tbuckley/cabot-search huggingface dataset:
Effects of combination of PI3Kγ and δ inhibitors on airway hyperresponsiveness in tobacco smoke-exposed mice
Authors: Yasuo Kizawa, Genki Kimura, Keitaro Ueda, Yuji Watanabe, Shouichi Eto, Tadashi Kusama, Kazuhiro Ito
Journal: European Respiratory Journal (2012)

PI3K δ and γ are known to be involved in inflammatory cell functions. We recently found upregulation of PI3Kδ in lung tissue of COPD patients and ability of a PI3Kδ inhibitor on restoration of steroid sensitivity in airway inflammation in tobacco-smoke (TS) exposed mice. Superior effects of combination of PI3Kγ and δ inhibitors to each inhibitor alone on airway inflammation in TS-exposed mice were also observed. The aim of this study is to evaluate role of PI3Kγ and PI3Kδ on airway hyperresponsiveness (AHR) in TS-exposed mice. A/J mice were exposed to TS for 11 days and IC87114 (IC), AS604850 (AS) and/or fluticasone propionate (FP) were administered intranasally twice a day for 3 days after the last TS exposure. Airway responsiveness was determined as the increment of airway resistance (Δ[sRaw/TV]) before and 1 min after histamine inhalation at 24 h after the last drug dosing. The effects of the PI3K inhibitors on the contractile response to carbachol in guinea-pig tracheal smooth muscle preparation were also evaluated by the isometric tension recording. The concentration-response curve of carbachol was shifted to rightward and reduced the maximal response by AS (10-100 µM), in contrast, the effects of IC (100 µM) was limited in the tracheal smooth muscle. The AHR induced by TS was significantly reduced by AS (4 mg/ml; by 56% inhibition) and IC (4 mg/ml; 43%) alone. The inhibitory effects were enhanced by combination treatment of AS and IC (69%). Moreover, the combination of IC and FP showed stronger inhibition (96%) on the AHR.Considering with our previous findings, the combination of a PI3Kδ or PI3Kγ/δ inhibitor with corticosteroid may offer potential treatment of COPD.
Plasmablastic lymphoma in HIV: A review of 131 cases
Authors: J. Castillo, B. J. Dezube, L. Pantanowitz
Journal: Journal of Clinical Oncology (2008)

19519 Background: Plasmablastic lymphoma (PBL) is a distinct subtype of B-cell lymphoma, described a decade ago with a strong occurrence in the oral cavity of HIV-infected individuals. We present, to the best of our knowledge, the first extensive review of the epidemiology, clinical findings, pathology, and outcome of HIV-associated PBL. Methods: We identified 131 cases of PBL in HIV- positive individuals from a literature search using Pubmed/MEDLINE with the keywords HIV, AIDS and plasmablastic lymphoma. Microlymphoma and Castleman’s disease were excluded. Data regarding patient age and gender, HIV status, initiation of highly active antiretroviral therapy (HAART), tumor extent, pathology, treatment, and outcome were recorded. Log-rank test was used to assess differences in survival by stage, EBV status and primary site of presentation. Results: The median age at presentation was 39 years with a male predominance of 7:1. Afflicted patients had a median CD4+ count of 173 cells/mm3. PBL presented on average 6 years after the initial diagnosis of HIV, while many (59%) patients were already on HAART. Common primary sites of presentation included the oral cavity, GI tract and lymph nodes. Most (95%) cases presented with stage I or IV disease. There was variable expression of B-cell markers (CD20 9%; CD79a 25%). Plasma cell markers were expressed in all cases. The average proliferation index was 83%. EBV was detected in 75% and human herpesvirus-8 (HHV8) in 16% of cases. Chemotherapy was used to treat 55% patients, and combined with radiotherapy in 24% cases. CR was obtained in 93% of the cases; the majority of these responses were seen after CHOP. Death occurred in 59% of patients, with a median survival of 14 months from diagnosis. Stage, EBV status and primary site failed to show an association with survival. Conclusions: PBL is an aggressive B-cell lymphoma that is likely to affect young HIV-positive men who have CD4+ counts <200 cells/mm3 and chronic HIV infection. Both oral and extra-oral sites of involvement are common. The loss of B-cell markers on plasmablasts may result in a potential misdiagnosis of this distinct lymphoma, which appears to be more commonly associated with EBV than HHV8. Despite an initial good response to therapy, the prognosis remains poor. Stage does not seem to be associated with survival in HIV-associated PBL. No significant financial relationships to disclose.
Mechanical ventilation induces a time-dependent reduction in diaphragmatic blood flow
Authors: Christian Bruells, Robert Davis, John Stabely, Bradley Behnke
Journal: European Respiratory Journal (2011)

