tbuckley/cabot-search huggingface dataset:
Analysis of signal pathway activation in hepatocellular carcinoma: Association with clinical outcomes to sorafenib in Chinese patients
Authors: Y. Ji, J. Fan, L. Zhang, Y. Tan, J. Zhou, H. Zeng, Z. Ren, J. Xu
Journal: Journal of Clinical Oncology (2009)

e15529 Background: The pathogenesis of hepatocellular carcinoma invovles multi-stage development of molecular aberrations affecting signaling pathways that regulate cancer growth and progression. Treatment strategies have focused on inhibition of the Ras effector pathway with inhibitors of Raf, such as sorafenib in HCC. Greater understanding of the cellular response to sorafenib is needed to tailor targeted therapy for individual patients and identify those more likely to benefit. Methods: We performed immunohistochemistry on a tissue microarray of tumor and adjacent liver tissue from 40 HBV-infected HCC patients who were treated with sorafenib, and 20 normal liver. We compared the levels of 8 signaling proteins including growth factor receptors (PDGFRa, VEGFR1, VEGFR2, VEGFR3, c-kit, c-met, IGF-R, EGFR), tumor suppressors (PTEN) and their downstream phosphorylated (p-) signal transducers (p-RAF, p-MEK1/2, p-ERK1/2; PI3K, p-AKT, NF kB , axin, β-catenin,p-GSK3β, p-mTOR, p-S6, p-70S6K, p-JNK, p-SRC, p-STAT3, c-fos, c-jun) in cancer cells and endothelial cells of HCC to those in non-neoplastic liver. Results: The overall profiles of signalling protein expression levels, activation states and subcellular distribution in HCC cells and endothelial cells were distinguishable from non-neoplastic hepatocytes. The ERK pathway activation was correlated with low level of nuclear β-cat and high level of p-mTOR (p&lt;0.05). Long survival (&gt;6m) patients were characterized by high level of nuclear pERK and low level of p-AKT, p-GSK3β (p&lt;0.05) in tumor cells. The high microvessel density and the presence of micrometastases correlated with high level of VEGFR, p-ERK and p-SRC in endothelial cells. Conclusions: Sorafenib may affect signalling through the Ras/Raf/MAPK/ERK pathway. HBV-related HCC patients with. overactivation of signal transduction cascade MAPK/ERK and PI3K/AKT pathways in tumor cells and/or endothelial cells may benefit from the targeted treatment. No significant financial relationships to disclose.
Preparedness for Pandemic Influenza in Nursing Homes: A 2-State Survey
Authors: Philip W. Smith, Valerie Shostrom, Al Smith, Michael Kaufmann, Lona Mody
Journal: JAMA (2008)

To the Editor: An influenza pandemic would be expected to have major social and economic consequences.Hospital bed capacity may be quickly overwhelmed in an influenza pandemic, 1 and government plans are looking at alternate care sites. 2 Nursing homes care for a very vulnerable population and may be expected to help with hospital patient overflow. 3,4The extent of influenza pandemic preparedness in nursing homes is largely unknown. 5 MethodsAll 656 state health department-registered nursing homes were identified in 2 states chosen as a convenience sample: Nebraska (n=231) and Michigan (n=425).A questionnaire to assess their pandemic preparedness was developed with input from various stakeholders and mailed to the directors of nursing in June 2007 with a follow-up mailing in July 2007.The questionnaire was designed to gather demographic data and information on aspects of
A one year double blind follow-up of blood gas tensions and haemodynamics in almitrine bismesylate therapy
Authors: C Prefaut, D Bourgouin-Karaouni, M Ramonatxo, FB Michel, J Macabies
Journal: European Respiratory Journal (1988)

Almitrine bismesylate, a chemoreceptor agonist, improves blood gases in chronic obstructive lung disease (COLD). Some authors have observed an increase in pulmonary artery pressure (Ppa) after single doses of almitrine bismesylate (A). This led to the present one year double blind placebo (P) controlled study to assess haemodynamic effects of long-term oral treatment in COLD (1.5 mg/kg/day for one year), together with clinical benefit and blood gas improvement. Twenty moderately severe patients entered the study, fifteen of whom completed it (eight in group (A), seven in group (P]. Blood gas values, minute ventilation (VE), mean pulmonary artery pressure (Ppa) and cardiac output (Qc) were periodically measured. Ppa and Qc remained unchanged in both groups throughout the study. We observed relevant clinical improvement without side effects and no significant increase in VE in group (A). Arterial oxygen tension (PaO2) showed a 1.2 kPa (9 mmHg) mean increase in group (A) and remained unchanged in group (P). These data and those from the literature seem to indicate that almitrine induces a vascular effect, especially after a single dose. However, as long as PaO2 improves simultaneously no long-term haemodynamic consequence is apparent. The discrepancy between immediate and long-term vascular effects of almitrine might be explained by the improvement in gas exchange which could reduce and/or counter-balance the vasoactive response. In conclusion, after one year of therapy almitrine bismesylate results in considerable clinical and blood gas improvements without significant haemodynamic change.
Nutritional Support for Adults and Children
Authors: S Gabe
Journal: Gut (2004)

