the short arm of chromosome 5, was shown to be ectopically expressed in developing leaves of the aneuploid plants. Expression profiling revealed that ~40% of the expressed genes in the trisomic region exhibited the expected 1.5 fold increased transcript levels while the remaining 60% of genes did not show altered expression even with increased gene dosage.

Conclusion

We found that the majority of genes with altered expression levels were located within the chromosomal regions affected by the segmental aneuploidy and exhibits dosage-dependent expression changes. A small number of genes exhibit higher levels of expression change not predicted by the dosage, or display altered expression even though they are not located in the aneuploid regions.
Clinical presentation and outcome of Tuberculosis in Human Immunodeficiency Virus infected children on anti-retroviral therapy
Authors: Walters Elisabetta , Cotton Mark F , Rabie Helena , Schaaf H Simon , Walters Lourens O , Marais Ben J
Published: January 2008

Background

The tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics are poorly controlled in sub-Saharan Africa, where highly active antiretroviral treatment (HAART) has become more freely available. Little is known about the clinical presentation and outcome of TB in HIV-infected children on HAART.

Methods

We performed a comprehensive file review of all children who commenced HAART at Tygerberg Children's Hospital from January 2003 through December 2005.

Results

Data from 290 children were analyzed; 137 TB episodes were recorded in 136 children; 116 episodes occurred before and 21 after HAART initiation; 10 episodes were probably related to immune reconstitution inflammatory syndrome (IRIS). The number of TB cases per 100 patient years were 53.3 during the 9 months prior to HAART initiation, and 6.4 during post HAART follow-up [odds ratio (OR) 16.6; 95% confidence interval (CI) 12.5–22.4]. A positive outcome was achieved in 97/137 (71%) episodes, 6 (4%) cases experienced no improvement, 16 (12%) died and the outcome could not be established in 18 (13%). Mortality was less in children on HAART (1/21; 4.8%) compared to those not on HAART (15/116; 12.9%).

Conclusion

We recorded an extremely high incidence of TB among HIV-infected children, especially prior to HAART initiation. Starting HAART at an earlier stage is likely to reduce morbidity and mortality related to TB, particularly in TB-endemic areas. Management frequently deviated from standard guidelines, but outcomes in general were good.
Preclinical evaluation of lime juice as a topical microbicide candidate
Authors: Fletcher Patricia S , Harman Sarah J , Boothe Adrienne R , Doncel Gustavo F , Shattock Robin J
Published: January 2008

Background

The continued growth of the global HIV epidemic highlights the urgent need to develop novel prevention strategies to reduce HIV transmission. The development of topical microbicides is likely to take a number of years before such a product would be widely available. This has resulted in a call for the rapid introduction of simpler vaginal intervention strategies in the interim period. One suggested practice would be vaginal douching with natural products including lime or lemon juice. Here we present a comprehensive preclinical evaluation of lime juice (LiJ) as a potential intervention strategy against HIV.

Results

Pre-treatment of HIV with LiJ demonstrated direct virucidal activity, with 10% juice inactivating the virus within 5 minutes. However, this activity was significantly reduced in the presence of seminal plasma, where inactivation required maintaining a 1:1 mixture of neat LiJ and seminal plasma for more than 5 minutes. Additionally, LiJ demonstrated both time and dose-dependent toxicity towards cervicovaginal epithelium, where exposure to 50% juice caused 75–90% toxicity within 5 minutes increasing to 95% by 30 minutes. Cervicovaginal epithelial cell monolayers were more susceptible to the effects of LiJ with 8.8% juice causing 50% toxicity after 5 minutes. Reconstructed stratified cervicovaginal epithelium appeared more resilient to LiJ toxicity with 30 minutes exposure to 50% LiJ having little effect on viability. However viability was reduced by 75% and 90% following 60 and 120 minutes exposure. Furthermore, repeat application (several times daily) of 25% LiJ caused 80–90% reduction in viability.

