tbuckley/cabot-search huggingface dataset:
Treatment of chronic respiratory failure: lung volume reduction surgery versus rehabilitation
Authors: M. Decramer
Journal: European Respiratory Journal (2003)

Several treatment options are available for end-stage chronic obstructive pulmonary disease (COPD). Respiratory rehabilitation and lung volume reduction surgery are reviewed here. Respiratory rehabilitation can now be considered a prime treatment for COPD. Indeed, it has been clearly shown to improve exercise capacity and health status in these patients. Improvements in the former fell just below the minimal clinically important difference, whereas those in the latter exceeded it. In addition, after a respiratory rehabilitation programme, a reduction in the number of hospital admissions and duration of each admission was demonstrated. It remains, however, difficult to predict accurately which patients will improve after rehabilitation and which will not. Factors that may contribute to this prediction are: baseline peak exercise ventilation/maximal voluntary ventilation, maximal inspiratory pressure, peripheral muscle force, and 6‐min walking distance. Several studies have clearly shown that training effects are as pronounced in patients with severe as in those with moderate airflow obstruction. This is the most significant insight in this area of the 1990s. Lung volume reduction surgery may also be of benefit in patients with end-stage COPD. It is clear that lung function, exercise capacity and health status improve after this procedure, although the results of only six randomised studies are currently available. It remains difficult to accurately predict which patients will benefit from the procedure. From a model analysis, the most important action mechanism appears to be resizing of the lungs. Only in patients with an increased residual volume/total lung capacity ratio are beneficial effects expected. The model analysis, however, did not fit the experimental data very well in a recent publication. Emphysema heterogeneity is also likely to be related to the response. The question remains as to whether or not lung volume reduction surgery accelerates the decline in forced expiratory volume in one second in the long run. The technique is undergoing considerable progress as numerous new surgical and endoscopic procedures are currently being developed. The results of these procedures have not yet been systematically evaluated.
CXCR4/SDF1 mediate hypoxia induced chondrosarcoma cell invasion through ERK signaling and increased MMP1 expression
Authors: Xiaojuan Sun, Lei Wei, Qian Chen, Richard M Terek
Journal: Molecular Cancer (2010)

Abstract Background Chondrosarcoma is a disease that does not respond to conventional cytotoxic chemotherapy and expression of MMP1 is a marker for a poor prognosis. The mechanism of increased MMP1 expression in chondrosarcoma is not completely known. Our goal is to identify molecular pathways that could serve as therapeutic targets. Chondrosarcoma become hypoxic as they grow, are capable of eliciting an angiogenic response, and typically metastasize to the lungs. The present study determined the effect of hypoxia and specifically HIF-1a on expression of CXCR4 and MMP1 and their role in chondrosarcoma cell invasion. Results CXCR4 and its ligand, SDF1, are upregulated in primary chondrosarcoma tumors compared to normal articular cartilage, and CXCR4 was upregulated in chondrosarcoma cell line JJ compared to normal chondrocytes. Hypoxia and specifically HIF-1a increased CXCR4 and MMP1 expression in JJ cell line and chondrosarcoma invasion in vitro . The hypoxia mediated increase in MMP1 expression and chondrosarcoma invasion could be inhibited by siRNA directed at HIF-1a or CXCR4, the CXCR4 inhibitor AMD3100, as well as with ERK inhibitor U0126 and ERK siRNA. Conclusions Chondrosarcoma cell invasion is increased by hypoxia induced expression of CXCR4 and MMP1 and is mediated by HIF-1a and ERK. Both invasion and MMP1 can be inhibited with CXCR4 blockade, suggesting that CXCR4/SDF1 signaling may be a therapeutic target for chondrosarcoma.
Improved Calibration of the Human Mitochondrial Clock Using Ancient Genomes
Authors: Adrien Rieux, Anders Eriksson, Mingkun Li, Benjamin Sobkowiak, Lucy A. Weinert, Vera Warmuth, Andres Ruiz-Linares, Andrea Manica, François Balloux
Journal: Molecular Biology and Evolution (2014)

