tbuckley/cabot-search huggingface dataset:
Pyruvate Kinase Triggers a Metabolic Feedback Loop that Controls Redox Metabolism in Respiring Cells
Authors: Nana-Maria Grüning, Mark Rinnerthaler, Katharina Bluemlein, Michael Mülleder, Mirjam M.C. Wamelink, Hans Lehrach, Cornelis Jakobs, Michael Breitenbach, Markus Ralser
Journal: Cell Metabolism (2011)

In proliferating cells, a transition from aerobic to anaerobic metabolism is known as the Warburg effect, whose reversal inhibits cancer cell proliferation. Studying its regulator pyruvate kinase (PYK) in yeast, we discovered that central metabolism is self-adapting to synchronize redox metabolism when respiration is activated. Low PYK activity activated yeast respiration. However, levels of reactive oxygen species (ROS) did not increase, and cells gained resistance to oxidants. This adaptation was attributable to accumulation of the PYK substrate phosphoenolpyruvate (PEP). PEP acted as feedback inhibitor of the glycolytic enzyme triosephosphate isomerase (TPI). TPI inhibition stimulated the pentose phosphate pathway, increased antioxidative metabolism, and prevented ROS accumulation. Thus, a metabolic feedback loop, initiated by PYK, mediated by its substrate and acting on TPI, stimulates redox metabolism in respiring cells. Originating from a single catalytic step, this autonomous reconfiguration of central carbon metabolism prevents oxidative stress upon shifts between fermentation and respiration.
Long term pharmacotherapy of depression
Authors: J G. Edwards
Journal: BMJ (1998)

The high rates of persistent morbidity, recurrence, and death among patients treated for depression 1-2 have highlighted the importance of long term psychological and pharmacological treatment. What evidence do we have that long term drug treatment is effective, and how should we choose between individual drugs?

Long term drug treatment comprises continuation and maintenance treatment. Continuation treatment helps to consolidate recovery from depressive episodes and prevent relapses (worsening of continuing or recently treated episodes). Maintenance or prophylactic treatment helps to prevent occurrence of new episodes and is usually recommended for patients who have had at least three depressive episodes in the preceding five years. The distinction between continuation and maintenance treatment is somewhat arbitrary and may not reflect underlying biological processes, but most researchers agree that four to six months' remission should occur before a recurrence is diagnosed.

Differences in methods between the many trials of long term pharmacological treatment make interpretation difficult, but about 60% of patients who respond to an antidepressant and are then given a placebo remain in remission for …
THE BLOOD CHLORIDES IN PROTEOSE INTOXICATION
Authors: Russell L. Haden, Thomas G. Orr
Journal: The Journal of Experimental Medicine (1928)

Dogs injected with proteose recovered from the intestinal contents of animals with obstruction at different levels show no significant changes in the blood chlorides even with a fatal intoxication. After the intravenous injection of lethal and sublethal doses of Witte's peptone there is little change in the chlorides. Autolyzing liver in the abdominal cavity produces no change in the blood chlorides even with a very great increase in the urea and nonprotein nitrogen. Proteose intoxication is probably not a factor in the characteristic fall in chlorides seen after intestinal and pyloric obstruction.
Identification of the Decay-Accelerating Factor CD55 as a Peanut Agglutinin–Binding Protein and Its Alteration in Non–Small Cell Lung Cancers
Authors: Mitsunori Higuchi, Yuichi Endo, Hiroyuki Suzuki, Fumihiko Osuka, Yutaka Shio, Koichi Fujiu, Ryuzo Kanno, Akio Oishi, Teizo Fujita, Mitsukazu Gotoh
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Peanut agglutinin (PNA) recognizes tumor-associated carbohydrates. In this study, we aimed to identify the core protein harboring PNA-binding sugars in the human lung and to explore the relationship with the pathology of primary non–small cell lung cancers (NSCLC). Experimental Design: PNA lectin blotting was used to detect PNA-binding proteins in the microsomal fraction of lung tissue from 24 patients with NSCLC. The 55- to 65-kDa core peptide PNA-binding protein was characterized by enzymatic treatment and identified by immunoprecipitation and affinity chromatography. The expression level and increase in size of the 55- to 65-kDa PNA-binding protein/decay-accelerating factor (DAF) were compared between normal and tumor regions of the tumor tissue by Western blotting and quantitative PCR. Results: The 55- to 65-kDa PNA-binding protein was observed in human lung. This was a glycosylphosphatidylinositol-anchored membrane protein carrying O-linked carbohydrates. This core protein was identified as DAF, one of the complementary regulatory proteins. DAF was enlarged to 65 to 75 kDa in NSCLC tumor lesions due to sialylation in the sugar moiety. At the transcription level, DAF levels were significantly lower in tumor regions, suggesting its down-regulation in NSCLC cells. Conclusions: DAF was identified as a new PNA-binding protein in the human lung. The down-regulation and heavy sialylation of DAF was associated with pathology in NSCLC, and these alterations make this protein a potential marker for NSCLC.
Towards a Data Sharing Culture: Recommendations for Leadership from Academic Health Centers
Authors: Heather A Piwowar, Michael J Becich, Howard Bilofsky, Rebecca S Crowley
Journal: PLoS Medicine (2008)

