tbuckley/cabot-search huggingface dataset:
Abstract #5444: Effect of ketoconazole on the pharmacokinetics of intravenous vinflunine in subjects with advanced cancer
Authors: Lisa Sheehan, Yun Shen, Barbara Zyry, Suzanne Jones, Laurent Nguyen, Francios Delgado, Leila Alland, Howard Burris
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Background: Vinflunine (VFL) is a novel microtubule inhibitor of the vinca alkaloid class that is metabolized by cytochrome P450 (CYP). VFL has one active metabolite, 4-O-deacetyl vinflunine (DVFL), which is not formed by the CYP system. Ketoconazole (KET) is a known inhibitor of CYP 3A4 and may affect the disposition of VFL. This Phase 1 study was conducted to assess the effect of KET on the single-dose pharmacokinetics (PK) of VFL and to assess the safety of VFL when administered alone at the recommended Phase 2/3 dose and when coadministered with KET in subjects with advanced cancer. Methods: In Cycle 1 of this open-label, sequential study, a standard 3+3 dose-escalation schema of VFL (dose range 80 to 240 mg/m2) coadministered with KET (400 mg orally daily for 8 days) was used to evaluate the effect of KET on the single-dose PK of VFL. In Cycle 2 and beyond, subjects received treatment with VFL 320 mg/m2 on Day 1 of each 21 day cycle. PK blood samples were collected predose and over 168 hours for Cycles 1 and 2 and analyzed for VFL and DVFL via LC/MS/MS methods. Results: A total of 18 subjects with advanced cancer ranging from 43 to 75 years of age were enrolled into each of three dose levels (VFL at 80 mg/m2, n = 3; 160 mg/m2, n = 14; 240 mg/m2, n = 1). In all of the 15 subjects with complete PK data on Day 1 of Cycles 1 and 2, VFL CL decreased when administered with KET. Coadministration of KET resulted in a 32% and 21% increase in dose-normalized VFL AUC(INF) and AUC(0-168h), and a 29% and 51% increase in dose-normalized DVFL AUC(0-96h) and AUC(0-168h). No DLTs were observed in subjects treated at 80 mg/m2. At the 160 mg/m2 dose level, one subject experienced a DLT (Grade 4 neutropenia that lasted 11 days during Cycle 1). The first subject who was treated at 240 mg/m2 had DLTs (Grade 3 febrile neutropenia, Grade 3 palmar-plantar erythrodysesthesia, and Grade 3 thrombocytopenia) and high VFL and DVFL exposures. After consultation between the investigator and sponsor, it was decided to expand the 160 mg/m2 dose level where 1/14 subjects experienced a DLT. Adverse events experienced by \#8805;10% subjects included constipation, anemia, fatigue, nausea, neutropenia, abdominal pain, vomiting, febrile neutropenia, and thrombocytopenia. Conclusions : Coadministration of KET with a 20 min IV infusion of VFL resulted in increased VFL and DVFL AUCs. The safety profile of VFL in this study, coadministered with KET or alone, was acceptable and consistent with that of single agent VFL in other studies. The coadministration of VFL 160 mg/m2 with 400 mg KET explored was tolerable and did not appear to have any major safety concerns.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5444.
Clinico-pathological and transcriptomic determinants of SLFN11 expression in invasive breast carcinoma
Authors: Gabriele Zoppoli, Sylvain Brohee, Christine Desmedt, Christos Sotiriou, Alberto Ballestrero
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts SLFN11 is a putative DNA/RNA helicase we discovered as causally associated with sensitivity to DNA damaging agents, such as platinum salts, topoisomerase I and II inhibitors, and other alkylators in the NCI-60 panel of cancer cell lines [[1][1]]. Later, SLFN11 was identified as an
Outcome of a pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL): Final results of the GRAALL-2003 study
Authors: F. Huget, A. Pigneux, X. Thomas, P. Chevallier, A. Buzyn, Y. Chalandon, E. Macintyre, M. Bene, N. Ifrah, H. Dombret
Journal: Journal of Clinical Oncology (2008)

