tbuckley/cabot-search huggingface dataset:
Heparan sulfate proteoglycan on leukemic cells is primarily involved in integrin triggering and its mediated adhesion to endothelial cells.
Authors: Y Tanaka, K Kimata, A Wake, S Mine, I Morimoto, N Yamakawa, H Habuchi, S Ashikari, H Yamamoto, K Sakurai, K Yoshida, S Suzuki, S Eto
Journal: The Journal of Experimental Medicine (1996)

Leukocyte migration from circulation into tissue depends on leukocyte integrin-mediated adhesion to endothelium, but integrins cannot function until activated. However, it remains to be understood how tumor cells adhere to endothelium and infiltrate into underlying tissue. We studied mechanisms of extravasation of leukemic cells using adult T cell leukemia (ATL) cells and report the following novel features of cell surface heparan sulfate proteoglycan on ATL cells in ATL cell adhesion to endothelium: ATL cells adhere to endothelial cells through already activated integrins without exogenous stimulation; different from any other hematopoietic cells, ATL cells express a characteristic heparan sulfate capable of immobilizing heparin-binding chemokine macrophage inflammatory protein (MIP)-1 beta, a potent T cell integrin trigger, produced by the cells themselves; competitive interruption of endogenous heparan sulfate proteoglycan synthesis reduces cell surface MIP-1 beta and prevents ATL cells from integrin-mediated adhesion to endothelial cells or intercellular adhesion molecule-1 triggered through G-protein. We propose that leukemic cells adhere to endothelial cells through the adhesion cascade, similar to normal leukocyte, and that the cell surface heparan sulfate, particularly on ATL cells, is pivotally involved in chemokine-dependent autocrine stimulation of integrin triggering by immobilizing the chemokine on them.
Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193-<b> <i>N</i> </b>-Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts
Authors: Erwin R. Boghaert, Latha Sridharan, Douglas C. Armellino, Kiran M. Khandke, John F. DiJoseph, Arthur Kunz, Maureen M. Dougher, Fan Jiang, Lyka B. Kalyandrug, Philip R. Hamann, Philip Frost, Nitin K. Damle
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Linking a cytotoxic anticancer drug to an antibody that recognizes a tumor-associated antigen can improve the therapeutic index of the drug. We asked whether a conjugate of the cytotoxic antibiotic N-acetyl γ calicheamicin dimethyl hydrazide (CalichDMH) and an antibody recognizing Lewisy (Ley) antigen could eliminate carcinomas that express Ley. Because Ley is highly expressed on carcinomas of colon, breast, lung, ovary, and prostate, a CalichDMH conjugate targeting Ley could provide a treatment option for various cancers. Experimental Design: The humanized anti-Ley antibody hu3S193 was conjugated to CalichDMH via the bifunctional AcBut linker. Selectivity and avidity of the conjugate (hu3S193-CalichDMH) for Ley-BSA or Ley+ cells was tested by BIAcore or flow cytometry. Cytotoxicity of hu3S193-CalichDMH was compared with toxicity of a control conjugate on monolayers of Ley+ and Ley− carcinoma cells. Inhibition of tumor growth by hu3S193-CalichDMH was assessed on three types of s.c. xenografts. Results: Hu3S193-CalichDMH had similar selectivity as hu3S193. The conjugate had lower affinity for Ley-BSA but not for Ley+ cells. When tested on monolayers of human Ley+ carcinoma cells, hu3S193-CalichDMH was more cytotoxic than a control conjugate. This difference in efficacy was not noted on Ley− cells. Efficacy of hu3S193-CalichDMH depended on the expression of Ley and on the sensitivity of the cells to CalichDMH. In vivo, hu3S193-CalichDMH inhibited growth of xenografted human gastric (N87), colon (LOVO), and prostate carcinomas (LNCaP). When used against N87 xenografts, hu3S193-CalichDMH arrested tumor growth for at least 100 days. Conclusion: Hu3S193-CalichDMH can specifically eliminate Ley+ tumors. These results support development of this conjugate for treatment of carcinomas.
Pitfalls in Experimental Design and Data Analysis
Authors: Keith Baggerly
Journal: Clinical Cancer Research (2006)

