tbuckley/cabot-search huggingface dataset:
Treatment of opioid-induced constipation in hospice patients with methylnaltrexone
Authors: T. A. Boyd, R. J. Israel
Journal: Journal of Clinical Oncology (2004)

8279 Background: Methylnaltrexone (MNTX) is a selective opioid-receptor antagonist that does not cross the blood-brain barrier in humans. It has the potential to counteract the debilitating peripheral side effects of narcotic pain therapy without interruption of centrally-mediated analgesia or precipitation of withdrawal. MNTX is being developed for the treatment of opioid-induced constipation (OIC) which is refractory to laxatives and stool softeners. Methods: The activity and tolerability of MNTX were investigated in a series of phase 1 and 2 clinical trials. Normal subjects as well as patients receiving chronic opioids were treated with various doses of MNTX administered via intravenous and subcutaneous routes. Relief of OIC by subcutaneous MNTX was evaluated in hospice patients in phase 2 trials. Results: Results from completed studies demonstrate that MNTX was generally well tolerated and significantly reduced or prevented OIC, urinary retention, as well as other peripheral side effects of opioids. Subcutaneous MNTX provided rapid relief of OIC (median time ≈ 1 hr) in approximately 60% of terminally ill patients receiving active doses (≥ 5 mg). The median number of laxations per week increased to between 4 to 6 from ≤ 2 prior to baseline. The most frequent adverse events were transient mild abdominal cramping and flatulence. No evidence of opioid withdrawal or reversal of analgesia was observed in any clinical trial. Conclusions: MNTX is well tolerated and active in relieving OIC and other debilitating side effects of narcotic pain therapy. These findings strongly support further evaluation of subcutaneous MNTX in hospice patients experiencing OIC. Two pivotal phase 3 clinical trials in this setting are currently underway in the United States. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Progenics Pharmaceuticals, Inc. Progenics Pharmaceuticals, Inc. Progenics Pharmaceuticals, Inc.
Respiratory muscle endurance training (RMET) with normocapnic hyperpnea (NH) improves ventilatory function and exercise performance in triathletes
Authors: Eva Bernardi, Enzo Melloni, Gaia Mandolesi, Luca Pomidori, Annalisa Cogo
Journal: European Respiratory Journal (2012)

Recent studies show that RMET reduces dyspnea perception, improves exercise performance and decreases VE during exercise in healthy subjects.  Aim: To evaluate the effect of 5 weeks of RMET with NH by means of Spirotiger® on respiratory function, cycling and running performance in triathletes.  Methods: 15M triathletes (aged 21-43) were allocated in 2 groups: RMET (10M) and Control (5M) group.  At baseline (T0) athletes underwent: pulmonary function tests (FEV1, FVC, MIP, MVV) and exercise tests (maximal incremental and endurance cardiopulmonary tests performed with both cycle ergometer and treadmill) and repeated the same tests after 5 weeks (T1).  RMET group trained at home for 5 weeks: 20 min daily at the same ventilation level measured at the RC point during incremental test.  Between T0 and T1 all subjects maintained the same training program.  Results are reported in Table1.  The trend of VO2, VE and RR showed lower values after RMET (p  No change was found in control group.  Conclusion: RMET significantly improves MIP and MVV in triathletes and increases exercise performance. Furthermore the VE becomes more efficient as shown by the reduction of VE, RR and by the lower dyspnea Borg score; the new data is the lower trend of VO2 during incremental test.
Abstract 245: Plasminogen Augments Cxcl12/cxcr4-regulated Stem Cell Homing And Contributes To Cardiac Repair After Myocardial Infarction.
Authors: Yanqing Gong, Yujing Zhao, Yi Fan, Jane Hoover-Plow
Journal: Circulation Research (2014)

