tbuckley/cabot-search huggingface dataset:
Direct inhibition of the Notch transactivation complex with stapled peptides in T-ALL
Authors: Raymond Moellering, Melanie Cornejo, Jennifer Rocnik, Cristina DelBianco, Steven Blacklow, Gary Gilliland, Gregory Verdine, James Bradner
Journal: Cancer Research (2008)

2547  The Notch signaling pathway is a highly conserved regulator of diverse biological processes including cellular differention, proliferation and death. Activation of Notch1 receptors results in cleavage and release of an intracellular domain (ICN1). Following translocation to the nucleus, ICN1 forms a ternary complex with the transcriptional repressor CSL bound to cognate DNA. This event triggers a repressor-to-activator switch, as an interfacial groove recruits the Mastermind-Like (MAML1) co-activator protein. Activating mutations in NOTCH1 are found in more than 50% of T-Cell Acute Lymphoblastic Leukemia (T-ALL) cases, promoting protein stability and establishing a direct link to disease pathogenesis. Despite efforts to inhibit the pathway with inhibitors of gamma-secretase, intervention at this step appears to impart growth inhibitory effects in only a subset of T-ALL cell lines, a result that has recently been explained in part by mutations in ubiquitin-ligases affecting protein turnover. Therefore, direct inhibitors of ICN1 function are highly desirable. Drawing upon insights afforded by the resolved crystal structure of the DNA-bound transactivation complex, we have designed synthetically constrained peptides predicted to disrupt complex assembly. Specifically, we have synthesized a series of hydrocarbon stapled alpha-helical peptides based on short stretches of the MAML protein (SAHMs) predicted to engage the composite ICN1:CSL interface. Direct, high-affinity binding to purified components of the Notch complex has been confirmed using surface plasmon resonance. Intracellular association with ICN1 and CSL has been established using bidirectional affinity chromatography and immunoblotting. SAHM1 induces a dose-dependent knockdown of endogenous Notch1 target genes including HES1, HEY1 and cMYC in T-ALL cell lines. Remarkably, inhibition of Notch signaling by SAHM1 induces apoptosis and selective cytotoxicity at 48 hours in a panel of T-ALL cell lines with known mutations in NOTCH1. Supporting an on-target mechanism of action, we have prepared a mutant analogue of SAHM1 containing a two-residue rearrangement (SAHM1D). SAHM1D possesses reduced binding affinity for the Notch complex by SPR and ligand affinity chromatography. Despite comparable intracellular access, SAHM1D lacks both transcriptional and cytotoxic effects on cultured T-ALL cell lines in vitro. Efficacy studies have also been performed in vivo using a novel murine model of T-ALL harboring clinically relevant mutations in NOTCH1. Remarkably, ex-vivo treatment with a single dose of SAHM1 prior to inoculation significantly reduces spleen weight and extends life when compared to vehicle alone. In summary, we report here the design, biochemical characterization and translational rationale supporting the first direct inhibitor of the Notch transactivation complex in T-ALL.
Surgical “salvage” therapy for intrathoracic chemorefractory metastases from non-seminomatous germ cell cancer of testicular origin: An institutional retrospective review
Authors: K. A. Kesler, J. L. Wilson, J. A. Cosgrove, A. Messiha, J. A. Brooks, T. R. Clouse, N. S. Fineberg, L. H. Einhorn
Journal: Journal of Clinical Oncology (2004)