Reliable estimates of the rate at which DNA accumulates mutations (the substitution rate) are crucial for our understanding of the evolution and past demography of virtually any species. In humans, there are considerable uncertainties around these rates, with substantial variation among recent published estimates. Substitution rates have traditionally been estimated by associating dated events to the root (e.g., the divergence between humans and chimpanzees) or to internal nodes in a phylogenetic tree (e.g., first entry into the Americas). The recent availability of ancient mitochondrial DNA sequences allows for a more direct calibration by assigning the age of the sequenced samples to the tips within the human phylogenetic tree. But studies also vary greatly in the methodology employed and in the sequence panels analyzed, making it difficult to tease apart the causes for the differences between previous estimates. To clarify this issue, we compiled a comprehensive data set of 350 ancient and modern human complete mitochondrial DNA genomes, among which 146 were generated for the purpose of this study and estimated substitution rates using calibrations based both on dated nodes and tips. Our results demonstrate that, for the same data set, estimates based on individual dated tips are far more consistent with each other than those based on nodes and should thus be considered as more reliable.
p120RasGAP-Mediated Activation of c-Src Is Critical for Oncogenic Ras to Induce Tumor Invasion
Authors: Po-Chao Chan, Hong-Chen Chen
Journal: Cancer Research (2012)

Ras genes are the most common targets for somatic gain-of-function mutations in human cancers. In this study, we found a high incidence of correlation between Ras oncogenic mutations and c-Src activation in human cancer cells. We showed that oncogenic Ras induces c-Src activation mainly on the Golgi complex and endoplasmic reticulum. Moreover, we identified p120RasGAP as an effector for oncogenic Ras to activate c-Src. The recruitment of p120RasGAP to the Golgi complex by oncogenic Ras facilitated its interaction with c-Src, thereby leading to c-Src activation, and this p120RasGAP-mediated activation of c-Src was important for tumor invasion induced by oncogenic Ras. Collectively, our findings unveil a relationship between oncogenic Ras, p120RasGAP, and c-Src, suggesting a critical role for c-Src in cancers evoked by oncogenic mutations in Ras genes.
Anti-tumor Effect of Integrin Targeted <sup>177</sup>Lu-3PRGD<sub>2</sub> and Combined Therapy with Endostar
Authors: Jiyun Shi, Di Fan, Chengyan Dong, Hao Liu, Bing Jia, Huiyun Zhao, Xiaona Jin, Zhaofei Liu, Fang Li, Fan Wang
Journal: Theranostics (2014)

Targeted radiotherapy (TRT) is an emerging approach for tumor treatment. Previously, 3PRGD2 (a dimeric RGD peptide with 3 PEG4 linkers) has been demonstrated to be of advantage for integrin αvβ3 targeting. Given the promising results of (99m)Tc-3PRGD2 for lung cancer detection in human beings, we are encouraged to investigate the radiotherapeutic efficacy of radiolabeled 3PRGD2. The goal of this study was to investigate and optimize the integrin αvβ3 mediated therapeutic effect of (177)Lu-3PRGD2 in the animal model.
Outcomes of Localized Prostate Cancer Following Conservative Management
Authors: Grace L. Lu-Yao, Peter C. Albertsen, Dirk F. Moore, Weichung Shih, Yong Lin, Robert S. DiPaola, Michael J. Barry, Anthony Zietman, Michael O'Leary, Elizabeth Walker-Corkery, Siu Long Yao
Journal: JAMA (2009)