Introduction: Continuous mandatory ventilation (CMV) induces atrophy of the diaphragm, contributing to ventilator induced diaphragmatic dysfunction (VIDD), which is significant after 6 h of CMV. However, the effects of prolonged CMV on diaphragmatic blood flow remain unknown. Therefore, we tested the hypothesis that long term CMV (6 h) will further decrease diaphragm perfusion versus that measured during acute CMV (30 min) and may contribute, in part, to VIDD due to reduced oxygen delivery.

Methods: Blood flow to the diaphragm and other skeletal muscle was assessed (via the radioactive microsphere technique) during spontaneous breathing (SB) and after 30 min and 6 h of CMV in female Sprague-Dawley rats (n= 42). Blood pressure and heart rate were monitored continuously throughout the protocol.

Results: In the midcostal portion of the diaphragm blood flow decreased by ∼ 32% from SB to 30 min CMV, with a further reduction in flow of ∼ 37% after 6 h CMV (i.e., SB 28.3±3.5 vs. CMV, 30 min 19.3±2.9; 6 h 8.8±0.6 ml/100 g/min; P<0.05). The other constituents of the diaphragm demonstrated a similar trend in perfusion over time. Blood flow to other hindlimb skeletal muscle did not decrease significantly at any time point.

Discussion: Our study demonstrates, for the first time, that there is a time-dependent reduction in diaphragmatic perfusion during prolonged CMV. Further, a decrease in blood flow over the same time period was not observed in other skeletal muscles, even with matched oxidative capacities (e.g., red. portion of the gastrocnemius). Our data indicate that prolonged CMV elicits vascular dysfunction in the diaphragm which may contribute, in part, to the ongoing process of VIDD.
Modulating the Oxygen Tension in Tumours by Hypothermia and Hyperbaric Oxygen
Authors: A H W Nias, P M Perry, A R Photiou
Journal: Journal of the Royal Society of Medicine (1988)

Hypothermia is associated with reduced metabolism of tissues and especially reduced oxygen consumption by tumours. If the blood supply to a hypothermic tumour can be maintained then the hypoxic fraction of cells should be reduced and the radiation response increased. This hypothesis has been tested with radiation under hyperbaric oxygen and increased tumour response has been demonstrated.
A phase II study of oral S-1 with pharmacokinetics and pharmacogenomic investigation in advanced or recurrent gastric cancer
Authors: S. Y. Rha, H. C. Jeung, H. K. Kim, S. Y. Kim, S. Y. Kim, H. Y. Lim, S. J. Kong, H. C. Chung
Journal: Journal of Clinical Oncology (2006)