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. Bone marrow (BM)-derived stem cells promote tissue repair and regeneration after MI. Thrombolytic treatment with plasminogen (Plg) activators significantly improves the clinical outcome in MI by restoration of cardiac perfusion. In addition to its canonical function, Plg is critical for cardiac repair, wound healing and liver injury, however, the mechanism for Plg-regulated tissue repair remains unclear. Here, we show a novel role of Plg in stem cell-mediated neovascularization and cardiac repair after MI. Our data show that Granulocyte colony-stimulating factor (G-CSF), a stem cell mobilizer, significantly increased neovascularization and decreased infarct size in the infarct area, and improved ejection fraction and LV internal diameter by echocardiogram in wild-type mice. No improvement in tissue repair and heart function was observed in Plg deficient (Plg-/-) mice indicating that Plg is required for stem cell-regulated cardiac repair after MI. In vivo tracking of GFP-expressing BM cells after BM transplantation revealed that in Plg-/- mice, recruitment of BM-derived stem cells (GFP+c-kit+ cells) to the infarcted heart and stem cell-derived vessels and arteries are dramatically decreased (by 11 fold) suggesting that Plg may regulate stem cell homing to the lesion sites and subsequently contribute stem cell-mediated tissue regeneration. Mechanistic studies show that Plg up-regulated CXCR4 expression on stem cell in vivo and in vitro, suggesting Plg may promotes stem cell homing by induction of CXCR4 expression in stem cells. Stem cell migration was enhanced by endogenous Plg in vitro, however, AMD3100, a CXCR4 antagonist, significantly inhibited Plg-regulated stem cell migration. Furthermore, lentiviral reconstitution of CXCR4 expression in BM cells rescued stem cell homing to the infarcted heart in Plg-/- mice, indicating that Plg mediates stem cell homing through regulating CXCR4 expression. These findings identified a novel role of Plg in cardiac repair by promoting stem cell homing to the injured heart after MI. Thus, targeting Plg may offer a new therapeutic strategy for strengthening stem cell-mediated cardiac repair and regeneration after MI.
Lepidic and non-lepidic adenocarcinomas have distinct gene expression signatures that correlate with aggressiveness
Authors: Pierre Fouret, Robert Fouret, Julien Laffaire
Journal: European Respiratory Journal (2013)

Method: A total of 103 lung adenocarcinomas from 57 never smokers and 56 ever smokers were studied using gene expression arrays.

Results: Unsupervised hierarchical clustering analysis revealed two groups of patients. In the first group, the tumor gene expression profile resembled that of normal lung. In the second group, there were two distinctive gene clusters, which were not seen in the first group. Gene Ontology terms associated with these two distinctive gene clusters were “cell proliferation” and “invasion”, respectively. The classification was associated with smoking status (p-value 0.01), lepidic component (p-value 0.00005) and EGFR (p-value 0.0002) or KRAS (p-value 0.02) mutation status.

View this table:

Table 1. Characteristics associated with gene expression profiles





Conclusion: Lung adenocarcinomas have gene expression profiles that correspond to their clinical and histological presentation. Our study confirms the greater aggressiveness of non-lepidic versus lepidic adenocarcinomas and offers new opportunities to uncover genetic alterations that drive clinical evolution.
Endoplasmic reticulum heat shock protein gp96/grp94 is a pro‐oncogenic chaperone, not a tumor suppressor
Authors: Saleh Rachidi, Shaoli Sun, Zihai Li
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the article by Chen et al. published in Hepatology.1 gp96, or grp94, is an endoplasmic reticulum (ER) heat shock protein 90 (HSP90) that chaperones many strategically important client proteins in oncogenesis including integrin, Toll‐like receptor, Wnt coreceptor, and insulin‐like growth factor. However, Chen et al. demonstrated that conditional deletion of hsp90b1 (encoding gp96) and Pten from mouse livers using Cre recombinase driven by albumin promoter (Alb‐Cre) increased liver tumorigenesis.1 Nevertheless, the gp96 status of these tumors was not reported, leaving open the possibility of gp96 being either a tumor suppressor (if tumors were gp96–) or a pro‐oncogenic chaperone (if gp96+). This diametrically opposed viewpoint is important to clarify, particularly because liver‐specific knockout of protumorigenic genes could result in paradoxical enhancement of tumorigenesis from cells that escaped cre‐mediated deletion.2 Herein, by crossing the same Alb‐cre mice with our independently generated hsp90b1flox/flox mice,3 we also probed the roles of gp96 in liver oncogenesis. We found that knockout (KO) mice were more susceptible to hepatocyte carcinogenesis than wild‐type (WT) mice in response to diethyl‐nitrosoamine (DENA), but the developing tumors were exclusively gp96+, due to an age‐dependent expansion of the residual WT hepatocytes (Fig. 1).Figure 1: Alb‐cre‐hsp90b1 flox/flox mice (KO) have increased liver carcinogenesis from residual gp96+ hepatocytes. (A) Representative images of WT and KO tumors. (B) Quantification of liver tumors from WT and KO mice 32 weeks post‐DENA injection.The development of gp96+ but not gp96– tumors in the same hosts illustrates its tumor‐promoting rather than tumor‐suppressive role. It might be prudent to examine if the Pten‐loss tumors in the study of Chen et al. were also gp96+, analogous to another study on ER chaperone grp78.5 It was found that liver cancer develops from escaping residual grp78+ hepatocytes after intended biallelic liver‐specific deletion of Pten and grp78 by way of Albumin‐Cre. The shared but apparently nonredundant cellular function of grp78 and gp96 in liver cancer underscores the critical oncogenic roles of both chaperones.
Anogenital Lichen Sclerosus in Women
Authors: R H Meyrick Thomas, C M Ridley, D H McGibbon, M M Black
Journal: Journal of the Royal Society of Medicine (1996)

