tbuckley/cabot-search huggingface dataset:
Mutations in the c-fes locus associated with colon cancer inhibit Fes protein-tyrosine kinase activity and suggest a novel role as a tumor suppressor
Authors: Frank J. Delfino, Heather M. Stevenson, Thomas E. Smithgall
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

3929 

The human c-fes locus encodes a 93 kDa protein-tyrosine kinase implicated in the differentiation of neuronal, endothelial and myeloid hematopoietic cells. Recent global sequence analysis of 133 protein-tyrosine kinase (PTK) and PTK-like genes in colorectal cancers identified Fes as one of only six PTK genes with mutations in more than one tumor (Bardelli et al. Science 300:949, 2003). Although four mutations were observed within the Fes kinase domain (M704V, R706Q, V743M, S759F), the consequences of these mutations on kinase activity have not been explored. To address this issue, Fes mutants with these substitutions were over-expressed in human 293T cells and kinase activity was assessed via immunoblot analysis with a phosphospecific antibody against the activation loop phosphotyrosine (Tyr 713). Surprisingly, M704V, R706Q, and V743M all substantially reduced basal autophosphorylation compared to wild-type Fes, while S759F had no effect on kinase activity. The R706Q and S759F mutants were also combined with an activating mutation (L145P) and expressed in S. cerevisiae. R706Q completely reversed the activating effect of L145P in yeast, indicating that this mutation inhibits Fes activity by affecting kinase structure independent of the mammalian cell context. The S759F mutation was without effect, consistent with the result in mammalian cells. The observations that all four colon cancer-associated mutations failed to activate Fes and in three cases blocked kinase activity suggest a role for Fes as a tumor suppressor rather than a dominant oncogene in colon cancer. To test this hypothesis, wild-type and mutant forms of Fes were stably expressed in the human colorectal adenocarcinoma cell line HT-29, and anchorage-independent growth was assessed using a soft agar assay. Expression of wild-type or kinase-defective Fes had little impact on soft-agar colony formation by HT-29 cells, consistent with the lack of kinase activity observed with these proteins on anti-phosphotyrosine immunoblots. However, expression of each of three different kinase-active forms of Fes dramatically reduced HT-29 cell soft-agar colony numbers and size. Moreover, endogenous Fes protein expression was undetectable by immunoblot analysis in parental HT-29 cells, suggesting that loss of Fes expression, like the inactivating mutations described here, may contribute to transformation. Our findings that c-fes mutations associated with colon cancer fail to activate and in most cases inhibit Fes kinase activity, together with direct evidence that kinase-active forms of Fes suppress HT-29 tumor cell growth, strongly implicate Fes as a tumor suppressor in colorectal cancer.
Leaky gut does not affect the risk of infectious complications and survival in liver transplant recipients: comparison with cirrhotic patients and healthy individuals
Authors: F.R. Ponziani, V. Valenza, M. Lorusso, M.E. Carvelli, R. Paone, M. Siciliano, A.W. Avolio, A. Grieco, S. Agnes, A. Gasbarrini, M. Pompili, G. Sganga
Journal: Journal of Hepatology (2017)
Secondary Hemophagocytic Syndrome
Authors: Vinicius R. P. Mattos, Michelle P. Silveira, Flávia M. Ferreira, Dirceu H. C. Campelo, Juliano Cordova Vargas, Clarissa L.M. Souza, Nelson Hamerschlak, Fabio P S Santos, Paulo A. A. Silveira
Journal: Blood (2014)
Dexamethasone Therapy for Bacterial Meningitis
Authors: Marc H. Lebel, Bishara J. Freij, George A. Syrogiannopoulos, Dale F. Chrane, M. Jean Hoyt, Sunita M. Stewart, Betsy D. Kennard, Kurt D. Olsen, George H. McCracken
Journal: New England Journal of Medicine (1988)