4072 Background: Present study describes the first phase II study of S-1 including pharmacokinetic and pharmacogenomic evaluation for extra-Japanese Asian population with advanced gastric cancer. Methods: Chemo-naive advanced gastric cancer with measurable disease was enrolled. Initial dose of S-1 was b.i.d. at 35, then 40 mg/m 2 according to devised dosing method (range, 90–160 mg/day) for 28 days every 6 weeks. Pharmacokinetic study was performed after 28-day administration at cycle 1 and 3. Microarray based CGH was performed with genomic DNA from peripheral mononuclear cells to detect the toxicity-related genetic changes. Results: When first 31 patients were enrolled, protocol was amended to conduct the study by two steps for additional patients at 40 mg/m 2 without dose escalation in initial 31 patients of 35 mg/m 2 , because these patients showed neither significant nor cumulative toxicity. Of 62 patients enrolled, median relative dose intensity was 0.99. Overall response rate was 19.3% (95% CI, 9.2–29.5). With 558-day follow-up duration, median TTP and OS were 126 and 264 days, respectively. One-year survival rate was 33.9%. Toxicity increased with dose escalation, but there was no grade 4 toxicity. The most common significant toxicity was anemia. Pharmacokinetics parameters were similar to those of Japanese population. In microarray-CGH, we selected 18 genes with different copy numbers of 13 amplified and 5 deleted genes in patients with anemia. Conclusions: Our phase II study showed the feasibility of S-1 in gastric cancer at the dose of 35 mg/m 2 , and we suggested that selected 18 genes might be candidate markers for predicting anemia with S-1 treatment. No significant financial relationships to disclose.
Application of adaptive study designs: Phase II and III results from the cediranib (CED) HORIZON (HZ) II and III studies.
Authors: D. Wilson, P. M. Hoff, H. Schmoll, J. D. Robertson, A. Stone
Journal: Journal of Clinical Oncology (2011)

3633^ Background: The HZ studies in patients (pts) with first-line metastatic colorectal cancer, HZII (CED + FOLFOX [FF] or XELOX [X] vs. placebo [PBO] + FF or X) and HZIII (CED + mFF6 vs bevacizumab [BEV] + mFF6), were designed as adaptive trials with only one CED dose arm continuing after a planned end-of-phase (EOP)2 analysis. The final study data showed CED had clinical activity but did not meet the primary endpoint in HZIII (progression-free survival [PFS] hazard ratio [HR]=1.10, 95% CI: 0.97,1.25, P=0.119) and had a statistically significant, but modest, effect on PFS in HZII (HR=0.84, P=0.012), but no effect on overall survival (HR=0.94, P=0.571). An evaluation of results at EOP2 and EOP3 is presented. Methods: HZII and III began with recruitment to two CED arms (20 and 30 mg) and a comparator arm (PBO or BEV), all plus chemotherapy. The EOP2 analysis was conducted by an independent data monitoring committee (IDMC); criteria related to tolerability and efficacy were pre-specified. Clear evidence of an efficacy difference favoring CED (PFS HR<0.8 in HZII and >10% increase in response rate [RR] in HZIII) was required to recommend a dose for trial continuation. After EOP2 analysis of 257 HZII pts (75 events, 29% maturity) and 226 HZIII pts, the IDMC stated that CED 20 mg met both criteria and it was chosen for continuation. Personnel other than IDMC were blinded to the extent to which EOP2 criteria were exceeded. Results: At the EOP2 decision, the PFS HR for CED 20 mg vs PBO in HZII was 0.66 (30 mg vs PBO, HR=0.89) and the RR improvement in HZIII was 14.6% for CED 20 mg vs BEV (CED 20 mg, 54.1%; CED 30 mg, 40.8%; BEV, 39.5%). These differences were not maintained at the final analyses. The HZII PFS HR=0.84 for both the overall (84% maturity) and EOP2 (87% maturity) populations. The HZIII RRs in the overall population were 46.3% for CED 20 mg and 47.3% for BEV, but a 12% difference was maintained in the EOP2 pts (CED 20 mg, 58.1%; BEV, 46.1%). Conclusions: The EOP2 data were positive for CED 20 mg in HZII and III, justifying continuation of 20 mg in both trials. Maturity of the phase II decision PFS endpoint and investigator experience with a new therapy are important considerations in applying an adaptive trial design and/or transitioning from phase II to III.
VEGF, sVEGFR-2, bFGF, and IL-8 as biomarkers of the pharmacological activity of BAY 57–9352, an oral VEGFR-2 receptor tyrosine kinase inhibitor, in patients with solid tumors
Authors: M. Zuehlsdorf, O. Christensen, D. Strumberg, K. Mross, F. Eskens, H. Gelderblom, J. Verweij, P. Rajagopalan, D. Voliotis, G. Wensing
Journal: Journal of Clinical Oncology (2006)

3035 Background: BAY 57–9352 (BAY) is a potent anti-angiogenic drug that inhibits VEGFR-2, as well as VEGFR-1, VEGFR-3, PDGFR-β, and c-Kit tyrosine kinases. Molecular biomarkers of angiogenesis (VEGF 165 , soluble VEGFR-2 [sVEGFR-2], basic FGF [bFGF], and interleukin-8 [IL-8]) were used to assess the pharmacodynamic effects of BAY. Methods: Patients with advanced solid tumors from two Phase I studies received oral BAY on either an intermittent 21 day cycle (14 days on drug, 7 days off drug) or continuous schedule (21 day cycle). Doses were escalated from 20 mg once daily (od) to 1500 mg twice daily (bid). Molecular biomarkers were measured at baseline, pre-dose, and 8 hours post-dose on Days 1 and 14 of each cycle. Pharmacokinetic parameters of BAY were also assessed. Results: Plasma samples from 130 patients were analyzed for angiogenic biomarkers. Increased VEGF 165 and decreased sVEGFR-2 clearly correlated with the dose of BAY, respectively. All clinical responders (as shown by tumor shrinkage) were located within the upper 10% of the total response distribution for these markers. Subgroup analysis in the three more prevalent tumors showed that patients with colorectal, renal cell, and hepatocellular carcinoma all showed biomarker responses exceeding the mean overall responses. Biomarker levels reached a plateau at daily doses of approximately 900 mg bid or 1800 mg, suggesting a saturated pharmacodynamic effect. There were no consistent changes in bFGF and IL-8. Conclusions: Both VEGF and sVEGFR-2 demonstrated a dose-dependent change with BAY 57–9352. VEGF and sVEGFR-2 may be appropriate biomarkers of the therapeutic effects of BAY, and may be useful as potential predictors of early response. [Table: see text]
Inhibitor of NFκB Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN
Authors: Janine Gotot, Eveline Piotrowski, Martin S. Otte, André P. Tittel, Guo Linlin, Chen Yao, Karl Ziegelbauer, Ulf Panzer, Natalio Garbi, Christian Kurts, Friedrich Thaiss
Journal: Journal of the American Society of Nephrology (2015)

The NF κ B transcription factor family facilitates the activation of dendritic cells (DCs) and CD4 + T helper (Th) cells, which are important for protective adaptive immunity. Inappropriate activation of these immune cells may cause inflammatory disease, and NF κ B inhibitors are promising anti–inflammatory drug candidates. Here, we investigated whether inhibiting the NF κ B–inducing kinase IKK2 can attenuate crescentic GN, a severe DC– and Th cell–dependent kidney inflammatory disease. Prophylactic pharmacologic IKK2 inhibition reduced DC and Th cell activation and ameliorated nephrotoxic serum–induced GN in mice. However, therapeutic IKK2 inhibition during ongoing disease aggravated the nephritogenic immune response and disease symptoms. This effect resulted from the renal loss of regulatory T cells, which have been shown to protect against crescentic GN and which require IKK2. In conclusion, although IKK2 inhibition can suppress the induction of nephritogenic immune responses in vivo , it may aggravate such responses in clinically relevant situations, because it also impairs regulatory T cells and thereby, unleashes preexisting nephritogenic responses. Our findings argue against using IKK2 inhibitors in chronic GN and perhaps, other immune–mediated diseases.
Health Related Quality of Life Focus on Physical and Mental Health in Breast Cancer Patients: Preliminary Study
Authors: Andree Kurniawan, Nata Pratama Hardjo Lugito, Susanti Susanti, Margaret Merlyn Tjiang, Theo Audi Yanto, Indra Wijaya, Resa Setiadinata, Steven Soemantri, Audrey Suryani Soetjipto, Jocevin Prasetyadhi
Journal: Annals of Oncology (2014)
Increasing participation in breast cancer research: (INSPIRE-BrC).
Authors: Brandi Robinson, Sandra M. Swain
Journal: Journal of Clinical Oncology (2014)