A study of 350 women with lichen sclerosus, originally made to elucidate the relationship between lichen sclerosus and autoimmunity, led to the amassing of a considerable amount of clinical material. Our review is confined to those with anogenital lesions (342), supplemented by some new cases (15), giving a total of 357 women with biopsy proven lichen sclerosus. It demonstrates the wide age range of the condition, the association with morphoea and lichen planus and the occurrence of squamous cell carcinoma in some cases. It also shows that inappropriate surgery has continued to be carried out for benign disease.
Professional practice patterns of U.S. psychiatrists
Authors: M Olfson, H A Pincus, T H Dial
Journal: American Journal of Psychiatry (1994)

The authors develop a classification of psychiatric practice based on primary and secondary work settings.Data from the 1988-1989 APA Professional Activities Survey were used to characterize seven practice groups: public psychiatrists, public psychiatrists with private secondary work settings, private psychiatric/general hospital psychiatrists, private office practice psychiatrists, private office practice psychiatrists with secondary private psychiatric/general hospital work settings, private office practice psychiatrists with secondary settings other than private hospitals, and psychiatrists in private organized outpatient settings. Psychiatrists primarily in government administrative agencies, medical schools, or nursing homes were among those excluded. Usable data were available from 16,135 psychiatrists (82.8% of the target respondents).The largest groups were private psychiatric/general hospital psychiatrists (19.6%), private office practice psychiatrists with secondary settings other than private hospitals (18.9%), and private office practice psychiatrists with secondary private psychiatric/general hospital work settings (17.4%), followed by public psychiatrists with private secondary work settings (14.5%), private office practice psychiatrists (11.7%), public psychiatrists (11.4%), and psychiatrists in private organized outpatient settings (6.6%). During a typical week, the practice groups varied in the average proportion of their outpatients who received assessments, therapy and medication, therapy and no medication, and medication management. The groups also varied in the mean number of patients they treated each month with affective disorders, schizophrenia, anxiety disorders, and other disorders.Only about one in 10 clinical psychiatrists is engaged exclusively in office-based private practice, and approximately half of the outpatients treated by the average psychiatrist receive medication. Work setting appears to exert a powerful influence over whom psychiatrists treat and what services they provide. Because a majority of psychiatrists work in more than one setting, most psychiatrists serve a broad range of patients and provide a variety of treatments.
<i>CCR</i> 20th Anniversary Commentary: Triple-Negative Breast Cancer in 2015—Still in the Ballpark
Authors: Steven A. Narod, Rebecca A. Dent, William D. Foulkes
Journal: Clinical Cancer Research (2015)

The research article by Dent and colleagues, which was published in the August 1, 2007, issue of Clinical Cancer Research, provided a clinical description of metastatic progression of triple-negative breast cancers. Finding successful treatment strategies for women with triple-negative breast cancer remains a challenge.
Glucocorticoids and indacaterol regulated gene expressions profiling in human bronchial epithelial cells
Authors: Taruna Joshi, Malcolm Johnson, Robert Newton, Mark Giembycz
Journal: European Respiratory Journal (2013)