We enrolled 200 infants and older children with bacterial meningitis in two prospective double-blind, placebo-controlled trials to evaluate the efficacy of dexamethasone therapy in addition to either cefuroxime (Study 1) or ceftriaxone (Study 2). Altogether, 98 patients received placebo and 102 received dexamethasone (0.15 mg per kilogram of body weight every six hours for four days). At the beginning of therapy, the clinical and demographic characteristics of the patients in the treatment groups were comparable. The mean increase in the cerebrospinal fluid concentration of glucose and the decreases in lactate and protein levels after 24 hours of therapy were significantly greater in those who received dexamethasone than in those who received placebo (glucose, 2.0 vs. 0.4 mmol per liter [36.0 vs. 6.9 mg per deciliter], P<0.001; lactate, 4.0 vs. 2.1 mmol per liter [38.3 vs. 19.8 mg per deciliter], P<0.001; and protein, 0.64 vs. 0.25 g per liter [64.0 vs. 25.3 mg per deciliter], P<0.05). One patient in the placebo group in Study 1 died. As compared with those who received placebo, the patients who received dexamethasone became afebrile earlier (1.6 vs. 5.0 days; P<0.001) and were less likely to acquire moderate or more severe bilateral sensorineural hearing loss (15.5 vs. 3.3 percent; P<0.01). Twelve patients in the two placebo groups (14 percent) had severe or profound bilateral hearing loss requiring the use of a hearing aid, as compared with 1 (1 percent) in the two dexamethasone groups (P<0.001). We conclude that dexamethasone is beneficial in the treatment of infants and children with bacterial meningitis, particularly in preventing deafness. (N Engl J Med 1988; 319:964–71.)
Analysis of standard versus non-standard treatment in senior adult oncology patients.
Authors: Amy R. MacKenzie, Ludmila De Oliveira Koch, Ulysses Williams, Thomas Wolf, James Cocroft, Scott W. Keith, Joshua Schoppe, Andrea Barsevick, Ronald Myers, Andrew E. Chapman
Journal: Journal of Clinical Oncology (2014)

e20521 Background: Over 50% of new cancer diagnoses occur in senior adult oncology (SAO) patients (≥65 years of age). However, as SAO patients may not be treated with standard care, it is important to assess treatment patterns among SAO patients. Methods: The research team performed a retrospective analysis of treatment patterns for SAO patients in a large, urban hospital. Age, gender, race, cancer stage, recurrence, curability, comprehensive geriatric assessment, Eastern Cooperative Oncology Group (ECOG) performance status, and type of care provided were abstracted from the medical record. Standard care was defined in terms of National Cancer Institute definitions as, “proper treatment for a certain type of disease and that is widely used by healthcare professionals.” Nonstandard care was defined as deviation from accepted guidelines. Univariate analyses were performed to identify factors associated with standard versus nonstandard care in terms of relative risks (RR) and 95% confidence intervals (CI). Results: Of the n=52 SAO patients analyzed, 77% received standard care. Stage II and III patients were significantly more likely than stage 0-1 and IV patients to receive non-standard care (RR=6.3; 95% CI: 1.5 – 26.0). Patients with curable disease tended to receive non-standard care more often than those with non-curable disease (RR=2.6; 95% CI: 0.7 – 10.8). Among the curable patients, those with functional limitations tended to receive non-standard care more often than the fully active (RR=6.6; 95% CI: 0.9 – 47.2). Conclusions: Delivery of standard care to SAO patients may be influenced by disease stage, curability, and functional status. More specifically, these data raise the question of whether or not curability of disease is as much of a driving factor in prescribing standard treatment for SAO patients as it usually is in younger patients. A prospective trial examining this, as well as the impact of a comprehensive geriatric assessment in SAO patients , is underway currently at our institution.
Liver stiffness based model predicts portal hypertension, esofageal varices and hepatocellular carcinoma in caucasian patients with hepatitis B virus-related cirrhosis responsive to antiviral therapy
Authors: C. Chialà, W.D. Venon, A. Tucci, M. Fadda, G.M. Saracco, A. Marzano
Journal: Journal of Hepatology (2017)
Cycloxygenase-2 expression in advanced undifferentiated nasopharyngeal carcinoma and the effect of selective cyclooxygenase-2 inhibitor celecoxib in nasopharyngeal carcinoma cell lines
Authors: Charles M. Chan, Brigette B. Ma, Cesar Wong, Anthony T. Chan
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5866 