Most newly diagnosed prostate cancers are clinically localized, and major treatment options include surgery, radiation, or conservative management. Although conservative management can be a reasonable choice, there is little contemporary prostate-specific antigen (PSA)-era data on outcomes with this approach.To evaluate the outcomes of clinically localized prostate cancer managed without initial attempted curative therapy in the PSA era.A population-based cohort study of men aged 65 years or older when they were diagnosed (1992-2002) with stage T1 or T2 prostate cancer and whose cases were managed without surgery or radiation for 6 months after diagnosis. Living in areas covered by the Surveillance, Epidemiology, and End Results (SEER) program, the men were followed up for a median of 8.3 years (through December 31, 2007). Competing risk analyses were performed to assess outcomes.Ten-year overall survival, cancer-specific survival, and major cancer related interventions.Among men who were a median age of 78 years at cancer diagnosis, 10-year prostate cancer-specific mortality was 8.3% (95% confidence interval [CI], 4.2%-12.8%) for men with well-differentiated tumors; 9.1% (95% CI, 8.3%-10.1%) for those with moderately differentiated tumors, and 25.6% (95% CI, 23.7%-28.3%) for those with poorly differentiated tumors. The corresponding 10-year risks of dying of competing causes were 59.8% (95% CI, 53.2%-67.8%), 57.2% (95% CI, 52.6%-63.9%), and 56.5% (95% CI, 53.6%-58.8%), respectively. Ten-year disease-specific mortality for men aged 66 to 74 years diagnosed with moderately differentiated disease was 60% to 74% lower than earlier studies: 6% (95% CI, 4%-8%) in the contemporary PSA era (1992-2002) compared with results of previous studies (15%-23%) in earlier eras (1949-1992). Improved survival was also observed in poorly differentiated disease. The use of chemotherapy (1.6%) or major interventions for spinal cord compression (0.9%) was uncommon.Results following conservative management of clinically localized prostate cancer diagnosed from 1992 through 2002 are better than outcomes among patients diagnosed in the 1970s and 1980s. This may be due, in part, to additional lead time, overdiagnosis related to PSA testing, grade migration, or advances in medical care.
Sequential Biochemotherapy Versus Chemotherapy for Metastatic Melanoma: Results From a Phase III Randomized Trial
Authors: Omar Eton, Sewa S. Legha, Agop Y. Bedikian, J. Jack Lee, Antonio C. Buzaid, Cynthia Hodges, Sigrid E. Ring, Nicholas E. Papadopoulos, Carl Plager, Mary Jo East, Feng Zhan, Robert S. Benjamin
Journal: Journal of Clinical Oncology (2002)

PURPOSE: The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b. PATIENTS AND METHODS: Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks. RESULTS: Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P = .001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P = .008); median survival was 11.9 and 9.2 months, respectively (P = .06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects. CONCLUSION: Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.
The Physiology of Stereopsis
Authors: B. G. Cumming, G. C. DeAngelis
Journal: Annual Review of Neuroscience (2001)

Binocular disparity provides the visual system with information concerning the three-dimensional layout of the environment. Recent physiological studies in the primary visual cortex provide a successful account of the mechanisms by which single neurons are able to signal disparity. This work also reveals that additional processing is required to make explicit the types of signal required for depth perception (such as the ability to match features correctly between the two monocular images). Some of these signals, such as those encoding relative disparity, are found in extrastriate cortex. Several other lines of evidence also suggest that the link between perception and neuronal activity is stronger in extrastriate cortex (especially MT) than in the primary visual cortex.
Mechanisms of the bronchoconstrictor effects of deep inspiration in asthmatic patients.
Authors: P Gayrard, J Orehek, C Grimaud, J Charpin
Journal: Thorax (1979)

A single deep inspiration (DI) is commonly followed by transient airflow obstruction in asthmatic patients. In some patients, however, DI results in a sustained response which suggests that more than one mechanism may be responsible. We have studied the characteristics of the response to repeated DI, and their modificatiion by various pharmacological agents, by measuring specific airway resistance (sRaw) in ten subjects who showed reproducible and consistent increases in sRaw after DI. Two types of reaction were observed: type A (n = 8) had an immediate maximum and usually short persistence; type B (n = 2) had a delayed maximum with a progressive increase. In type A reactions repetition of DI showed different patterns of response--either a reproducible reaction to each DI or a plateau effect. In type B reactions the response spontaneously increased with repeated DI. Type A responses to DI were inhibited completely by a beta-adrenergic stimulant (BAS), largely by an anticholinergic drug (AC, ipratropium bromide), but in no case by disodium cromoglycate (DSCG). Type B responses were inhibited completely by BAS, largely by DSCG, and partially by AC. These findings suggest that the response to DI is due to bronchoconstriction, which in type A reactions is of reflex origin, vagally mediated, and is due in part or wholly to mediator-release in type B reactions.
Effects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age.
Authors: Hestien J I Vreugdenhil, Froukje M E Slijper, Paul G H Mulder, Nynke Weisglas-Kuperus
Journal: Environmental Health Perspectives (2002)