4528 Background: Cisplatin-based chemotherapy (CTx) followed by surgical extirpation of residual disease represents the usual sequence of curative therapy for metastatic non-seminomatous germ cell cancer of testicular origin (NSGCT). Occasionally residual disease is chemorefractory in the form of either persistent NSGCT or degeneration into non-germ cell cancer (NGCC). This retrospective review evaluated patients (pts) undergoing “salvage” surgery to remove chemorefractory cancer metastatic to the thorax. Methods: From 1981–2001, 438 pts with NSGCT had surgery to remove residual intrathoracic disease after CTx at Indiana University Hospital. A subset of 134 pts who underwent 186 thoracic surgical procedures to remove chemorefractory cancer is the basis of this review. Eighty-one (60.4%) pts underwent second line CTx prior to surgery and 72 (53.7%) had elevated serum tumor markers at the time of surgery. The mean age was 27 yrs. Eighty-four pts had removal of pulmonary metastases, 74 mediastinal metastases, and 26 had removal of both pulmonary and mediastinal metastases. Surgical pathology demonstrated 84 pts with persistent NSGCT, 38 with NGCC, and 12 had both malignant pathologic categories. Sixty-eight pts with persistent NSGCT received CTx after surgery. Results: There were 4 (2.1%) operative deaths. The median survival was 67 months in operative survivors with 55 (41%) pts alive and well after a mean follow-up of 49 months. Twenty-seven variables were analyzed using Cox regression. Of these, older age (p<0.01) and pulmonary (vs. mediastinal) metastases (p=0.01) were significantly predictive of poorer long-term survival. Log rank analysis additionally identified preoperative BHCG≥1,000ng/ml (p<0.04) and ≥ 4 metastases (p<0.01) as negative predictors for survival. Conclusions: Aggressive “salvage” surgical therapy to remove chemorefractory cancer metastatic to the thorax can result in long-term survival. We have identified variables which appear to influence survival for this subset of NSGCT pts. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Risk of Bladder Tumors Among Benzidine Workers and Their Serum Properdin Levels
Authors: A. Wesley Horton, Eula L. Bingham
Journal: JNCI Journal of the National Cancer Institute (1977)

Serum properdin levels were determined for 21 benzidine operators at 6-month intervals for 2 years after termination of exposure to this carcinogen. Of this group, 7 developed bladder cancers within a 4-month period prior to the initial assay, and all 7 showed properdin levels below the median for the group as a whole. Two of the 3 workers who had had a brief exposure previously to beta-naphthylamine developed benign bladder tumors but had no malignant neoplasms up to 13 years later. The properdin assays of these 3 men remained consistently at or above the median values. No man developed a bladder tumor who was exposed less than 6 years to benzidine, even though 2 of these men showed low properdin levels. Of the 4 whose properdin levels were initially above the median but dropped below in subsequent assays, 3 developed bladder cancers 0.5, 4, and 9 years later. Only 1 man whose properdin level remained high in 1958-59 developed a bladder cancer 7 years later, and his immunologic picture may have been complicated by recovery from a larynx tumor in 1954. Recurrence of bladder tumors among the original 9 cases has occurred only among the 5 whose properdin levels remained below the median. The 1 whose ranking fell most dramatically (from 13 to 19) has had 13 recurrences in 13 years.
Interaction of EGFR and IGF-1R signals to modulate the anti-proliferative and biochemical responses of head and neck squamous cancer (HNSCC) cells to EGFR inhibitors
Authors: C. Y. Thomas, M. Jameson, A. Beckler
Journal: Journal of Clinical Oncology (2007)

6045 Background: Epidermal growth factor receptor (EGFR) inhibitors improve the efficacy of radiotherapy for HNSCC and as single-agents induce tumor responses or stabilization in a minority of patients. The molecular mechanisms that dictate the spectrum of observed responses are not well understood. Methods/Results: Exposure of the HNSCC lines SCC-9 and SCC-25 in vitro to the EGFR inhibitors PD158780, lapitinib, or cetuximab suppressed cell proliferation and cell cycle progression into S-phase. Immunoblots showed that PD158780 inhibited autocrine activation of the EGFR, reduced phosphorylation of the downstream signaling proteins AKT and Erk, and affected cell cycle regulatory molecules (reduced Rb phosphorylation, decreased cyclin D1 levels, and induced p27kip1). However, stimulation of the cells with an insulin-like growth factor-1 (IGF-1) analog produced a dose-dependent resistance to the anti-proliferative effects of the EGFR inhibitors. The resistance of SCC-25 cells correlated with IGF-1-induced maintenance of AKT and Rb phosphorylation and cyclin D1 expression. Conversely, the EGFRs also acted downstream of the activated IGF-1 receptors as concomitant EGFR inhibition dampened the proliferative response of the cells, reduced Erk phosphorylation and increased p27kip1 expression. Experiments with the metalloproteinase inhibitor TAPI-2 suggested that the IGF-1 activates the EGFRs through proteolytic cleavage of precursor forms of EGFR ligands. Conclusions: The proliferative and biochemical responses of HNSCC cells to EGFR inhibitors are influenced by cross-talk between the EGFR and IGF-1 receptors. One implication of this work is that the clinical response of HNSCCs to EGFR inhibitors may depend on the relative contribution of autocrine EGFR signaling to activation of specific downstream growth factor signaling pathways, whether or not these receptors are the primary or secondary source of these signals. No significant financial relationships to disclose.
Are high mastectomy rates associated with unwanted variation in other aspects of breast cancer treatment? An overview of practice patterns in Alberta, Canada in 2009-2010.
Authors: Sarah Morrissey, May Lynn Quan
Journal: Journal of Clinical Oncology (2013)