Around 50% of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) develop disease recurrence following radiotherapy (RT). Cyclooxygenase-2 (COX-2) expression is upregulated and prognostic in other cancers and Celecoxib is a selective COX-2 inhibitor that has preclinical anti-proliferative activity. In this study, we evaluated the prognostic significance of COX-2 expression in locoregionally advanced NPC, and the effect of celecoxib on growth and apoptosis in NPC cell lines. Method: COX-2 expression of 83 primary NPC biopsies taken from participants of a prospective clinical trial was analyzed immunohistochemically, and correlated with disease stage, recurrence and survival following chemoradiation. For the preclinical study, COX-2 protein and mRNA expression in 3 NPC cell lines, HK-1 Hone-1 and CNE-2 were characterized by Western Blot and RT-PCR, respectively. Increasing concentrations of celecoxib at 0, 30, 50 and 80 uM, were added to culture medium and incubated for up to 72 hours. Cell viability was assessed at 24, 48 and 72 hours using MTT assay. Apoptosis was evaluated using a commercially available apoptosis detection kit which detects cytoplasmic nucleosomes after exposure with celecoxib at concentrations of 0, 50, 80 μM. Result: COX-2 was expressed in 83% (69/83) of the NPC biopsies and no significant correlations with survival or disease recurrence were found, except a trend toward an association between advanced N-stage (N3) and moderate to strong COX-2 staining (p=0.05, chi-square). COX-2 protein was expressed in HK-1 cells only, while COX-2 mRNA was expressed in all 3 cell lines. Irrespective of COX-2 expression, celecoxib inhibited growth in all 3 cell lines in a dose-dependent manner: CNE-2 (GI50 of 41.04 +/–1.22 μM), Hone-1 (GI50 of 49.68 +/–1.12 μM) and HK-1 (GI50 of 51.74 +/–3.89 μM). Celecoxib also induced dose-dependent apoptosis in all 3 cell lines (see Figure 1). Conclusion: Although COX-2 expression is upregulated in advanced NPC, it does not predict prognosis following chemoradiation. Furthermore, Celecoxib induced apoptosis and growth inhibition in NPC cell lines probably through non-COX-2 dependent mechanisms.
Short duration treatment with AL-335 and odalasvir, with or without simeprevir, in treatment naïve patients with hepatitis C infection with or without cirrhosis
Authors: E. Gane, C. Stedman, M. McClure, D. Apelian, C. Westland, J. Vuong, M. Patel, T. Kakuda, S. Chanda, L. Blatt, L. Beigelman, D. Smith, J. Fry
Journal: Journal of Hepatology (2017)
microRNA-34a and natural killer cells: an immuno-epigenetic approach to halt hepatocellular carcinoma progression
Authors: A.K. Abdelhamid, R.A. Yacoub, I.O. Fawzy, A. Gomaa, K. Hosny, M.T. Hamza, G. Esmat, I. Waked, A.I. Abdelaziz
Journal: Journal of Hepatology (2017)
The use of prophylactic strategies using hepatitis B immunoglobulin for hepatitis B recurrence after liver transplantation in routine clinical practice in Spain. Preliminary results of the 1st round of a delphi panel
Authors: M. Prieto, S. Lens, M. Buti, J.M. Pascasio, I. Fernandez, M. Mareque, C. Torres, M.Á. Casado
Journal: Journal of Hepatology (2017)
Elbasvir/grazoprevir plus sofosbuvir in treatment-naive and treatment-experienced cirrhotic patients with hepatitis C virus genotype 3 infection treated for 8, 12, or 16 weeks: final results of the C-ISLE study
Authors: G.R. Foster, K. Agarwal, M.E. Cramp, S. Moreea, S. Barclay, J. Collier, A.S. Brown, S.D. Ryder, A. Ustianowski, D.M. Forton, R. Fox, F. Gordon, W.M. Rosenberg, D.J. Mutimer, J. Du, C.L. Gilbert, M. Robertson, E. Barr, B. Haber
Journal: Journal of Hepatology (2017)
Inflammatory breast cancer (IBC) in Tunisia from 2005 to 2010: Epidemiologic and anatomo-clinical transition within a cohort of 208 patients.
Authors: Hamouda Boussen, Nesrine Mejri, Sounaya Labidi, Hatem Bouzaien, Mehdi Afrit, Farouk Benna, Rahal Khaled
Journal: Journal of Clinical Oncology (2015)