Polychlorinated biphenyls (PCBs) and dioxins are known as neurotoxic compounds that may modulate sex steroid hormones. Steroid hormones play a mediating role in brain development and may influence behaviors that show sex differences, such as childhood play behavior. In this study we evaluated the effects of perinatal exposure to environmental levels of PCBs and dioxins on childhood play behavior and whether the effects showed sex differences. As part of the follow-up to the Dutch PCB/dioxin study at school age, we used the Pre-School Activity Inventory (PSAI) to assess play behavior in the Rotterdam cohort (n = 207). The PSAI assesses masculine or feminine play behavior scored on three subscales: masculine, feminine, and composite. Prenatal exposure to PCBs was defined as the sum of PCB 118, 138, 153, and 180 in maternal and cord plasma and breast milk. For breast milk we measured additional PCBs as well as 17 dioxins. Respondents returned 160 questionnaires (age 7.5 years +/- 0.4). Effects of prenatal exposure to PCBs, measured in maternal and cord plasma, on the masculine and composite scales were different for boys and girls (p <.05). In boys, higher prenatal PCB levels were related with less masculinized play, assessed by the masculine scale (p(maternal) =.042; p(cord) =.001) and composite scale (p(cord) =.011), whereas in girls higher PCB levels were associated with more masculinized play, assessed by the composite scale (p(PCBmilk) =.028). Higher prenatal dioxin levels were associated with more feminized play in boys as well as girls, assessed by the feminine scale (p =.048). These effects suggest prenatal steroid hormone imbalances caused by prenatal exposure to environmental levels of PCBs, dioxins, and other related organochlorine compounds.
Human Rhomboid Family-1 Suppresses Oxygen-Independent Degradation of Hypoxia-Inducible Factor-1α in Breast Cancer
Authors: Zhuan Zhou, Fangfang Liu, Zhi-Song Zhang, Feifei Shu, Yangyang Zheng, Li Fu, Lu-Yuan Li
Journal: Cancer Research (2014)

Abstract Intermittent oxygen deficiency in cancers promotes prolonged inflammation, continuous angiogenesis, and increased drug resistance. Hypoxia-inducible factor-1 (HIF1) has a pivotal role in the regulation of cellular responses to oxygen deficiency. The α-subunit of HIF1 (HIF1α) is degraded in normoxia but stabilized in hypoxia. However, the molecular mechanism that controls oxygen-independent degradation of HIF1α has remained elusive. Human rhomboid family-1 (RHBDF1) is a member of a large family of nonprotease rhomboids whose function is basically unknown. We report here that RHBDF1 expression in breast cancer is highly elevated and is strongly correlated with escalated disease progression, metastasis, poor prognosis, and poor response to chemotherapy. We show that RHBDF1 interaction with the receptor of activated protein-C kinase-1 (RACK1) in breast cancer cells prevents RACK1-assisted, oxygen-independent HIF1α degradation. In addition, we show that the HIF1α-stabilizing activity of RHBDF1 diminishes when the phosphorylation of a tyrosine residue on the RHBDF1 molecule is inhibited. These findings are consistent with the view that RHBDF1 is a critical component of a molecular switch that regulates HIF1α stability in cancer cells in hypoxia and that RHBDF1 is of potential value as a new target for cancer treatment. Cancer Res; 74(10); 2719–30. ©2014 AACR.
Calorie Restriction, Aging, and Cancer Prevention: Mechanisms of Action and Applicability to Humans
Authors: Stephen D. Hursting, Jackie A. Lavigne, David Berrigan, Susan N. Perkins, J. Carl Barrett
Journal: Annual Review of Medicine (2003)

