tbuckley/cabot-search huggingface dataset:
Effect of neoadjuvant ixabepilone (ixa) on cell cycle genes and tumor-initiating cell (TIC) signature in breast cancer (BC).
Authors: H. Chang, C. E. Horak, P. Mukhopadhyay, C. Lowery, J. Baselga, J. A. Sparano
Journal: Journal of Clinical Oncology (2011)

1064 Background: Ixa is active in taxane-refractory metastatic and neoadjuvant BC. In the neoadjuvant ixa study CA163-080 (080), pre-treatment (tx) and post-tx tumor specimens were assessed by gene expression profiling. Standard neoadjuvant chemotherapy (ctx) may de-bulk tumor, leaving resistant TICs. We assessed the impact of ixa on gene expression changes, with emphasis on changes in TIC enrichment. Methods: Pre-tx Affymetrix gene expression data were available from 136 patients (pts) (100 pts also with surgical specimens). Primary site T-A and T-B or T-C and T-D subjective pathologic responses (by Sataloff) were categorized as ‘Responders’ and ‘Non-Responders’, respectively. BC subtype was defined by ER, PR and HER2 status and intrinsic subtype by PAM50. Pre- vs post-ixa gene expression was assessed by ANOVA. Gene Set Enrichment Analysis (GSEA), Ingenuity Pathway Analysis (IPA), and a previously derived TIC signature were applied to both pre- and post-tx profiles. Results were validated using the GSE18726 published dataset with expression data from BC pts prior to (n=21) and after one cycle (n=14) of neoadjuvant docetaxel + capecitabine. Results: Functional categories most significantly downregulated by ixa were proliferation and cell cycle control (confirmed in GSE18726). Wnt/beta-catenin and progenitor cell genes (indicative of a pluripotent tumor or ‘stem’ cell phenotype) were differentially expressed in pre- vs post-tx samples in 080 by IPA (not confirmed in the other dataset). In both studies, tx enriched pluripotent TIC and the signature score were significantly higher in post- vs pre-tx samples (-0.07 vs -0.16, p = 1.15e-7 in 080, and -0.06 vs -0.15, p = 0.066 in GSE18726). The highest change in TIC score was in HER2-enriched vs other subtypes. Consistent with ‘de-bulking’, signature score changes after tx were higher in ‘Responders’ vs ‘Non-Responders’ in both datasets. Conclusions: Ixa tx increased expression of TIC signature, similar to that observed in smaller datasets with other ctx and suggesting enrichment for a pluripotent, chemoresistant TIC population. These data provide rationale for the combination of ixa with TIC targeting agents.
Multimodality therapy including surgical resection (SR) and intraoperative electron radiotherapy (IOERT) for locoregionally recurrent (LRR) or advanced primary malignancies of the urinary bladder (UB) or ureter.
Authors: C. L. Hallemeier, R. J. Karnes, T. M. Pisansky, B. Davis, L. L. Gunderson, B. C. Leibovich, M. G. Haddock, R. Choo
Journal: Journal of Clinical Oncology (2011)

277 Background: For patients (pts) with LRR or advanced primary tumors of the UB or ureter, limited therapeutic options exist. Outcomes of combined SR and IOERT are reported here. Methods: From 1983 to 2009, a total of 17 pts with urothelial (16 pts) or squamous cell carcinoma (1 pt) of the UB (n=13) or ureter (n=4) were treated with SR and IOERT. Pts had LRR after radical cystoprostatectomy or nephroureterectomy (n=15) or advanced primary tumor (n=2). Extent of SR was R0 (microscopic negative margins), R1 (microscopic positive margins), and R2 (gross residual tumor) in 7, 1, and 9 pts, respectively. After maximal SR, IOERT was delivered to the tumor bed. Median IOERT dose and energy delivered were 12.5 Gy (range; 10-20) and 9 MeV (range; 6-18), respectively, with 1 (n=15), 2 (n=1), or 3 (n=1) IOERT fields. Sixteen pts also received perioperative external beam radiotherapy (EBRT) with a median dose of 50.4 Gy (range; 21.6- 60). Five pts received concurrent chemotherapy (CT) with perioperative EBRT. Overall (OS), disease-free survival (DFS) and relapse patterns were estimated from the date of SR and IOERT using the Kaplan-Meier method. Results: The median pt age was 63 years (yrs) (range; 51-76). The median follow-up of surviving pts was 3.6 yrs (range; 1.1-10.0). OS and DFS at 1, 2, and 5 yrs were 53%, 31%, and 16%, and 24%, 18%, and 18%, respectively. Central (within the IOERT field), locoregional (tumor bed or first echelon draining lymphatics), and distant relapse at 2 yrs were 15%, 49%, and 67%, respectively. Seven pts received systemic CT after relapse. Mortality within 30 days of SR and IOERT was 0%. Two pts (12%) experienced grade 4-5 (NCI-CTCAE v. 4) toxicity potentially related to the multimodality therapy. Conclusions: For pts with LRR or advanced primary tumor of the UB or ureter, this multimodality therapy including SR and IOERT resulted in durable OS and DFS in a small but significant number of pts. Both LRR and distant relapse were common, indicating a need for more effective systemic therapy along with more refined locoregional therapy. No significant financial relationships to disclose.
Genomic Analysis Reveals Hypoxia Adaptation in the Tibetan Mastiff by Introgression of the Grey Wolf from the Tibetan Plateau
Authors: Benpeng Miao, Zhen Wang, Yixue Li
Journal: Molecular Biology and Evolution (2016)