102 Background: The Canadian Partnership Against Cancer recently released a system performance report identifying large variation in breast cancer treatment across Canada. Contrary to provincial guidelines, Alberta had higher than average rates of mastectomy (56%); however, factors driving this variation remain unknown. We sought to (1) determine if practice patterns of primary breast surgery and adjuvant therapy adhered to guidelines and (2) to describe influencing factors on treatment practices between the two major cancer programs in Alberta to inform future knowledge translation strategies for guideline implementation. Methods: All patients diagnosed with breast cancer (ICD 9-174) between January 2009 and December 2010 were identified from the Alberta Cancer Registry. Demographic, surgical, treatment, and pathology data were abstracted from the electronic health record. Descriptive statistics and t-testing comparing mastectomy rates, axillary surgery and adjuvant therapy between the two major cancer programs were performed. Results: There were 2,817 surgeries for early breast cancer in the study cohort between 2009 and 2010. Conclusions: Practice patterns identify variance from current guidelines. Mastectomy rates are influenced by surgeon volume and tumor size. Management of positive SN and adjuvant therapy is variable and may reflect under treatment. Further investigation of drivers for mastectomy and adjuvant therapy are necessary. [Table: see text]
Effectiveness of carboplatin, etoposide, and bleomycin combination chemotherapy in good-prognosis metastatic testicular nonseminomatous germ cell tumors.
Authors: A Horwich, D P Dearnaley, J Nicholls, G Jay, M Mason, S Harland, M J Peckham, W F Hendry
Journal: Journal of Clinical Oncology (1991)

The combination of carboplatin, etoposide, and bleomycin (CEB) was evaluated as initial chemotherapy in 76 patients with good-prognosis metastatic nonseminomatous germ cell tumors (NSGCT) between 1984 and 1988. The classification of eligible patients included Royal Marsden Hospital (RMH) stages IM, IIA, IIB, IIC, IIIA, IIIB, IV0ABCL1, and IV0ABL2. Four courses of combination chemotherapy were administered in a 21-day cycle, and surgical excision of residual mass was performed in 27 cases (23 laparotomies and four thoracotomies). At the time of analysis, median follow-up was 24 months from start of chemotherapy (range, 6 to 54 months). The 2-year cause-specific survival probability was 98.5%, the single cause-related mortality being caused by bleomycin pneumonitis. Five patients failed CEB chemotherapy, but all have been successfully salvaged with a combination of surgery and intensive chemotherapy, follow-up from completion of all treatment being 35 to 44 months. The toxicity of CEB included bone marrow suppression and alopecia in all patients but no significant neurotoxicity or ototoxicity, and minimal renal toxicity. Only four (5%) patients had a decrease in the glomerular filtration rate greater than 15%. In 51% of patients, the hemoglobin fell below 10 g/dL. The WBC count nadir was less than 1,500/microL in 11% of treatment cycles and in 16% the platelet nadir fell below 50,000/microL. Decreases in the WBC and platelet counts were of very brief duration. Only one of 310 CEB cycles was complicated by neutropenic sepsis, and there were no episodes of thrombocytopenic purpura or bleeding. We conclude that the CEB combination represents an effective alternative to cisplatin-based chemotherapy in good-prognosis NSGCT and that the replacement of cisplatin by carboplatin leads to reduced toxicity.
Retention of an Ancestral Polymorphism in the Mbuna Species Flock (Teleostei: Cichlidae) of Lake Malawi
Authors: Moran, P, Kornfield, I
Journal: Molecular Biology and Evolution (1993)