Edited by T Bowling. Oxford: Radcliffe Medical Press, 2004, £24.95, pp 181. ISBN 1 85775 831 5

On behalf of BAPEN (British Association of Parenteral and Enteral Nutrition), Tim Bowling has managed to bring together three doctors (one physician, one paediatrician, and one surgeon), two nurse specialists, two pharmacists, as …
Adaptations mediated by Akt via ATP citrate lyase and glycogen synthase kinase-3 to enhance glycolysis in astrocytoma pseudopodia
Authors: Marie E. Beckner, Naomi R. Agostino, Zhe Zhang, Billy W. Day, Ian F. Pollack
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1816 

Malignant astrocytomas are lethal brain tumors that resist all therapies. Astrocytoma cell lines (U87 and LN229) display robust migration despite inhibition of mitochondria respiration, such as encountered in hypoxia. Whereas acidosis regulates glycolysis in normal cells, especially when they are disconnected from the vasculature, activated Akt putatively promotes mechanisms in tumor cells to remove metabolic acids intracellularly. Previous studies investigated Akt mediated signaling that putatively promoted removal of lactic acid via gluconeogenesis and glycogenesis. Akt’s phosphorylation of glycogen synthase kinase-3 (GSK3) that led to removal of GSK3’s constitutive inhibition of glycogen synthase (GS) by phosphorylation was associated with only a slight plateau of extracellular levels of lactic acid released by actively migrating cells under hypoxic conditions. Glycolytic migration was sensitive to inhibition of gluconeogenesis and control of Akt by phosphatase and tensin homolog (PTEN) and inhibition of phosphatidylinositol-3 kinase (PI3K). Lactic acid levels from intact cells rose when PTEN was restored to mutated cells (Beckner et al., Lab Invest, (in press) online 9/19/05). Citric acid with 3 carboxyl groups constitutes another potential contribution to acidosis in hypoxia. As the first intermediate of the Kreb’s cycle, citric acid is released by inactive mitochondria to the cytosol. Akt phosphorylates ATP citrate lyase (ACL) (Berwick et al., J Biol Chem 277:33895-900, 2002). ACL metabolizes cytosolic citrate to products that can be incorporated into cell constituents ([Fig. 1][1]). ACL is the most abundant endogenous protein increased in U87 pseudopodia compared to whole cells, as identified in 1D gels. Increased pseudopodial ACL was confirmed on U87 and LN229 immunoblots. Radicicol, an inhibitor of ACL (Ki et al., J Biol Chem 15:39231-6, 2000), inhibited (p < 0.01) hepatocyte growth factor-stimulated U87 migration in dose curves (at least 68.5 μM). Both ACL and GS, as a result of Akt’s activity, potentially mediate avoidance of metabolic acidosis to permit glycolysis in hypoxic conditions such as invasion. Funding from the Nick Eric Wichman Foundation. 

![Figure][2]  [1]: #F1
 [2]: pending:yes
Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: a Randomized Medical Research Council/European Organization for Research and Treatment of Cancer study.
Authors: S B Kaye, G M Mead, S Fossa, M Cullen, R deWit, I Bodrogi, C van Groeningen, R Sylvester, L Collette, S Stenning, L De Prijck, E Lallemand, P deMulder
Journal: Journal of Clinical Oncology (1998)

