tbuckley/cabot-search huggingface dataset:
Incorporating Bevacizumab and Erlotinib in the Combined-Modality Treatment of Stage III Non–Small-Cell Lung Cancer: Results of a Phase I/II Trial
Authors: Mark A. Socinski, Thomas E. Stinchcombe, Dominic T. Moore, Scott N. Gettinger, Roy H. Decker, W. Jeffrey Petty, A. William Blackstock, Garry Schwartz, Scott Lankford, Amir Khandani, David E. Morris
Journal: Journal of Clinical Oncology (2012)

Bevacizumab and erlotinib have been shown to improve survival in stage IV non-small-cell lung cancer (NSCLC). This phase I/II trial was designed to incorporate these agents with induction and concurrent chemoradiotherapy in stage III NSCLC.Patients received induction chemotherapy (carboplatin area under the curve [AUC] 6, paclitaxel 225 mg/m(2), and bevacizumab 15 mg/kg on days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly with bevacizumab 10 mg/kg every other week for four doses) and thoracic conformal radiation therapy (TCRT) to 74 Gy. In the phase I portion, cohort 1 received no erlotinib, whereas cohorts 2 and 3 received erlotinib at 100 and 150 mg, respectively, Tuesday through Friday, during TCRT. Consolidation therapy with erlotinib (150 mg daily) and bevacizumab (15 mg/kg every 3 weeks) was planned 3 to 6 weeks later for six cycles.Forty-five eligible patients were enrolled. The objective response rates to induction and overall treatment were 39% (95% CI, 24% to 55%) and 60% (95% CI, 44% to 75%), respectively. The median progression-free and overall survival times were 10.2 months (95% CI, 8.4 to 18.3 months) and 18.4 months (95% CI, 13.4 to 31.7 months), respectively. The principal toxicity was esophagitis (29% grade 3 or 4 esophagitis, with one patient with grade 3 tracheoesophageal fistula), which was often prolonged. Consolidation therapy with bevacizumab and erlotinib was not feasible.The use of bevacizumab and erlotinib as administered in this trial is not recommended given the lack of an efficacy signal and the substantial risk of esophageal toxicity.
Diagnostic Assay Based on hsa-miR-205 Expression Distinguishes Squamous From Nonsquamous Non–Small-Cell Lung Carcinoma
Authors: Danit Lebanony, Hila Benjamin, Shlomit Gilad, Meital Ezagouri, Avital Dov, Karin Ashkenazi, Nir Gefen, Shai Izraeli, Gideon Rechavi, Harvey Pass, Daisuke Nonaka, Junjie Li, Yael Spector, Nitzan Rosenfeld, Ayelet Chajut, Dalia Cohen, Ranit Aharonov, Mahesh Mansukhani
Journal: Journal of Clinical Oncology (2009)

