tbuckley/cabot-search huggingface dataset:
Quantitative bone scan lesion area as an early surrogate outcome measure indicative of overall survival in metastatic castration-resistant prostate cancer.
Authors: Matthew S. Brown, Hyun J. Kim, Gregory H. Chu, Martin Allen-Auerbach, Cheryce Fischer, Benjamin Levine, Pawan Gupta, Christiaan Schiepers, Jonathan Goldin
Journal: Journal of Clinical Oncology (2015)

179 Background: Bone Scan Lesion Area (BSLA) is a biomarker that can be computed semi-automatically from whole-body scintigraphic imaging as a measure of overall bone tumor burden. Initial development and validation, including correlation with outcomes, was performed in trial cohorts from a single drug treatment with controls in subjects with metastatic castrate-resistant prostate cancer (CRPC). A 30% increase/decrease in BSLA was defined as progression/response on bone scan. We hypothesize that, when applied to an independent treatment trial cohort with a different mechanism of drug action, baseline BSLA and Week 12 change post-treatment are predictive of a subject's overall survival. Methods: From an anonymized imaging research database a cohort of 198 CRPC subjects was identified who enrolled in a treatment trial (127 treated, 71 placebo). This cohort was independent of those used for biomarker development and initial validation, and involved a different mechanism of drug action. Subjects underwent standard of care whole-body bone scintigraphy with 99m Tc-Methyl diphosphonate ( 99m Tc-MDP). BSLA was calculated at baseline and response at Week 12. Multivariate Cox regression was used to test whether (1) baseline BSLA, and (2) early changes in BSLA (12 weeks post treatment) were predictive of overall survival. Results: BSLA &lt; 2000 mm 2 at baseline was a prognostic factor (HR=0.6; p=0.003) and predictive of longer survival (HR=0.4; p&lt;0.001). Subjects without PD by BSLA at Week 12 had significantly longer survival than subjects with PD: median 170 days vs. 186 days in the placebo group and 260 days vs. 392 days in the treatment group. The overall survival rates between non-PD and PD subjects were statistically different (HR=0.64, p=0.007). Conclusions: BSLA is calculated semi-automatically from bone scans and provides a quantitative and objective treatment response assessment. Baseline BSLA and early changes post treatment were found to be predictive of overall survival in patients with metastatic castration-resistant prostate cancer. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different drug treatments.
Patterns of adaptation to children's food allergies
Authors: D. A. Fedele, E. L. McQuaid, A. Faino, M. Strand, S. Cohen, J. Robinson, D. Atkins, J. O'B Hourihane, M. D. Klinnert
Journal: Allergy (2015)