53 Background: Increasing black patients’ participation in cancer clinical trials is particularly important because of the population’s lower survival rate. Accrual to clinical trials remains low among the general population (1 to 3%), with recruitment of blacks the lowest of all groups at 0.5 to 1.5%. Clinical trials are key to developing new methods to prevent, detect, and treat cancer. INSPIRE-BrC aims to increase trial participation rates among black patients with breast cancer and examine the relationship between the intervention and attitudes/beliefs on the decision to participate. Methods: A sample size of 123 black patients with breast cancer at five MedStar sites will view a 15 minute, culturally tailored video about clinical trials, which targets six cultural and attitudinal barriers to participation. A pre-test/post-test method is used to determine the impact of the video on three variables — likely participation in therapeutic clinical trials; attitudes toward therapeutic clinical trials (assessed based on the 6 barriers); and actual trial enrollment. Expected Findings: We hypothesize that the intervention will increase clinical trial enrollment compared to our 2012 clinical trial enrollment baseline rate of 6% (22/384) for black patients with breast cancer in five MedStar hospitals. The primary outcome measure is the proportion of black patients with breast cancer who agree to participate in a therapeutic clinical trial among those who sign consent to INSPIRE-BrC. Study findings have the potential to increase patient recruitment as a promising tool for rapid dissemination of a theory-driven, evidence-based model to enhance clinical trial accrual among black patients with cancer. [Table: see text]
<i>MUC5B</i> Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis
Authors: Yasushi Nakano, Ivana V. Yang, Avram D. Walts, Alan M. Watson, Britney A. Helling, Ashley A. Fletcher, Abigail R. Lara, Marvin I. Schwarz, Christopher M. Evans, David A. Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Abstract 11995: Auraptene, a Citrus Flavonoid, Prevents the Worsening of Systolic Function Following Myocardial Infarction in Rats
Authors: Yoichi Sunagawa, Shogo Kawaguchi, Yasufumi Katanasaka, Hidetoshi Suzuki, Akira Murakami, Hiromichi Wada, Tadashi Hashimoto, Akira Shimatsu, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation (2013)
Abstract 5817: A Proatherogenic Role for HMGB1 in Atherosclerosis
Authors: Alex Bobik, Peter Kanellakis, Alex Agrotis, Christine Koulis, Ingo Ahrens, Karlheinz Peter, Shuji Mori, Nideo K Takahashi, Keyue Liu, Masahiro Nishibori
Journal: Circulation (2009)

HMGB1 is a highly conserved nuclear protein that modulates chromatin structure. It is exported from the nucleus into the cytoplasm and secreted by immune cells and is also released by necrotic cells. In vitro, HMGB1 is a chemoattractant for inflammatory and smooth muscle cells and stimulates cytokine secretion by macrophages. Since it is highly expressed in human atherosclerotic lesions we tested the hypothesis that extracellular HMGB1 may be proatherogenic, augmenting development of atherosclerotic lesions in ApoE−/− mice. Initially we confirmed that like human atherosclerotic lesions, lesions in ApoE−/− mice also express HMGB1. To determine its significance for atherosclerosis, ApoE−/− mice were injected i.v. twice weekly with a HMGB1 monoclonal neutralising antibody and fed a high fat diet over 8 weeks. Treatment with the antibody attenuated atherosclerosis by 55%. Macrophage accumulation was reduced by 43% whilst expression of VCAM-1 and MCP-1 were reduced by 48 and 72% respectively. The total (CD11c+) dendritic cell population was reduced by 65% and mature (CD83+) dendritic cells were reduced by nearly 60% suggesting a major effect on the dendritic cell population. Treatment also reduced CD4+ T-cell numbers by 50% and attenuated smooth muscle cell accumulation within developing lesions but did not affect endothelial cells. To determine whether HMGB1 differentially affected the CD4+ T-cell Th1 and Th2 populations we measured Tim3 and Tim1 mRNA levels. Tim 1, a marker for Th2 cells was not detectable in lesions of control ApoE−/− mice or mice treated with the neutralising antibody, but Tim3 mRNA was reduced by 55% with the neutralising antibody. Since in vitro HMGB1 stimulates secretion of proinflammatory cytokines by macrophages we also examined whether proinflammatory cytokine expression was affected in lesions. mRNAs encoding TNF-alpha and IL-1 beta were unchanged but IFN-alpha and IL-6 were reduced by nearly 50% by the neutralising antibody. Also, mRNA encoding ABCA1 was unaffected but mRNA encoding FABP4 was elevated 5-fold. We conclude that HMGB1 contributes to atherosclerosis development by augmenting intima development, stimulating dendritic cell migration, thereby increasing CD4+ Th1T-cell accumulation as well as IFN-alpha and IL-6.
Theorize it both ways?
Authors: Tim Rakow
Journal: Behavioral and Brain Sciences (2001)