Purpose Recent advances in treatment of lung cancer require greater accuracy in the subclassification of non–small-cell lung cancer (NSCLC). Targeted therapies which inhibit tumor angiogenesis pose higher risk for adverse response in cases of squamous cell carcinoma. Interobserver variability and the lack of specific, standardized assays limit the current abilities to adequately stratify patients for such treatments. In this study, we set out to identify specific microRNA biomarkers for the identification of squamous cell carcinoma, and to use such markers for the development of a standardized assay. Patients and Methods High-throughput microarray was used to measure microRNA expression levels in 122 adenocarcinoma and squamous NSCLC samples. A quantitative real-time polymerase chain reaction (qRT-PCR) platform was used to verify findings in an independent set of 20 NSCLC formalin-fixed, paraffin-embedded (FFPE) samples, and to develop a diagnostic assay using an additional set of 27 NSCLC FFPE samples. The assay was validated using an independent blinded cohort consisting of 79 NSCLC FFPE samples. Results We identified hsa-miR-205 as a highly specific marker for squamous cell lung carcinoma. A microRNA-based qRT-PCR assay that measures expression of hsa-miR-205 reached sensitivity of 96% and specificity of 90% in the identification of squamous cell lung carcinomas in an independent blinded validation set. Conclusion Hsa-miR-205 is a highly accurate marker for lung cancer of squamous histology. The standardized diagnostic assay presented here can provide highly accurate subclassification of NSCLC patients.
Detection of Obliterative Bronchiolitis after Lung Transplantation by Indexes of Ventilation Distribution
Authors: MARC ESTENNE, ALAIN VAN MUYLEM, CHRISTIANE KNOOP, MARTINE ANTOINE
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Obliterative bronchiolitis (OB) is the first cause of death of long-term survivors of lung transplantation. The diagnosis is based on pathology and/or on an irreversible decrease in forced expiratory volume in 1 s (FEV1) below 80% of the best postoperative value. We tested whether indexes of ventilation distribution may provide evidence of OB before conventional pulmonary function tests (PFTs). Fifty-seven patients with heart-lung (n = 47) or double-lung (n = 10) transplantation were monitored with conventional PFTs and measurements of the slope of the alveolar plateau for He (SHe), SF6 (SSF6), and N2 (SN2) obtained during single-breath washouts. The date at which a functional variable showed an irreversible change outside the 97.5% confidence interval was compared with the date at which a greater than 20% fall in FEV1 was observed. A total of 1,929 tests (median, 30 tests per patient) were performed during the 1,215 d (range, 164–2,829 d) of follow-up. Eighteen patients showed an irreversible and greater than 20% fall in FEV1 during the course of the study. This alteration was preceded by a rise in SHe in 17 patients and by a rise in SN2 in 16 patients, which indicated a more heterogeneous ventilation. The median time interval between the change in SHe and SN2 and the 20% decrease in FEV1 was 356 and 168 d, respectively, with seven patients showing an interval of 18 mo or more. Conventional PFTs, including midexpiratory flow rates, deteriorated after indexes of ventilation distribution. Thirty-nine patients did not show any significant and irreversible alteration in conventional PFTs over the study period; only seven of these patients developed significant alterations in ventilation distribution. We conclude that measurements of ventilation distribution detect posttransplant OB much earlier than conventional PFTs.
Studies on the mechanism of inhibition of chemotactic tripeptide stimulated human neutrophil polymorphonuclear leucocyte superoxide production by chloroquine and hydroxychloroquine.
Authors: N P Hurst, J K French, L Gorjatschko, W H Betts
Journal: Annals of the Rheumatic Diseases (1987)

The effect of chloroquine and hydroxychloroquine on neutrophil superoxide release stimulated by the chemotactic tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) was examined. Both drugs caused time and dose dependent inhibition of superoxide release but had no effect on equilibrium binding of [3H]FMLP to its receptor. Preliminary experiments suggest that these drugs may exert their inhibitory effect on superoxide release by inhibiting the FMLP stimulated hydrolysis of phosphoinositides.
Post Hoc Subgroup Analysis of the HEART2D Trial Demonstrates Lower Cardiovascular Risk in Older Patients Targeting Postprandial Versus Fasting/Premeal Glycemia
Authors: Itamar Raz, Antonio Ceriello, Peter W. Wilson, Chakib Battioui, Eric W. Su, Lisa Kerr, Cate A. Jones, Zvonko Milicevic, Scott J. Jacober
Journal: Diabetes Care (2011)

To identify the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) trial subgroups with treatment difference.In 1,115 type 2 diabetic patients who had suffered from an acute myocardial infarction (AMI), the HEART2D trial compared two insulin strategies targeting postprandial or fasting/premeal glycemia on time until first cardiovascular event (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome). The HEART2D trial ended prematurely for futility. We used the classification and regression tree (CART) to identify baseline subgroups with potential treatment differences.CART estimated the age of >65.7 years to best predict the difference in time to first event. In the subgroup aged>65.7 years (prandial, n=189; basal, n=210), prandial patients had a significantly longer time to first event and a lower proportion experienced a first event (n=56 [29.6%] vs. n=85 [40.5%]; hazard ratio 0.69 [95% CI 0.49-0.96]; P=0.029), despite similar A1C levels.Older type 2 diabetic AMI survivors may have a lower risk for a subsequent cardiovascular event with insulin targeting postprandial versus fasting/premeal glycemia.
Spontaneous and Persisting Decrease in Maximal Acid Output
Authors: H. G. Desai, M. P. Zaveri, F. P. Antia
Journal: BMJ (1971)

A spontaneous decrease in maximal acid output was observed in three control subjects and in seven patients with duodenal ulcer. The decreased output was due to a decrease in volume and to a lower concentration in six subjects and to a decrease in volume in four subjects. In some cases the decrease in output occurred within a period of weeks. Patients with a pronounced decrease remained asymptomatic for a prolonged period.
Evidence for systemic rather than pulmonary effects of interleukin-5 administration in asthma
Authors: E L J van Rensen
Journal: Thorax (2001)