Calorie restriction (CR) is the most effective and reproducible intervention for increasing lifespan in a variety of animal species, including mammals. CR is also the most potent, broadly acting cancer-prevention regimen in experimental carcinogenesis models. Translation of the knowledge gained from CR research to human chronic disease prevention and the promotion of healthy aging is critical, especially because obesity, which is an important risk factor for several chronic diseases, including many cancers, is alarmingly increasing in the Western world. This review synthesizes the key biological mechanisms underlying many of the beneficial effects of CR, with a particular focus on the insulin-like growth factor-1 pathway. We also describe some of the opportunities now available for investigations, including gene expression profiling studies, the development of pharmacological mimetics of CR, and the integration of CR regimens with targeted, mechanism-based interventions. These approaches will facilitate the translation of CR research into strategies for effective human chronic disease prevention.
Obama calls on Congress to pass health reform and explains his plan
Authors: J. Hopkins Tanne
Journal: BMJ (2009)

President Barack Obama spelled out his plan for reforming US health care in a speech last night. He insisted that it was the moral thing to do and now was the time to do it.

Previously he has laid out broad principles and relied on Congress to come up with a detailed plan, which led to acrimony and confusion.

“The plan I’m announcing tonight would meet three basic goals,” he said. They are stability and security for people who have health insurance so that they don’t lose it if they change jobs or become ill; insurance for people who don’t have it; and slowing the growth in healthcare costs.

The president spoke before a rare joint session of both houses of Congress, which also included members of his cabinet, justices of the Supreme Court, and dignitaries. His speech was carried live by the major television networks except the conservative Fox News.

“I am not the first president to take up this cause, but I am determined to be the last,” President Obama said, recalling that it was nearly a century since Theodore Roosevelt first called for healthcare reform. Failure to meet the challenge “has led us to a breaking point,” where the working middle class can’t get insurance through their jobs, can’t afford to buy a policy, or …
CLINICAL NOTES ON CHOLERA
Authors: W. L. Lindsay
Journal: BMJ (1854)

Tais subject appears never, in this country especially, to have attracted that amount of scientific attention which its important bearing, not only on the natural history of cholera, but of epidemic diseases in general, unquestionably warrnts and demands.In various parts of the continent and India, and to a slight extent in Scotland, observations on cholera-epizootics and on the diseases of the lower, par- ticulrly the more familiar domestic animals, during epi- demics of cholera, have occasionally been recorded: but this may be said to comprise the bulk of our extant literature on the subject.Notwithstanding that thousands have had daily opportunities during the present and former epi- demies, in country districts-where observations of this kind may be easily made-it is remarkable that few or no facts bearing on this point have been recorded.It is matter of regret that, while a countless amount of labour has been expended in repeatedly going over ground that has been trodden till it is almost barren, in recording mere symptoms or the results of empiric treatment, a boundless field for original research, which promises to be productive of the most valuable results, lies undisturbed before us, or only trenched upon by a few of the more bold and enterprising pioneers of medical science.Many observers in this country deny or disbelieve that the lower animals are subject to cholera, or to any disease having a semblance thereto, maintaining, on the contrary, that cholera is peculiar to man; many more hold in derision the opinion that cholera is transmissible between different species and genera of ani- mals; and very few indeed will be found ready to believe that cholera is propagable from man to the domestic ani- mals, and vice verad, or that such a phenomenon as the transmissibility of disease from man to the brutes is within the bounds of possibility.Though we possess little real in.formation on these points, we have accumulated sufficient data to convince us that these phenomena are not mere speculations or theories, but can be proved to be facts.It is the object of my present paper to point out to observers that this subject and its congeners constitute a wide and important gap in the study of the natural history of cholera, which must be filled up before we can expect to make ad- vances in our knowledge of the intimate nature of this dis- ease; to indicate their important connexion with the study of the laws of epidemics and with medical science in general; and to mention shortly, in detail, the heads of the inquiry which appear to me more immediately to invite re- search and elucidation.Observations ought to be carefully 1. Predisposition.2. Transmissibility, etc., as above.3. Symptomatology.a. Essential symptoms.b.Accidental or accessory symptoms.4. Experimentation on artificial propagability.a. Between different individuals, species, and genera.6.