Sharing biomedical research and health care data is important but difficult.Recognizing this, many initiatives facilitate, fund, request, or require researchers to share their data [1][2][3][4][5] .These initiatives address the technical aspects of data sharing, but rarely focus on incentives for key stakeholders [6].Academic health centers (AHCs) have a critical role in enabling, encouraging, and rewarding data sharing.The leaders of medical schools and academic-affiliated hospitals can play a unique role in supporting this transformation of the research enterprise.We propose that AHCs can and should lead the transition towards a culture of biomedical data sharing.
Mortality caused by stomach cancer after remote partial gastrectomy for benign conditions: 40 years of follow up of an Amsterdam cohort of 2633 postgastrectomy patients.
Authors: G J Offerhaus, A C Tersmette, K Huibregtse, J van de Stadt, K W Tersmette, T Stijnen, P J Hoedemaeker, J P Vandenbroucke, G N Tytgat
Journal: Gut (1988)

Mortality caused by stomach cancer was analysed in a cohort of 2633 postgastrectomy patients who underwent surgery for benign conditions in the academic medical centre of the University of Amsterdam between 1931-1960. In comparison with mortality from gastric cancer in the general Dutch population, the observed versus expected ratio in the postgastrectomy group was significantly increased among women, after a postoperative latency of more than 15 years (O/E: 4.77; p = 0.011) and among men after a postoperative latency of more than 25 years (O/E: 3.13; p = 0.005). The analysis confirms that the discrepancies in risk appraisal which seem to exist between reports published in Europe and the USA may be explained by the differences in length of follow up in these studies.
Spirometric Pulmonary Function in Healthy Preschool Children
Authors: HOWARD EIGEN, HARVEY BIELER, DEBRA GRANT, KATHY CHRISTOPH, DELANA TERRILL, DOUGLAS K. HEILMAN, WALTER T. AMBROSIUS, ROBERT S. TEPPER
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The purpose of this study was to evaluate spirometric lung function in normal children ages 3 to 6 yr. Spirometric measurements were obtained at nursery and daycare centers by experienced pediatric pulmonary function technicians. Of 307 children recruited, 259 fulfilled our criteria as normal. Of these, 82.6% (214) were able to perform technically acceptable and reproducible maneuvers during a testing session limited to 15 min. The regression model with log-transformed parameters of pulmonary function and height had the best correlations. After accounting for height in the model, other physical traits and health questionnaire items did not contribute significantly. PEFR, FVC, FEV1, and FEF25–75 all increased with increasing height; correlation coefficients were 0.73, 0.93, 0.92, and 0.67, respectively. The group mean coefficients of variation for replicate measurements of PEFR, FVC, FEV1, and FEF25–75 were 7.8%, 2.5%, 2.7%, and 8.3%, respectively. There was a significant decrease in the ratio FEV1/FVC with increasing height; the mean predicted FEV1/FVC was 0.97 at 90 cm height and 0.89 at 125 cm height. In conclusion, reproducible spirometry can be obtained in the majority of preschool children and has the potential to improve our assessment and management of pulmonary disease.
Tyrosine Phosphoproteomics Identifies Both Codrivers and Cotargeting Strategies for T790M-Related EGFR-TKI Resistance in Non–Small Cell Lung Cancer
Authors: Takeshi Yoshida, Guolin Zhang, Matthew A. Smith, Alex S. Lopez, Yun Bai, Jiannong Li, Bin Fang, John Koomen, Bhupendra Rawal, Kate J. Fisher, Ann Y. Chen, Michiko Kitano, Yume Morita, Haruka Yamaguchi, Kiyoko Shibata, Takafumi Okabe, Isamu Okamoto, Kazuhiko Nakagawa, Eric B. Haura