The Tibetan Mastiff (TM), a native of the Tibetan Plateau, has quickly adapted to the extreme highland environment. Recently, the impact of positive selection on the TM genome was studied and potential hypoxia-adaptive genes were identified. However, the origin of the adaptive variants remains unknown. In this study, we investigated the signature of genetic introgression in the adaptation of TMs with dog and wolf genomic data from different altitudes in close geographic proximity. On a genome-wide scale, the TM was much more closely related to other dogs than wolves. However, using the 'ABBA/BABA' test, we identified genomic regions from the TM that possibly introgressed from Tibetan gray wolf. Several of the regions, including the EPAS1 and HBB loci, also showed the dominant signature of selective sweeps in the TM genome. We validated the introgression of the two loci by excluding the possibility of convergent evolution and ancestral polymorphisms and examined the haplotypes of all available canid genomes. The estimated time of introgression based on a non-coding region of the EPAS1 locus mostly overlapped with the Paleolithic era. Our results demonstrated that the introgression of hypoxia adaptive genes in wolves from the highland played an important role for dogs living in hypoxic environments, which indicated that domestic animals could acquire local adaptation quickly by secondary contact with their wild relatives.
Obesity Is a Risk Factor for Recurrent Venous Thrombosis in Young and Middle-Aged Women. Results From Tehs-Follow up, a Nested Cohort Study On 1394 Women with VTE.
Authors: Maria Ljungqvist, Kristina Sonnevi, Annica Bergendal, Margareta Holmstrom, Helle Kieler, Gerd Larfars
Journal: Blood (2012)
PS01.53: First-Line Atezolizumab Plus Chemotherapy in Chemotherapy-Naive Patients with Advanced NSCLC: A Phase III Clinical Program
Authors: Robert M. Jotte, Mark A. Socinski, Martin Reck, Vassiliki Papadimitrakopoulou, Howard J. West, Tony Mok, Alan Sandler, Simonetta Mocci, Shelley Coleman, Takashi Asakawa, Federico Cappuzzo
Journal: Journal of Thoracic Oncology (2016)
Efficacy of cetuximab plus platinum agent in advanced, triple-negative breast carcinoma: Results of a retrospective analysis.
Authors: P. Rivera, T. Filleron, L. Gladieff, J. Delord, E. Mery, H. Roche, F. Dalenc
Journal: Journal of Clinical Oncology (2011)