PURPOSE The aim of this randomized trial was to assess the potential therapeutic advantage of an intensive induction-sequential chemotherapy schedule (bleomycin, vincristine, cisplatin [BOP])/etoposide, ifosfamide, cisplatin, and bleomycin [VIP-B]), compared with a regimen based on bleomycin, etoposide, and cisplatin (BEP) (BEP/etoposide and cisplatin [EP]) for the treatment of patients with poor-prognosis metastatic nonseminomatous germ cell tumors (NSGCTs). PATIENTS AND METHODS Patients had one or more of the following: a retroperitoneal mass &gt; or = 10 cm in diameter; mediastinal or supraclavicular mass &gt; or = 5 cm in diameter; at least 20 lung metastases (any size); liver, bone, or brain metastases; and serum beta human chorionic gonadotropin (betaHCG) &gt; or = 10,000 IU/L or alfa fetoprotein (AFP) &gt; or = 1,000 IU/L. A total of 380 patients were accrued between May 1990 and June 1994 into this joint Medical Research Council (MRC)/European Organization for Research and Treatment of Cancer (EORTC) trial; of these, nine patients were deemed ineligible. RESULTS There was no significant difference between the two arms in the proportion of patients who achieved a complete response (CR) with chemotherapy alone, ie, 79 of 185 assessable patients (57%) with BEP/EP and 72 of 186 (54%) with BOP/VIP-B (P = 0.687). With a median follow-up of 3.1 years (maximum, 5.8), a total of 107 patients (28%) had progressive disease. There was no significant difference in time to first disease progression, or failure-free or overall survival between the two arms (P = 0.21, 0.101, and 0.190, respectively). The 1-year failure-free survival rates for BEP/EP and BOP/VIP-B were 60% (95% confidence interval [CI], 53% to 67%) and 53% (95% CI, 47% to 61%). Grade 3 or 4 myelosuppression, febrile neutropenia, and weight loss were more pronounced with BOP/VIP-B than with BEP/EP, and there were more toxic deaths with BOP/VIP-B than BEP/EP (18 [9%] v nine [5%]). CONCLUSION The intensive BOP/VIP-B therapy was associated with more toxicity, but there was no evidence of an improvement in response rate or survival compared with treatment with BEP/EP.
The management of post-intubation/tracheostomy stenosis with silicone stent
Authors: Ji-Hyun Kim, Jeong-Eun Kim, Kyung Woo Kang
Journal: European Respiratory Journal (2011)

Benign tracheal stenosis in adult patients may occur as a complication of intubation, tracheostomy or surgical procedure. Silicone airway stenting has opened up a new way to treat patients with post-intubation stenosis.We investigated the clinical efficacy through a review of patients with post-intubation stenosis who underwent consecutive Natural silicone stent.

Between January 2005 and December 2009, 19 patients underwent ballooning, ablation using electro-surgical unit, or bougienation by rigid bronchoscopy, followed by placement of the Natural stent. All patients reported subjective symptomatic relief immediately after stent placement. Spirometry data was collected at baseline, 3 month, and 24 month. The baseline and follow-up spirometry data was available in 11 patient. The baseline median FEV1% predicted was 40% (range, 22% to 62%). Follow-up spirometry data showed 37% improvement (range, 19% to 74%) at 3 month later, and 41% improvement (range, 21% to 77%) at 24 month later:

![Figure][1] 



The Natural stent were removed successfully in 10 patients (52.6%) after median of 16months. Other 5 patients (26.3%) were required re-stenting, and 4 patients died due to acute pulmonary edema with ESRD, myocardial infarction, intracranial hemorrhage.The Natural silicone stent proved to be effective and feasible therapeutic modality in improving quality of life with relief of dyspnea.

 [1]: pending:yes
Acidotic hypercapnia: Beyond type 1 and type 2 respiratory failure
Authors: Ambika Talwar, Vikas Punamiya, Shiva Bikmalla, Sushil Agarwal, Ben Beauchamp, Rahul Mukherjee
Journal: European Respiratory Journal (2012)

Introduction: The indications of non-invasive ventilation (NIV) have widened in the recent years, which is now used in treating hypercapnia with acidosis in a variety of patients. However, in many of the patients treated with NIV, the acidosis may have preceded the hypercapnia. The current case series from our 11-bedded ward based NIV unit describes such acidotic hypercapnia: hypercapnic respiratory failure following metabolic acidosis.

Methods: Time series of Arterial Blood Gas (ABG) findings in 4 patients with acidotic hypercapnia with a background of COPD confirmed with spirometry.