Psychologists' lack of methodological uniformity reflects their greater breadth of enquiry than experimental economists. The need for a theoretical understanding of one-shot decisions validates research undertaken without the repetition of trials. Theories tested only with financial incentives may not reliably predict some classes of decision such as those involving health. Undue emphasis on the importance of replication risks the proliferation of theories with limited generalizability.
The 2nd meeting of the Campania Society of Oncology Immunotherapy (SCITO): focus on hepatocellular carcinoma, kidney and bladder cancer
Authors: Bruno Daniele, Bruno Sangro, Daniel Petrylak, Fabio Calabrò, Giacomo Cartenì, Vincenzo Montesarchio, Sabino De Placido, Paolo A. Ascierto
Journal: Journal for ImmunoTherapy of Cancer (2016)

In this paper, we review recent advances in immuno-oncology with particular focus on liver, kidney, and bladder cancers as discussed at the 2nd meeting of the Campania Society of Oncology Immunotherapy (SCITO).
Natural killer cell receptor repertoire following HLA-matched allogeneic hematopoietic stem cell transplantation
Authors: M. Boyiadzis, J. M. Carson, S. A. Memon, R. Dean, S. Pavletic, C. Kasten-Sportes, D. Fowler, M. R. Bishop, R. E. Gress, F. T. Hakim
Journal: Journal of Clinical Oncology (2004)

6635 Background: Following hematopoietic stem cell transplantation (HSCT), natural killer (NK) cells are among the first lymphocytes to recover, returning to normal levels within six weeks after HSCT. NK cells may mediate anti-tumor effects and regulate graft versus host disease (GVHD); modulation of the relative frequency and intensity of expression of the cytotoxic NK receptors may influence NK activity post transplant. Methods: We compared the NK receptor expression in seven patients at one month following non-myeloablative HLA-matched allogeneic HSCT with that of donors and healthy volunteers. NK cells were divided into two subsets based on expression of CD56 and CD16. Both subsets were assessed for three main classes of receptors that trigger or inhibit cytotoxicity: natural cytotoxicity receptors (NCR), killer immunoglobulin-like receptors (KIR) and C-type lectin receptors. Results: Compared to donors, the expression of the NCR NKp46 increased significantly in all patients, whereas NKp30 increased in the CD 56+ bright subset only in patients that developed acute GVHD. Expression of KIR receptors (CD158A, CD158B) did not change or decreased slightly. In contrast the C-type lectin receptor CD 94 was upregulated on most NK cells. The heterodimeric partners of CD94, NKG2A and NKG2C, were also increased, but the increase in frequency of cells expressing the inhibitory receptor NKG2A was greater than that of the activating receptor NKG2C. The homodimeric activating receptor NKG2D increased in all patients. No significant differences in NK receptor expression between the donors and healthy volunteers was observed Conclusions: These results demonstrate changes in the NK receptor repertoire during the early post-transplant period that may have an impact on NK cells mediated cytotoxicity. No significant financial relationships to disclose.