e12633 Background: To report epidemiologic and anatomo-clinical transition of IBC in Tunisia. Methods: Data including clinico-pathological aspects of 208 cases of T4d or PEV 3 non metastatic breast cancer diagnosed between 2005 and 2010 were collected from patient’s records. Chi2 and Z tests were used to compare variables with other series: two Tunisian historical series (Boussen el al. Cancer, 2010 and Labidi I et al. Ann Oncol, 2008) and a series about Arab-American patients (Hirko et al. Springerplus, 2013). Results: Thirty three percent of our patients had their first child before 23 year-old and 56% had their menarche before 12 year-old, 75% never received oral contraception. Obesity was observed in 42% of women and IBC occurred during pregnancy in 13% of cases. Tumor grade was II-III in 90% of cases, HR were negative in 52%, HER2 was over expressed in 31% and more than 3 invaded axillary nodes occurred in 18% of patients. We observed a pCR rate of 19% after neoadjuvant treatment (Anthracyline-Taxane used in 79%, trastuzumab in 27% of cases). Compared to historical Tunisian series (since 1996), IBC epidemiology remained stable in terms of median age, menopausal status and obesity. However we observed a significant decrease in median clinical tumor size and number of positive axillary lymph nodes. Comparison to IBC in Arab-Americans, showed a significant difference in terms of median age, menopausal status, positivity of hormonal receptors and educational level. Conclusions: Epidemiologic transition shows a reduction of clinco-pathological stage of IBC, keeping the same characteristics as compared to Tunisian historical series over a period of 14 years. Features seem to be different in Arab-American patients probably related to migration, “occidentalization” of life style and improvement in socio-economic level
Phenotypes contribute to treatments
Authors: Yingmeng Ni, Guochao Shi
Journal: European Respiratory Journal (2017)

Chronic obstructive pulmonary disease (COPD) is now considered a markedly complex and heterogeneous disease [1]. In the latest update of the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2017) [2], the definition of COPD has been revised to emphasise the heterogeneity of this disease. The phrase "airway and/or alveolar abnormalities" replaces "an enhanced chronic inflammation" in the definition of GOLD 2016. The two most common forms of pathology, namely small airway disease (chronic bronchitis) and parenchymal destruction, both cause chronic airflow limitation, but to different degrees over time [2]. Thus, distinct phenotypes exist and represent single or combined disease components that define the differences between individuals with COPD, as they relate to clinically meaningful outcomes, such as symptoms, exacerbation, rate of disease progression or death, and response to treatment [3]. More exact COPD phenotyping will provide more precise and personalised treatment for patients <http://ow.ly/y3h6309fY9Y>
Adherence to SmPC recommendations in real-world practice in the treatment of monoinfected patients with chronic genotype 1 or 4 HCV infection with direct-acting antivirals
Authors: B. Ruiz-Antorán, D. Rincón, C. Perelló, I. Fernandez, F. Gea, Z. Mariño, J. García-Samaniego, V. Hontangas, J. Cabezas, B. Sacristan, J.M. Pascasio, R.M. Morillas, J. Turnes, J. Llaneras, M.A. Serra, X. Torras, M. Diago, F. Jorquera, C. Fernández, M.A. Simón, M.F. Bermejo, J.J.S. Ruano, J. Arenas, R.J. Andrade, J. Ampuero, L. Bonet, J. Crespo, J.L.C. Panero
Journal: Journal of Hepatology (2017)
A low incidence of hepatocellular carcinoma in patients with genotype 1b compensated cirrhosis treated with paritaprevir/ritonavir, ombitasvir and dasabuvir ± ribavirin in a tertiary center: a matter of better selection?
Authors: S. Chiriac, A. Trifan, C. Stanciu, C.C. Prelipcean, G. Stefanescu, C. Mihai, C. Sfarti, C. Cojocariu, T. Cuciureanu, F. Mihai, A.M. Singeap
Journal: Journal of Hepatology (2017)
Clinical impact of 18F-FDG–PET in breast cancer: Survival analysis and comparison of intrinsic subtypes with standardized uptake value.
Authors: Sung Gwe Ahn, Hak Min Lee, Seung Ah Lee, Tae Joo Jeon, Young Hoon Yoo, Eun Joo Sohn, Joon Jeong, Hy-De Lee
Journal: Journal of Clinical Oncology (2013)