PL-26  High-throughput molecular assays have the potential to provide us with dozens of new disease markers, which in turn can be used to improve therapy. These markers are often found by using advanced tools to analyze the data, as these tools are very good at finding structure. However, tools that are sensitive enough to pick up subtle shifts in biology are also sensitive enough to pick up shifts due to other causes.In this talk, we will explore the continued need for zeroth-order data analysis, ensuring that potentially large but unwanted effects are excluded before subtle effects are sought. To do this, we will take a pictorial tour through the raw data from case studies, looking for interesting structure both in a single experiment and over mulitple experiments. Unfortunately, in these cases what the data most clearly shows is not biological structure, but rather the need for careful expeimental design, data cleaning, and data preprocessing to ensure that the structure found is not due to systematic bias.These issues are not new, but they remain important as we struggle to validate and regulate new markers.
ONE-STEP GROWTH CURVES OF VARIOUS STRAINS OF INFLUENZA A AND B VIRUSES AND THEIR INHIBITION BY INACTIVATED VIRUS OF THE HOMOLOGOUS TYPE
Authors: Werner Henle, Evelyn B. Rosenberg
Journal: The Journal of Experimental Medicine (1949)

One-step growth curves of five strains of influenza A, one strain of swine influenza, and three strains of influenza B virus have been analyzed. The influenza A and swine influenza strains showed constant periods of 5 to 6 hours before newly formed virus was liberated from the infected cells, whereas 8 to 10 hours elapsed in the case of the influenza B strains. The yield of virus in the allantoic fluids, i.e. the number of ID(50) released for every ID(50) of seed virus adsorbed, was consistently higher in the case of the influenza A and swine influenza strains than in that of the influenza B viruses. Interruption of the cycle by injection of inactivated virus subsequent to infection can be achieved by any of the strains of the homologous type. However, cross-tests between influenza A and swine influenza virus led only to partial inhibition of virus growth.
Expression of targeting protein for xklp2 associated with both malignant transformation of respiratory epithelium and progression of squamous cell lung cancer.
Authors: Ying Ma, Dongmei Lin, Wenyue Sun, Ting Xiao, Jinsong Yuan, Naijun Han, Suping Guo, Xiaoli Feng, Kai Su, Yousheng Mao, Shujun Cheng, Yanning Gao
Journal: Clinical Cancer Research (2006)

Abstract PURPOSE: Expression of targeting protein for Xklp2 (TPX2), a microtubule-associated protein, is tightly cell cycle regulated. Abnormally expressed TPX2 has been reported in various malignancies, but less is known in lung cancer. The present study appraised the significance of TPX2 aberrant expression for tumorigenesis and progression of human squamous cell carcinoma (SCC) in lung. EXPERIMENTAL DESIGN AND RESULTS: The expressive status of TPX2 was firstly examined with lung cancer (L, PAa, and PG) and immortalized bronchial epithelial (C45, M-BE, Tr, and Y-BE) cell lines, and TPX2 expression was detected at both RNA and protein levels by reverse transcription-PCR and Western blotting, respectively. Immunofluorescence staining on M-BE cells showed that the subcellular localization of TPX2 protein is in nucleus at interphase and mitotic spindle at metaphase. Immunohistochemical analyses were subsequently done on the precancerous lesions derived from 114 patients and the tumor tissues of 432 patients with SCC in lung. Extremely low levels of TPX2 protein were found in the normal bronchial epithelia and alveoli, whereas gradually increased TPX2 protein levels were observed in the squamous metaplasia, dysplasia, carcinoma in situ, and invasive tumor tissues. Statistical analysis showed that the TPX2 immunohistochemistry labeling index was correlated with the differentiation grade, stage, and lymphous metastasis of SCC in lung and that TPX2 overexpression is significantly associated with decreased 5-year survival rate of the patients. CONCLUSIONS: Aberrant expression of TPX2 may play important role(s) in both malignant transformation of respiratory epithelium and progression of squamous cell lung cancer and could serve as a prognostic predictor for the disease.
Promoter variants in tissue inhibitor of metalloproteinase-3 (TIMP-3) protect against susceptibility in pigeon breeders' disease
Authors: M R Hill
Journal: Thorax (2004)