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Irreversible EGFR-tyrosine kinase inhibitors (TKI) are thought to be one strategy to overcome EGFR-TKI resistance induced by T790M gatekeeper mutations in non–small cell lung cancer (NSCLC), yet they display limited clinical efficacy. We hypothesized that additional resistance mechanisms that cooperate with T790M could be identified by profiling tyrosine phosphorylation in NSCLC cells with acquired resistance to reversible EGFR-TKI and harboring T790M. Experimental Design: We profiled PC9 cells with TKI-sensitive EGFR mutation and paired EGFR-TKI–resistant PC9GR (gefitinib-resistant) cells with T790M using immunoaffinity purification of tyrosine-phosphorylated peptides and mass spectrometry–based identification/quantification. Profiles of erlotinib perturbations were examined. Results: We observed a large fraction of the tyrosine phosphoproteome was more abundant in PC9- and PC9GR-erlotinib–treated cells, including phosphopeptides corresponding to MET, IGF, and AXL signaling. Activation of these receptor tyrosine kinases by growth factors could protect PC9GR cells against the irreversible EGFR-TKI afatinib. We identified a Src family kinase (SFK) network as EGFR-independent and confirmed that neither erlotinib nor afatinib affected Src phosphorylation at the activation site. The SFK inhibitor dasatinib plus afatinib abolished Src phosphorylation and completely suppressed downstream phosphorylated Akt and Erk. Dasatinib further enhanced antitumor activity of afatinib or T790M-selective EGFR-TKI (WZ4006) in proliferation and apoptosis assays in multiple NSCLC cell lines with T790M-mediated resistance. This translated into tumor regression in PC9GR xenograft studies with combined afatinib and dasatinib. Conclusions: Our results identified both codrivers of resistance along with T790M and support further studies of irreversible or T790M-selective EGFR inhibitors combined with dasatinib in patients with NSCLC with acquired T790M. Clin Cancer Res; 20(15); 4059–74. ©2014 AACR.
Longitudinal Evaluation of Airway Function 21 Years after Preterm Birth
Authors: Indra Narang, Mark Rosenthal, David Cremonesini, Mike Silverman, Andrew Bush
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

There are limited longitudinal data about respiratory morbidity and lung function after preterm birth into adulthood.To determine the evolution of respiratory symptoms, spirometry, and airway hyperresponsiveness of ex-preterm subjects from childhood into adulthood.Ex-preterm subjects (median birth weight, 1,440 g; median gestation, 31.5 wk), recruited at birth (not treated with surfactant), had excess respiratory symptoms, airway obstruction, and increased airway hyperresponsiveness in mid-childhood. At a median age of 21.7 years, 60 of these subjects (the index study group) and 50 healthy term control subjects were recruited to determine respiratory morbidity and spirometry.Respiratory symptom questionnaire, spirometry, and methacholine challenge test. The index study group had significantly more respiratory symptoms (16 of 60) than did control subjects (4 of 50) (odds ratio, 4.2; 95% confidence interval, 1.3 to 13.5; P = 0.01), but no significant difference in measured spirometry. Specifically, in the index study group and control subjects, the mean z scores (95% confidence interval of the group difference) for the FEV(1) were -0.60 and -0.58 (-0.44 to 0.49), respectively (P = 0.92); for the forced mid-expiratory flow they were -1.02 and -0.86 (-0.33 to 0.64), respectively (P = 0.52); and for the FVC they were -0.29 and -0.33 (-0.46 to 0.38), respectively (P = 0.85). Ex-preterm adults did not show evidence of increased airway hyperresponsiveness compared with control subjects, 23 and 19%, respectively (P = 0.89).There are still excess respiratory symptoms 21 years after preterm birth. Reassuringly, this longitudinal study did not show evidence of persistent airway obstruction or airway hyperresponsiveness in ex-preterm adults.
Therapeutic drug management: is it the future of multidrug-resistant tuberculosis treatment?
Authors: Shashikant Srivastava, Charles A. Peloquin, Giovanni Sotgiu, Giovanni Battista Migliori
Journal: European Respiratory Journal (2013)