Families with food allergy (FA) are at risk of reduced quality of life and elevated anxiety. A moderate level of anxiety may be beneficial to sustain vigilance for food avoidance; however, excessive anxiety may increase risk for burden and maladjustment. The current study presents a framework for understanding the patterns of adaptation to FA across families and to identify typologies of families that would benefit from intervention.Participants included 57 children, 6-12 years old with documented FA, and their mothers. Families were assessed using the Food Allergy Management and Adaptation Scale. Families also completed measures of quality of life, anxiety, FA management, and psychosocial impairment.A hierarchical cluster analysis revealed that 56 of the 57 families of food-allergic children were categorized into four groups that differed on their adequacy of family FA management, levels of anxiety, and balanced psychosocial functioning: balanced responders (n = 23; 41%), high responders (n = 25; 45%), and low responders (n = 3; 5%). The fourth group, anxious high responders (n = 5; 9%), was characterized by extremely high maternal FA anxiety scores and low scores for balanced integration of FA management and psychosocial functioning. Families in clusters differed across illness and psychosocial outcome variables.Families with FA were characterized by patterns of FA management, anxiety, and ability to integrate FA demands into daily life. Identified adaptation patterns correspond with clinical impressions and provide a framework for identifying families in need of intervention.
Phase I Trial of Multiple Cycles of High-Dose Carboplatin, Paclitaxel, and Topotecan With Peripheral-Blood Stem-Cell Support as Front-Line Therapy
Authors: Russell J. Schilder, James M. Gallo, Michael M. Millenson, Michael A. Bookman, Louis M. Weiner, André Rogatko, Barbara Rogers, Kristin Padavic-Shallers, Matthew Boente, Norman Rosenblum, Andrea L. Adams, Suzanne Ciccotto, Robert F. Ozols
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell (PBSC) support. PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with either filgrastim alone or in combination with cyclophosphamide and paclitaxel. Patients then received three or four cycles of high-dose carboplatin (area under the concentration-time curve [AUC] 16), paclitaxel (250 mg/m 2 ), and topotecan (10-15 mg/m 2 ), with the latter two agents administered as 24-hour infusions and supported with PBSC and filgrastim. Cycles were repeated every 28 days. RESULTS: Twenty patients were enrolled onto the trial and were assessable for toxicity and clinical outcome. Dose-limiting toxicities were stomatitis and prolonged hematopoietic recovery. The maximum-tolerated dose of topotecan was 12.5 mg/m 2 when given with high-dose carboplatin and paclitaxel for three cycles. Four cycles were able to be given with a dose of topotecan of 10 mg/m 2 . The pharmacokinetics of each compound were not affected by the other agents. Eleven (85%) of 13 patients with assessable disease responded. CONCLUSION: Multiple cycles of high-dose carboplatin, paclitaxel, and topotecan can be safely administered with filgrastim and PBSC support. The recommended doses for phase II study are carboplatin AUC 16, paclitaxel 250 mg/m 2 , and topotecan 10 mg/m 2 . Trials are currently being conducted with this regimen as front-line treatment in patients with advanced ovarian cancer and extensive small-cell carcinoma. This approach remains experimental and should be used only in the context of a clinical trial.
BMS-354825 potently inhibits multiple selected oncogenic tyrosine kinases and possesses broad-spectrum antitumor activities in vitro and in vivo
Authors: Francis Y. Lee, Louis Lombardo, Amy Camuso, Stephen Castaneda, Krista Fager, Christine Flefleh, Ivan Inigo, Kathy Johnson, David Kan, Roger Luo, Kelly McGlinchey, Suhong Pang, Russell Peterson, Mei-Li Wen, Robert Wild, Craig Fairchild, Tai Wong, Robert Borzilleri, Robert Kramer
Journal: Cancer Research (2005)

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BMS-354825 is a novel 2-substituted aminopyrimidinyl-thiazole-5-carboxamide analog currently being developed by Bristol-Myers Squibb for the treatment of solid tumors and Imatinib-resistant and -sensitive leukemias (Shah et al, Science , 305, 399-401, 2004). BMS-354825 competes with ATP for the ATP-binding site in the kinase domain of selected and related oncogenic receptor and non-receptor protein tyrosine kinases (PTKs), including BCR-ABL, SRC family kinases, c-KIT, EPH and PDGF receptors. These PTKs have been strongly linked to multiple forms of human cancers and their dysregulations are critical to the pathophysiology of malignancies: uncontrolled proliferation, inappropriate adhesion, heightened motility and metastatic potential, resistance to apoptosis, and angiogenesis promotion. In in vitro kinase assays, BMS-354825 potently inhibits these PTKs at subnanomolar to low nanomolar concentrations: with IC50 as follows: SRC family kinases (SRC = 0.55 nM, LCK = 1.1 nM, YES = 0.41 nM, FYN = 0.2 nM); BCR-ABL (<3 nM); c-KIT (13 nM); EPHA2 (17 nM) and PDGFβ receptor (28 nM). In cellular assays, BMS-354825 at clinically achievable concentrations (< 1.0 μM) inhibited the proliferation of 11 of 23 lung (48%), 9 of 31 colon (29%) and 7 of 23 breast (30%) cancer cell lines tested todate using the MTS assay. In preclinical chemotherapy trials against a random panel of thirteen solid tumors grown in mice, BMS-354825 significantly inhibited the growth of 6 of 13 xenografts (46%) at doses producing drug exposure similar to those currently achieved in ongoing phase I clinical trials. Responsive tumor types include breast, prostate, colon, pancreatic, sarcoma and small cell lung cancers. These results suggest that BMS-354825 may have therapeutic utilities in a broad-spectrum of cancer types. BMS-354825 is currently in clinical trials in both BCR-ABL dependent leukemias and in solid malignancies.
Kinetics of functionalised carbon nanotube distribution in mouse brain after systemic injection: Spatial to ultra-structural analyses
Authors: Julie T.-W. Wang, Noelia Rubio, Houmam Kafa, Enrica Venturelli, Chiara Fabbro, Cécilia Ménard-Moyon, Tatiana Da Ros, Jane K. Sosabowski, Alastair D. Lawson, Martyn K. Robinson, Maurizio Prato, Alberto Bianco, Frederic Festy, Jane E. Preston, Kostas Kostarelos, Khuloud T. Al-Jamal
Journal: Journal of Controlled Release (2015)