<b>Background:</b> Tissue inhibitors of metalloproteinases (TIMPs) play a major role in extracellular matrix turnover in the lung. However, in chronic lung disorders such as idiopathic pulmonary fibrosis (IPF) and pigeon breeders' disease (PBD), TIMPs may promote an adverse non-degradative environment. We hypothesised that polymorphisms in TIMP-3 could affect susceptibility to IPF and PBD. <b>Methods:</b> Two promoter variants, −915A&gt;G and −1296T&gt;C, were genotyped in 323 healthy subjects, 94 subjects with IPF, 115 with PBD, and 90 exposed to avian antigen but without PBD. The severity of fibrosis in lung tissue and the clinical outcome after 1 year was determined in the PBD group. <b>Results:</b> The variants did not influence susceptibility to IPF, but the rare alleles of both variants appeared to be protective against susceptibility to PBD (odds ratio (OR) for carriage of at least one rare allele from either variant 0.48, 95% CI 0.30 to 0.76, p = 0.002). Haplotype analysis of positions −915 and −1296 estimated four haplotypes: *A*T, *G*T, *A*C and *G*C, respectively. Their frequencies differed overall between subjects with PBD and healthy subjects (p = 0.0049) and this was attributable primarily to the *G*C haplotype (OR 0.53, 95% CI 0.36 to 0.77, p = 0.001). The severity of fibrosis correlated with poorer outcome in the PBD group (<i>r</i> = 0.73, p&lt;0.01) but no relationship was seen between the *G*C haplotype and outcome or fibrosis. However, PBD subjects with the *G*C haplotype did have proportionally fewer lymphocytes in their bronchoalveolar fluid than those with the common *A*T haplotype (p = 0.029). <b>Conclusions:</b> TIMP-3 variants appear to contribute to susceptibility to PBD. This may be through the inflammatory reaction rather than the fibrotic reaction.
Severe acute respiratory syndrome (SARS)
Authors: M. Woodhead, S. Ewig, A. Torres
Journal: European Respiratory Journal (2003)

In the second week of March of this year, the World Health Organization (WHO) received reports of >150 cases of acute respiratory illness associated with pneumonia 1. The majority of these cases were from the South-East Asian countries of China (including Hong Kong), Vietnam, Indonesia, the Philippines and Singapore. The appearance of many cases over a short time period, the absence of a clear causative pathogen, the apparent spread between countries and the death of some cases led to the issue of a global alert. The subsequent increase in the number of cases in this region and the identification of possible cases in distant countries, such as Germany, Canada and the UK (table 1⇓), increased alarm that a transmissible agent was causing an epidemic that was being further spread by easy access to air travel. Alarm was fed by the prior report of the deaths of two members of a family from Hong Kong with H5 N1 influenza virus infection presumed to have been acquired from birds on the Chinese mainland and the reporting of an earlier outbreak of respiratory infection of unknown cause in the Guangdong Province in China that had affected >300 individuals of whom three died.

View this table:

Table 1 
Cumulative number of reported cases of severe acute respiratory syndrome (SARS) to March 29 2003



The WHO took a pivotal role in the investigation of the outbreak, with the development of a case definition for severe acute respiratory syndrome (SARS) (fig. 1⇓) 1. Global Outbreak Alert and Response teams assisted in outbreak management and the collection of epidemiological and clinical data to improve the understanding of the condition. A …
Type 2 diabetes severely impairs structural and functional adaptation of rat resistance arteries to chronic changes in blood flow
Authors: Eric J. Belin de Chantemèle, Emilie Vessières, Anne-Laure Guihot, Bertrand Toutain, Maud Maquignau, Laurent Loufrani, Daniel Henrion
Journal: Cardiovascular Research (2008)

Endothelial dysfunction in resistance arteries (RAs) leads to end-organ damage in type 2 diabetes. Remodelling of RAs in response to chronic increases in blood flow depends on the integrity of the endothelium. Since type 2 diabetes impairs endothelial sensitivity to flow and increases oxidative stress, we hypothesized that flow-induced remodelling in RAs would be impaired in diabetes. Thus, we studied the structural and functional adaptation of RAs from Zucker diabetic fatty (ZDF) and lean Zucker (LZ) rats to chronic changes in flow.Mesenteric RAs were alternatively ligated so that one artery was submitted to high flow (HF) and compared with normal-flow (NF) arteries located at distance. After 3 weeks, arteries were studied in vitro (n = 10 rats per group). Arterial diameter (468 vs. 394 +/- 8 microm) and endothelial (acetylcholine)-dependent dilation (91 +/- 8 vs. 75 +/- 6% dilation) were higher in HF than in NF arteries in LZ rats. In ZDF rats, diameter (396 +/- 9 vs. 440 +/- 17 microm) and acetylcholine-mediated dilation (42 +/- 8 vs. 75 +/- 7%) were lower in HF than in NF arteries. Nevertheless, endothelial NO synthase and NADP(H) oxidase subunits (gp91, p67) expression level and superoxide production (dihydroethidium staining) were higher in HF than in NF arteries in both strains, suggesting an efficient flow-sensing process in ZDF rats. In ZDF rats, basal oxidative stress was higher compared with LZ rats: dihydroethidium staining was higher in NF and HF arteries from ZDF rats, and acetylcholine-mediated dilation was improved by an acute antioxidant (tempol) in NF and HF arteries from ZDF rats. Thus, superoxide overproduction in ZDF rats impaired NO-dependent dilation and HF remodelling. Indeed, a chronic treatment with tempol increased HF artery diameter and endothelium-dependent dilation in ZDF rats.In type 2 diabetic rats, a chronic increase in blood flow failed to induce outward remodelling and to improve endothelium-dependent dilation, mainly because of superoxide overproduction.
Patients' Expectations about Effects of Chemotherapy for Advanced Cancer
Authors: Jane C. Weeks, Paul J. Catalano, Angel Cronin, Matthew D. Finkelman, Jennifer W. Mack, Nancy L. Keating, Deborah Schrag
Journal: New England Journal of Medicine (2012)

