tbuckley/cabot-search huggingface dataset:
Common PIK3CA Mutants and a Novel 3′ UTR Mutation Are Associated with Increased Sensitivity to Saracatinib
Authors: John J. Arcaroli, Kevin S. Quackenbush, Rebecca W. Powell, Todd M. Pitts, Anna Spreafico, Marileila Varella-Garcia, Lynne Bemis, Aik Choon Tan, Jaclyn M. Reinemann, Basel M. Touban, Arvind Dasari, S. Gail Eckhardt, Wells A. Messersmith
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K) and Src signaling pathways commonly occur in colorectal cancer. Mutations in the PIK3CA gene are associated with an increase in severity of disease and worse clinical outcomes. Elevated levels of Src have been identified in premalignant lesions and are suggested to play a central role in tumor progression. Because these pathways appear to enhance tumor growth and metastasis, molecularly targeted agents for both pathways are currently being evaluated in early-phase clinical trials. Experimental Design: We used colorectal cancer cell lines and a patient-derived explant model to investigate the efficacy of saracatinib. Mutations in the PIK3CA were evaluated to examine the association between mutations in the PIK3CA gene and sensitivity to saracatinib. Results: We have identified a subset of patients with a PIK3CA (exon 9 and 20) mutation with increased sensitivity to saracatinib. A novel 3′ untranslated region (UTR) mutation was also shown to be associated with increased sensitivity to saracatinib and have a reduced affinity for miR-520a and miR-525a. Importantly, we show that Src inhibition reduces the interaction between Src and p85, subsequently decreasing Akt-dependent signaling. Conclusion: These results indicate that a personalized approach in targeting Src in PIK3CA-mutant patients with colorectal cancers may prove effective in a subset of patients with this genetic alteration. Clin Cancer Res; 18(9); 2704–14. ©2012 AACR.
Optical Detection of Buccal Epithelial Nanoarchitectural Alterations in Patients Harboring Lung Cancer: Implications for Screening
Authors: Hemant K. Roy, Hariharan Subramanian, Dhwanil Damania, Thomas A. Hensing, William N. Rom, Harvey I. Pass, Daniel Ray, Jeremy D. Rogers, Andrej Bogojevic, Maitri Shah, Tomasz Kuzniar, Prabhakar Pradhan, Vadim Backman
Journal: Cancer Research (2010)

We have recently developed a novel optical technology, partial wave spectroscopic (PWS) microscopy, which is exquisitely sensitive to the nanoarchitectural manifestation of the genetic/epigenetic alterations of field carcinogenesis. Our approach was to screen for lung cancer by assessing the cheek cells based on emerging genetic/epigenetic data which suggests that the buccal epithelium is altered in lung field carcinogenesis. We performed PWS analysis from microscopically normal buccal epithelial brushings from smokers with and without lung cancer (n = 135). The PWS parameter, disorder strength of cell nanoarchitecture (L(d)), was markedly (>50%) elevated in patients harboring lung cancer compared with neoplasia-free smokers. The performance characteristic was excellent with an area under the receiver operator characteristic curve of >0.80 and was equivalent for both disease stage (early versus late) and histologies (small cell versus non-small cell lung cancers). An independent data set validated the findings with only a minimal degradation of performance characteristics. Our results offer proof of concept that buccal PWS may potentially herald a minimally intrusive prescreening test that could be integral to the success of lung cancer population screening programs.
The Immunoglobulin (Ig)α and Igβ Cytoplasmic Domains Are Independently Sufficient to Signal B Cell Maturation and Activation in Transgenic Mice
Authors: Yih-Miin Teh, Michael S. Neuberger
Journal: The Journal of Experimental Medicine (1997)

The B cell antigen receptor, composed of membrane immunoglobulin (Ig) sheathed by the Igα/Igβ heterodimer plays a critical role in mediating B cell development and responses to antigen. The cytoplasmic tails of Igα and Igβ differ substantially but have been well conserved in evolution. Transfection experiments have revealed that, while these tails share an esssential tyrosine-based activation motif (ITAM), they perform differently in some but not all assays and have been proposed to recruit distinct downstream effectors. We have created transgenic mouse lines expressing chimeric receptors comprising an IgM fused to the cytoplasmic domain of each of the sheath polypeptides. IgM/α and IgM/β chimeras (but not an IgM/β with mutant ITAM) are each independently sufficient to mediate allelic exclusion, rescue B cell development in gene-targeted Igμ− mice that lack endogenous antigen receptors, as well as signal for B7 upregulation. While the (IgM/α) × (IgM/β) double-transgenic mouse revealed somewhat more efficient allelic exclusion, our data indicate that each of the sheath polypeptides is sufficient to mediate many of the essential functions of the B cell antigen receptor, even if the combination gives optimal activity.
Combination therapy with maintenance budesonide and formoterol in COPD
Authors: A.R.L. Medford
Journal: European Respiratory Journal (2004)