7005 Retrospective comparisons have demonstrated that adolescents with ALL significantly benefit from pediatric rather than adult chemotherapy regimens. One explanation may be the larger amounts of steroids, vincristine (VCR), and L-asparaginase (L-aspa) administered in pediatric patients. However, the issue of whether a pediatric approach might also improve the outcome of older adults remained open. Two hundred twenty-five adults aged 15–60 years with Philadelphia chromosome-negative ALL were thus enrolled in the pediatric-inspired GRAALL- 2003 protocol. Treatment included a 5-drug induction, high dose-intensity consolidation blocks, delayed intensification, and 2-year maintenance. The comparison with the former LALA-94 adult protocol showed a 8.6-fold, 3.7-fold, and 16-fold increase in cumulative doses of prednisone, VCR, and L-aspa, respectively. Some adult options, such as allogeneic stem cell transplantation in first remission for patients with high-risk ALL, were nevertheless retained. Complete remission (CR) rate was 93.5%. At 48 months, EFS and overall survival were estimated at 55% (95% CI, 48 to 62%) and 58% (95% CI, 51 to 65%), respectively. At that time, cumulative incidence of relapse and death in first CR were estimated at 32% (95% CI, 26 to 38%) and 9% (95% CI, 6 to 14%), respectively. In patients eligible for stem cell transplantation (SCT) in first CR, no difference in outcome was observed in the donor versus no-donor group. In those who received chemotherapy, cumulative incidence of toxic deaths was significantly higher in patients aged more than 45 years, leading to lower EFS in older patients (46% [95% CI, 30 to 60] versus 58% [95% CI, 49 to 67]) despite a similar incidence of relapse. These results compared very favorably with those observed in the historical LALA-94 adult protocol, with more than 20% gain in relapse incidence, EFS, and OS. This study shows that a pediatric-inspired therapy markedly improved the outcome of adults with ALL at least up to the age of 45 years. The place of SCT should thus be re-evaluated in this new context. No significant financial relationships to disclose.
Respiratory Flutter Syndrome
Authors: ELIOT S. KATZ, ESTELLE GAUDA, THOMAS CRAWFORD, FOLASADE OGUNLESI, MAUREEN A. LEFTON-GREIF, SHARON McGRATH-MORROW, CAROLE L. MARCUS
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

We report the clinical and respiratory data of three neonates with flutter of the diaphragm and intercostal muscles, presenting soon after birth with respiratory failure. The breathing pattern was dirhythmic with superimposed frequencies, one regular and slow (60/min) representing the underlying respiratory rate, the other fast ( > 300/min) and limited to inspiration. Nasal continuous positive airway pressure immediately normalized the breathing pattern in one infant, and improved ventilation in the two others. Pharmacologic therapy with chlorpromazine terminated the respiratory flutter and permitted weaning of ventilatory support within a few hours. Coexistent dysphagia suggested a disorder of brainstem function, although the children were otherwise developmentally normal at 8, 10, and 26 mo old. Laryngomalacia and gastroesophageal reflux were also present. We propose that the occurrence of respiratory flutter, dysphagia, laryngomalacia, and gastroesophageal reflux in a neonate constitutes a distinct clinical entity, termed the "respiratory flutter syndrome." The diagnosis of three infants with this presentation during an 18-mo period suggests that this may be a more frequent cause of respiratory failure in newborns than previously recognized.
BRCA1/2 Testing: Complex Themes in Result Interpretation
Authors: Beth N. Peshkin, Tiffani A. DeMarco, Barbara M. Brogan, Caryn Lerman, Claudine Isaacs
Journal: Journal of Clinical Oncology (2001)