<h3>BACKGROUND</h3> Interleukin 5 (IL-5) has an important role in mobilisation of eosinophils from the bone marrow and in their subsequent terminal differentiation. A study was undertaken to determine whether inhaled and intravenous IL-5 could induce pulmonary eosinophilia and bronchial hyperresponsiveness (BHR) independently of these effects. <h3>METHODS</h3> Nine mild asthmatics received inhaled (15 μg) or intravenous (2 μg) IL-5 or placebo in random order in a double blind, crossover study. Blood samples were taken before and at 0.5, 1, 2, 3, 4, 5, 24, and 72 hours following IL-5 or placebo, and bronchial responsiveness (PC<sub>20</sub> methacholine) and eosinophil counts in induced sputum were determined. <h3>RESULTS</h3> Serum IL-5 levels were markedly increased 30 minutes after intravenous IL-5 (p=0.002), and sputum IL-5 levels increased 4 and 24 hours after inhaled IL-5 (p&lt;0.05). Serum eotaxin was raised 24 hours after intravenous IL-5 but not after inhaled IL-5 or placebo. Blood eosinophils were markedly reduced 0.5–2 hours after intravenous IL-5 (p&lt;0.05), followed by an increase at 3, 4, 5, and 72 hours (p&lt;0.05). Sputum eosinophils rose significantly in all three groups at 24 hours but there were no differences between the groups. Bronchial responsiveness was not affected by IL-5. <h3>CONCLUSION</h3> The effects of IL-5 appear to be mainly in the circulation, inducing peripheral mobilisation of eosinophils to the circulation without any effect on eosinophil mobilisation in the lungs or on bronchial responsiveness.
Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data
Authors: Rikke Sørensen, Morten L Hansen, Steen Z Abildstrom, Anders Hvelplund, Charlotte Andersson, Casper Jørgensen, Jan K Madsen, Peter R Hansen, Lars Køber, Christian Torp-Pedersen, Gunnar H Gislason
Journal: The Lancet (2009)
An Extra-Adrenal Factor Essential for Chronic Renal Sodium Retention in Presence of Increased Sodium-Retaining Hormone
Authors: JAMES O. DAVIS, JOHN E. HOLMAN, CHARLES C. J. CARPENTER, JOHN URQUHART, JAMES T. HIGGINS
Journal: Circulation Research (1964)

Evidence is presented for an extra-adrenal factor which is necessary for aldosterone or DCA to produce chronic renal Na retention. To study this factor, the left kidney was transplanted to the neck, both adrenal glands and the right kidney were removed and the thoracic inferior vena cava was constricted in six dogs. For a period of two to three weeks, injection of 25 mg/day of DCA resulted in marked Na retention by the transplanted kidney and ascites formed. Neither renal venous hypertension nor the renal nerves were essential for renal Na retention under these circumstances since the transplanted kidney was denervated and its venous drainage was into the external jugular vein with a normal venous pressure. Removal of the caval ligature in four of the dogs was followed by a diuresis and loss of ascites in spite of continued injection of 25 mg/day of DCA. Similar changes occurred during the injection of aldosterone instead of DCA. Measurements of renal hemodynamic function, first, during Na retention and ascites formation and, later, after removal of the caval ligature showed levels of GFR and RPF during Na retention as high as or higher than those observed during the diuresis and subsequent Na balance. In three hypophysectomized dogs with a very low GFR and RPF, Na retention failed to occur during injection of 25 mg/day of DCA. Also, in three adrenalectomized dogs, administration of a large dose of DCA failed to produce chronic Na retention. Finally, four dogs with a large aortic-caval fistula were given 25 mg/day of DCA; sustained Na retention occurred in all four animals and ascites developed in two of the four dogs. A low rate of Na excretion in these animals was present despite a large postprandial rise in GFR. Available evidence indicates that the extra-adrenal factor is either 1) a humoral agent, or 2) some as yet undefined renal functional change.
THE FATE OF AVIRULENT HEMOLYTIC STREPTOCOCCI INJECTED INTO THE SKIN OF NORMAL AND SENSITIZED RABBITS
Authors: D. Murray Angevine
Journal: The Journal of Experimental Medicine (1934)