To the Editors: 

Calverley et al. 1 provide further evidence for combination therapy with inhaled corticosteroids and long-acting β-agonists in severe chronic obstructive pulmonary disease (COPD) as maintenance therapy. In addition, a previous study, also confirming …
Carboplatin/Paclitaxel or Carboplatin/Vinorelbine Followed by Accelerated Hyperfractionated Conformal Radiation Therapy: Report of a Prospective Phase I Dose Escalation Trial From the Carolina Conformal Therapy Consortium
Authors: Lawrence B. Marks, Jennifer Garst, Mark A. Socinski, Gregory Sibley, A. William Blackstock, James E. Herndon, Sumin Zhou, Timothy Shafman, Andrea Tisch, Robert Clough, Xiaoli Yu, Andrew Turrisi, Mitchell Anscher, Jeffrey Crawford, Julian Rosenman
Journal: Journal of Clinical Oncology (2004)

Purpose To prospectively determine the maximum-tolerated dose of accelerated hyperfractionated conformal radiotherapy (RT; 1.6 Gy bid) for unresectable locally advanced lung cancer (IIB to IIIA/B) following induction carboplatin/paclitaxel (C/T) or carboplatin/vinorelbine (C/N). Methods Induction chemotherapy, C/T or C/N, was followed by escalating doses of conformally-planned RT (73.6 to 86.4 Gy in 6.4-Gy increments). Concurrent boost methods delivered 1.6 and 1.25 Gy bid to the gross and clinical target volumes, respectively. Results Between November 1997 and February 2002, 44 patients were enrolled (median age, 59 years; 59% male; stage III, 98%; median tumor size, 4 cm). Thirty-nine patients completed induction chemotherapy: 19 had a partial response, seven progressed, 15 had no response, and three were not assessable. Chemotherapy-associated toxicities were similar in the two chemotherapy groups. The incidence of grade ≥ 3 RT-induced toxicity was 1/13, 2/14, and 4/12 at 73.6, 80, and 86.4 Gy, respectively, thus defining the maximum tolerated dose at ≈80 Gy. Toxicities were in both lung and esophagus and were similar in the two chemotherapy arms. With a median followup of 34 months in the survivors, the actuarial 2-year survival was 47%, the median survival was 18 months. Fifteen patients had tumor relapse: 5 local failures in the high-dose volume, 2 regional failures outside of the high-dose volume, and 8 distant metastases. Conclusion High-dose conformal twice-daily radiation therapy to approximately 80 Gy appears tolerable in well-selected patients with unresectable lung cancer following either C/T or C/N. Dose-limiting toxicities are mainly pulmonary and esophageal.
Can Medical Repatriation Be Ethical? Establishing Best Practices
Authors: Mark Kuczewski
Journal: The American Journal of Bioethics (2012)