e12005 Background: [ 18 F] fluorodeoxyglucose positron emission tomography (18F-FDG–PET) scans are known as an important imaging study with their reflection biological activity in various malignancies. To investigate clinical impact of 18F-FDG–PET in breast cancer, we performed survival analysis with maximum standardized uptake values (SUV max ), and compared SUV max according to breast cancer subtypes. Methods: We reviewed the medical records of 462 patients with breast cancer who underwent primary surgery between April 2004 and December 2008 at single institute. Patients were classified as 4 subtypes: luminal A, luminal B, HER2 and triple negative. The entire patients were randomly assigned as training set (n=220) and validation set (n=242). Results: High SUV max vs. low SUV max group was defined with cut-off points of 4 in a training set.At a median follow-up of 6.03 years, the patients with high SUV max had a shorter disease-free survival in a validation set (p = 0.018, log-rank test). Using multivariate analysis for disease-free survival in the entire patients, high SUV max was demonstrated as a poor prognostic factor (hazard ratio 2.34, 95% confidence interval 1.18-4.67). In the comparison among subtypes, mean of SUV max was higher in triple negative type and HER2 type. Also, high SUV max was significantly associated with larger tumor size, positive node, high Ki67 (≥14%), ER negative, and high histologic grade, and HER2 positive. Conclusions: In breast cancer, the patients with higher SUV max showed a shorter disease-free survival. Higher SUV max found in HER-2 and triple negative type suggests that 18F-FDG PET could reflect molecular signature.
Abstract 358: Pacemaker Induced Transient Asynchrony (PITA) Restores Contractile Reserve in Synchronous Heart Failure
Authors: Jonathan A Kirk, Khalid Chakir, Kyounghwan Lee, Gianluigi Pironti, Mark J Ranek, Richard S Tunin, Pieter de Tombe, Sudha K Shenoy, Howard A Rockman, Roger Craig, David A Kass
Journal: Circulation Research (2015)

Heart failure (HF) with dyssynchrony treated with biventricular pacing (CRT) displays enhanced global and cellular function even compared to always synchronous HF. This suggests while HF is worsened by sustained dyssynchrony, it may paradoxically be improved by brief periods of Pacemaker Induced Transient Asynchrony (PITA). We tested this hypothesis in dogs tachypaced for 6 wks to induce HF. The HF group received atrial pacing and was compared to PITA (atrial pacing during day; right ventricular pacing, producing dyssynchrony, from 0000-0600). PITA blunted dilation (end diastolic and end systolic volumes reduced by 11 and 19%, respectively), reduced end-diastolic pressures from 22 to 13 mmHg, and improved the contractile response to dobutamine by 29%. Myocyte sarcomere shortening and calcium transient amplitude were depressed in HF and little improved by β adrenergic (βA) stimulation. PITA improved baseline function slightly, but virtually restored βA stimulated reserve. Membrane βA receptor density increased with PITA by 36% as well. Another contributor to the change in functional reserve was found in myofilament maximal calcium activated force (Fmax) normalized to cell cross sectional area (CSA). This declined ~40% in HF vs. Control, but was fully restored by PITA. However, as CSA was greater in HF and normalized by PITA, raw Fmax was similar despite hypertrophy in HF, suggesting HF myocytes had dysfunctional myofilaments, which PITA prevented. Electron microscopy confirmed normal myofilament structure in Control and PITA, whereas 40% of HF sarcomeres displayed deteriorated z-disks and loss of normal registration of the thick and thin filaments. In HF, 39% of HF isolated myofibrils produced virtually zero maximal force, whereas Control and PITA fibers functioned normally. Thus, there are two populations of myofibrils within HF hypertrophied cells, with ~40% structurally and functionally disrupted. PITA reverses this to restore force-calcium activation and with improved βA receptor signaling, restores functional reserve, suppressing chronic maladaptive remodeling. This surprising finding indicates PITA can ameliorate HF pathobiology and improve reserve function. Further studies are needed to test if such benefits translate to humans.
An evaluation of the drug interaction potential of netupitant with digoxin.
Authors: Sybille Baumann, Silvia Olivari Tilola, Tulla Spinelli, Wolfgang Timmer
Journal: Journal of Clinical Oncology (2012)