Introduction: Inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA) combination therapy proved to be effective in asthma management, but it was not rationally designed. In the present study, we describe using, the relationship between the intrinsic activities of GR ligands and the ability of the ultra-LABA, indacaterol, to enhance glucocorticoid (GC) dependent gene transcription. Methods: BEAS-2B airway epithelial cells were used as an experimental model. Expressions of glucocorticoid induced anti-inflammatory genes such as glucocorticoid-induced leucine zipper (GILZ), kinase inhibitor protein 2 of 57 kDa (p57kip2), cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) and a side effect gene pyruvate dehydrogenase kinase 4 (PDK4) were examined by qPCR. Results: Concentration-response curves were constructed to six GR ligands (Fluticasone furoate [FF], Dexamethasone [dex], desisobutyryl-ciclesonide [DC], GW870086X [GW], mifepristone [Mif] and ORG34517). Relative to Dex, a reference full agonist (intrinsic activity (α) = 1), DC, GW and Mif were partial agonists (α = 0.55, 0.36 and 0.02 respectively). Indacaterol significantly augmented expression of p57kip2, PDK4 and luciferase genes depending on the intrinsic activity of the GC. However, augmentation of expression of GILZ, CRISPLD2 in presence of indacaterol was independent of the intrinsic activity of the GC. Conclusions: We submit that the generation of glucocorticoid-inducible, gene “fingerprints” will provide important information that could assist the rational design of optimised ICS/LABA therapy for asthma and allied inflammatory diseases that hitherto, has not been possible.
Part I: The Role of Maintenance Therapy in Patients With Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation
Authors: Philip L. McCarthy
Journal: Journal of the National Comprehensive Cancer Network (2013)

Multiple myeloma remains a highly treatable but incurable disease. New agents with improved efficacy have increased the response to induction treatment. These agents have been adapted for use in maintenance therapy strategies to improve responses and delay relapse/progression with the ultimate goal of improved overall survival. Recent trials have shown that the immunomodulatory drugs thalidomide and lenalidomide; the proteasome inhibitor bortezomib; and the bisphosphonate zoledronate improve time to progression and overall survival. Introduction of new therapies, alone or in combination with existing agents, may lead to increased improvement and prolongation of disease control after autologous hematopoietic stem cell transplantation for transplant-eligible patients.
Early stage ovarian cancer: a randomized clinical trial comparing whole abdominal radiotherapy, melphalan, and intraperitoneal chromic phosphate: a National Cancer Institute of Canada Clinical Trials Group report.
Authors: D Klaassen, W Shelley, A Starreveld, M Kirk, D Boyes, A Gerulath, M Levitt, R Fraser, J Carmichael, Y Methot
Journal: Journal of Clinical Oncology (1988)

Two hundred fifty-seven eligible patients with stage I, IIA "high risk" ovarian carcinoma and IIB, IIIO (disease confined to pelvis), were randomized to either total abdominal radiotherapy (arm A) 2,250 rad in 20 fractions (107 patients), melphalan (arm B) 8 mg/m2/d X 4 every 4 weeks X 18 courses (106 patients), or intraperitoneal chromic phosphate (arm C) 10 to 20 mCi (44 patients). All patients were initially treated with pelvic radiotherapy; arm A, 2,250 rad in ten fractions; and arms B and C, 4,500 rad in 20 fractions. Entry to arm C was discontinued early because of toxicity. In a multifactor analysis using proportional hazards models, no significant difference in survival was observed although there was a marginally significant difference in disease-free survival (P = .015) with arm B being superior to arm A. Stage (P less than .0001), grade (P less than .0001), and histology (P less than .008) were predictors of survival in the multifactor analysis. Performance status, age, and residual disease were significant predictors in the single factor analysis but were not predictive when correction was made for the effects of stage, grade, and histology. Five-year survival rates are 62% for arm A, 61% for arm B, and 66% for arm C. Median duration of follow-up is 8 years. Long-term complications of radiotherapy were seen in 19 patients on arm A, 11 on arm B, and 11 on arm C. Four patients who had received melphalan developed either a myelodysplastic syndrome or acute leukemia. Violations in covering the whole abdominal target volume were correlated with survival.
Lymphangioleiomyomatosis: Functional and morphological characteristics in 36 patients
Authors: Marina Kameneva, Ivetta Dvorakovskaya, Olga Baranova
Journal: European Respiratory Journal (2013)