Results: The ABGs for cases 1 and 2 showed a rising CO2 following the onset of a metabolic acidosis; a mixed metabolic and respiratory acidosis in patients 3 & 4 - with the acidosis preceding hypercapnia (Case 3) or being out of proportion to CO2 rise (Case 4). All four patients improved with initiation of NIV combined with active fluid/electrolyte management. A sample ABG time series (Case 3) showing initial eucapnia with acidosis leading to hypercapnia is shown:

View this table:

Acidosis preceding hypercapnia on ABG Time series





Discussion: Acidotic hypercapnia could be a further subtype of respiratory failure (akin to previously described Type 4 or shock-muscle hypoperfusion related respiratory failure) for which larger confirmatory studies and prospective trials to establish the efficacy and timing of NIV are required.
Sex and the Physician-Patient Relationship
Authors: SHELDON H. KARDENER
Journal: American Journal of Psychiatry (1974)

In a psychodynamic discussion of why sexual relationships between physician and patient are not therapeutically beneficial, the author explores the concept of the physician as parent surrogate and its relationship to the incest taboo, the need to be loved, and the physician`s position of power vis-a-vis his patients. The author points out that these concerns must also be applied to the growing number of nonphysicians who engage in various modes of quasi-psychotherapy.
Mitoguazone therapy in patients with refractory or relapsed AIDS-related lymphoma: results from a multicenter phase II trial.
Authors: A M Levine, A Tulpule, D Tessman, L Kaplan, F Giles, B D Luskey, D T Scadden, D W Northfelt, I Silverberg, J Wernz, B Espina, D Von Hoff
Journal: Journal of Clinical Oncology (1997)

PURPOSE Patients with AIDS-related lymphoma usually have extensive lymphomatous disease, with relatively frequent involvement of the CNS. Approximately half may achieve complete remission after chemotherapy. Mitoguazone, an inhibitor of polyamine biosynthesis, has demonstrated efficacy in patients with de novo recurrent lymphoma. The drug is relatively nonmyelotoxic and may cross the blood-brain barrier. The current study was designed to assess the safety and potential efficacy of mitoguazone in patients with relapsed or refractory AIDS-lymphoma. PATIENTS AND METHODS Thirty-five patients were accrued, all of whom had failed one (51%) or multiple (two to six) prior regimens. Mitoguazone (600 mg/m2) was given intravenously on days 1 and 8, and then every 2 weeks, until best response, progression, or toxicity. RESULTS The median age was 39 years. High-grade lymphoma was diagnosed in 29 patients (83%). Extranodal disease was present in 30 patients (86%), with multiple extranodal sites (two to seven) in 18 (51%). The median CD4 cell count at study entry was 66/dL (range, zero to 549). Twenty-six patients were assessable for response. The objective response rate was 23% (95% confidence interval [CI], 6.9 to 39.3), with complete remission in three patients (11.5%), and partial remission (PR) in three patients (11.5%). Six patients experienced stable disease. Median survival from study entry was 2.6 months for the group as a whole; 21.5 months (range, 3.8 to 29.1) in complete responders, 5.6 months (range, 3.8 to 34.8) in partial responders. The most common toxicities occurred solely during drug infusion and included vasodilation (63%), paresthesia (86%), and somnolence (17%). Fourteen patients (40%) experienced nausea and 16 (46%) vomiting (grade 3 in one). Ten patients (29%) developed stomatitis, including grade 3 in two and grade 4 in one. Seven patients (20%) developed neutropenia, with grade 4 in one. Thrombocytopenia occurred in nine patients (26%). While on study, three patients developed sepsis, four had pneumonia, and two developed opportunistic infections. CONCLUSION Mitoguazone is an effective agent in patients with multiply relapsed or refractory AIDS-related lymphoma, with acceptable toxicity. Further study in patients with newly diagnosed disease is warranted.
Genomic and transcriptomic predictors of triglyceride response to regular exercise
Authors: Mark A Sarzynski, Peter K Davidsen, Yun Ju Sung, Matthijs K C Hesselink, Patrick Schrauwen, Treva K Rice, D C Rao, Francesco Falciani, Claude Bouchard
Journal: British Journal of Sports Medicine (2015)

