tbuckley/cabot-search huggingface dataset:
Endocytic Ark/Prk Kinases Play a Critical Role in Adriamycin Resistance in Both Yeast and Mammalian Cells
Authors: Tsutomu Takahashi, Takemitsu Furuchi, Akira Naganuma
Journal: Cancer Research (2006)

Abstract To elucidate the mechanism of acquired resistance to Adriamycin, we searched for genes that, when overexpressed, render Saccharomyces cerevisiae resistant to Adriamycin. We identified AKL1, a gene of which the function is unknown but is considered, nonetheless, to be a member of the Ark/Prk kinase family, which is involved in the regulation of endocytosis, on the basis of its deduced amino acid sequence. Among tested members of the Ark/Prk kinase family (Ark1, Prk1, and Akl1), overexpressed Prk1 also conferred Adriamycin resistance on yeast cells. Prk1 is known to dissociate the Sla1/Pan1/End3 complex, which is involved in endocytosis, by phosphorylating Sla1 and Pan1 in the complex. We showed that Akl1 promotes phosphorylation of Pan1 in this complex and reduces the endocytic ability of the cell, as does Prk1. Sla1- and End3-defective yeast cells were also resistant to Adriamycin and overexpression of Akl1 in these defective cells did not increase the degree of Adriamycin resistance, suggesting that Akl1 might reduce Adriamycin toxicity by reducing the endocytic ability of cells via a mechanism that involves the Sla1/Pan1/End3 complex and the phosphorylation of Pan1. We also found that HEK293 cells that overexpressed AAK1, a member of the human Ark/Prk family, were Adriamycin resistant. Our findings suggest that endocytosis might be involved in the mechanism of Adriamycin toxicity in yeast and human cells. (Cancer Res 2006; 66(24): 11932-7)
Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen
Authors: Heyu Ni, Cécile V. Denis, Sangeetha Subbarao, Jay L. Degen, Thomas N. Sato, Richard O. Hynes, Denisa D. Wagner
Journal: Journal of Clinical Investigation (2000)

We used intravital microscopy to observe the formation of platelet plugs in ferric chloride–injured arterioles of live mice. With this model, we evaluated thrombus growth in mice lacking von Willebrand factor (vWF) and fibrinogen (Fg), the two key ligands known to mediate platelet adhesion and aggregation. In vWF–/– mice, despite the presence of arterial shear, delayed platelet adhesion occurred and stable thrombi formed. In many mice, a persisting high-shear channel never occluded. Abundant thrombi formed in Fg–/– mice, but they detached from the subendothelium, which ultimately caused downstream occlusion in all cases. Surprisingly, mice deficient in both vWF and Fg successfully formed thrombi with properties characteristic of both mutations, leading to vessel occlusion in the majority of vessels. Platelets of these doubly deficient mice specifically accumulated fibronectin in their α-granules, suggesting that fibronectin could be the ligand supporting the platelet aggregation.
The relation between information provision and health-related quality of life, anxiety and depression among cancer survivors: a systematic review
Authors: O. Husson, F. Mols, L.V. van de Poll-Franse
Journal: Annals of Oncology (2010)

Providing information that is congruent with patients' needs is an important determinant for patient satisfaction and might also affect health-related quality of life (HRQoL) and anxiety and depression levels of cancer survivors.The authors systematically reviewed the available literature on the relationship between information provision and HRQoL, anxiety and depression. A PubMed literature search for original articles published until February 2010 was carried out. Twenty-five articles, all conducted between 1996 and 2009, which met the predefined inclusion criteria, were subjected to a quality checklist.Satisfied patients, patients with fulfilled information needs, and patients who experience less information barriers, in general have a better HRQoL and less anxiety and depression. Out of eight intervention studies that aimed to improve information provision, only one showed a positive association with better HRQoL.Health care providers must pay more attention to patient-centred information provision. Additional research is needed to make definitive conclusions about information interventions as most results did not reach statistical significance due to methodological constraints. The quick development of the relatively young research field of patient-reported outcomes in cancer survivorship will make it possible to conduct better quality studies in the future.
Hypercapnic Acidosis Attenuates Endotoxin-induced Acute Lung Injury
Authors: John G. Laffey, Dave Honan, Natalie Hopkins, Jean-Marc Hyvelin, John F. Boylan, Paul McLoughlin
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Deliberate induction of prophylactic hypercapnic acidosis protects against lung injury after in vivo ischemia–reperfusion and ventilation-induced lung injury. However, the efficacy of hypercapnic acidosis in sepsis, the commonest cause of clinical acute respiratory distress syndrome, is not known. We investigated whether hypercapnic acidosis—induced by adding CO2 to inspired gas—would be protective against endotoxin-induced lung injury in an in vivo rat model. Prophylactic institution of hypercapnic acidosis (i.e., induction before endotoxin instillation) attenuated the decrement in arterial oxygenation, improved lung compliance, and attenuated alveolar neutrophil infiltration compared with control conditions. Therapeutic institution of hypercapnic acidosis, that is, induction after endotoxin instillation, attenuated the decrement in oxygenation, improved lung compliance, and reduced alveolar neutrophil infiltration and histologic indices of lung injury. Therapeutic hypercapnic acidosis attenuated the endotoxin-induced increase in the higher oxides of nitrogen and nitrosothiols in the lung tissue and epithelial lining fluid. Lung epithelial lining fluid nitrotyrosine concentrations were increased with hypercapnic acidosis. We conclude that hypercapnic acidosis attenuates acute endotoxin-induced lung injury, and is efficacious both prophylactically and therapeutically. The beneficial actions of hypercapnic acidosis were not mediated by inhibition of peroxynitrite-induced nitration within proteins.
Hypoplasia of the left first rib in a child with Down's syndrome and an endocardial cushion defect
Authors: D. B. Altman, C. E. Anagnostopoulos, C. F. Kittle
Journal: Thorax (1972)