Molecular genetic variation was examined within and among species of the rock­ dwelling cichlid fishes (mbuna) of Lake Malawi. Phylogenetic relationships among mbuna mitochondrial DNA (mtDNA) haplotypes were estimated by using restric­ tion-fragment-length polymorphisms. The distribution of these lineages among mbuna species is of particular significance for phylogenetic systematic study of this fauna. Some species were found to-he polymorphic for divergent haplotypes that substantially predate their isolation from sister taxa. Repeated speciation events among numerous closely related taxa appear to have been so recent that mtDNA lineage sorting among species is incomplete. Thus, the mtDNA gene tree is not congruent with the putative species tree. These results indicate that analysis of mtDNA alone will not be sufficient for resolution of phylogenetic relationships in the mbuna. Clarification of these relationships will require examination ofmultiple nuclear loci, because many of these new markers are also likely to retain ancestral polymorphisms.
Abstract 16824: Even Standard Dose of Furosemide is Associated with Chronic Kidney Injury in Patients with Chronic Heart Failure
Authors: Takumi Kondo, Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Takashi Naito, Tadao Fujimoto, Kentaro Ozu, Kaoruko Sengoku, Hironori Yamamoto, Tsutomu Kawai, Satoshi Takahashi, Masatake Fukunami
Journal: Circulation (2012)

Background : High dose of loop diuretics has been associated with poor outcome in heart failure patients. However, it remains to be fully clarified whether even standard dose of diuretics would be ...
Can I Eat Yet?
Authors: Armen Yerevanian
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Prospective Evaluation of Two Multi-Gene Assays in Node-Negative, Estrogen Receptor-Positive (Er+) Breast Cancer Patients to Aid Adjuvant Clinical Decision Making in a Community-Based Study
Authors: E. Martinez de Dueñas, A. Lluch-Hernandez, A. Llombart, A. Rodriguez-Lescure, D. Salas, J. Miranda Garcia
Journal: Annals of Oncology (2014)
Elevation of cerebrospinal fluid catecholamine metabolites in patients with intracranial tumors of neuroectodermal origin.
Authors: B Bostrom, B L Mirkin
Journal: Journal of Clinical Oncology (1987)

The concentrations of homovanillic acid (HVA), hydroxymethoxyphenylethyleneglycol (HMPG), and vanillylmandelic acid (VMA) were determined in lumbar cerebrospinal fluid (CSF) specimens. The study population consisted of the following groups: control subjects with malignancies of nonneuroectodermal origin (mostly leukemia in remission), neuroblastoma (extracranial and intracranial or cranial metastases), brain tumors (neuroectodermal and glial), and retinoblastoma. A significant increase in the CSF concentration of HVA was observed in patients with brain tumors (neuroectodermal), neuroblastoma (intracranial or cranial metastases), and retinoblastoma when compared with age-matched controls. In contrast, HMPG and VMA concentrations did not differ from controls except in patients with neuroblastoma (intracranial or cranial metastases) and brain tumors (neuroectodermal) who had significant elevations in HMPG and VMA, respectively. An inverse correlation was noted between the CSF concentration of HVA and clinical response to therapy. Nonresponding patients exhibited increases in HVA when compared with pretreatment values. These data suggest that the quantitative determination of catecholamine metabolites in lumbar CSF is an effective method for diagnosing intracranial tumors of neuroectodermal origin and assessing their response to therapy.
Radiation pneumonitis (RP) in lung cancer patients treated with chemotherapy (CT) and thoracic radiation (TR): Retrospective analyses of patients treated at a comprehensive cancer center
Authors: P. Vishnu, S. Srinivasan, L. Heilbrun, R. Venkataramanamoorthy, A. Wozniak, A. Soubani, S. M. Gadgeel
Journal: Journal of Clinical Oncology (2007)