e11581 Background: Most triple-negative breast cancers present similar pathogenic pathways with cancers arising in BRCA-mutation carriers, suggesting susceptibility to DNA damaging agents as platinum salts. Epidermal Growth Factor Receptor [EGFR] expression is also increased and few studies investigated EGFR inhibitors associated with platinum agents in this tumor group. Methods: We investigated an association of platinum agents plus cetuximab in advanced triple-negative breast cancers. Patients received cisplatin 50 mg/m² on day 1 and 15 (or carboplatin AUC3 in case of toxicity) and cetuximab 250 mg/m² every week after a first administration with 400 mg/m² by intravenous infusion. We report a retrospective analysis of this experience analyzing objective response rate as the first end-point. Duration of response, time to progression and toxicity were the secondary end-points. Survival rates were estimated using Kaplan-Meier methods. Results: We analyzed 43 patients whom median age at diagnosis was 49 years-old [25-80]. Most of them (81.4%) received platinum and cetuximab as second line or more. Twenty patients had visceral metastasis at baseline. Median treatment duration was 2.3 months [0.3-13.7]. Main toxicities were neuropathy (14%), emesis (9.3%) and renal toxicity (9.3%) conducting to carboplatin administration instead of cisplatin. The objective response rate was 45.9% among 37 evaluable patients. Median time to progression was 2.3 months (95%CI = [1.9-4.0]). After a median follow-up of 13.3 months, 31 patients were deceased and the median overall survival was 7.7 months (95%CI = [6.7;10.7]). Conclusions: Even if progression occurred quickly, the association of cetuximab and platinum agent is interesting in term of objective response rate. Deciphering tumor biology and markers of “EGF-R addictive pathway” will certainly improve patient’s selection and efficacy.
Conversion of Danger Signals into Cytokine Signals By Hematopoietic Stem and Progenitor Cells for Regulation of Stress-Induced Hematopoiesis
Authors: Jimmy L. Zhao, Chao Ma, Ryan O'Connell, Arnav Mehta, Jun Wang, Christopher S. Seet, Gay M. Crooks, Dinesh S. Rao, James Heath, David Baltimore
Journal: Blood (2014)
Multiple rechallenges (ReCs) with docetaxel (DOC) as an option after first-line therapy in patients (pts) with castration-resistant prostate cancer (CRPC).
Authors: O. Caffo, S. Brugnara, A. Caldara, A. Ferro, M. Frisinghelli, V. Murgia, B. Soini, F. Valduga, A. Veccia, E. Galligioni
Journal: Journal of Clinical Oncology (2011)

165 Background: Responder pts to first-line DOC, who have stopped the treatment in absence of progression, usually experience a disease progression within few months. In recent years, ReC with DOC has emerged as a therapeutic option for these pts, able to achieve again a response. The available data usually report on the clinical outcome of pts who have received one or two ReCs, but it is unclear whether more ReCs may be offered to these pts and if there is a maximum number of affordable ReCs. Methods: We retrospectively reviewed the clinical record of the pts with CRPC treated in our Department with DOC from March, 2002 to September, 2010. We selected pts who received multiple ReCs until the appearance of a true resistance to DOC: we consider as DOC-resistant pts showing a clinical and/or biochemical progression during DOC treatment. Results: We have identified a consecutive series of 26 pts, who have received a median number of 2 ReCs (range 2- 6). The median age was 68 yrs (range 58-82 yrs). The ReC consisted of DOC q 3 wks in 7 cases, DOC + estramustine q 3 wks in 38, weekly DOC + estramustine in 23. Multiple ReCs were well tolerated with no more than grade 1 hematological and non-hematological toxicities. To date, 11 pts are still DOC-sensitive (after 2-6 ReCs, median 2) and are receiving ReCs or are in the off-therapy period after ReCs. After a median follow-up of 30 months, 14 pts are dead and 12 alive. The median survival is 40 mos and the projected 3-years overall survival is 54%. Conclusions: In our experience multiple DOC ReCs may be administered in DOC-sensitive pts with CRPC. This may provide a long-term disease control with remarkable survival rate compared to those of DOC pivotal studies (19 mos) and a second line treatment may be retarded until the appearance of a true DOC-resistance. [Table: see text] No significant financial relationships to disclose.
Consciousness weaves our internal view of the outside world
Authors: Moshe Gur
Journal: Behavioral and Brain Sciences (2016)

Low-level consciousness is fundamental to our understanding of the world. Within the conscious field, the constantly changing external visual information is transformed into stable, object-based percepts. Remarkably, holistic objects are perceived while we are cognizant of all of the spatial details comprising the objects and of the relationship between individual elements. This parallel conscious association is unique to the brain. Conscious contributions to motor activity come after our understanding of the world has been established.
Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Estimating mean overall survival (OS) for health economic analyses from a phase III trial (TROPIC).
Authors: S. Oudard, F. Joulain, A. De Geer, A. O. Sartor
Journal: Journal of Clinical Oncology (2011)