ABSTRACT: Since the cloning of BRCA1 and BRCA2, genetic testing for breast and ovarian cancer susceptibility has become more widespread. However, interpretation of test results is not always straightforward. To illustrate this point, five vignettes adapted from actual cases are presented. As these cases demonstrate, in many high-risk families, a deleterious mutation in BRCA1 or BRCA2 is not identified in an affected proband. There are several potential explanations for such a finding, namely that an undetected mutation in BRCA1 or BRCA2 may exist, or there could be a mutation in a rare or undiscovered gene. In addition, the possibility that women with breast cancer represent sporadic cases within hereditary cancer families must also be considered. Finally, the occurrence of BRCA1/2 variants of uncertain significance, often missense mutations, further complicates the risk assessment. In some of these instances, extending testing to relatives can be helpful to clarify results. When hereditary breast cancer cannot be ruled out, individuals may still be at increased risk for cancer and therefore need to obtain appropriate surveillance. The process of genetic counseling is critical both before and after testing to ensure that patients understand the potential medical and psychosocial implications of testing and are aware of available options and resources. A multidisciplinary approach to service delivery, which includes clinicians in genetics and oncology, can facilitate patients’ decision making and provide continued access to information and support.
The empirical basis of generalized anxiety disorder
Authors: T A Brown, D H Barlow, M R Liebowitz
Journal: American Journal of Psychiatry (1994)

The authors review the empirical data on generalized anxiety disorder, a diagnostic category that has been among the more conceptually challenging in psychiatric nosology.Published studies and recent findings that were considered by the Generalized Anxiety Disorder Subcommittee of the DSM-IV Anxiety Disorders Work Group are reviewed. Among the issues examined are diagnostic reliability, comorbidity, boundaries with other disorders, and clinical features.A variety of data on the reliability and validity of generalized anxiety disorder have been produced. Some authors have suggested that generalized anxiety disorder is better conceptualized as a vulnerability that should be located on axis II, and others have recommended that the category be eliminated. Although the diagnostic reliability of generalized anxiety disorder is lower than that of other anxiety disorders, the features constituting the diagnostic criteria for generalized anxiety disorder have been found to be reliable. An important development has been the determination of a set of somatic symptoms associated with generalized anxiety disorder that differs substantially from those for other anxiety disorders. These findings led to reduction in the number of items in the symptom criterion, from 18 in DSM-III-R to six in DSM-IV. Another substantial revision is greater emphasis on the uncontrollability of worry.Whereas the data on construct and discriminant validity, age at onset, course, familial transmission, and response to treatment generally support the DSM-IV definition of generalized anxiety disorder, the construct continues to have weaknesses and further research is needed.
Prevalence of tobacco dependence and withdrawal
Authors: J R Hughes, S W Gust, T F Pechacek
Journal: American Journal of Psychiatry (1987)

In a sample of 1,006 middle-aged male smokers drawn from the general population, 90% (N = 905) fulfilled DSM-III criteria and 36% (N = 362) fulfilled Fagerstrom's criteria for tobacco dependence. Among the 875 who had stopped smoking in the past for at least 24 hours, 21% (N = 184) fulfilled DSM-III criteria and 46% (N = 403) fulfilled the authors' own criteria for tobacco withdrawal. Concordance of results among the criteria for diagnosing tobacco dependence and withdrawal was low. These results suggest that the DSM-III criteria for tobacco dependence are overinclusive and that there is little consensus among the definitions of tobacco dependence and withdrawal.
Abstract 4911: miR-200c is Up-regulated by Oxidative Stress and Induces Endothelial Cell Apoptosis and Senescence
Authors: Alessandra Magenta, Gianluca Sarra Ferraris, Fabio Martelli, Maurizio C Capogrossi
Journal: Circulation (2009)

Background. microRNAs (miR) are small non-coding RNAs that inhibit translation of messenger RNAs (mRNA) into proteins and play a key role in the modulation of cell function. The objective of this work was to examine the effect of oxidative stress on human umbilical vein endothelial cells (HUVEC) miR expression. Methods and results. HUVEC were exposed to 200 μ M H 2 O 2 for 8 to 24 hours; out of 254 miRNAs examined only 2 increased &gt; 8-fold, miR-200c (28.30 ± 8.8 fold vs control; p &lt; 0.01) and the co-transcribed miR-141(26.72 ± 10.23 fold vs control; p &lt; 0.02); peak expression was achieved after 16 hours exposure to oxidative stress. All other members of the miR-8 gene family to which miR-200c and miR-141 belong, i.e. miR429, miR200a and miR200b were induced by H 2 O 2 , albeit to a lower level: i.e. 4 – 8 fold increase. This response to oxidative stress was not limited to HUVEC since a similar increase in miR-200c was also found in C2C12 cells growing or differentiated in myotubes exposed to H 2 O 2 . Further, oxidative stress induced with 0.25 mM BCNU also up-regulated miR-200c (3.18 ± 0.96 fold; p &lt; 0.02) and this response was prevented by pre-incubation with the free radical scavenger NAC (10 mM). Over-expression of miR-200c in HUVEC induced cell growth arrest, enhanced apoptosis (3.36 ± 1.05 fold vs control; p &lt; 0.01) and induced cellular senescence as indicated by positive beta-galactosidase ( β -gal)staining (scramble miR:12.66% ± 2.27 β -gal positive cells; miR-200c: 87.36%± 4.85 β -gal positive cells); all these effects on cell proliferation, apoptosis and senescence are known to be caused by oxidative stress. ZEB1 is a well-known target of miR-200c and lack of ZEB1 has been linked to an enhanced cellular senescence. It was found that under our experimental conditions in HUVEC exposed to H 2 O 2 both ZEB1 mRNA and protein decreased and the over-expression of miR-200c in HUVEC down-regulates ZEB1 mRNA and protein. Conclusions. Oxidative stress markedly increases miR-200c and its family members and down-regulates ZEB1, which is a known miR-200c target. Further, the over-expression of miR-200c induces cell growth arrest, enhances apoptosis and induces cell senescence. Thus, miR-200c may play a key role in mediating the effect of oxidative stress on cell function and survival.
NIV improves sleep fragmentation in patients with ALS
Authors: Bart Vrijsen, Dries Testelmans, Catharina Belge, Bertien Buyse
Journal: European Respiratory Journal (2013)

As alveolar hypoventilation occurs, non-invasive ventilation (NIV) is used to reduce hypercapnia and its symptoms. Only few studies in neuromuscular diseases performed research on sleep quality after initiation of NIV. This is the first prospective analysis on sleep quality by polysomnography (PSG) before and shortly after initiation of NIV in amyotrophic lateral sclerosis (ALS) patients.

PSG, with incorporation of transcutaneous CO2 (PtcCO2) measurement and Trilogy 100 ventilator software, was analyzed visually epoch by epoch in 6 patients (62 ± 9 years) with ALS (VC 55 ± 9 %pred). After diagnostic PSG, patients were titrated during 3 nights. PSG during NIV was performed at discharge and 1 month later. Median time of nocturnal PtcCO2 > 55 mmHg decreased from 44% (diagnostic) to 0% on NIV at discharge.

At discharge, arousal/awakening index (AAI) already clinically improved (55.9 ± 51.1 vs 16.3 ± 8.2/h sleep). After 1 month of NIV use, the AAI was 15.3 ± 7.6/h sleep (p<.05 vs diagnostic). A low prevalence of patient ventilator asynchronies (PVA) was observed at discharge (4.5 ± 5.2/h sleep) and this remained similar after 1 month (4.7 ± 6.7/h sleep). Only a small fraction of these PVA caused arousals/awakenings (0.5 ± 0.6 at discharge and 0.2 ± 0.2/h sleep at 1 month). The number of leaks causing arousals/awakenings was 5.3 ± 8.9 at discharge and 2.5 ± 2.3/h sleep after 1 month. The occurrence of respiratory events (central and obstructive) causing arousals/awakening was 3.6 ± 4.3 at discharge and 1.8 ± 1.9/h sleep after 1 month.

In conclusion, sleep fragmentation significantly improved after initiation of NIV with a very low occurrence of PVA. PVA, respiratory events and leaks remained stable after 1 month.
Examination of Children by Clinical and Laboratory Methods.
Authors: F. F. Tisdall
Journal: JAMA (1927)

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Rosacea: Classification and Treatment
Authors: Thomas Jansen, Gerd Plewig
Journal: Journal of the Royal Society of Medicine (1997)