1. A relatively avirulent strain of hemolytic streptococci injected into the skin of normal rabbits seldom diminished and usually increased in number during the first 5 hours after inoculation but after 12 hours save in exceptional instances the organisms diminished rapidly and disappeared. 2. Hemolytic streptococci injected into the skin of normal rabbits passed rapidly from the site of injection to the regional lymph nodes from which they were recovered in considerable number within 15 minutes. Passage of bacteria from the skin of the abdomen to the inguinal lymph node was greatest within 2 hours after injection and gradually decreased so that few organisms were recovered from the lymph nodes after 7 hours. 3. Hemolytic streptococci that reached the inguinal lymph node passed in small numbers to the distal or iliac lymph node, but this passage save in exceptional instances of progressive infection was limited to a period within 1 hour after inoculation. 4. Avirulent hemolytic streptococci injected into the skin of normal animals penetrated into the blood; they were seldom recovered from the circulating blood but were more frequently found in the spleen. 5. When hemolytic streptococci were injected into the skin of sensitized rabbits they multiplied at the site of injection during the first 5 hours after inoculation and at corresponding time intervals a larger number of organisms were recovered from the sensitized than from normal control animals. Streptococci diminished and disappeared earlier from the skin of control than from that of sensitized rabbits. 6. Hemolytic streptococci injected into the skin of the flank of sensitized rabbits reached the inguinal lymph node in much smaller numbers than in normal rabbits, and this passage from the site of injection to the lymph node save in an occasional instance of progressive local infection ceased after the 1st hour. No streptococci passed from the inguinal to the iliac lymph nodes of sensitized animals and none were found in the blood or internal organs. 7. Histological examination showed that the inflammatory reaction following the injection of hemolytic streptococci into rabbits sensitized to this organism began sooner than in the normal animal; edema was more extensive and both polymorphonuclear leucocytes and large mononuclear cells appeared sooner. The lesion of a sensitized animal was more sharply circumscribed and there was necrosis of tissue, seldom seen in the normal animals. 8. In sensitized animals local injury with necrosis favors the multiplication of relatively avirulent streptococci at the site of entry and explains their survival at a time when they have disappeared in the controls. 9. In association with greater local injury and a more intense inflammatory reaction in the sensitized animal as compared with the normal streptococci are fixed at their site of entry; they pass to adjacent lymph nodes in much smaller number and fail to reach the blood and internal organs.
IDENTIFYING DRUG COMPOUNDS TARGETING TUMOR METABOLISM IN GLIOBLASTOMAS
Authors: G. Zadeh
Journal: Neuro-Oncology (2014)

BACKGROUND: Rapidly proliferating tumour cells preferentially use aerobic glycolysis over oxidative phosphorylation (OXPHOS) to support growth and survive unfavorable microenvironment conditions. This metabolic reprogramming is referred to as the “Warburg effect”. We have shown that glycolytic enzyme hexokinase 2 (HK2) is crucial for the Warburg effect in human glioblastoma multiforme (GBM). We also demonstrate that loss of HK2 sensitizes GBM cells in-vitro and in-vivo to chemo and radiation therapy, significantly prolonging survival in intracranial models. We also show that loss of HK2 is most relevant in hypoxia. Given these results and that HK2 is an enzyme with little to no expression in normal brain, it provides an attractive target for targeting in GBMs. However, no direct inhibitor of HK2 that crosses the blood brain barrier exists. We therefore explored whether a system biology approach to identify gene networks regulated by or associated with HK2 that could lead to promising treatment strategies. METHODS: Using HK2 knockdown by siRNA in established GBM cell lines and primary GBM cultures we established gene signatures and networks associated with HK2 expression, identifying 1000 genes with a 2 fold change with p-value <0.01 and false discovery rate of <1%. Using a drug screen of 30 compounds that were predicted to repress HK2 expression and associated metabolic gene signatures we identified the azole class of antifungals as inhibitors of tumour metabolism by reducing proliferation, lactate production, glucose uptake and increasing O2 consumption in GBM cells but not primary normal human astrocytes or normal neural stem cells. RESULTS: We evaluated the in vivo efficacy of these azole compounds in pre-clinical orthotopic xenograft mouse models and transgenic models of GBM. The compounds in combination with standard chemo and radiation therapy significantly restrict tumor growth, alter tumor hypoxia and ROS production. We also show that there is a altered response to DNA damage pathways using these compounds, suggesting novel metabolic mechanisms by which these antifungals sensitize GBMs to treatment. CONCLUSIONS: The azole class of antifungals may represent a new way of targeting tumour metabolism in tumours dependent on HK2. SECONDARY CATEGORY: Tumor Biology.
The oesophageal string test: a novel, minimally invasive method measures mucosal inflammation in eosinophilic oesophagitis
Authors: Glenn T Furuta, Amir F Kagalwalla, James J Lee, Preeth Alumkal, Brian T Maybruck, Sophie Fillon, Joanne C Masterson, Sergei Ochkur, Cheryl Protheroe, Wendy Moore, Zhaoxing Pan, Katie Amsden, Zachary Robinson, Kelley Capocelli, Vince Mukkada, Dan Atkins, David Fleischer, Lindsay Hosford, Mark A Kwatia, Shauna Schroeder, Caleb Kelly, Mark Lovell, Hector Melin-Aldana, Steven J Ackerman
Journal: Gut (2012)