128^ Background: TROPIC evaluated the efficacy and safety of the novel taxane cabazitaxel in men with mCRPC previously treated with docetaxel. Median OS was significantly improved, as previously reported (12.7 months in mitoxantrone arm vs 15.1 months in cabazitaxel arm, HR=0.72 [0.61 – 0.84], p&lt;0.0001- updated OS results). Median OS is the most useful descriptive statistic for physicians and patients as it reflects a point estimate in time by which 50% patients may survive regardless of disease status or progression. It avoids assumptions on long-term survival beyond the follow-up period of the clinical trial. Payers however are interested in making a coverage and reimbursement decisions based on the overall therapeutic benefit relative to its risk, and the expected impact on healthcare expenditures. Analyses such as cost-effectiveness analysis therefore require the estimation of mean OS. Methods: Mean OS is only observable when the last patient has died. Its estimation can be derived via an extrapolation of the trial Kaplan-Meier curve using a survival function. Several parametric distributions (exponential, weibull, lognormal, loglogistic and Gompertz) were tested. The parametric distribution that best fitted the trial Kaplan-Meier curves was selected using the Akaike's Information criteria (AIC), the Bayesian Information Criteria (BIC) and graphical method to evaluate the goodness of fit of the distributions. Mean OS from the best fitted model was generated to support payer decision making. Results: Using AIC/BIC and graphical method, the Weibull survival function, S(t)=exp(-l t s ) where l is a scale parameter and s a shape parameter, was selected as the distribution that best fitted the TROPIC data. Results of the estimated mean survival assuming a Weibull function are described in the table. Conclusions: Assuming a Weibull distribution, mean OS is estimated at 14.5 months in mitoxantrone arm vs 18.5 months in cabazitaxel arm, leading to 4 months OS difference in favour of cabazitaxel. [Table: see text] [Table: see text]
Content encapsulation in consciousness is likely to be incomplete
Authors: Demis Basso
Journal: Behavioral and Brain Sciences (2016)

Abstract Although the passive frame theory (PST) seems to be very plausible, the encapsulation of content generation deserves further elaboration. Many concepts and data considering the capacity theory, perception, and higher cognitive processes seem to contradict this principle. In general, PST can be suitable in many cases, but it needs to be completed by other mechanisms.
Immune responses in prostate tumor tissue following neoadjuvant sipuleucel-T in patients with localized prostate cancer.
Authors: Lawrence Fong, Vivian K. Weinberg, John M Corman, Christopher L Amling, Robert A Stephenson, Carl Formaker, Stephen E Chan, Jeffrey Simko, Robert Brownell Sims, Peter Carroll, Eric Jay Small
Journal: Journal of Clinical Oncology (2012)

181 Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To better understand the immunologic effects of sipuleucel-T, an open-label Phase 2 study (P07‐1; NCT00715104 ) of sipuleucel-T prior to radical prostatectomy (RP) was undertaken in patients with localized prostate cancer. Methods: Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to RP. Prostate biopsies (pre-treatment) and tissue from RP (post-treatment) were assessed for the presence of lymphocytes by immunohistochemistry (IHC). Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP infusions of sipuleucel-T. To date, tissue IHC analysis has been completed in 19 patients. Treatment-related AEs were manageable and reversible. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (&gt;10% of patients) were fatigue, headache, and myalgia. Significant increases (&gt;2‐fold) in CD3 + and CD4 + T cells populations were observed at the tumor rim (where benign and malignant glands interface), compared with the pre-treatment biopsy (ANOVA post hoc Newman-Keuls test: p=0.0002, 0.0002, respectively). CD8 + T cells or CD56 + cells were not significantly increased at the tumor rim compared with benign biopsy regions. Conclusions: Neoadjuvant sipuleucel-T treatment appears to result in an increased frequency of T cells in prostate cancer tissue at the rim between the benign and malignant glands. These data suggest that sipuleucel-T may modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response within the prostate tumor tissue and in the peripheral blood.
Youth sports injury prevention: keep calm and play on
Authors: Cynthia R LaBella, Gregory D Myer
Journal: British Journal of Sports Medicine (2016)

In recent years, there has been extensive media focus on youth sports injuries, especially concussions. While youth sports training and competition are more intense than ever, the focus on the ‘injury risk’ downside of youth sport is unfortunate because the benefits of sports participation (improvements in overall health1 and bone density;2 lower rates of overweight/obesity,3 cardiovascular disease,3 diabetes,3 risk-taking behaviours,4 depression4 and teen pregnancy;5 and enhanced self-esteem4 and peer socialisation4) far outweigh the risks for children and teens. In fact, the injury risk for youth aged 6–12 years in organised sports, even in contact/collision sports such as American football, is well below the risk of injury in typical recreational activities such as riding a bicycle or playing on a playground. Additionally, the recent focus on improving safety in organised youth sports has led to rule changes that have reduced specific acute injuries (eg, breakaway bases in baseball/softball, securing movable goalposts in soccer, limiting contact/collision drills and teaching safer tackling techniques in …
Real-World Evidence — What Is It and What Can It Tell Us?
Authors: Rachel E. Sherman, Steven A. Anderson, Gerald J. Dal Pan, Gerry W. Gray, Thomas Gross, Nina L. Hunter, Lisa LaVange, Danica Marinac-Dabic, Peter W. Marks, Melissa A. Robb, Jeffrey Shuren, Robert Temple, Janet Woodcock, Lilly Q. Yue, Robert M. Califf
Journal: New England Journal of Medicine (2016)