Multidrug- and extensively drug-resistant (M/XDR) tuberculosis (TB) are emerging public health concerns [1, 2]. In 2011, the World Health Organization (WHO) estimated 12 million prevalent cases of TB globally, which is equivalent to 170 cases per 100 000 population, out of these an estimated 630 000 cases were affected by MDR Mycobacterium tuberculosis strains [3]. Among the newly diagnosed patients ∼3.7% were infected by MDR-TB strains, but the worrisome fact is that the prevalence of MDR-TB among new cases in some Former Soviet Union countries exceeds 30% [4, 5], XDR-TB has been identified in 84 countries and the average proportion of MDR-TB cases with an XDR-TB pattern is 9.0% [3]. Further adding to the problem are the reports of “totally drug resistant” TB [6, 7], a term currently not recognised by WHO [8, 9].

Treatment of drug resistant TB is more expensive and more toxic if compared with that prescribed for drug-susceptible TB, and currently takes up to 2 years of therapy [10]. The cost per patient to treat MDR-TB cases is incredibly high [11, 12] and, in spite of international public health efforts, the treatment outcome is not very promising [13–15]. Diel et al. [16] showed that direct treatment-related costs of MDR-TB patients can amount to €52 259 in Germany (table 1).

View this table:

Table 1– Direct costs of multidrug-resistant tuberculosis (MDR-TB) therapy in a European low-income country 

In the largest MDR-TB cohort analysed to date [13] the proportion of cases treated successfully was 62%, with 7% failing or relapsing, 9% dying and 17% defaulting; in the XDR-TB subgroup 40% achieved treatment success, 22% failed treatment or relapsed, whereas 15% died and 16% defaulted [14, 15].

In this issue of the …
BLT1 antagonist LSN2792613 reduces infarct size in a mouse model of myocardial ischaemia–reperfusion injury
Authors: Vince C. de Hoog, Sandra M. Bovens, Saskia C.A. de Jager, Ben J. van Middelaar, Amerik van Duijvenvoorde, Pieter A. Doevendans, Gerard Pasterkamp, Dominique P.V. de Kleijn, Leo Timmers
Journal: Cardiovascular Research (2015)

Restoration of coronary blood flow is crucial in the treatment of acute myocardial infarction. Reperfusion, however, induces ischaemia–reperfusion (IR) injury, which further deteriorates myocardial function. The innate immune system plays an important role in this process, mediating rapid influx of immune cells into the reperfused myocardium. Leukotriene B4 is an important leucocyte chemoattractant, performing its actions through binding to its specific receptor BLT1. We hypothesized that treatment with LSN2792613, a selective BLT1 antagonist, reduces infarct size (IS) in a mouse model of myocardial IR injury. Male C57Bl/6J mice were subjected to myocardial ischaemia for 30 min by surgical coronary artery ligation, followed by reperfusion. Mice received either LSN2792613 or vehicle, three times daily (orally) for up to 72 h after reperfusion. BLT1 inhibition with LSN2792613 reduced IS compared with vehicle treatment (26.9 ± 2.7 vs. 34.9 ± 2.2%, P = 0.030) at 24 h after reperfusion. The levels of IL-6 and keratinocyte chemoattractant were reduced in the infarcted tissue of LSN2792613-treated mice. Reduced apoptosis in LSN2792613-treated mice was suggested by increased levels of phosphorylated JNK and GSK3α/β, and confirmed by flow cytometric analysis showing less apoptotic and necrotic cardiomyocytes in the infarcted myocardium. Echocardiography at 4 weeks after myocardial IR showed a slightly higher ejection fraction and stroke volume in mice treated with LSN2792613 compared with vehicle-treated mice, whereas left ventricular volumes were comparable. Selective BLT1 inhibition with LSN2792613 reduces inflammation and apoptosis following IR, resulting in reduced IS, and therefore might be a promising strategy to prevent myocardial IR injury.
Solving the Cardiac Hypertrophy Riddle
Authors: Daniela Zablocki, Junichi Sadoshima
Journal: Circulation Research (2013)