<h3>Objective</h3> Eosinophil predominant inflammation characterises histological features of eosinophilic oesophagitis (EoE). Endoscopy with biopsy is currently the only method to assess oesophageal mucosal inflammation in EoE. We hypothesised that measurements of luminal eosinophil-derived proteins would correlate with oesophageal mucosal inflammation in children with EoE. <h3>Design</h3> The Enterotest diagnostic device was used to develop an oesophageal string test (EST) as a minimally invasive clinical device. EST samples and oesophageal mucosal biopsies were obtained from children undergoing upper endoscopy for clinically defined indications. Eosinophil-derived proteins including eosinophil secondary granule proteins (major basic protein-1, eosinophil-derived neurotoxin, eosinophil cationic protein, eosinophil peroxidase) and Charcot–Leyden crystal protein/galectin-10 were measured by ELISA in luminal effluents eluted from ESTs and extracts of mucosal biopsies. <h3>Results</h3> ESTs were performed in 41 children with active EoE (n=14), EoE in remission (n=8), gastro-oesophageal reflux disease (n=4) and controls with normal oesophagus (n=15). EST measurement of eosinophil-derived protein biomarkers significantly distinguished between children with active EoE, treated EoE in remission, gastro-oesophageal reflux disease and normal oesophagus. Levels of luminal eosinophil-derived proteins in EST samples significantly correlated with peak and mean oesophageal eosinophils/high power field (HPF), eosinophil peroxidase indices and levels of the same eosinophil-derived proteins in extracts of oesophageal biopsies. <h3>Conclusions</h3> The presence of eosinophil-derived proteins in luminal secretions is reflective of mucosal inflammation in children with EoE. The EST is a novel, minimally invasive device for measuring oesophageal eosinophilic inflammation in children with EoE.
<i>Tip30</i> Deletion in MMTV-Neu Mice Leads to Enhanced EGFR Signaling and Development of Estrogen Receptor–Positive and Progesterone Receptor–Negative Mammary Tumors
Authors: Chengliang Zhang, Mikito Mori, Shenglan Gao, Aimin Li, Isamu Hoshino, Mark D. Aupperlee, Sandra Z. Haslam, Hua Xiao
Journal: Cancer Research (2010)

Abstract Estrogen receptor–positive and progesterone receptor–negative (ER+/PR−) breast cancers account for 15% to 25% of all human breast cancers and display more aggressive malignant characteristics than ER+/PR+ cancers. However, the molecular mechanism underlying development of ER+/PR− breast cancers still remains elusive. We show here that Tip30 deletion dramatically accelerated the onset of mammary tumors in the MMTV-Neu mouse model of breast cancer. The mammary tumors arising in Tip30−/−/MMTV-Neu mice were exclusively ER+/PR−. The growth of these ER+/PR− tumors depends not only on estrogen but also on progesterone despite the absence of detectable PR. Tip30 is predominantly expressed in ER+ mammary epithelial cells, and its deletion leads to an increase in the number of phospho-ERα–positive cells in mammary glands and accelerated activation of Akt in MMTV-Neu mice. Moreover, we found that Tip30 regulates the EGFR pathway through controlling endocytic downregulation of EGFR protein level and signaling. Together, these findings suggest a novel mechanism in which loss of Tip30 cooperates with Neu activation to enhance the activation of Akt signaling, leading to the development of ER+/PR− mammary tumors. Cancer Res; 70(24); 10224–33. ©2010 AACR.