Hospitals in the United States have been engaging in the practice of returning immigrant patients, usually undocumented immigrant patients, to their country of origin when the patient has long-term medical needs for which no reimbursement is available. I argue that for such an action to be ethical, it must be done in accordance with the mission and values of hospitals. I describe three standards that an individual instance of repatriation must meet to be ethical: (1) patient best interests, (2) medical due diligence, and (3) informed consent. I argue that these should form the basis for best practices in regard to medical repatriation for all hospitals in the United States.
Standard Chemotherapy With or Without High-Dose Chemotherapy for Aggressive Non-Hodgkin's Lymphoma: Randomized Phase III EORTC Study
Authors: H. C. Kluin-Nelemans, V. Zagonel, A. Anastasopoulou, D. Bron, K. J. Roozendaal, E. M. Noordijk, H. Musson, I. Teodorovic, B. Maes, A. Carbone, P. Carde, J. Thomas
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: The long-term outcome for patients with aggressive non-Hodgkin's lymphoma (NHL) is poor. Consequently, the European Organization for Research and Treatment of Cancer Lymphoma Group designed a prospective randomized trial to investigate whether high-dose chemotherapy plus autologous bone marrow transplantation (ABMT) after standard combination chemotherapy improves long-term survival. Methods: Patients aged 15–65 years with aggressive NHL received three cycles of CHVmP/BV polychemotherapy (i.e., a combination of cyclophosphamide, doxorubicin, teniposide, and prednisone, with bleomycin and vincristine added at mid-cycle). After these three cycles, patients with a complete or partial remission and at that time no lymphoma involvement in the bone marrow were randomly assigned to the ABMT arm (a further three cycles of CHVmP/BV followed by BEAC [i.e., a combination of carmustine, etoposide, cytarabine, and cyclophosphamide] chemotherapy and ABMT) or to the control arm (five more cycles of CHVmP/BV). All statistical tests are two-sided. Results: From December 1990 through October 1998, 311 patients (median age = 44 years) were registered and received the first three cycles of CHVmP/BV, and 194 patients were randomly assigned to the treatment arms. Approximately 70% (140 patients) of these patients were of low or low–intermediate International Prognostic Index (IPI) risk. After a median follow-up of 53 months, an intention-to-treat analysis showed a time to disease progression and overall survival at 5 years of 61% (95% confidence interval [CI] = 51% to 72%) and 68% (95% CI = 57% to 79%), respectively, for the ABMT arm and 56% (95% CI = 45% to 67%) and 77% (95% CI = 67% to 86%), respectively, for the control arm. Differences between arms were not statistically significant. A subset analysis on IPI risk groups, although too small for reliable statistical analysis, yielded similar results. Conclusions: Standard combination therapies remain the best choice for most patients with aggressive NHL. We recommend that patients with IPI low or low–intermediate risk not be subjected to high-dose chemotherapy and ABMT as a first-line therapy.
Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. VII. Idiotype-specific suppression of plaque-forming cell responses.
Authors: D H Sherr, S T Ju, J Z Weinberger, B Benacerraf, M E Dorf
Journal: The Journal of Experimental Medicine (1981)

The ability of suppressor cells induced by the intravenous administration of 4-hydro-3-nitrophenyl acetyl (NP)-modified syngeneic cells to reduce an idiotypic B cell response was studied in both an in vivo and an in vitro system. Idiotype-positive B cells were assayed by the ability of guinea pig anti-idiotypic antiserum to specifically inhibit idiotype-positive plaque formation. It was found that up to 57% of the PFC response in vivo and 100% of the PFC response in vitro was inhibitable with antiidiotypic antiserum. The expression of these idiotype-positive B cells could be suppressed by the transfer of spleen cells form mice treated 7 d previously with NP coupled syngeneic cels. T cells are both required and sufficient for the transfer of idiotype specific suppression. The induction of these idiotype-specific T suppressor cells directly with antigen suggests that recognition of unique determinants on cell surfaces is important for regulation of lymphoid cell interactions. The role of idiotype-specific suppressor cells in the network of lymphoid interactions is discussed.
United Healthcare, Five Oncology Practices Try Bundled Payments
Authors: M. Goozner
Journal: JNCI Journal of the National Cancer Institute (2010)

The nation’s largest health insurer recently launched an experimental cancer care payment program that disconnects physician reimbursement from drug sales and encourages oncologists to follow standardized regimens. The goal is not just to reduce costs — although United Healthcare (UHC) does hope that the pilot program will save money by reducing the overuse of expensive oncology drugs. The architects of the program also hope that the bundled, or “episode-of-care,” payment for a standardized treatment will improve outcomes and quality of care. An episode of care under the plan, which was announced last October, is the treatment used for a specifi c stage of a certain cancer. UHC’s payment is based on actual drug costs plus a case management fee. The bundled payment does not include offi ce visits, drug administration costs, radiation treatments, or lab tests, which will still be reimbursed on a fee-for-service basis. The company expects that bundled payments and standardized regimens will reduce errors, remove incentives for deploying ineffective interventions, and ultimately generate information about which regimens worked best, according to Lee Newcomer, M.D., director of oncology at UHC. Five community
A randomized study comparing a high and a standard dose of cisplatin in combination with etoposide in the treatment of advanced non-small-cell lung carcinoma.
Authors: J Klastersky, J P Sculier, P Ravez, P Libert, J Michel, G Vandermoten, P Rocmans, Y Bonduelle, M Mairesse, T Michiels
Journal: Journal of Clinical Oncology (1986)