e19530 Background: The new, highly selective neurokinin-1 receptor antagonist netupitant (NETU) has been developed to provide protection from nausea and vomiting in patients receiving emetogenic chemotherapy. There is evidence from in vitro studies that NETU is a substrate for and a weak inhibitor of the P-glycoprotein (Pgp). Pgp plays a major role in the pharmacokinetics of digoxin (DIG), a cardiac glycoside with a narrow therapeutic index. The possible interaction between NETU and Pgp has been assessed by analysing the effect of NETU on DIG pharmacokinetics. Safety parameters have also been assessed. Methods: This study was an open-label, fixed-sequence design to evaluate the effect of NETU on DIG at steady state in 16 healthy volunteers (8 male and 8 female). A loading dose of 3 x 0.5 mg DIG (0.5 mg every 6 hours) was given on day 1, followed by a daily oral dose of 0.25 mg DIG for 11 consecutive days (days 2-12); NETU was administered as single oral dose of 450mg on day 8. Serial blood and urine samples were collected for the determination of the pharmacokinetic parameters. Physical examination, vital signs, electrocardiogram (ECG), adverse events, clinical chemistry, hematology, urinalysis, and overall tolerability were reported. Results: Based on the AUC (0-24h) parameter at steady-state, the extent of DIG exposure was not influenced by NETU coadministration. The confidence interval of C min was within the 80-125% equivalence limits, while the observed C max was slightly over 125%, which was not considered clinically relevant. The excretion of DIG in urine was 57% after NETU coadministration compared to 55% of DIG alone. There were no gender-specific differences in the extent of absorption (AUC) for DIG, and no safety-related influence of DIG or NETU was observed on safety and laboratory assessments, vital signs, or ECG parameters. Based on historical data NETU pharmacokinetics was not affected by DIG coadministration. Conclusions: No clinically relevant interactions occurred between NETU and DIG. The results of this study suggest that the coadministration of NETU with Pgp substrates may not require dose adjustments. Study treatments were well tolerated.
Does treadmill running performance, heart rate and breathing rate response during maximal graded exercise improve after volitional respiratory muscle training?
Authors: K Radhakrishnan, VK Sharma, SK Subramanian
Journal: British Journal of Sports Medicine (2017)

Maximal physical exertion in sports usually causes fatigue in the exercising muscles, but not in the respiratory muscles due to triggering of the Respiratory muscle metabo-reflex, a sympathetic vasoconstrictor response leading to preferential increment in blood flow to respiratory muscles.
TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence
Authors: Ke Li, Feng Wang, Wen-Bin Cao, Xiao-Xi Lv, Fang Hua, Bing Cui, Jiao-Jiao Yu, Xiao-Wei Zhang, Shuang Shang, Shan-Shan Liu, Jin-Mei Yu, Ming-Zhe Han, Bo Huang, Ting-Ting Zhang, Xia Li, Jian-Dong Jiang, Zhuo-Wei Hu
Journal: Cancer Cell (2017)