Earlier studies proved the success of using chemically functionalised multi-walled carbon nanotubes (f-MWNTs) as nanocarriers to the brain. Little insight into the kinetics of brain distribution of f-MWNTs in vivo has been reported. This study employed a wide range of qualitative and quantitative techniques with the aim of shedding the light on f-MWNT's brain distribution following intravenous injection. γ-Scintigraphy quantified the uptake of studied radiolabelled f-MWNT in the whole brain parenchyma and capillaries while 3D-single photon emission computed tomography/computed tomography imaging and autoradiography illustrated spatial distribution within various brain regions. Raman and multiphoton luminescence together with transmission electron microscopy confirmed the presence of intact f-MWNT in mouse brain, in a label-free manner. The results evidenced the presence of f-MWNT in mice brain parenchyma, in addition to brain endothelium. Such information on the rate and extent of regional and cellular brain distribution is needed before further implementation into neurological therapeutics can be made.
Phase I study of irinotecan and cisplatin with granulocyte colony-stimulating factor support for advanced non-small-cell lung cancer.
Authors: N Masuda, M Fukuoka, S Kudoh, Y Kusunoki, K Matsui, K Nakagawa, T Hirashima, M Tamanoi, T Nitta, T Yana
Journal: Journal of Clinical Oncology (1994)

PURPOSE Since leukopenia was one of the dose-limiting toxicities of the combination of irinotecan (CPT-11) and cisplatin in a previous trial, we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-11 dose in combination with a fixed cisplatin dose. PATIENTS AND METHODS Twenty previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) were treated with CPT-11 on days 1, 8, and 15 in combination with cisplatin 80 mg/m2 intravenously on day 1. In addition, rhG-CSF (2 micrograms/kg/d) was administered on days 4 to 21, except on the days of CPT-11 treatment. The starting dose of CPT-11 was 70 mg/m2, and the CPT-11 dose was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS Diarrhea was the dose-limiting toxicity at 90 mg/m2. Two of six patients experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CPT-11 dose from 80 to 90 mg/m2 resulted in a marked increase in the plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38). Occurrence of diarrhea was well correlated with the peak plasma concentration (Cmax) of SN-38 (P = .035). There were 10 partial responses (50%) among 20 patients. CONCLUSION The recommended dose for phase II studies is 80 mg/m2 of CPT-11, and 80 mg/m2 of cisplatin plus rhG-CSF. With the use of rhG-CSF, the CPT-11 dose can be increased 33% above that in the original regimen (60 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin).
A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST).
Authors: J. C. Trent, K. Wathen, M. von Mehren, B. L. Samuels, A. P. Staddon, E. Choy, J. E. Butrynski, R. Chugh, W. A. Chow, D. A. Rushing, C. A. Forscher, L. H. Baker, S. Schuetze
Journal: Journal of Clinical Oncology (2011)