A series of studies conducted 20 years ago, documenting the cardiac hypertrophy phenotype and its underlying signaling mechanism induced by angiotensin II (Ang II) and mechanical stress, showed a remarkable similarity between the effect of the Gαq agonist and that of mechanical forces on cardiac hypertrophy. Subsequent studies confirmed the involvement of autocrine/paracrine mechanisms, including stretch-induced release of Ang II in load-induced cardiac hypertrophy. Recent studies showed that the Ang II type 1 (AT1) receptor is also directly activated by mechanical forces, suggesting that AT1 receptors play an important role in mediating load-induced cardiac hypertrophy through both ligand- and mechanical stress-dependent mechanisms.
Vaccination Against Dengue: Challenges and Current Developments
Authors: Bruno Guy, Jean Lang, Melanie Saville, Nicholas Jackson
Journal: Annual Review of Medicine (2015)

Dengue is a growing threat worldwide, and the development of a vaccine is a public health priority. The completion of the active phase of two pivotal efficacy studies conducted in Asia and Latin America by Sanofi Pasteur has constituted an important step. Several other approaches are under development, and whichever technology is used, vaccine developers face several challenges linked to the particular nature and etiology of dengue disease. We start our review by defining questions and potential issues linked to dengue pathology and presenting the main types of vaccine approaches that have explored these questions; some of these candidates are in a late stage of clinical development. In the second part of the review, we focus on the Sanofi Pasteur dengue vaccine candidate, describing the steps from research to phase III efficacy studies. Finally, we discuss what could be the next steps, before and after vaccine introduction, to ensure that the vaccine will provide the best benefit with an acceptable safety profile to the identified target populations.
Photocrosslinkable Gelatin Hydrogel for Epidermal Tissue Engineering
Authors: Xin Zhao, Qi Lang, Lara Yildirimer, Zhi Yuan Lin, Wenguo Cui, Nasim Annabi, Kee Woei Ng, Mehmet R. Dokmeci, Amir M. Ghaemmaghami, Ali Khademhosseini
Journal: Advanced Healthcare Materials (2015)

Natural hydrogels are promising scaffolds to engineer epidermis. Currently, natural hydrogels used to support epidermal regeneration are mainly collagen‐ or gelatin‐based, which mimic the natural dermal extracellular matrix but often suffer from insufficient and uncontrollable mechanical and degradation properties. In this study, a photocrosslinkable gelatin (i.e., gelatin methacrylamide (GelMA)) with tunable mechanical, degradation, and biological properties is used to engineer the epidermis for skin tissue engineering applications. The results reveal that the mechanical and degradation properties of the developed hydrogels can be readily modified by varying the hydrogel concentration, with elastic and compressive moduli tuned from a few kPa to a few hundred kPa, and the degradation times varied from a few days to several months. Additionally, hydrogels of all concentrations displayed excellent cell viability (&gt;90%) with increasing cell adhesion and proliferation corresponding to increases in hydrogel concentrations. Furthermore, the hydrogels are found to support keratinocyte growth, differentiation, and stratification into a reconstructed multilayered epidermis with adequate barrier functions. The robust and tunable properties of GelMA hydrogels suggest that the keratinocyte laden hydrogels can be used as epidermal substitutes, wound dressings, or substrates to construct various in vitro skin models.
Intra- and Interspecific Variation of the CCR5 Gene in Higher Primates
Authors: Yun-wu Zhang, Oliver A Ryder, Ya-ping Zhang
Journal: Molecular Biology and Evolution (2003)

We have evaluated the molecular evolution of the chemokine receptor CCR5 in primates. The chemokine receptor CCR5 serves as a major co-receptor for human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection. Knowledge of evolution of the CCR5 molecule and selection on the CCR5 gene may shed light on its functional role. The comparison of differences between intraspecific polymorphisms and interspecific fixed substitutions provides useful information regarding modes of selection during the course of evolution. There is marked polymorphism in the CCR5 gene sequence within different primate species, whereas sequence divergence between different species is small. By using contingency tests, we compared synonymous (SS) and nonsynonymous (NS) CCR5 mutations occurring within and between a broad range of primates. Our results demonstrate that CCR5 evolution did not follow expectations of strict neutrality at the level of the whole gene. The proportion of NS to SS at the intraspecific level was significantly higher than that observed at the interspecific level. These results suggest that most CCR5 NS polymorphisms are slightly deleterious. However, at domains more closely correlated with its known biological functions, there was no obvious evidence to support deviation from neutrality.