Conclusion

These data demonstrate that the virucidal activity of LiJ is severely compromised in the presence of seminal plasma. Potentially, to be effective against HIV in vivo, women would need to apply a volume of neat LiJ equal to that of an ejaculate, and maintain this ratio vaginally for 5–30 minutes after ejaculation. Data presented here suggest that this would have significant adverse effects on the genital mucosa. These data raise serious questions about the plausibility and safety of such a prevention approach.
Effect of shoe heel height on vastus medialis and vastus lateralis electromyographic activity during sit to stand
Authors: Edwards Lindsay , Dixon John , Kent Jillian R , Hodgson David , Whittaker Vicki J
Published: January 2008

Background

It has been proposed that high-heeled shoes may contribute to the development and progression of knee pain. However, surprisingly little research has been carried out on how shoe heel height affects muscle activity around the knee joint. The purpose of this study was to investigate the effect of differing heel height on the electromyographic (EMG) activity in vastus medialis (VM) and vastus lateralis (VL) during a sit to stand activity. This was an exploratory study to inform future research.

Methods

A repeated measures design was used. Twenty five healthy females carried out a standardised sit to stand activity under 4 conditions; barefoot, and with heel wedges of 1, 3, and 5 cm in height. EMG activity was recorded from VM and VL during the activity. Data were analysed using 1 × 4 repeated measures ANOVA.

Results

Average rectified EMG activity differed with heel height in both VM (F2.2, 51.7 = 5.24, p < 0.01), and VL (F3, 72 = 5.32, p < 0.01). However the VM: VL EMG ratio was not significantly different between conditions (F3, 72 = 0.61, p = 0.609).

Conclusion

We found that as heel height increased, there was an increase in EMG activity in both VM and VL, but no change in the relative EMG intensity of VM and VL as measured by the VM: VL ratio. This showed that no VM: VL imbalance was elicited. This study provides information that will inform future research on how heel height affects muscle activity around the knee joint.
Extracellular calcium increases bisphosphonate-induced growth inhibition of breast cancer cells
Authors: Journé Fabrice , Kheddoumi Naïma , Chaboteaux Carole , Duvillier Hugues , Laurent Guy , Body Jean-Jacques
Published: January 2008

Introduction

Bisphosphonates have become standard therapy for the treatment of skeletal complications related to breast cancer. Although their therapeutic effects mainly result from an inhibition of osteoclastic bone resorption, in vitro data indicate that they also act directly on breast cancer cells, inhibiting proliferation and inducing apoptosis.

Methods

The present study examined the effects of calcium (from 0.6 to 2.0 mmol/l) on the antitumour activity of the bisphosphonate ibandronate (1 to 1,000 nmol/l) on MDA-MB-231 and MCF-7 breast cancer cells. Cell culture densities were determined using crystal violet staining assay. Apoptotic cell death was assessed by annexin V-phycoerythrin and 7-amino-actinomycin double staining.

Results

At low calcium concentration, 30 μmol/l ibandronate had no effect on MDA-MB-231 cells growth and only slightly inhibited MCF-7 cells growth. Higher calcium levels significantly increased growth inhibition as well as cell apoptosis induced by ibandronate. We observed similar effects with zoledronic acid. Of note, enhancement of ibandronate-induced growth inhibition was also observed in other breast cancer cell lines (T-47D, ZR-75, Hs-578T and BT-549 cells). The growth inhibitory effect of ibandronate in the presence of high concentrations of calcium was partly suppressed by the calcium chelator EGTA (ethylene glycol tetra-acetic acid). In addition, in the presence of calcium at high concentrations, cells accumulated more [14C]ibandronate than at low calcium concentrations. We obtained further evidence of enhancement of cellular ibandronate accumulation by calcium by demonstrating that high calcium levels increased the inhibition of protein prenylation induced by the bisphosphonate.

Conclusion

Altogether, our data suggest that extracellular calcium, probably through its binding to ibandronate, markedly increased its cellular accumulation and its inhibitory activity on breast tumour cells. Thus, calcium released during the process of tumour-induced osteolysis might enhance the antitumour effects of bisphosphonates and contribute to their therapeutic efficacy.
Causes of metabolic acidosis in canine hemorrhagic shock: role of unmeasured ions
Authors: Bruegger Dirk , Kemming Gregor I , Jacob Matthias , Meisner Franz G , Wojtczyk Christoph J , Packert Kristian B , Keipert Peter E , Faithfull N Simon , Habler Oliver P , Becker Bernhard F , Rehm Markus
Published: January 2008

Introduction

Metabolic acidosis during hemorrhagic shock is common and conventionally considered to be due to hyperlactatemia. There is increasing awareness, however, that other nonlactate, unmeasured anions contribute to this type of acidosis.