Aim: To investigate the functional and morphological features of LAM.  Material and methods. The 36 cases of LAM had been diagnosed in women (m.age 41.9±12.6 yr). The CT, pulmonary function tests, conventional histological techniques, immunohistochemistry (IHC) tests with monoclonal antibodies to actin, desmin, HMB-45, estrogen (Ers) and progesterone (Prs) receptors were performed.  Results: The microscopic picture of early stages of the disease was characterized by multicentric foci of small smooth muscle proliferates in the alveolar septa, the walls of blood vessels with deformation of their lumen. IHC study confirmed the smooth muscle nature of proliferates. There was mild airway obstruction (FEV1 69.6±18.5%Pred).  With progression of the disease, tendency to increase and fusion of foci with cyst formation, destruction, violation of the lung tissue architectonics was determined that significantly changed lung mechanics. Along with the smooth muscle proliferates desmoplastic was observed. Desmin expression indicates the relationship between desmoplastic and smooth muscle proliferates and depends on the stage of morphogenesis. The sharp change in the parameters characterizing airway obstruction (FEV1 45.2±16.9%Pred), increasing the RV (RV/TLC 176±16.9%Pred) and decreased lung elasticity (CR 0.19±0.07 kPa/l) were the functional markers of this process. A reduction of DLco was observed in all patients.  Conclusion: A reduction of lung elasticity is a significant functional marker of changes of normal lung tissue architectonics. The character and severity of functional impairment in LMA are determined by morphological changes in the lungs and should be considered in determination of treatment strategy.
Rituximab rapid compared to standard infusion rate in a busy oncology practice.
Authors: E. Paszkiewicz-Kozik, J. Romejko-Jarosinska, A. Borawska, B. Ostrowska, L. Poplawska, M. Osowiecki, M. Szymczyk, K. Domanska-Czyz, E. Kraszewska, J. A. Walewski
Journal: Journal of Clinical Oncology (2010)

e18534 Background: Rituximab is part of nearly all protocols for treatment of B-cell lymphoma and long infusion time demanded by the product monograph has created a burden for busy hemato-oncology units and limited the number of patients who may receive treatment on time. Looking for a solution we performed an exploratory non-randomized study to evaluate safety of rapid infusion as described by Sehn et al (Blood 2007). Methods: Between January and December 2008, 125 patients with B-cell CD20+ lymphoma: DLBCL n= 80, BL n=6, FL n=22, MZL n=11, MCL n=4, CLL n=2, were enrolled into the study. Treatment regimens were: R-CHOP n=82, R-CVP n=22, BFM-like n=14, monotherapy n=5, rituximab maintenance n=2. All patients received first rituximab dose (375 mg/sqm) by standard procedure. Subsequently, patients received rapid (528 doses) or standard-rate infusion (n=123) if appropriate by physician's judgment. Results: Median number of rapid rituximab infusions was 5 (range: 1-9), and median infusion time was 111 minutes (range: 90-180). During the first delivery 8 of 123 patients (6.5%) had minor infusion reactions including hypertension, tachycardia, rash, chills, sore throat, and fever. These patients had no reactions on subsequent rapid infusions. During a total of 528 rapid infusions, there were 14 grade 1 or grade 2 reactions (2.7%) in 11 patients, including hypertension, hypotension, anxiety with shortness of breath, or bradycardia. There were no reactions on subsequent standard-rate infusions (n=123). We were unable to identify factors predicting for occurrence of infusion reactions: infusion rate standard vs. rapid (HR=1.53, 95% CI [0.68, 3.45], p=0.306), sex, age, histology, B symptoms, bulky disease, were all non-significant. Conclusions: With 1 year follow up, we conclude that abbreviated rituximab delivery starting from the second cycle is equally safe as a standard-rate infusion and may be routinely used in clinical practice. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche