tbuckley/cabot-search huggingface dataset:
Study of brain and whole blood PK/PD of bortezomib in rat models
Authors: L. J. Yu, B. Riordan, P. Hatsis, A. Brockman, S. Daniels, N. Stagliano, S. Finklestein, J. Ren, M. Milton, G. Miwa
Journal: Journal of Clinical Oncology (2006)

12036 Background: Bortezomib (Btz) is the first in class proteasome inhibitor and has been approved for treatment of multiple myeloma patients who have received at least 1 prior therapy. The potential for Btz to penetrate the CNS was examined in the rat under two conditions: intact blood brain barrier (BBB) and compromised BBB induced by middle cerebral artery occlusion (MCAO). Methods: Intact BBB: healthy rats received an iv bolus followed by a constant infusion of Btz to steady-state (SS). The blood and brain samples were collected for determination of concentration (Conc) of Btz (PK) and of 20S proteasome activity (PD). The brain samples were collected after a perfusion with saline. Inulin was included in the study in order to determine blood contamination in brain tissues. Compromised BBB: rats underwent MCAO surgery and 1 h later were administered Btz via an iv bolus of 0, 0.1, 0.2 or 0.35 mg/kg. The blood and brain samples were collected through 24 h postdose. Conc of Btz was determined by an LC/MS/MS method. The 20S proteasome activity was measured using an ex vivo assay. Results: 1) Intact BBB: at SS the mean blood Conc of Btz was 140 ng/mL, and proteasome activity in the blood was inhibited by ∼80% compared to the vehicle group (p &lt; 0.0001). In contrast, the brain Conc of Btz was extremely low (∼3 ng/g) with the brain-to-blood ratio of ∼0.02. No difference was observed in brain proteasome activity between the vehicle and Btz-treated groups. 2)The MCAO rat: the PK/PD relationship in the blood was best described by a sigmoid E max model with an EC 50 of 110 ng/mL and gamma factor of 3.8. The model also suggests that there is no proteasome inhibition (PI) when the blood Conc is &lt;40 ng/mL (no effective blood Conc, NOEBC). In the brain, the C max of Btz was 22.0 ng/g from the highest dose group, in contrast to the blood C max of 164 ng/mL. The increased exposure in the brain of a MCAO rat relative to a normal rat was anticipated as its BBB is impaired. However, the brain Concs were all below the NOEBC. No significant PI was observed in all brain tissues (P&gt;0.1). Conclusion: Very poor brain penetration was observed for Btz in rats. Btz showed PI in whole blood but not in the brain either of normal or MCAO rats following administration of Btz. [Table: see text]
The Relevance of the Affordable Care Act for Improving Mental Health Care
Authors: David Mechanic, Mark Olfson
Journal: Annual Review of Clinical Psychology (2015)

Provisions of the Affordable Care Act provide unprecedented opportunities for expanded access to behavioral health care and for redesigning the provision of services. Key to these reforms is establishing mental and substance abuse care as essential coverage, extending Medicaid eligibility and insurance parity, and protecting insurance coverage for persons with preexisting conditions and disabilities. Many provisions, including Accountable Care Organizations, health homes, and other structures, provide incentives for integrating primary care and behavioral health services and coordinating the range of services often required by persons with severe and persistent mental health conditions. Careful research and experience are required to establish the services most appropriate for primary care and effective linkage to specialty mental health services. Research providing guidance on present evidence and uncertainties is reviewed. Success in redesign will follow progress building on collaborative care and other evidence-based practices, reshaping professional incentives and practices, and reinvigorating the behavioral health workforce.
Pre-pre-B acute lymphoblastic leukemia: high frequency of alternatively spliced ALL1-AF4 transcripts and absence of minimal residual disease during complete remission
Authors: JW Janssen, WD Ludwig, A Borkhardt, U Spadinger, H Rieder, C Fonatsch, DK Hossfeld, J Harbott, AS Schulz, R Repp
Journal: Blood (1994)
Clinical and microbiological assessment of patients with a long-term diagnosis of human immunodeficiency virus infection and Candida oral colonization
Authors: A.C.D. Delgado, R. de Jesus Pedro, F.H. Aoki, M.R. Resende, P. Trabasso, A.L. Colombo, M.S.M. de Oliveira, Y. Mikami, M.L. Moretti
Journal: Clinical Microbiology and Infection (2009)
SLFN11: Achilles' Heel or Troublemaker
Authors: Heinrich Kovar
Journal: Clinical Cancer Research (2015)

SLFN11 expression correlates with sensitivity of tumors to topoisomerase and DNA-targeting drugs and consequently with prognosis. Regulation of SLFN11 by ETS factors opens new avenues to treatment optimization, maximizing antitumor activity and minimizing adverse side effects. Interrogating drug-induced gene expression signatures for SLFN11 modulations may affect the design of therapeutic regimens.
Efficacy of FUFOX regimen in the treatment of a selected population with metastatic colorectal cancer (MCC)
Authors: M. C. Garassino, K. Borgonovo, N. La Verde, P. Sburlati, C. Bianchi, S. Cobelli, R. Rovej, M. Tomirotti, V. Torri, G. Farina
Journal: Journal of Clinical Oncology (2007)

14596 Background: FOLFOX is usually employed as first line treatment of MCC. Some patients (pts), for both clinical reasons and poor compliance, are not eligible for CVD insertion. At the moment, it is not clear if FUFOX (with 5-FU bolus) is less active than FOLFOX (with 5-FU infusion). We evaluated the outcome of MCC pts treated, as first line, with FUFOX. Primary end-point is efficacy. Secondary endpoints are time to progression (TTP) and overall survival (OS). Toxicity is also reported. Materials and Methods: We analysed all consecutive MCC patients who referred to our centre, without CVD, treated with the Hochster regimen: Oxaliplatin 85 mg/m 2 days 1, 15; Leucovorin 20 mg/m 2 and 5-FU 500 mg/m 2 bolus days 1, 8, 15 - every 28 days. Response rate was evaluated with RECIST criteria. TTP and OS were analysed with Kaplan-Meier methods. Results: From July 2003 to October 2006 we treated 25 MCC pts. Main characteristics were: median age 71 years (range 46–79), 12 males, 13 females; PS 0–1; metastatic sites: liver 15 pts; lung 6; abdominal 10. 2 pts are early. A total of 128 courses were administered (5,4 median courses/pt, range 3–9). 5/23 pts (21.7% 90%CI: 9.0%-40.4%) had a PR and 2 achieved a secondary complete surgery. 15/23 pts (65.2%: 90%CI: 46.0%-81.4%) had a SD and 3 pts (13.0%: 90%CI: 3.7%- 30.4%) had a PD. At the moment of analysis 14 pts are still alive with a median follow up of 25 months; the median time to progression is 7.2 months. This combination was well tolerated with no grade 3–4 toxicities observed. G1-G2 peripheral neurotoxicity is reported in 15/25 pts (60%). Other common toxicities are: G1–2 haematological in 10 pts (40%); G1–2 gastrointestinal in 7 pts (28%); asthenia 5 pts (20%). Conclusions: We observed a low response rate, but high number of stable disease. Toxicity was acceptable. Although this is a not controlled study, this regimen seems to be less effective than infusional regimens but, due to the high control rate of disease (86.9%) we can consider it an alternative choice for patients that refuse or cannot receive continuous infusion. No significant financial relationships to disclose.
Death (of a toy)
Authors: R. Penson
Journal: BMJ (2015)

The development of severe childhood asthma may be influenced by several factors including environmental and infectious stimuli. The causal relationship between infectious viral responses, such as respiratory syncytial virus (RSV), and severe asthma during early childhood is unclear. In these studies, the ability for an initial RSV infection to exacerbate and promote a more severe asthmatic-type response was investigated by combining established murine models of disease. We examined the ability of RSV to induce exacerbation of allergic disease over a relatively long period, leading to development of severe airway responses including airway inflammation and hyperreactivity. The preferential production of IL-13 during a primary RSV infection appears to play a critical role for the exacerbation of cockroach allergen-induced disease. The depletion of IL-13 during RSV infections inhibited the exacerbation and acceleration of severe allergen-induced airway hyperreactivity. This was indicated by decreases in airway hyperreactivity and changes in lung chemokine production. These data suggest that the airway responses during asthma can be greatly affected by a previous RSV infection, even when infection occurs before allergen sensitization. Overall, infection of the airways with RSV can induce an IL-13-dependent change in airway function and promotes an environment that contributes to the development of severe allergic asthmatic responses.
Estimation of evolutionary distance for reconstructing molecular phylogenetic trees.
Authors: F Tajima, N Takezaki
Journal: Molecular Biology and Evolution (1994)