10006 Background: Dasatinib is an oral tyrosine kinase inhibitor of KIT, PDGFR, ABL and SRC with a distinct binding affinity for KIT and PDGFR. We performed a phase II trial to assess antitumor activity of dasatinib in patients (pts) with advanced GIST who were refractory to imatinib (IM) and sunitinib malate (SM). Methods: Pts received dasatinib 70mg PO BID. Computer tomographic response rates (ORR) was evaluated every 8 wks by Choi criteria. The primary endpoint was a target progression-free survival at 6 months (PFS-6) of >30% with <10% deemed inactive by a Bayesian approach. Objective response rate (ORR) per Choi criteria was also determined. Results: From 8/2008 to 7/2010, 50 pts were accrued (47 evaluable for response). Median age was 60(range, 20-78), 62% were male, and median ECOG PS=1. The most common site of primary disease was stomach (59%) and metastasis was liver (56%). Primary median tumor size at diagnosis was 8.7 cm(range 3.7-26) and mitotic rate was >5/50 hpf in 74% of patients. Tumor morphology was spindled (63%), epithelioid (18%) or mixed (18%). The median number of prior therapies was 2[range 1-6, IM (100%), SM (80%)]. Genotype was available for 15 pts: 6(40%) KIT exon 11, 6(40%) WT, 2(13%) KIT exon 9, and 1(7%) had PDGFR D842V. The median number of cycles was 2 (range, 1-24). The PR rate was 32% (15/47) by Choi criteria. 21% patients (10/47) were progression-free >6 months. Median PFS and OS were 2.0 months and 19 months. Median PFS for patients with WT GIST was 8.4 months (range 1.2-27). Toxicity was assessed in all pts: 14 grade 3 events (28%; constitutional, GI, respiratory, and myelosuppression) and 1 grade 4 event (2%, pain). There were no deaths related to dasatinib. Conclusions: Dasatinib has significant activity by ORR in IM and SM-refractory GIST but did not meet the predefined 6 month PFS rate of 30%. Mutational and molecular correlates are forthcoming.
Comparative Genomics Identifies Epidermal Proteins Associated with the Evolution of the Turtle Shell
Authors: Karin Brigit Holthaus, Bettina Strasser, Wolfgang Sipos, Heiko A Schmidt, Veronika Mlitz, Supawadee Sukseree, Anton Weissenbacher, Erwin Tschachler, Lorenzo Alibardi, Leopold Eckhart
Journal: Molecular Biology and Evolution (2015)

The evolution of reptiles, birds, and mammals was associated with the origin of unique integumentary structures. Studies on lizards, chicken, and humans have suggested that the evolution of major structural proteins of the outermost, cornified layers of the epidermis was driven by the diversification of a gene cluster called Epidermal Differentiation Complex (EDC). Turtles have evolved unique defense mechanisms that depend on mechanically resilient modifications of the epidermis. To investigate whether the evolution of the integument in these reptiles was associated with specific adaptations of the sequences and expression patterns of EDC-related genes, we utilized newly available genome sequences to determine the epidermal differentiation gene complement of turtles. The EDC of the western painted turtle (Chrysemys picta bellii) comprises more than 100 genes, including at least 48 genes that encode proteins referred to as beta-keratins or corneous beta-proteins. Several EDC proteins have evolved cysteine/proline contents beyond 50% of total amino acid residues. Comparative genomics suggests that distinct subfamilies of EDC genes have been expanded and partly translocated to loci outside of the EDC in turtles. Gene expression analysis in the European pond turtle (Emys orbicularis) showed that EDC genes are differentially expressed in the skin of the various body sites and that a subset of beta-keratin genes within the EDC as well as those located outside of the EDC are expressed predominantly in the shell. Our findings give strong support to the hypothesis that the evolutionary innovation of the turtle shell involved specific molecular adaptations of epidermal differentiation.
Effect of a Smac Mimetic (TL32711, Birinapant) on the Apoptotic Program and Apoptosis Biomarkers Examined with Validated Multiplex Immunoassays Fit for Clinical Use
Authors: Apurva K. Srivastava, Soumya Jaganathan, Laurie Stephen, Melinda G. Hollingshead, Adam Layhee, Eric Damour, Jeevan Prasaad Govindharajulu, Jennifer Donohue, Dominic Esposito, James P. Mapes, Robert J. Kinders, Naoko Takebe, Joseph E. Tomaszewski, Shivaani Kummar, James H. Doroshow, Ralph E. Parchment
Journal: Clinical Cancer Research (2015)