Abstract A case is reported of a child with Down's syndrome having a hypoplastic left first rib and an endocardial cushion defect. To our knowledge, a similar entity has not been reported.
The effectiveness of a structured education pulmonary rehabilitation programme for improving the health status of people with moderate and severe chronic obstructive pulmonary disease in primary care: the PRINCE cluster randomised trial
Authors: Dympna Casey, Kathy Murphy, Declan Devane, Adeline Cooney, Bernard McCarthy, Lorraine Mee, John Newell, Eamon O'Shea, Carl Scarrott, Paddy Gillespie, Collette Kirwan, Andrew W Murphy
Journal: Thorax (2013)

<h3>Objective</h3> To evaluate the effectiveness of a structured education pulmonary rehabilitation programme on the health status of people with chronic obstructive pulmonary disease (COPD). <h3>Design</h3> Two-arm, cluster randomised controlled trial. <h3>Setting</h3> 32 general practices in the Republic of Ireland. <h3>Participants</h3> 350 participants with a diagnosis of moderate or severe COPD. <h3>Intervention</h3> Experimental group received a structured education pulmonary rehabilitation programme, delivered by the practice nurse and physiotherapist. Control group received usual care. <h3>Main outcome measure</h3> Health status as measured by the Chronic Respiratory Questionnaire (CRQ) at baseline and at 12–14 weeks postcompletion of the programme. <h3>Results</h3> Participants allocated to the intervention group had statistically significant higher mean change total CRQ scores (adjusted mean difference (MD) 1.11, 95% CI 0.35 to 1.87). However, the CI does not exclude a smaller difference than the one that was prespecified as clinically important. Participants allocated to the intervention group also had statistically significant higher mean CRQ Dyspnoea scores after intervention (adjusted MD 0.49, 95% CI 0.20 to 0.78) and CRQ Physical scores (adjusted MD 0.37, 95% CI 0.14 to 0.60). However, CIs for both the CRQ Dyspnoea and CRQ Physical subscales do not exclude smaller differences as prespecified as clinically important. No other statistically significant differences between groups were seen. <h3>Conclusions</h3> A primary care based structured education pulmonary rehabilitation programme is feasible and may increase local accessibility to people with moderate and severe COPD. <h3>Trial registration</h3> ISRCTN52403063.
Treatment of talar osteochondral lesions using local osteochondral talar autograft mid term results
Authors: Evangelos Evangelou, Thanos Badekas
Journal: British Journal of Sports Medicine (2011)

Background Osteochondral lesion of the talus (OLT) is a broad term used to describe an injury or abnormality of the talar articular cartilage and adjacent bone. A variety of treatment methods exist for OLT. The use of local Osteochondral talar autograft is an established treatment method for such articular cartilage defects. We present a series of patients treated this way for osteochondral defects of the ankle, and assess the functional and clinical long-term results. Materials and methods From March 2005 to December 2008, 11 patients underwent implantation of local osteochondral talar autograft for OLT, 6 male and 5 female. The graft was harvested from the medial or lateral talar articular facet on the same side of the lesion. Graft sizes ranged from 4 to 8 mm in diameter. Age ranged from 19 to 53 (mean 38) years. Sports related injury concerned eight patients and the duration of symptoms was mean 65 months (range 6–98). Mean follow-up was 41 months (range 16–61). Preoperative and postoperative results evaluated used the American Orthopaedic Foot &amp; Ankle Society (AOFAS) score. Special diagnostics studies performed preoperative, MRI (11 patients), computed axial tomography (11 patients), bone scan 2 patients and weight-bearing radiographs to all of them to evaluate the injury. Results All osteotomies healed. The AOFAS average score improved from mean 65 pre- to 89 postop. The AOFAS score was slightly higher in patients under 40 years of age and in those without pre-existing joint arthritis. Concerned satisfaction all the patients would have the procedure again. The most common post op complaint was a mold ache at anteromedial joint line of the ankle. There were no complications in the study group. Most returned to pre injury level of activity. Two patients had a second look arthroscopy one 6 and one 12 months post because of impingement of lateral malleolus the first and debridement of anterior tibial margin the second. Both of them had incorporation of the graft into the surrounding talar dome cartilage. Conclusion We believe treatment of talar osteochondral lesions using local osteochondral talar autograft is a reliable treatment method. The long-term results confirm that it is a well-accepted procedure from the patients with no high risk of complications compared to other procedures.
Mouse Mammary Tumor Virus–like Sequences in Human Breast Cancer
Authors: James S. Lawson, Wendy K. Glenn, Brian Salmons, Yulan Ye, Benjamin Heng, Patrick Moody, Harpreet Johal, William D. Rawlinson, Warick Delprado, Louise Lutze-Mann, Noel J. Whitaker
Journal: Cancer Research (2010)