Chemotherapy for metastatic lung or colorectal cancer can prolong life by weeks or months and may provide palliation, but it is not curative.We studied 1193 patients participating in the Cancer Care Outcomes Research and Surveillance (CanCORS) study (a national, prospective, observational cohort study) who were alive 4 months after diagnosis and received chemotherapy for newly diagnosed metastatic (stage IV) lung or colorectal cancer. We sought to characterize the prevalence of the expectation that chemotherapy might be curative and to identify the clinical, sociodemographic, and health-system factors associated with this expectation. Data were obtained from a patient survey by professional interviewers in addition to a comprehensive review of medical records.Overall, 69% of patients with lung cancer and 81% of those with colorectal cancer did not report understanding that chemotherapy was not at all likely to cure their cancer. In multivariable logistic regression, the risk of reporting inaccurate beliefs about chemotherapy was higher among patients with colorectal cancer, as compared with those with lung cancer (odds ratio, 1.75; 95% confidence interval [CI], 1.29 to 2.37); among nonwhite and Hispanic patients, as compared with non-Hispanic white patients (odds ratio for Hispanic patients, 2.82; 95% CI, 1.51 to 5.27; odds ratio for black patients, 2.93; 95% CI, 1.80 to 4.78); and among patients who rated their communication with their physician very favorably, as compared with less favorably (odds ratio for highest third vs. lowest third, 1.90; 95% CI, 1.33 to 2.72). Educational level, functional status, and the patient's role in decision making were not associated with such inaccurate beliefs about chemotherapy.Many patients receiving chemotherapy for incurable cancers may not understand that chemotherapy is unlikely to be curative, which could compromise their ability to make informed treatment decisions that are consonant with their preferences. Physicians may be able to improve patients' understanding, but this may come at the cost of patients' satisfaction with them. (Funded by the National Cancer Institute and others.).
Where Does Photodynamic Therapy Fit in the Esophageal Cancer Treatment Jigsaw Puzzle?
Authors: Keyvan Moghissi
Journal: Journal of the National Comprehensive Cancer Network (2012)

Traditional treatment options for esophageal cancer have centered on the triad of surgery, chemotherapy, and radiotherapy. Although surgery remains the gold standard for operable disease, photodynamic therapy (PDT) is emerging as a valid minimally invasive option for select patients with inoperable disease. Years of experience with PDT for esophageal cancer seem to suggest that it may be particularly useful for treatment of early unresectable lesions, palliation of locally advanced disease, and salvage therapy for stent blockage or local tumor recurrence. Further investigation into the ideal role for PDT, perhaps through a comparative study with other nonsurgical options, may help clarify where it fits in the treatment armamentarium for esophageal cancer.
Effective Combination Therapy for Malignant Glioma with TRAIL-Secreting Mesenchymal Stem Cells and Lipoxygenase Inhibitor MK886
Authors: Seong Muk Kim, Ji Sun Woo, Chang Hyun Jeong, Chung Heon Ryu, Jung Yeon Lim, Sin-Soo Jeun
Journal: Cancer Research (2012)