To support clinical pharmacodynamic evaluation of the Smac mimetic TL32711 (birinapant) and other apoptosis-targeting drugs, we describe the development, validation, and application of novel immunoassays for 15 cytosolic and membrane-associated proteins indicative of the induction, onset, and commitment to apoptosis in human tumors.
Interpreting the null result
Authors: Frances Healey
Journal: BMJ (2008)

Evidence that multifaceted interventions in acute hospitals are ineffective is limited,1 with most studies based on rehabilitation units2 and only one other large cluster randomised controlled trial in an acute setting.3 This showed a significant reduction in falls after the introduction of multifaceted interventions, as did other large acute hospital studies of before and after design.4 So what explains the disparity in the results? It is …
Chemopreventive effects of a specific COX-2 inhibitor (Celecoxib) and a novel HDAC inhibitor (SK-7041) on azoxymethane-initiated and dextran sulfate sodium-promoted mouse colon carcinogenesis
Authors: Jeong-Sang Lee, Hyun Soo Kim, Tae-Young Oh, Marie Yeo, Ki-Baik Hahm, Yung-Jue Bang, Young-Joon Surh
Journal: Cancer Research (2005)

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Multiple lines of compelling evidence support the causal relationship between inflammation and cancer. In an attempt to clarify the contribution of ulcerative colitis to colon carcinogenesis, we treated male ICR mice with a single i.p dose (10 mg/kg body weight) of azoxymethane (AOM) followed by 2% dextran sulfate sodium salt (DSS) in drinking water for consecutive 7 days. DSS administration caused chronic inflammation, which markedly enhanced the incidence and the burden of AOM-initiated colon tumors. At the 16 week of AOM and DSS treatment, 80% of mice developed colorectal carcinoma, mostly in rectal and descending colon, whereas only 22% of AOM-treated and none of DSS-treated mice developed tumors. These findings suggest ulcerative colitis induced by DSS effectively promotes colon carcinogenesis in mice. Cyclooxygenase-2, inducible nitric oxide synthase, p16, and mutated p53 were markedly up-regulated in the AOM-initiated and DSS-promoted colon tumors. The serum levels of nitric oxide and proinflammatory cytokines, including interleukin (IL)-8, IL-1β, and IL-6, were also elevated in the colon tumors. In addition, the mRNA expression of matrix metalloproteinases (MMPs), such as MMP2, MMP9, MMP13, and MT2-MMP, was increased after AOM plus DSS treatment. On the contrary, the tissue inhibitor of MMP2 (TIMP2) was down-regulated by the same treatment. By utilizing the same mouse model, we evaluated chemopreventive activities of a selective inhibitor of COX-2 (Celecoxib) and a novel histone deacetylase (HDAC) inhibitor (SK-7041). Oral administration of Celecoxib (0.1 or 0.25 mmole/kg) by gavage for 14 weeks significantly lowered the AOM plus DSS-induced tumor incidence and multiplicity (75% and average 3.67 tumors/mouse in the AOM plus DSS group; 44.44% and 1.78/mouse in the low dose Celecoxib group; 40.0% and 1.00/mouse in the high dose Celecoxib group). When the HDAC inhibitor was administrated by i.p. injection 5 times at three-day intervals after AOM and DSS treatment, the tumor incidence and multiplicity were substantially reduced (80% and 3.70/mouse in the AOM plus DSS group; 60% and 2.20/mouse in the 10 mg/kg SK-7041 group; 55.83% and 1.53/mouse in the 30 mg/kg SK-7041). In conclusion, we have established a reliable and effective short-term two-stage mouse colon carcinogenesis model that can be utilized in chemoprevention studies.
Systems Analysis of Immunity to Influenza Vaccination across Multiple Years and in Diverse Populations Reveals Shared Molecular Signatures
Authors: Helder I. Nakaya, Thomas Hagan, Sai S. Duraisingham, Eva K. Lee, Marcin Kwissa, Nadine Rouphael, Daniela Frasca, Merril Gersten, Aneesh K. Mehta, Renaud Gaujoux, Gui-Mei Li, Shakti Gupta, Rafi Ahmed, Mark J. Mulligan, Shai Shen-Orr, Bonnie B. Blomberg, Shankar Subramaniam, Bali Pulendran
Journal: Immunity (2015)