The most commonly used measure of evolutionary distance in molecular phylogenetics is the number of nucleotide substitutions per site. However, this number is not necessarily most efficient for reconstructing a phylogenetic tree. In order to evaluate the accuracy of evolutionary distance, D(t), for obtaining the correct tree topology, an accuracy index, A(t), was proposed. This index is defined as D'(t)/square root of[D(t)], where D'(t) is the first derivative of D(t) with respect to evolutionary time and V[D(t)] is the sampling variance of evolutionary distance. Using A(t), namely, finding the condition under which A(t) gives the maximum value, we can obtain an evolutionary distance which is efficient for obtaining the correct topology. Under the assumption that the transversional changes do not occur as frequently as the transitional changes, we obtained the evolutionary distances which are expected to give the correct topology more often than are the other distances.
Disparity of Mixed Lymphocyte Reactivity to Cultured Cells of Human T and B Lymphoid Lines&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: J L Pauly, J Minowada, T Han, G E Moore
Journal: JNCI Journal of the National Cancer Institute (1975)

Repeated attempts with difference assays and experimental conditions failed to detect significant peripheral blood lymphocyte reactivity in one-way mixed lymphocyte reactions to irradiated or mitomycin C-treated cells of the "leukemic" T lymphoid line RPMI 8402. In contrast, consistently high levels of peripheral blood lymphocyte reactivity were obtained with cells of six B lymphoid lines established from the same blood sample used to initiate this T lymphoid line. Although attempts to define the reason why these cultured T cells did not initiate a mixed lymphocyte reaction were not successful, evidence indicates that this inability may be an intrinsic characteristic common to three other T lymphoid lines (MOLT-4, CCRF-CEM, and CCRF-HSB-2), also established from patients with relapsed acute lymphoblastic leukemia.
Nicotine dependence and readiness to quit smoking in the North Indian population
Authors: Gopal Chawla, Amrit Pal Kansal, Vishal Chopra, Komaldeep Kaur, Naresh Kumar
Journal: European Respiratory Journal (2014)

As the burden of tobacco epidemic is increasing in developing countries like India, there is urgent need of smoking cessation intervention studies to be conducted in such countries.  We conducted a study in 207 patients in the Tobacco Cessation Clinic of teaching hospital to observe smoking cessation behaviour according to Trans theoretical Model(TTM) of and its relationship with nicotine dependence(according to Fagerstrom Nicotine Dependence FTND Scale) along with sociodemographic profile.  Results: Mean age of patient participating in study was 50.74 ± 14.7years, mean age of starting smoking was 21.57± 7.47 years. Mean duration of patients smoking was 29.43 years. 64.3% belonged to low socoeconomic status and 69.4% lived in rural area.Majority of smokers 116 (56%) started smoking under influence of friends followed by relatives which was 25.1%. 104 (50.3%) smoked first bidi or cigarette in first ten minutes of getting up. According to Prochaska and DiClemente9s model for assessing a person readiness to change a variety of behaviour(TTM), 57 patients were in Preparation stage, of which 89.5% had nicotine dependence score ≤6. 137 patients were in Pre contemplation and contemplation stage, 57.6% were highly nicotine dependent with FTND scale >6.While rest 13 were in Action stage before starting cessation interventions.  This shows Nicotine dependence significantly affected stage at presentation, patients with high nicotine dependence score were in Pre contemplation and Contemplation stage, and with lower score were in preparation stage. Smoking cessation programmes should be addressed to reduce dependence, help smokers to progress through the stages of change, consequently, reduce prevalence of smokers.
N-Ethyl-N-nitrosourea-Induced Spinal Tumors in an Inbred Strain of W Albino Rats2
Authors: M. J. Pfaffenroth, G. D. Das
Journal: JNCI Journal of the National Cancer Institute (1979)