Aim We performed genome-wide and transcriptome-wide profiling to identify genes and single nucleotide polymorphisms (SNPs) associated with the response of triglycerides (TG) to exercise training. Methods Plasma TG levels were measured before and after a 20-week endurance training programme in 478 white participants from the HERITAGE Family Study. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using the Illumina BeadStation 500GX platform. Affymetrix HG-U133+2 arrays were used to quantitate gene expression levels from baseline muscle biopsies of a subset of participants (N=52). Genome-wide association study (GWAS) analysis was performed using MERLIN, while transcriptomic predictor models were developed using the R-package GALGO. Results The GWAS results showed that eight SNPs were associated with TG training-response (ΔTG) at p&lt;9.9×10 −6 , while another 31 SNPs showed p values &lt;1×10 −4 . In multivariate regression models, the top 10 SNPs explained 32.0% of the variance in ΔTG, while conditional heritability analysis showed that four SNPs statistically accounted for all of the heritability of ΔTG. A molecular signature based on the baseline expression of 11 genes predicted 27% of ΔTG in HERITAGE, which was validated in an independent study. A composite SNP score based on the top four SNPs, each from the genomic and transcriptomic analyses, was the strongest predictor of ΔTG (R 2 =0.14, p=3.0×10 −68 ). Conclusions Our results indicate that skeletal muscle transcript abundance at 11 genes and SNPs at a number of loci contribute to TG response to exercise training. Combining data from genomics and transcriptomics analyses identified a SNP-based gene signature that should be further tested in independent samples.
Endothelial dysfunction and systemic inflammation during acute exacerbations of COPD
Authors: Matthias Urban, Arschang Valipour, Dora Kiss, Philipp Eickhoff, Georg-Christian Funk, Otto Chris Burghuber
Journal: European Respiratory Journal (2012)

Background Systemic inflammation is a potential determinant for the excess cardiovascular risk in COPD. Endothelial dysfunction, a marker of subclinical atherosclerosis correlates with circulating inflammatory markers in stable COPD. Acute exacerbations of COPD are characterized by a transient aggravation of systemic inflammation and might be accompanied by deteriorated endothelial function. Aim We aim to assess endothelial dysfunction and systemic inflammation during acute exacerbations of COPD and after clinical restitution. Methods We enrolled patients admitted to hospital due to an acute exacerbation of COPD. Study related procedures comprised spirometry, measurement of systemic inflammatory markers (i.e. C-reactive protein [CRP] and leukocyte count) and endothelial dysfunction by means of the flow-mediated dilation technique (FMD). The entire spectrum of measurements was scheduled within two days of hospital admission and thereafter when having confirmed clinical stability. Results We recruited 28 patients (female: n=20) during acute exacerbation. Baseline characteristics were as follows: age: 64±8 years, BMI: 24.6±5.9 FEV1: 36.5±12.1, %pred. During the acute exacerbations patients showed a median CRP of 7.0 (2.0-28), mg/l, leukocytes of 9.7±3.4 G/l and a FMD of 6.8±3.6% indicating severe endothelial dysfunction. After confirmed clinical stability we observed a decrease of systemic inflammation (CRP: 4.0 (2.0-7.0) mg/l; leukocytes: 8.2±2.9 G/l) and a simultaneous improvement in FMD (10.0±3.4%). Conclusion Our results indicate endothelial dysfunction in COPD patients. Furthermore, acute exacerbations deteriorate endothelial function in COPD, probably via aggravation of systemic inflammation.
Abdominal muscle action during sustained hypoxia
Authors: Michael Ji, Masato Katagiri, Teresa Kieser, Paul Easton
Journal: European Respiratory Journal (2012)

Introduction: Classical studies suggest that expiratory neuronal activity is inhibited by hypoxia, and action of expiratory muscles during hypoxia is controversial. Isocapnic hypoxia sustained 20-60 minutes elicits a biphasic ventilatory response (roll-off), with initial peak followed by decline to a plateau. We demonstrated during sustained hypoxia, parasternal muscle activity rolls off with ventilation (ERJ 2011;38.S55).  Aim: To study ventilation and action of the abdominal expiratory muscle, Transversus Abdominis (TA), during sustained hypoxia in awake canines.  Methods: After implantation of sonomicrometry transducers and EMG electrodes in TA, and full recovery, we measured airflow, SpO2, ETCO2, mavg EMG and shortening (SHORT) of TA, during room air breathing (BASE) followed by 25 minutes of isocapnic hypoxia (mean 79.9% SpO2). The canines were awake, breathing through a mask. We report results 2-3 min after reaching SpO2 80% (PEAK) and final 5 min (PLATEAU) of sustained hypoxia, then room air breathing (RECOVERY).  Results: For N=9 (mean 28.7 kg, 27 days post implant), minute ventilation and tidal volume increased significantly from BASE to PEAK, then decreased to PLATEAU (p  Conclusion: During sustained isocapnic hypoxia, the abdominal expiratory muscle, TA, is markedly activated during initial hypoxia, then attenuated with prolonged hypoxia.