We conducted a randomized trial comparing a high (120 mg/m2 day 1) v a standard (60 mg/m2 day 1) dose of cisplatin in combination with etoposide (120 mg/m2 days 3, 5, and 7) in advanced non-small-cell lung carcinoma (NSCLC). Two hundred forty-one patients were evaluable for survival and 207 for response. We obtained a 25% objective response rate in the standard-dose arm and 29% in the high-dose arm; this difference was not statistically significant. There was no significant improvement in the overall survival or survival of responders with the high-dose regimen. However, toxicity (mainly myelosuppression) was significantly increased in the patients receiving the higher dose of cisplatin. An analysis of prognostic factors showed that disease progression, loss of body weight, performance status, and prior therapy were predictive parameters of survival.
Retrospective Analysis of Topoisomerase IIa Amplifications and Deletions As Predictive Markers in Primary Breast Cancer Patients Randomly Assigned to Cyclophosphamide, Methotrexate, and Fluorouracil or Cyclophosphamide, Epirubicin, and Fluorouracil: Danish Breast Cancer Cooperative Group
Authors: Ann S. Knoop, Helle Knudsen, Eva Balslev, Birgitte B. Rasmussen, Jens Overgaard, Kirsten V. Nielsen, Andreas Schonau, Katrín Gunnarsdóttir, Karen E. Olsen, Henning Mouridsen, Bent Ejlertsen
Journal: Journal of Clinical Oncology (2005)

The aim of the study was to evaluate the predictive value of HER2 and topoisomerase IIalpha gene (TOP2A) for the efficacy of epirubicin in the adjuvant setting of breast cancer patients.In the Danish Breast Cancer Cooperative Group trial 89D, 980 pre- and postmenopausal primary patients were randomly allocated to either CMF (cyclophosphamide, methotrexate, and fluorouracil; n = 500) or CEF (cyclophosphamide, epirubicin, and fluorouracil; n = 480) times 9, between January 1990 and November 1999. Tumor tissue was retrospectively identified from 805 patients and was analyzed for HER2-positivity and for TOP2A-amplifications and deletions.HER2-positivity was found in 33% of the 805 investigated tumors and was not a predictive marker for epirubicin sensitivity. TOP2A changes were identified in 23% of the 773 investigated tumors: 12% had TOP2A amplifications and 11% had TOP2A deletions. We found that patients with TOP2A amplification had an increased recurrence-free (RFS; hazard ratio [HR], 0.43; 95% CI, 0.24 to 0.78) and overall survival (OS; HR, 0.57; 95% CI, 0.29 to 1.13), respectively if treated with CEF compared with CMF, and that patients with TOP2A deletions had an almost identical hazard ratio (RFS: HR, 0.63; 95% CI, 0.36 to 1.11; OS: HR, 0.56; 95% CI, 0.30 to 1.04). This is in contrast to patients with a normal TOP2A genotype for whom similar outcome was observed in both treatment arms (RFS: HR, 0.90; 95% CI, 0.70 to 1.17; OS: HR, 0.88; 95% CI, 0.66 to 1.17).TOP2A amplification-and possibly deletion-seems to be predictive markers for the effect of adjuvant epirubicin containing therapy in primary breast cancer, but a final conclusion has to await a confirmative study or a meta-analysis.
Blockade of Nucleoside Transport Is Required for Delivery of Intraarterial Adenosine Into the Interstitium
Authors: Alfredo Gamboa, Andrew C. Ertl, Fernando Costa, Ginnie Farley, M. Lisa Manier, David L. Hachey, André Diedrich, Italo Biaggioni
Journal: Circulation (2003)

Adenosine, a known mediator of preconditioning, has been infused into the coronary circulation to induce therapeutic preconditioning, eg, in preparation for angioplasty. However, results have been disappointing. We tested the hypothesis that endothelial nucleoside transporter acts as a barrier impeding the delivery of intravascular adenosine into the underlying myocardium and that this can be overcome with dipyridamole, a nucleoside transporter blocker.We infused saline or adenosine (0.125 and 0.5 mg/min) into the brachial artery while monitoring forearm blood flow (FBF) and interstitial adenosine levels with microdialysis probes implanted in the flexor digitorum superficialis of the forearm in 7 healthy volunteers during intravenous administration of saline or dipyridamole (loading dose, 0.142 mg/kg per min for 5 minutes followed by 0.004 mg/kg per min). Adenosine produced near maximal forearm vasodilation, increasing FBF from 4.0+/-0.7 to 10.4+/-1.9 and 13.1+/-1.6 mL/100 mL per min for the low and high doses, respectively, but did not increase muscle dialysate adenosine concentration (from 88+/-21 to 65+/-23 and 85+/-26 nmol/L). Intravenous dipyridamole enhanced resting muscle dialysate adenosine (from 77+/-25 to 147+/-50 nmol/L), adenosine-induced increase in FBF (from 4.1+/-0.8 to 12.6+/-3 and 15.1+/-3 mL/100 mL per min for the low and high dose, respectively), and the delivery of adenosine into the interstitium (to 290+/-80 and 299+/-143 nmol/L for the low and high dose, respectively, P=0.04).Intravascular adenosine is likely ineffective in inducing myocardial preconditioning because of poor interstitial delivery. This can be overcome by blocking the nucleoside transporter with dipyridamole.
Case volume and mortality in haematological patients with acute respiratory failure
Authors: L. Lecuyer, S. Chevret, B. Guidet, P. Aegerter, P. Martel, B. Schlemmer, É. Azoulay
Journal: European Respiratory Journal (2008)