Mouse mammary tumor virus (MMTV) sequences have been reported to be present in some human breast cancers, but it is unclear whether they have any causal role. In mice, MMTV promotes tumor formation indirectly by insertional mutagenesis of Wnt oncogenes that lead to their activation. In this study, we investigated the status of Wnt-1 in human breast cancers harboring MMTV-like sequences encoding viral envelope (env) genes. We confirmed the detection of env sequences in the nucleus of human breast cancer specimens that are similar in appearance to mouse mammary tumors expressing MMTV env sequences. MMTV env sequences in human breast cancers were also nearly indistinguishable from env sequences in mouse MMTV isolates. Further, Wnt-1 expression was higher in specimens of env-positive ductal carcinoma in situ and invasive ductal carcinoma, relative to env-negative specimens. Our findings extend the evidence that MMTV sequences found in naturally occurring mouse mammary tumors can be found in some human breast cancers, prompting further evaluation of causal roles in these settings.
Radiation induced small bowel "web" formation is associated with acquired microvascular dysfunction
Authors: O. A. Hatoum, D. G. Binion, Shane Phillips, C. O'Loughlin, R. A. Komorowski, D. D. Gutterman, M. F. Otterson
Journal: Gut (2005)

<b>Background and aims:</b> Radiation therapy of abdominal and pelvic solid tumours results in late intestinal toxicity of a severe nature in approximately 5% of cases. These manifestations may include ischaemia and stricture formation, which may present as “webs”. These webs are likely to play a role in the pathogenesis of recurrent bowel obstruction. The mechanisms of microvascular injury to the bowel in the setting of radiation have not been defined. We hypothesised that microvascular dysfunction with impaired vasodilation to acetylcholine (Ach) would be an acquired pathophysiological abnormality in radiation and “web” formation. <b>Methods:</b> A 40 year old patient treated with radiation, two years previously, for an anal squamous cell cancer presented with recurrent small bowel obstruction. “Webs” in the distal ileum were detected using wireless capsule endoscopy, after small bowel barium radiographs failed to demonstrate a lesion. Following resection, freshly isolated 50–150 μm diameter arterioles from the “web” and adjacent normal calibre bowel were analysed with histology and microvessel physiological studies. <b>Results:</b> After constriction (30–50%) with endothelin, dilation to graded doses of Ach (10<sup>−9</sup>–10<sup>−4</sup> M) was observed in vessels dissected from the stricture and the adjacent normal calibre area. Ach dilation was reduced in vessels from “web” (mean diameter 7 (2)%; n = 3, p&lt;0.01) compared with the adjacent unaffected bowel (mean diameter 85 (5)%). Dihydroethidine and dichlorofluorescein diacetate intravital staining demonstrated increased reactive oxygen species production in microvessels from “web” compared with adjacent normal calibre bowel. Histology from the strictured bowel demonstrated narrowing of the arterial lumen due to intimal and muscularis propria fibrosis, with endothelial preservation. <b>Conclusions:</b> External radiation is associated with acquired microvascular endothelial dysfunction and “web” formation in the small bowel.
Molecular Determinants of Dofetilide Block of HERG K <sup>+</sup> Channels
Authors: Eckhard Ficker, Wolfgang Jarolimek, Johann Kiehn, Arnd Baumann, Arthur M. Brown
Journal: Circulation Research (1998)