Abstract The apoptotic ligand TRAIL is believed to have promise as a cancer gene therapy, yet many types of cancer, including gliomas, have exhibited resistance to TRAIL-induced apoptosis. Here, we show that therapeutic combination of the lipoxygenase inhibitor MK886 and TRAIL-secreting human mesenchymal stem cells (MSC-TRAIL) provide targeted and prolonged delivery of TRAIL both in vitro and in orthotopic mouse models of glioma. Treatment of either TRAIL-sensitive or TRAIL-resistant human glioma cells with MK886 and MSC-TRAIL resulted in significantly enhanced apoptosis compared with each agent alone. MK886 effectively increased the sensitivity to TRAIL-induced apoptosis via upregulation of the death receptor 5 and downregulation of the antiapoptotic protein survivin in human glioma cell lines and in primary glioma cells. This regulation was accompanied by a substantial increase in caspase activation after combined treatment. Furthermore, in vivo survival experiments and imaging analysis in orthotopic xenografted mice showed that MSC-based TRAIL gene delivery combined with MK886 into the tumors had greater therapeutic efficacy than single-agent treatment. Together, our findings indicate that MK886 combined with MSC-based TRAIL gene delivery may represent a novel strategy for improving the treatment of malignant gliomas. Cancer Res; 72(18); 4807–17. ©2012 AACR.
MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation
Authors: M.-C. Londono, A. Cardenas, M. Guevara, L. Quinto, D. d. l. Heras, M. Navasa, A. Rimola, J.-C. Garcia-Valdecasas, V. Arroyo, P. Gines
Journal: Gut (2007)

<b>Background/Aims:</b> Serum sodium predicts prognosis in cirrhosis and may improve the prognostic accuracy of the model for end-stage liver disease (MELD) score, but the available information is limited. The aim of the present study was to assess the prognostic value of serum sodium in the prediction of survival at 3 and 12 months after listing in patients with cirrhosis awaiting liver transplantation, and to compare its predictive value with that of the MELD score. <b>Patients and methods:</b> 308 consecutive patients with cirrhosis listed for transplantation during a 5-year period were included in the study. The end-point was survival at 3 and 12 months before transplantation. Variables obtained at the time of listing were analysed for prognostic value using multivariable analysis. Accuracy of prognostic variables was analysed by receiver operating characteristic (ROC) curves. <b>Results:</b> The MELD score and serum sodium concentration were the only independent predictors of survival at 3 and 12 months after listing. Low serum sodium was associated with an increased risk of death in all subpopulations of patients with cirrhosis categorised according to the major complication developed before listing. The area under the ROC curves for serum sodium and MELD score was not significantly different both at 3 months (0.83 vs 0.79, respectively) and at 12 months (0.70 vs 0.77, respectively). The addition of serum sodium did not significantly improve the accuracy of the MELD score in the prediction of survival at 3 and 12 months. <b>Conclusion:</b> In patients with cirrhosis awaiting liver transplantation, serum sodium and MELD were found to be independent predictors of survival. Larger studies are needed to determine whether the addition of serum sodium to MELD can improve its prognostic accuracy.
Risks for End-Stage Renal Disease, Cardiovascular Events, and Death in Hispanic versus Non-Hispanic White Adults with Chronic Kidney Disease
Authors: Carmen A. Peralta, Michael G. Shlipak, Dongjie Fan, Juan Ordon[Combining Tilde]ez, James P. Lash, Glenn M. Chertow, Alan S. Go
Journal: Journal of the American Society of Nephrology (2006)

Rates of ESRD are rising faster in Hispanic than non-Hispanic white individuals, but reasons for this are unclear. Whether rates of cardiovascular events and mortality differ among Hispanic and non-Hispanic white patients with chronic kidney disease (CKD) also is not well understood. Therefore, this study examined the associations between Hispanic ethnicity and risks for ESRD, cardiovascular events, and death in patients with CKD. A total of 39,550 patients with stages 3 to 4 CKD from Kaiser Permanente of Northern California were included. Hispanic ethnicity was obtained from self-report supplemented by surname matching. GFR was estimated from the abbreviated Modification of Diet in Renal Disease equation, and clinical outcomes, patient characteristics, and longitudinal medication use were ascertained from health plan databases and state mortality files. After adjustment for sociodemographic characteristics, Hispanic ethnicity was associated with an increased risk for ESRD (hazard ratio [HR] 1.93; 95% confidence interval [CI] 1.72 to 2.17) when compared with non-Hispanic white patients, which was attenuated after controlling for diabetes and insulin use (HR 1.50; 95% CI 1.33 to 1.69). After further adjustment for potential confounders, Hispanic ethnicity remained independently associated with an increased risk for ESRD (HR 1.33; 95% CI 1.17 to 1.52) as well as a lower risk for cardiovascular events (HR 0.82; 95% CI 0.76 to 0.88) and death (HR 0.72; 95% CI 0.66 to 0.79). Among a large cohort of patients with CKD, Hispanic ethnicity was associated with lower rates of death and cardiovascular events and a higher rate of progression to ESRD. The higher prevalence of diabetes among Hispanic patients only partially explained the increased risk for ESRD. Further studies are required to elucidate the cause(s) of ethnic disparities in CKD-associated outcomes.