Exposure to N-ethyl-N-nitrosourea (ENU) either transplacentally via the maternal bloodstream or postnatally by direct injection into the cerebellum or the cisterna magna resulted in a high incidence of spinal tumors in an inbred strain of W albino rats. After prenatal exposure to 60 mg ENU/kg maternal body weight, as many as 92% of the offspring developed 1 or more tumors in the spinal cord, whereas after postnatal exposure to 0.2 mg ENU/animal, 50% of the animals eventually developed spinal tumors. These tumors included relatively pure oligodendrogllomas, astrocytomas, and the usual mixed gllomas. Obvious clinical symptoms of paralysis of the limbs and weight loss accompanying the high incidence of tumors in the spinal cord make this system pertinent to the study of carcinogenesis in the central nervous system as well as to the study of related problems to the incidence of these tumors are discussed.
Interaction of &lt;italic&gt;H-2&lt;/italic&gt; and Non-&lt;italic&gt;H-2&lt;/italic&gt; Genes in Spontaneous Resistance to Adenocarcinoma ADK-1t in F&lt;sub&gt;1&lt;/sub&gt; Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: G Forni, G Serrati, L Giordano, M Giovarelli, S Rendine, S Landolfo
Journal: JNCI Journal of the National Cancer Institute (1980)

The genetic control of spontaneous resistance in vivo to increasing doses of a poorly immunogenic spontaneous adenocarcinoma (ADK-1t) of BALB/c origin was studied in F1 hybrid mice. The spontaneous resistance of homozygous parental BALB/c mice was not increased in F1 hybrids of BALB/c and BALB.B or BALB.K mice, even with small tumor challenges (10(3) cells). By contrast, it was significantly enhanced in F1 hybrids of BALB/c and several strains on A or B10 background. Resistance due to the acquisition of a new set of background genes was, however, markedly enhanced or suppressed by the presence of particular alleles located within or closely linked to the H-2 complex, as demonstrated by increasing the tumor challenge to 10(4) or 10 (5) cells. Spontaneous resistance, effective even with high tumor inocula, thus depended on a complex interplay between background and H-2 genes.
Multicenter, Randomized, Phase III Trial of CD8<sup>+</sup> Tumor-Infiltrating Lymphocytes in Combination With Recombinant Interleukin-2 in Metastatic Renal Cell Carcinoma
Authors: Robert A. Figlin, John A. Thompson, Ronald M. Bukowski, Nicholas J. Vogelzang, Andrew C. Novick, Paul Lange, Gary D. Steinberg, Arie S. Belldegrun
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8 + tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients. PATIENTS AND METHODS: Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8 + TILs (5 × 10 7 to 3 × 10 10 cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 × 10 6 IU/m 2 by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs. RESULTS: Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board. CONCLUSION: Treatment with CD8 + TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.
TNF neutralization ameliorates urethane-induced lung carcinogenesis
Authors: Sophia P. Karabela, Georgios T. Stathopoulos
Journal: European Respiratory Journal (2011)

Background:  Previous work has identified protumorigenic functions of tumor necrosis factor (TNF) in the lungs.   Aim:  To preclinically investigate the therapeutic potential of TNF blockade against lung carcinogenesis.   Methods:  Long-term studies: Balb/c mice received four weekly doses of intraperitoneal urethane (1g/kg), followed by twice-weekly sTNFR:Fc (etanercept; Amgen-Wyeth; 10 mg/kg) during weeks 0-4 (early), 20-24 (late), or 0-32 (continuous) post-urethane. End-points were lung tumor number (ν) and diameter (δ) at 32 weeks. Short-term studies: Balb/c mice received urethane or saline followed by twice-weekly sTNFR:Fc or saline. End-point was BAL inflammatory cells and mediators at 7 days.   Results:  Compared with controls (ν=16.2±1.6; δ=1.01±0.07mm), early sTNFR:Fc-treated mice had fewer lung tumors of equal size (ν=10.0±1.3, P 0.05), but late sTNFR:Fc-treated mice had equal numbers of smaller lung tumors (ν=14.1±1.2, P>0.05; δ=0.71±0.07mm, P   Conclusion:  TNF blockade halts lung tumorigenesis in mice, and may be useful in lung cancer chemoprevention.  Financial support: Hellenic Thoracic Society, Thorax Foundation.
Parasternal intercostal function during sustained hypoxia
Authors: Michael Ji, Tetsunori Ikegami, Paul Easton
Journal: European Respiratory Journal (2011)