The human ether-a-go-go-related gene (HERG) encodes a K+ channel with biophysical properties nearly identical to the rapid component of the cardiac delayed rectifier K+ current (IKr). HERG/IKr channels are a prime target for the pharmacological management of arrhythmias and are selectively blocked by class III antiarrhythmic methanesulfonanilide drugs, such as dofetilide, E4031, and MK-499, at submicromolar concentrations. By contrast, the closely related bovine ether-a-go-go channel (BEAG) is 100-fold less sensitive to dofetilide. To identify the molecular determinants for dofetilide block, we first engineered chimeras between HERG and BEAG and then used site-directed mutagenesis to localize single amino acid residues responsible for block. Using constructs heterologously expressed in Xenopus oocytes, we found that transplantation of the S5-S6 linker from BEAG into HERG removed high-affinity block by dofetilide. A point mutation in the S5-S6 linker region, HERG S620T, abolished high-affinity block and interfered with C-type inactivation. Thus, our results indicate that important determinants of dofetilide binding are localized to the pore region of HERG. Since the loss of high-affinity drug binding was always correlated with a loss of C-type inactivation, it is possible that the changes observed in drug binding are due to indirect allosteric modifications in the structure of the channel protein and not to the direct interaction of dofetilide with the respective mutated site chains. However, the chimeric approach was not able to identify domains outside the S5-S6 linker region of the HERG channel as putative candidates involved in drug binding. Moreover, the reverse mutation BEAG T432S increased the affinity of BEAG K+ channels for dofetilide, whereas C-type inactivation could not be recovered. Thus, the serine in position HERG 620 may participate directly in dofetilide binding; however, an intact C-type inactivation process seems to be crucial for high-affinity drug binding.
Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study
Authors: Christophe Hézode, Gideon M Hirschfield, Wayne Ghesquiere, William Sievert, Maribel Rodriguez-Torres, Stephen D Shafran, Paul J Thuluvath, Harvey A Tatum, Imam Waked, Gamal Esmat, Eric J Lawitz, Vinod K Rustgi, Stanislas Pol, Nina Weis, Paul J Pockros, Marc Bourlière, Lawrence Serfaty, John M Vierling, Michael W Fried, Ola Weiland, Maurizia R Brunetto, Gregory T Everson, Stefan Zeuzem, Paul Y Kwo, Mark Sulkowski, Norbert Bräu, Dennis Hernandez, Fiona McPhee, Megan Wind-Rotolo, Zhaohui Liu, Stephanie Noviello, Eric A Hughes, Philip D Yin, Steven Schnittman
Journal: Gut (2014)

<h3>Objective</h3> To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. <h3>Design</h3> In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA&lt;lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR<sub>24</sub>) among genotype 1-infected patients. <h3>Results</h3> Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR<sub>24</sub> was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR<sub>24</sub> versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR<sub>24</sub> rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. <h3>Conclusions</h3> The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR<sub>24</sub> rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4. <h3>Trial registration number</h3> NCT01125189.
Autophagy Opposes p53-Mediated Tumor Barrier to Facilitate Tumorigenesis in a Model of <i>PALB2</i>-Associated Hereditary Breast Cancer
Authors: Yanying Huo, Hong Cai, Irina Teplova, Christian Bowman-Colin, Guanghua Chen, Sandy Price, Nicola Barnard, Shridar Ganesan, Vassiliki Karantza, Eileen White, Bing Xia
Journal: Cancer Discovery (2013)

Abstract Hereditary breast cancers stem from germline mutations in susceptibility genes such as BRCA1, BRCA2, and PALB2, whose products function in the DNA damage response and redox regulation. Autophagy is an intracellular waste disposal and stress mitigation mechanism important for alleviating oxidative stress and DNA damage response activation; it can either suppress or promote cancer, but its role in breast cancer is unknown. Here, we show that similar to Brca1 and Brca2, ablation of Palb2 in the mouse mammary gland resulted in tumor development with long latency, and the tumors harbored mutations in Trp53. Interestingly, impaired autophagy, due to monoallelic loss of the essential autophagy gene Becn1, reduced Palb2-associated mammary tumorigenesis in a Trp53–wild-type but not conditionally null background. These results indicate that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, p53 is a barrier to cancer development, whereas autophagy facilitates cell survival and tumorigenesis. Significance: Our findings directly show a tumor-promoting role of autophagy in a new model of hereditary breast cancer. Given the close functional relationship and the genetic similarity between PALB2 and BRCA1/2, our results further suggest that inhibition of autophagy may represent a new avenue to the prevention or treatment of a significant portion of hereditary breast cancers, namely those associated with DNA damage and oxidative stress. Cancer Discov; 3(8); 894–907. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 826
Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous oestrogen used for infertility treatment
Authors: S Yano
Journal: Thorax (2002)

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease that affects women in the reproductive years. It is occasionally associated with tuberous sclerosis, especially in the incomplete form. As it is likely that oestrogen plays a central role in disease progression, exogenous oestrogen will cause a deterioration in LAM. However, the early stage of this disease is easy to miss unless the physician is a specialist. Although there have been some reports in menopausal women given exogenous oestrogen for osteoporosis, this is the first report of pulmonary LAM caused by exogenous oestrogen used for the treatment of infertility.