Methods

Eleven anesthetized dogs were hemorrhaged to a mean arterial pressure of 45 mm Hg and were kept at this level until a metabolic oxygen debt of 120 mLO2/kg body weight had evolved. Blood pH, partial pressure of carbon dioxide, and concentrations of sodium, potassium, magnesium, calcium, chloride, lactate, albumin, and phosphate were measured at baseline, in shock, and during 3 hours post-therapy. Strong ion difference and the amount of weak plasma acid were calculated. To detect the presence of unmeasured anions, anion gap and strong ion gap were determined. Capillary electrophoresis was used to identify potential contributors to unmeasured anions.

Results

During induction of shock, pH decreased significantly from 7.41 to 7.19. The transient increase in lactate concentration from 1.5 to 5.5 mEq/L during shock was not sufficient to explain the transient increases in anion gap (+11.0 mEq/L) and strong ion gap (+7.1 mEq/L), suggesting that substantial amounts of unmeasured anions must have been generated. Capillary electrophoresis revealed increases in serum concentration of acetate (2.2 mEq/L), citrate (2.2 mEq/L), α-ketoglutarate (35.3 μEq/L), fumarate (6.2 μEq/L), sulfate (0.1 mEq/L), and urate (55.9 μEq/L) after shock induction.

Conclusion

Large amounts of unmeasured anions were generated after hemorrhage in this highly standardized model of hemorrhagic shock. Capillary electrophoresis suggested that the hitherto unmeasured anions citrate and acetate, but not sulfate, contributed significantly to the changes in strong ion gap associated with induction of shock.
Slow waves in fractures filled with viscous fluid
Authors: Korneev Valeri
Published: January 2008

Stoneley guided waves in a fluid-filled fracture generally have larger amplitudes than other waves; therefore, their properties need to be incorporated into more realistic models. A fracture is modeled as an infinite layer of viscous fluid bounded by two elastic half-spaces with identical parameters. For small fracture thickness, a simple dispersion equation for wave-propagation velocity is obtained. This velocity is much smaller than the velocity of a fluid wave in a Biot-type solution, in which fracture walls are assumed to be rigid. At seismic prospecting frequencies and realistic fracture thicknesses, the Stoneley guided wave has wavelengths on the order of several meters and a quality factor [Formula: see text] exceeding 10, which indicates the possibility of resonance excitation in fluid-bearing rocks. The velocity and attenuation of Stoneley guided waves are distinctly different at low frequencies for water and for oil. The predominant role of fractures in fluid flow at field scales is supported by permeability data, showing an increase of several orders of magnitude when compared with values obtained at laboratory scales. The data suggest that Stoneley guided waves should be taken into account in theories describing seismic wave propagation in fluid-saturated rocks.
Influence of microheterogeneity on effective stress law for elastic properties of rocks
Authors: Ciz Radim , Siggins Anthony F. , Gurevich Boris , Dvorkin Jack
Published: January 2008

Understanding the effective stress coefficient for seismic velocity is important for geophysical applications such as overpressure prediction from seismic data as well as for hydrocarbon production and monitoring using time-lapse seismic measurements. This quantity is still not completely understood. Laboratory measurements show that the seismic velocities as a function of effective stress yield effective stress coefficients less than one and usually vary between 0.5 and 1. At the same time, theoretical analysis shows that for an idealized monomineral rock, the effective stress coefficient for elastic moduli (and therefore also for seismic velocities) will always equal one. We explore whether this deviation of the effective stress coefficient from unity can be caused by the spatial microheterogeneity of the rock. The results show that only a small amount (less than 1%) of a very soft component is sufficient to cause this effect. Such soft material may be present in grain contact areas of many rocks and may explain the variation observed experimentally.