High case volume is associated with improved survival in medical and surgical conditions. The present study sought to determine whether intensive care unit (ICU) case volume was associated with survival of critically ill patients with haematological malignancies and acute respiratory failure (ARF). A regional database containing data from 1,753 haematological patients with ARF admitted to 28 medical ICUs from 1997 to 2004 was used. Multivariate analysis using mixed models was performed to adjust for severity of illness and other confounding factors, including a propensity score that incorporates differences between ICUs with different case volumes. The three case volume tertiles were: low volume (&lt;12 admissions per year), intermediate volume (12–30 admissions per year), and high volume (&gt;30 admissions per year). In univariate analyses, ICU case volume was not associated with ICU mortality. After adjusting for prognostic factors for ICU mortality and the propensity score, patients in high-volume ICUs had lower mortality than other patients. A case volume increase of one admission per year led to a significant mortality reduction with an odds ratio of 0.98 (95% confidence limits 0.97–0.99). Mortality was independently associated with severity of organ dysfunction. In intensive care units admitting larger numbers of critically ill haematological patients with acute respiratory failure, mortality was lower than in other intensive care units. The mechanisms of the relationship between volume and outcome among haematological patients with acute respiratory deserve additional studies.
Catechol<i>O</i>-Methyltransferase Polymorphism and Eye Tracking in Schizophrenia: A Preliminary Report
Authors: Gunvant K. Thaker, Ikwunga Wonodi, Matthew T. Avila, L. Elliot Hong, O. Colin Stine
Journal: American Journal of Psychiatry (2004)

This study examined associations between functional polymorphism (Val(108/158) Met) in the catechol O-methyltransferase (COMT) gene and eye tracking measures in schizophrenia.Predictive pursuit and closed-loop gains of 62 patients with schizophrenia and 53 healthy comparison subjects with Val-Val, Val-Met, and Met-Met genotypes were compared.There was a significant diagnosis-by-genotype interaction: patients with the Met-Met genotype showed poor predictive pursuit. The Met-Met genotype in healthy subjects was associated with significantly higher predictive pursuit gain values than the Val-Val genotype in healthy subjects. The COMT genotype explained about 10% of the variance in each group's predictive pursuit performance.These preliminary data suggest that the COMT gene is associated with predictive eye tracking performance in healthy subjects. Predictive pursuit abnormality in schizophrenia is not attributable to the Val allele. These findings suggest a complex interaction with other etiological factors (e.g., another gene), and/or with prefrontal cortical dopaminergic activity.
MicroRNAs 221 and 222 Bypass Quiescence and Compromise Cell Survival
Authors: Ricardo Medina, Sayyed K. Zaidi, Chang-Gong Liu, Janet L. Stein, Andre J. vanWijnen, Carlo M. Croce, Gary S. Stein
Journal: Cancer Research (2008)

Abstract MicroRNAs (miRNA) have tumor suppressive and oncogenic potential in human cancer, but whether and how miRNAs control cell cycle progression is not understood. To address this question, we carried out a comprehensive analysis of miRNA expression during serum stimulation of quiescent human cells. Time course analyses revealed that four miRNAs are up-regulated and &amp;gt;100 miRNAs are down-regulated, as cells progress beyond the G1-S phase transition. We analyzed the function of two up-regulated miRNAs (miR-221 and miR-222) that are both predicted to target the cell growth suppressive cyclin-dependent kinase inhibitors p27 and p57. Our results show that miR-221 and miR-222 both directly target the 3′ untranslated regions of p27 and p57 mRNAs to reduce reporter gene expression, as well as diminish p27 and p57 protein levels. Functional studies show that miR-221 and miR-222 prevent quiescence when elevated during growth factor deprivation and induce precocious S-phase entry, thereby triggering cell death. Thus, the physiologic up-regulation of miR-221 and miR-222 is tightly linked to a cell cycle checkpoint that ensures cell survival by coordinating competency for initiation of S phase with growth factor signaling pathways that stimulate cell proliferation. [Cancer Res 2008;68(8):2773–80]