Introduction:  In humans and other mammals, sustained isocapnic hypoxia for 20-60 minutes elicits a biphasic ventilatory response (roll-off), with initial peak ventilation followed by decline to a plateau. The activities of the respiratory muscles during the sustained hypoxic response are not known.   Aim:  To study ventilation and actions of the chest wall muscles, specifically Parasternal Intercostal (PARA) during sustained hypoxia in awake canines.   Methods:  After implantation of sonomicrometry transducers and EMG electrodes in PARA, and complete recovery, we measured airflow, oxygen saturation, end tidal CO2, moving average EMG and shortening (SHORT) of PARA, during room air ventilation (BASE), followed by 25 minutes of isocapnic hypoxia (mean 78% SpO2). The canines were awake, breathing through a snout mask. We report results 2-3 min after reaching SpO2 80% (PEAK) and final 5 min (PLATEAU) of sustained hypoxia, then room air breathing (RECOVERY).   Results:  For N=7 (mean 28.9 kg, 28 days post implant), minute ventilation (VI) and tidal volume (VT) increased significantly from BASE to PEAK, then decreased to an intermediate PLATEAU (p   Conclusion:  As minute ventilation “rolls off” during sustained isocapnic hypoxia, there is a concurrent decline in shortening and EMG activity of the chest wall muscle, the Parasternal Intercostal.
Clinical, Radiologic, and Induced Sputum Features of Chronic Obstructive Pulmonary Disease in Nonsmokers
Authors: Surinder S. Birring, Christopher E. Brightling, Peter Bradding, James J. Entwisle, Dhiraj D. Vara, Jonathan Grigg, Andrew J. Wardlaw, Ian D. Pavord
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Epidemiologic studies show that 5–12% of subjects with chronic obstructive pulmonary disease (COPD) are nonsmokers. Little is known about the pathophysiology of the fixed airflow obstruction in these subjects. We have prospectively identified 25 patients with COPD who had never smoked or had a less than 5 pack years smoking history and present the clinical, radiologic, and induced sputum features. Our population represented 5.7% of total referrals with fixed airflow obstruction over 2 years. Patients had a mean age of 70 years, were predominantly female (86%), and had a mean duration of respiratory symptoms of 7 years. The mean FEV1 was 58%, and the FEV1/FVC was 55%. Features on high-resolution computed tomographic scanning were nonspecific and were considered typical of a wider population with COPD. An induced sputum differential inflammatory cell count suggested the presence of two distinct groups. Nine had significant sputum eosinophilia (mean, 8.1%; normal, less than 1.9%), and the remaining 13 had a normal sputum eosinophil and tended to have a raised sputum neutrophil count (mean, 70.1%; normal, less than 65%). Organ-specific autoimmune disease was present in 7 of the 22 patients (32%) and was particularly prevalent in those without sputum eosinophilia (6 of 13). In conclusion, COPD in nonsmokers predominantly affects females and has at least two pathologic subgroups, one of which may be associated with organ-specific autoimmune disease. Further investigation of this group may disclose novel mechanisms of fixed airflow obstruction.
Phylogenetic relationships in Drosophila: a conflict between molecular and morphological data.
Authors: R H Thomas, J A Hunt
Journal: Molecular Biology and Evolution (1993)

Grimaldi's recent cladistic classification of genera in the family Drosophilidae, based on adult morphological characters, is evaluated for those taxa for which alcohol dehydrogenase DNA sequences are also available. These data allow us to look at relationships of the Drosophila subgenera Sophophora and Drosophila with the Hawaiian Drosophila (Idiomyia) and with Scaptomyza, when Scaptodrosophila is used as an outgroup. The molecular data give strong support for the broad relationships hypothesized by Throckmorton, who contended that the subgenus Sophophora is a sister group to the remaining ingroup taxa. The Drosophila subgenus Engiscaptomyza, which Throckmorton regarded as intermediate between the Idiomyia (Hawaiian Drosophila) and Scaptomyza, is shown to be much more closely allied with Scaptomyza, in agreement with Grimaldi's results from adult morphology. The Hawaiian taxa, both Idiomyia and Scaptomyza, are firmly located as a sister group to the subgenus Drosophila, and these in turn all form a sister group to the subgenus Sophophora. Grimaldi's classification of these taxa is quite different and places the Hawaiian Drosophila (Idiomyia) as sister group to the remaining ingroup taxa (Scaptomyza and the subgenera Sophophora and Drosophila). Our results show that Grimaldi's new classification of these taxa results in paraphyletic groups, just as does the traditional classification under Throckmorton's interpretation of relationships. Additional data are required to produce a robust classification of this huge paraphyletic genus.