The FDA is developing guidance on the use of “real-world evidence” — health care information from atypical sources, including electronic health records, billing databases, and product and disease registries — to assess the safety and effectiveness of drugs and devices.
Five minutes with . . . Lucy Obolensky
Authors: Abi Rimmer
Journal: BMJ (2016)

The GP talks expedition medicine, David Attenborough, and Planet Earth II 

“I was very lucky in that I got to go along to support David [Attenborough] on his trips, not that he really needed much support. I was there just in case. He was amazing, and I was so honoured to meet and work with someone who is so knowledgeable and passionate yet humble about what they do.

“When …
Phase I of weekly nab-paclitaxel in combination with weekly liposomal encapsulated doxorubicin as first-line treatment for HER2 negative metastatic breast cancer patients: preliminary results
Authors: A. Fabi, P. Malaguti, S. Vari, P. Papaldo, C. Nisticò, G. Ferretti, D. Giannarelli, F. Cognetti
Journal: Annals of Oncology (2015)
Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) As Frontline Therapy for Older Patients with Acute Lymphoblastic Leukemia (ALL): Interim Result of a Phase II Clinical Trial
Authors: Koji Sasaki, Elias J. Jabbour, Susan M. O'Brien, Farhad Ravandi, Deborah A Thomas, Guillermo Garcia-Manero, Naval Daver, Gautam Borthakur, Nitin Jain, Marina Konopleva, Nicholas J. Short, Naveen Pemmaraju, Yesid Alvarado, Jovitta Jacob, Rebecca Garris, Philip A Thompson, Jorge E. Cortes, Hagop M. Kantarjian
Journal: Blood (2016)
Pioglitazone-induced improvements in insulin sensitivity occur without concomitant changes in muscle mitochondrial function
Authors: Sudip Bajpeyi, Magdalena Pasarica, Kevin E. Conley, Bradley R. Newcomer, Sharon A. Jubrias, Cecilia Gamboa, Kori Murray, Olga Sereda, Lauren M. Sparks, Steven R. Smith
Journal: Metabolism (2016)
Quantification of docetaxel plasma concentrations using a novel nanoparticle-based immunoassay.
Authors: S. J. Salamone, H. Zhang, R. L. Harney, G. D. Lundell, D. J. Cline, H. Raiz, Y. Li, J. B. Courtney
Journal: Journal of Clinical Oncology (2011)

e11545 Background: Docetaxel is a commonly used antineoplastic agent of the taxoid family. The pharmacokinetic profile of docetaxel has up to 10-fold inter-patient variability in total clearance and up to 7-fold in total exposure (AUC). This variability may result in severe toxicities and poor outcomes. Docetaxel AUC was shown to be a significant predictor of time to progression (TTP) and severe adverse events in non-small cell lung cancer. A new nanoparticle-based docetaxel immunoassay provides a rapid, simple and cost-effective drug concentration measurement as compared to current chromatographic methods. Methods: Novel antibodies to docetaxel were covalently linked to nanoparticles to develop a prototype automated, homogenous immunoassay. The assay was applied to the Beckman Coulter AU400 clinical analyzer. Total imprecision and linearity of the assay were evaluated by testing normal human plasma pools spiked with different levels of docetaxel. Background was determined by measuring >200 normal human plasma samples. Results: Within a quantitation range of 50 to 1000ng/mL and using instrument auto-dilution, plasma levels of docetaxel can be measured up to 10,000ng/mL with only 2µl sample size. This test range covers clinically relevant drug concentrations and can be used to calculate the systemic exposure (AUC) of docetaxel. Time-to-first result was < 9min, and 400 samples per hour could be measured. The total imprecision of plasma pools spiked with docetaxel at four concentrations across the assay range was <6% CV and the assay was linear from 50 to 1000ng/mL. Background of the assay was found to be < 10 ng/mL. The assay cross-reactivity to docetaxel hydroxy-tertbutyl carbamate, the major metabolite of docetaxel, was 20%, and <1% for 10-deacetylbaccatin, a degradation product of docetaxel. These were shown to have no significant impact on the quantitation of docetaxel. Conclusions: This rapid immunoassay is suitable for routine measurement of plasma docetaxel concentrations with only 2ul sample size and within ten minutes and could provide a tool for optimization of docetaxel blood levels for pharmacokinetic-guided dosing.