Systems approaches have been used to describe molecular signatures driving immunity to influenza vaccination in humans. Whether such signatures are similar across multiple seasons and in diverse populations is unknown. We applied systems approaches to study immune responses in young, elderly, and diabetic subjects vaccinated with the seasonal influenza vaccine across five consecutive seasons. Signatures of innate immunity and plasmablasts correlated with and predicted influenza antibody titers at 1 month after vaccination with >80% accuracy across multiple seasons but were not associated with the longevity of the response. Baseline signatures of lymphocyte and monocyte inflammation were positively and negatively correlated, respectively, with antibody responses at 1 month. Finally, integrative analysis of microRNAs and transcriptomic profiling revealed potential regulators of vaccine immunity. These results identify shared vaccine-induced signatures across multiple seasons and in diverse populations and might help guide the development of next-generation vaccines that provide persistent immunity against influenza.
Obstructive sleep apnea accelerates decline in FEV1 in asthmatic patients
Authors: Tsai-Yu Wang, Yu-Lun Lo, Han-Pin Kuo
Journal: European Respiratory Journal (2014)

Background 

Although the prevalence of both obstructive sleep apnea (OSA) and asthma are increasing, little is known about the impact of OSA on the natural history of lung function in asthmatic patients.

Methods 

A total of 466 patients with polysomnography results from our sleep laboratory (January 2011 to Aug 2011) were retrospectively enrolled. Of them, 77 patients (16.5%) had asthma with regular follow-up for more than 5 years. Clinical characteristics, pulmonary function, emergent room (ER) visits and results of polysomnography were analyzed.

Results 

Patients were divided into three groups according to the severity of apnea-hypopnea index (AHI). The decline in FEV1 among asthma patients with severe OSA (AHI>30/h) was 72.4±61.7 ml/year (N=34), as compared with 41.9±45.3 ml/year (N=33, P=0.020) in those with mild to moderate OSA (5<AHI<30) and 24.3±27.5 ml/year (N=10, P=0.016) in those without OSA (AHI<5). For those patients with severe OSA, the decline of FEV1 significantly decreased after continuous positive airway pressure (CPAP) treatment. (41.2±3.6 ml/year vs. 66.2±4.4 ml/year, p=0.028, N=13). In univariate analysis, age, body mass index, apnea-hypopnea index, oxygen desaturation index and ER visits were significantly associated with the decline of FEV1. After multivariate stepwise regression analysis, the apnea-hypopnea index and ER visits were independent factors for the decline of FEV1.

Conclusions 

In a sample of the sleep-laboratory population, asthma patients who were identified as OSA had substantially greater declines in FEV1 in 5-year follow-up than those who were not. Moreover, CPAP treatment alleviated the decline of FEV1 in asthma patients with severe OSA.