Rosacea is a chronic skin disorder affecting the facial convexities, characterized by frequent flushing, persistent erythema, and telangiectases. During episodes of inflammation additional features are swelling, papules and pustules. The disease was originally called acne rosacea, a misleading term that unfortunately persists1. Rosacea is a common disease, especially in fair-skinned people of Celtic and northern European heritage; it has been called the curse of the Celts. It is rare in American and African blacks2. Women are more often affected than men, but they seldom suffer the gross tissue and sebaceous gland hyperplasia of rhinophyma. Onset is usually between ages 30 and 50. In a recent epidemiological study the prevalence was 10%, most of the patients having only a red face3. In young patients especially, there may be a history of acne and the conditions may coexist.
The 2007-2013 trends in the prevalence of allergic rhinitis and asthma in primary schoolchildren in Budapest
Authors: Gabriella Gálffy, Andor Hirshberg, Gábor Katona, Mónika Sultész
Journal: European Respiratory Journal (2014)

The aim of our study was to assess the changes in the prevalence of allergic rhinitis and allergy in 6-12-year-old schoolchildren in 2007 and 2013 in Budapest.

Twocross-sectional surveys according to the ISAAC protocol were carried out in the same 21 randomly selected primary schools in Budapest in 2007 and 2013. A school-based sample of 6335 participants in the 2007 survey and 6441 participants in the 2013 survey was the study population.

Results: The response rates in 2007 and 2013 were 62.08% and 52.97% respectively.

The physician-diagnosed allergic rhinitis was 11.6% (n=413) in 2007 and 11.1% (n=380) in 2013, so it remained stable. There is an increase in 12-month prevalence of allergic rhinitis from 14.9% (n=530) to 23.3% (n=796) and cumulative allergic rhinitis from 26.5% (n=943) to 34.5% (n=1176). The prevalence of all diagnosed allergic diseases decreased between 2007 (34%; n=1212) and 2013 (15.5%; n=510). The prevalence of eczema and the prevalence of food allergy increased from 10.2% to 15.4%, from 4.8% to 6.2%. The prevalence of asthma and physician-diagnosed allergic rhinitis decreased from 6.2% to 5.7% and from 11.6% to 11.1%.

Family history of atopy ( p< 0.001), frequent upper airway infection ( p< 0,001), antibiotics given in the first year of life ( p< 0.001), living in a weedy area ( p< 0.001), were all significant risk factors of allergic rhinitis symptoms in both studies.

By comparingour two surveys we observe that cumulative allergic rhinitis, 12-month prevalence of allergic rhinitis, and from the diagnosed allergic diseases eczema and food allergy have become increasingly prevalent.The prevalence of all diagnosed allergic diseases decreased.
Verification of pulmonary tuberculosis in HIV-infected patients with low CD4
Authors: Anna Lazareva, Pavel Gavrilov, Viacheslav Zhuravlev, Eugeniya Reshetneva, Piotr Yablonskii
Journal: European Respiratory Journal (2014)

Diagnosis of TB in patients with HIV infection is often difficult because of the low frequency allocation MBT in the sputum, and not the typical radiographic manifestations.  Material and methods. The study enrolled 52 patients with verified respiratory tuberculosis in the presence of HIV infection and CD4   Results. Only 4 ( 7.69 % ) were detected by microscopy for acid- sticks . In 33 ( 63.46 %) MBT culture identified by PCR in sputum. Identification MBT by PCR of 100% was confirmed by seeding a liquid culture medium ( BACTEC MGIT 960) . In 14 (26.92%) patients by PCR identified MDR MBT. In 14 ( 26.92 %) patients diagnosed with tuberculosis installed biopsy of peripheral or intrathoracic lymph nodes. When analyzing the CT picture only 36 (69%) patients revealed well-defined nodules, typical of tuberculosis. Cavities were observed 19 (36.5%) patients. While 18 (34.6%) in the CT picture dominated interstitial infiltrates and ground-glass nodules. Adenopathy noted in 39 (75%) cases. In 50 (96.2%) patients had a combination of several syndromes CT.  Conclusion. As immunosuppression progresses, the CT pattern of respiratory tuberculosis in the presence of HIV infection shows as atypical syndromes (unclearly defined frosted glass-type focal changes, interstitial infiltrations). A marked polymorphism in changes and a high rate of lymph node involvement are characteristic. Microscopy is not effective to detect MBT in patients with HIV infection and low CD4. For verification of tuberculosis, a broader application of molecular genetic techniques and lymph node biopsies.