tbuckley/cabot-search huggingface dataset:
Combinations of Endocrine and Biological Agents: Present Status of Therapeutic and Presurgical Investigations
Authors: Stephen RD Johnston
Journal: Clinical Cancer Research (2005)

Abstract There is an increasing rationale to develop effective combinations of endocrine agents with novel therapeutics that target aberrant signal transduction pathways in estrogen receptor–positive breast cancer. Acquired resistance to endocrine therapy is associated with an increase in peptide growth factor signaling that results in crosstalk activation of estrogen receptor, and various signal transduction inhibitors (STI) can target these pathways to inhibit hormone-resistant growth. In experimental models of hormone-sensitive breast cancer, combinations of endocrine agents with STIs provide significantly greater growth inhibition than either alone, delaying the emergence of resistance. There are now several trials assessing the efficacy of combinations of tyrosine kinase inhibitors with various endocrine agents in the tamoxifen-resistant/second-line setting, together with five randomized phase II/III trials in the first-line setting. Similar work is ongoing with both farnesyltransferase inhibitors and mTOR antagonists where there are strong preclinical data to suggest additive or synergistic effects for either of these agents in combination with tamoxifen or estrogen deprivation therapies. More recently, presurgical studies with biological primary end points are being utilized as an alternative approach to investigate whether combined endocrine/STI therapy is a more effective strategy than endocrine therapy alone. This article reviews the rationale and current status of clinical trials in this area as well as the challenges that lie ahead for the development of these therapeutic combinations for breast cancer.
Pilot study to evaluate a novel advance-care planning tool to identify informed health care proxies in an oncology palliative care clinic.
Authors: Eric Roeland, Melanie Benn, Sean Heavey, Ashleigh Campillo, Carolyn Revta, Rabia S. Atayee, Joseph D. Ma
Journal: Journal of Clinical Oncology (2014)

136 Background: To increase the probability that cancer patients receive care consistent with their wishes, medical providers require simple, practical, and effective communication tools to initiate and complete meaningful advance care planning (ACP) discussions. Ideally, ACP discussions occur in the non-emergent setting with a selected health care proxy and trusted medical provider and may lead to completion of an advance directive (AD). The primary aim of this study is to determine the proportion of advanced cancer patients who identify an informed health care proxy implementing a novel ACP tool. Methods: In an American Cancer Society funded pilot study, advanced cancer patients were evaluated in an academic oncology palliative care clinic (n=35). Subjects engaged in a 1-hour ACP intervention completed by a licensed clinical social worker utilizing a novel ACP tool developed by the investigators. The ACP tool identifies a health care proxy and defines three key elements an informed health care proxy must know. Details of this ACP conversation were documented in the electronic medical record with the goal of completing an AD. After subject’s death, health care proxies were contacted to determine if end-of-life wishes were honored. Results: 35 subjects (51% woman, 71% Caucasian, 54% married) were enrolled with a mean age ± SD of 57.4 ± 14.1 years with gastrointestinal as the most common primary cancer (13/35). The ACP intervention was completed in 80% in 1-2 clinic visits. After the ACP intervention, 94% of subjects (33/35) identified an informed health care proxy. The most common identified health care proxies were either a spouse (17/35) or child (11/35). 43% of subjects (15/35) completed an AD after the ACP intervention. As of July 2014, 69% (24/35) of subjects had died and 71% of these (17/24) died in a setting consistent with their end-of-life wishes. Mean time to death from ACP intervention was 4.5 ± 3.2 months. 11 subjects remain in surveillance. Conclusions: Results suggest that this novel ACP tool facilitates successful identification of an informed health care proxy. Despite low AD completion, death consistent with end-of-life wishes was achieved in the majority of patients.
Abstract 3012: Impact of Thromboaspiration during Primary PCI on Microvascular Damage and Infarct Size: Acute and Long term ce-MRI Evaluation.
Authors: Gennaro Sardella, Massimo Mancone, Raffaele Scardala, Leonardo De Luca, Chiara Bucciarelli Ducci, Angelo Di Roma, Iacopo Carbone, Francesco Fedele
Journal: Circulation (2007)

Background: In patients with ST-elevatrion myocardial infarction (STEMI), impairment of microcirculatory function is a negative independent predictor of myocardial function recovery. Compared with conventional stenting, thrombectomy during primary percutaneous coronary intervention (PCI) seems to improve the parameters of myocardial tissue perfusion. We sought to evaluate the impact of thromboaspiration on procedural outcomes and microascualr damage and infarct size by contrast enhanced-MRI (ce-MRI) as compared to conventional primary PCI. Methods:We randomized 75 patients (mean age 64.3±10.2, 55 male) referred to our Hospital with a STEMI (&lt;9 hours from symptoms onset) and an occlusive thrombus at basal angiography, to thromboaspiration with a manual device (Export ®-Medtronic (n=38) (group 1)) and standard PCI (n=37) (group 2). 3 days after procedure and 3 months later a ce-MRI was performed to assess the microvascular damage (as hypoenhancement (HO)) and infarct size (as hyperenhancement(HR)) in the 2 groups. The primary end points were the angiographic result in terms of the TIMI ≥ II flow , MBG ≥ 2 and ST-segment resolution (STr)≥ 70% post-stenting and the microvascular damage (grams/g) and infarct size (grams/g) evaluated by ce-MRI. Results: No differences on baseline, clinical and angiographic preprocedural findings were observed between the two groups. After trombectomy, a TIMI II flow was present in in 38.6 vs 19.6% (p=0.054) and TIMI III was 30.7 vs 72.5% (for group 1 and 2, respectively, p&lt;0.001). Postprocedural MBG ≥2 was 70,3% vs 28,7% (p&lt;0.001) and 90′ ST-segment resolution was 80% vs 37.5% (for group 1 and 2, respectively, p&lt;0.001). Ce-MRI showed an HO of 4.04±5.87g at 3 days vs 0.12±0.4g at 3 months (p= 0.04) in group 1, and 3.7±5.04 vs 2.7±2.3 (3 d and 3 m. respectively)(p=ns) in group 2. At 3 days HR was 17.39±15.6g vs 11.01±8.07g at 3 months in group 1 (p=0.04) and 14.02±7.5g vs 13.6±12.7g ( 3 d. and 3 m. respectively) (p=ns) in group 2. Conclusion:Compared with conventional stenting, a pretreatment with thrombectomy during primary PCI, improves epicardial flow and procedural outcomes. The long term ce-MRI evaluation suggests a reduction in microvascular damage and infarct size compared with the acute evaluation in the thrombectomy group.
Granulocyte-macrophage colony-stimulating factor mitigates the neutropenia of combined interferon alfa and zidovudine treatment of acquired immune deficiency syndrome-associated Kaposi's sarcoma.
Authors: D T Scadden, H A Bering, J D Levine, J Bresnahan, L Evans, C Epstein, J E Groopman
Journal: Journal of Clinical Oncology (1991)

The combined use of zidovudine (ZDV) and interferon (IFN) alfa-2a has been shown to have antiretroviral and antitumor potential benefit in the treatment of acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). However, the clinical use of this combination is frequently complicated by the overlapping myelotoxicity of these agents. We report here the results of a phase I/II study in which granulocyte-macrophage colony-stimulating factor (GM-CSF) was used for those KS patients who became neutropenic while receiving ZDV (1,200 mg/d) and IFN (9 x 10(6) U/d). Nineteen of 29 patients (66%) developed an absolute neutrophil count (ANC) of less than 1,000 cells per cubic millimeter and were begun on GM-CSF. All experienced a prompt increase in the ANC. Those patients receiving GM-CSF/ZDV/IFN alfa-2a had an improved end of study ANC when compared with the ZDV/IFN alfa-2a group, but did not have an increased rate of tumor response, end of study CD4 cell count, or improvement in any other hematologic variable. The use of GM-CSF was not associated with increased toxicity and, in particular, was not associated with a change in serum human immunodeficiency virus (HIV) p24 antigen. Tumor response was noted in 50% of the assessable patients (33% overall) despite "high-risk" characteristics in 80%. Of the responding patients, seven were on GM-CSF and might have otherwise required an alteration in ZDV/IFN alfa-2a dose level. Further study of GM-CSF as an alternate to dose modification of this (ZDV/IFN alfa-2a) and other combination therapies for AIDS patients is warranted.
Investigate which PKC isoform play an important role in human lung cancer cells against TRAIL-induced apoptosis
Authors: Chuan-Chou Tu, Wen-Jen Wu
Journal: European Respiratory Journal (2013)

Tumor nercrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent as it selectively kills tumor cells but spares normal cells. Resistance to TRAIL by tumor cells limits its therapeutic use in clinic. TRAIL-induced apoptosis is mediated by binding with death receptors, DR4 and DR5, but the decoy receptors (DcR1 and DcR2) on the surface of tumor cells collapse TRAIL-mediated apoptosis. Recently, several articles have demonstrated that some tumor cell lines exhibit TRAIL-resistance and this resistance may be not associated with decoy receptors. Some receptors indicated that PKC activation was an important factor for cell to protect apoptosis from TRAIL. Therefore, we analyzed the sensitivity of nine human non-small lung cancer (NSCLC) cell lines to TRAIL. We found the expression of PKCe is higher in TRAIL-resistant cell lines (H1355 and H520) than those of in TRAIL-sensitive cell lines (H460 and H358). In order to investigate the role of PKCe in TRAIL-resistant cell lines, we used PKCe shRNA to block PKCe activity, and then observed their effect on TRAIL-induced apoptosis. Knockdown of PKCe expression by shRNA resulted in enhanced sensitivity to TRAIL in H1355 and H520 cell lines. Some references pointed out that PKCe is an oncogene. In this research, we investigated the role of PKCe gene in lung cancer cells. We found out when used PKCe shRNA to suppress PKCe expression, it would decrease cell growth and increase sensitivity to TRAIL-induced apoptosis. Finally, the similar results were observed in animal tumor model.
Therapeutic efficacy of macrolides, minocycline and tosufloxacin against macrolide-resistant Mycoplasma pneumoniae pneumonia in pediatric patients
Authors: Naoyuki Miyashita, Mika Kubo, Yasuhiro Kawai, Kazunobu Ouchi, Niro Okimoto
Journal: European Respiratory Journal (2012)

Background and objective: Since 2000 the prevalence of macrolide-resistant (MR) Mycoplasma pneumoniae in pediatric patients has increased in Japan. The purpose of our study was to investigate differences in the clinical course, bacteriological effect and therapeutic efficacy against MR M. pneumoniae among macrolides, minocycline and tosufloxacin.

Methods: We performed a multicenter prospective epidemiological study of MR M. pneumoniae for the first time. A total of 152 children with M. pneumoniae pneumonia confirmed by polymerase chain reaction (PCR) were analyzed. A search for mutations at sites 2063, 2064, and 2617 in the M. pneumoniae 23S rRNA domain V gene region was performed.

Results: One hundred nine patients of 152 children with M. pneumoniae pneumonia were determined to have a MR gene. Fever disappeared within 48 hours after antibiotics administration in the MR patients was seen in 25% of the macrolides group, 83% in the minocycline group, and 81% in the tosufloxacin group. The DNA copy numbers in the MR patients showed little decrease after macrolide administration, but rapid decrease after administration of minocycline or tosufloxacin.

Conclusions: The number of M. pneumoniae in the MR patients decreased promptly after 48 hours' minocyclne and tosufloxacin treatment and had a close relationship with clinical outcome. In contrast, we found that the clinical and bacteriological efficacy of macrolides for treating cases of MR patients was low. Our results might be indicate that minocycline and tosufloxacin considered as the first choice drugs for treatment of M. pneumoniae pneumonia in Japanese situation.
Frequency of pulmonary hypertension in patients with COPD - Clean-up workers of Chernobyl catastrophe
Authors: Olena Apostolova, Viktor Sushko, Olga Tatarenko
Journal: European Respiratory Journal (2013)

Aim: The aim of the study was designed to investigate the pulmonary hypertension (PH) frequency and its relations in COPD patients - clean-up workers of the Chernobyl catastrophe (ChC) and comparable group of COPD patients that have not undergone radiation exposure. Methods and Results : The study was a retrospective review of patients with COPD defined as a smoking history, Pulmonary function tests (PFT) and echocardiogram within stable status. PH was defined as systolic pulmonary artery pressure >35 mmHg. The main study group were patients with COPD – 248 clean-up workers of ChC in 1986 (doses ranged from 250 to 750 mSv). Age of main group of patients was (59.8 ± 1.4) years. Comparison group - 234 patients with COPD who were not undergone to radiation exposure (age - (63.5 ± 2.9) years). Only males were included into the study. The prevalence of PH was found more frequent in main group. It was more prominent in moderate level COPD cases (56,7% and 37,3%, p<0.001). Both groups had airflow limitation, hypercapnia and hypoxemia, but no differences were found in terms of PaCO(2) and PaO2. However, FEV1 % was lower in COPD patients clean-up workers of ChC compared with the noniradiated patients (p<0,005). Conclusion: The study demonstrated that PH frequency is higher in group of COPD patients clean-up workers of ChC than in patients with COPD who were not undergone to radiation exposure. The influence of FVC % on the risk of a person having PH increased with increasing COPD level.
Abstract 13350: Improvement of Left Ventricular Diastolic Property is a Crucial Factor for Benefits from Cardiac Resynchronization Therapy
Authors: Mika Maeda, Hideaki Kanzaki, Makoto Amaki, Takuya Hasegawa, Akira Funada, Hiroyuki Takahama, Masanori Asakura, Masafumi Kitakaze
Journal: Circulation (2010)

Background: Cardiac resynchronization therapy (CRT) can improve heart failure symptoms prior to left ventricular (LV) reverse remodeling. LV diastolic dysfunction is a condition leading to symptom, morbidity, hospitalizations and death, independently from LV systolic function. This study aimed to assess the changes of LV diastolic property by CRT. Methods: One hundred three patients who had undergone CRT (LVEF 23±8%, QRS 166±39 msec) were studied with a GE Vivid 7. Left atrial volume and LV end-systolic volume were measured using the modified biplane Simpson's method and indexed to body surface area (LAVi and LVESVi, respectively). Both LAVi and pulmonary vascular resistance (PVR) were determined as a marker of LV diastolic property at baseline and 6 months of CRT. PVR was calculated as 80 multiplied by the ratio of peak tricuspid regurgitant velocity to the right ventricular outflow tract time-velocity integral. Responders to CRT were defined as improvement of at least one NYHA class 6 months after CRT, ...
The alpha 1-adrenergic agonist methoxamine and the "loop" diuretic frusemide reduce nasal potential difference
Authors: AM Wood, AT Dinh Xuan, G Cremona, A Lockhart, TW Higenbottam
Journal: European Respiratory Journal (1991)

Pretreatment by inhalation with the alpha 1-adrenergic agonist methoxamine and the "loop" diuretic frusemide reduces the bronchial response to certain airway challenges in asthma. To test whether these drugs may act by altering airway epithelial ion and water transport, their effect on nasal potential difference (PD) when applied topically in eight normal volunteers was measured. For comparison, the effect of the Na(+)-channel blocking drug amiloride and the beta 2-adrenergic agonist salbutamol was also tested. Both methoxamine and frusemide significantly reduced PD: at the highest concentration given (10(-3) mol.l-1), there was a mean drop in PD from baseline of 39.5% following methoxamine treatment (p less than 0.05) and a mean drop of 30.2% following frusemide (p less than 0.05). Neither drug was as effective as amiloride, which caused a mean drop in PD of 27.5% from baseline at 10(-6) mol.l-1 and a drop of 71.6% at 10(-3) mol.l-1 (p less than 0.01 for each concentration). Salbutamol had no significant effect on PD (p greater than 0.05). We conclude that methoxamine and frusemide may derive their protective effect on some bronchial challenge, at least in part, from their effect on airway epithelial ion flux.
Differences in cancer dynamics may explain why prostate screening has cut metastatic disease while breast screening has not
Authors: Susan Mayor
Journal: BMJ (2015)

<h3>ABSTRACT</h3> Neuropeptide Y (NPY) is an abundant neurohormone in the central and peripheral nervous system involved in feeding behavior, energy balance, nociception, and anxiety. Several NPY receptor (NPYR) subtypes display elevated expression in many cancers including in breast cancer where this is exploited for imaging and diagnosis. Here, we show that NPY1R and NPY5R mRNA abundance is induced by hypoxia in a Hypoxia Inducible Factor (HIF)-dependent manner in breast cancer cell lines MCF7 and MDA-MB-231. The HIFs bind to several genomic regions upstream of the <i>NPY1R</i> and <i>NPY5R</i> transcription start sites. The MAPK/ERK pathway is activated more rapidly upon NPY5R stimulation in hypoxic cells compared to normoxic cells. This pathway requires IGF1R activity in normoxia, but not in hypoxic cells where they display resistance to the radiosensitizer and IGF1R inhibitor AG1024. Hypoxic cells proliferate and migrate more when stimulated with NPY relative to normoxic cells, with a more robust response observed with a Y5-specific agonist. Our data suggest that hypoxia induced NPYRs render hypoxic cells more sensitive to NPY stimulation. Considering that breast tissue receives a constant supply of NPY, and hypoxia is a common feature of the tumor microenvironment, breast tumors are the perfect storm for hyperactive NPYR. This study not only highlights a new relationship between the HIFs and NPYR expression and activity, but may inform the use of chemotherapeutics targeting NPYRs and hypoxic cells.
The treatment of chronic uremia by means of intermittent hemodialysis
Authors: B H Scribner, R Buri, J E Caner, R Hegstrom, J M Burnell
Journal: Journal of the American Society of Nephrology (1998)

Journal of the American Society of Nephrology : JASN 9(4):p 719-726, April 1998. | DOI: 10.1681/ASN.V94719
Increased complexity in carcinomas: Analyzing and modeling the interaction of human cancer cells with their microenvironment
Authors: Mira Stadler, Stefanie Walter, Angelika Walzl, Nina Kramer, Christine Unger, Martin Scherzer, Daniela Unterleuthner, Markus Hengstschläger, Georg Krupitza, Helmut Dolznig
Journal: Seminars in Cancer Biology (2015)
Cardiac MRI derived right ventriculo-arterial coupling in pulmonary hypertension as a predictor of survival
Authors: Melanie Brewis, Robert Naeije, Alessandro Bellofiore, Naomi Chesler, Andrew Peacock
Journal: European Respiratory Journal (2014)

It is possible to estimate right ventriculo-arterial (VA) coupling using cardiac MRI (CMR) derived stroke volume (SV) and end systolic volume (ESV) as the ratio (SV/ESV). SV/ESV is equivalent to a ratio of elastances with a common pressure, and in principle is preload independent.

Methods: 121 group 1 treatment naive pulmonary hypertension (PH) patients underwent CMR at diagnosis. 46 underwent repeat CMR after minimum of 3 months of therapy.

Results: SV/ESV was predictive of survival (P=0.001, table1), but did not improve significantly with therapy (table2).

Conclusion: SV/ESV predicts survival in PH, but does not seem to provide added value over ejection fraction (RVEF) and does not change with specific treatment. Correlation with invasive data is needed to assess if SV/ESV is an accurate reflection of VA coupling.

![Figure][1] 



Table1: Age and gender adjusted survival predictors. Abbreviations RVEDVI right ventricular (RV) end diastolic volume index; RVESVI RV end systolic volume index; LVEDVI left ventricular end diastolic volume index

![Figure][1] 



Table2: baseline and follow up CMR variables after minimum of 3 months of therapy (mean ±SD or median (IQR)).

 [1]: pending:yes
Drug-Induced Megaloblastic Anemia
Authors: Charles S. Hesdorffer, Dan L. Longo
Journal: New England Journal of Medicine (2015)

Many common drugs induce megaloblastic anemia by interfering with folate or vitamin B12 absorption, altering B12 metabolism, or blocking pathways in which these vitamins play a role. Supplements to overcome these effects or discontinuation of the drug may be necessary.
Bacteremia in children: a 2-year review of experience with a pediatric blood culture protocol using BacT/Alert standard bottles
Authors: Roberto Ceccarelli, Candida Palmero, Enrico Mantero, Francesco Campone, Giuseppe Russo, Rosanna Frulio, Elisabetta Ugolotti, Marialuisa Belli, Clotilde Jannuzzi
Journal: Clinical Microbiology and Infection (1997)
Beta Blockers and Cardiac Arrhythmias
Journal: Thorax (1993)

cases diagnosed as a result of the contact tracing described in this paper is small, however, and it would be a pity if the possibility of late tuberculosis were discounted on the grounds that no such cases were found in South Glamorgan.We recently reported on a child who was found to have a tuberculous pleural effusion six months after being a close contact of a patient with smear positive tuberculosis.'This child had been thought to be negative on being screened six weeks after the last contact.In children at least, longer follow up may be appropriate.
Statin use and risk of exacerbations in individuals with COPD: The Copenhagen general population study
Authors: Truls Ingebrigtsen, Jacob Marott, Børge Nordestgaard, Peter Lange, Jesper Hallas, Jørgen Vestbo
Journal: European Respiratory Journal (2014)

Aim : We tested the hypothesis that statin use in individuals with chronic obstructive pulmonary disease (COPD) is associated with reduced risk of exacerbations.   Methods and study population : From participants in the Copenhagen General Population Study (2003-2008), we identified 5,798 individuals with COPD and inflammatory biomarkers measured at the examination, including C-reactive protein (CRP). Exacerbations, defined by hospital admissions or medically treated exacerbations, during 3 years of follow-up were recorded. We applied a case-control design, matching on age, gender, COPD severity, comorbidity and smoking, and the association between statin use prior to exacerbation and risk of exacerbations was estimated. Furthermore, the association between statin use and high CRP (> 3 mg/L), and the association between high CRP and future risk of exacerbations was examined.   Results : Statin use in COPD was associated with reduced odds of exacerbations in univariable, OR=0.68 (95% confidence interval 0.51-0.91, p=0.01), and multivariable analysis, OR=0.67 (0.48-0.92, p=0.01) compared to no use of statins. Furthermore, statin use was associated with reduced odds of high CRP (vs. low CRP), OR=0.69 (0.56-0.85, p   Conclusions : Statin use was associated with reduced risk of exacerbations in individuals with COPD in the general population. Part of this relationship may be explained by statins reducing CRP.