19642 Background: Combined CT and TR is the current standard for locally advanced non-small cell lung cancer (NSCLC) and SCLC. Severe RP, an important adverse effect of TR, is reported in clinical trials to occur in 10% of patients receiving CT and TR. The rate in routine care may be higher as patients are not selected based on lung function. We conducted a retrospective study to assess the incidence of RP in lung cancer patients treated with CT and TR. Methods: Retrospective identification of patients who underwent combined modality therapy (concurrent or sequential CT and TR) for lung cancer (NSCLC &amp; SCLC) at our cancer center between January 2001 and December 2004. Demographic features, RP incidence and grade (RTOG criteria), hospitalization rate and overall survival (OS) were assessed. Results: 51 patients who met the selection criteria were analyzed. The demographic features were - males 61%; Caucasians - 53%; African Americans - 39%; history of pulmonary disorder - 45%; NSCLC - 82%; CT - 62% received Cisplatin/Etoposide, while 24% received Carboplatin/Paclitaxel; 92% received concurrent CT and TR. The median dose of TR was 5940 cGy. 20 patients (39%) developed RP; 13 (25%) had grade = 3 RP. Median time to development of RP was 4.4 months. Rate of RP in females and males was 50% vs. 32% (p=0.25). Rate of RP in patients with pulmonary disorder at baseline was 52% vs. 29% in others (p=0.15). 1 year hospitalization rate was 75% and 42% in RP and non-RP patients (p=0.025). For all 51 patients, the median overall survival (OS) was 16.4 months (95% CI 11.8 - 23.3). Length of OS did not differ significantly (p = 0.36) between the 20 patients who had RP vs. the 31 who had no RP (median OS: 22.2 vs. 14.5 months, respectively). Conclusions: The RP rate in these 51 lung cancer patients treated off- protocol with CT and TR is higher than that reported in clinical trials. Despite higher morbidity in patients with RP (i.e., increased hospitalization), survival duration did not differ significantly based on RP status. No significant financial relationships to disclose.
Disparities in Diabetic Retinopathy Screening Rates Within Minority Populations: Differences in Reported Screening Rates Among African American and Hispanic Patients
Authors: Yang Lu, Lilian Serpas, Pauline Genter, Christina Mehranbod, David Campa, Eli Ipp
Journal: Diabetes Care (2015)

Diabetic retinopathy (DR) screening is essential for early detection and treatment of diabetes-related visual impairment and blindness. Yet, it is commonly underutilized among low-income minority patients (1,2). To examine perceived barriers to DR screening in these vulnerable populations, we collected survey data from 101 patients with diabetes, including 71 Hispanics and 27 African Americans (AAs), at a large safety-net clinic in South Los Angeles.

Patients surveyed demonstrated typical characteristics for a safety-net population. Among patients surveyed, 50% reported <$10,000 in annual household income, 56% were unemployed, and 33% had a high school diploma/GED or above.

The survey revealed that most patients were aware of DR as a potential complication of diabetes and more than 75% acknowledged that a physician had recommended DR screening, yet only 55% reported screening in the previous year, similar to previously reported rates in underserved populations (1). However, compared with Hispanic patients, AA patients were …
Chemotherapy is superior to sequential hemibody irradiation for remission consolidation in multiple myeloma: a Southwest Oncology Group study.
Authors: S E Salmon, D Tesh, J Crowley, S Saeed, P Finley, M S Milder, L F Hutchins, C A Coltman, J D Bonnet, B Cheson
Journal: Journal of Clinical Oncology (1990)

Six hundred fourteen previously untreated patients with multiple myeloma were evaluated on this phase III Southwest Oncology Group (SWOG) trial. For remission induction, two noncross-resistant drug combinations (vincristine, melphalan, cyclophosphamide, and prednisone [VMCP] and vincristine, carmustine [BCNU], Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], and prednisone [VBAP]) were administered with either a direct alternating or a syncopated schedule. Pretreatment serum beta-2 microglobulin (beta 2M) was the single most important prognostic factor for survival (P less than .0001). There was no difference in toxicity, response, or survival by induction chemotherapy schedule (P greater than .7). For consolidation, 180 eligible and responsive patients were randomized to receive either an additional year of VMCP or sequential hemibody radiation (HBI) with vincristine and prednisone (VP) administered between the two HBI courses. Relapse-free survival (26 months) and overall survival (median, 36 months) were better with VMCP than with HBI (median, 20 months and 28 months; P = .04 and .018, respectively). HBI was also evaluated on a nonrandomized basis in 66 patients who achieved either a partial response (PR) or who were nonresponders to induction therapy. While HBI converted 24% of the PR patients to remission status, this effect was only seen in 5% of nonresponding patients. The survival of responsive and nonresponding patients receiving HBI was similar. All HBI groups had an inferior outcome to those receiving VMCP consolidation. Myelosuppression was also significantly worse after HBI. Survival from the time of relapse did not differ between patients randomized to receive VMCP or HBI. Thus HBI induced less durable remissions, but did not render patients less amenable to postrelapse chemotherapy. Our findings do not support the use of HBI in either chemotherapy responsive or nonresponding patients with multiple myeloma.