tbuckley/cabot-search huggingface dataset:
Abstract 15498: Selective Inhibition of the Immunoproteasome Attenuates Adverse Left Ventricular Remodeling, Improves Cardiac Function, and Prevents Heart Failure After Myocardial Infarction
Authors: Sharlene M Day, Jaime Yob, Frank Davis, Ping Wang, Kimber L Converso, Xuejun Wang, Saul R Powell
Journal: Circulation (2013)

We have previously shown proteasome (Prot) activation after myocardial infarction (MI) in mice. Here we use pharmacologic inhibitors to discriminate between effects of constitutive and immunoproteasome (iProt) activation to test the hypothesis that the iProt mediates cardiac dysfunction after MI.   Methods/Results:  Mice underwent permanent ligation of the left coronary artery or sham surgery. At 2 weeks, protein levels of β5 i  (a key iProt subunit) were increased by 70% (P i: β5 active site ratio after MI compared to sham. Mice were administered bortezomib (BZM, 0.2 mg/kg, IP daily), a non-selective Prot inhibitor, ONX 0914 (5 or 10 mg/kg, SC 3X/wk), a selective iProt inhibitor, or vehicle for 2 wks post-MI. Echocardiographic measurements at baseline and 2 wks were compared by 2-way RM ANOVA. BZM exacerbated adverse ventricular remodeling and systolic dysfunction compared to vehicle (Table). BZM also aggravated heart failure, as evidenced by higher lung weights and a higher E/E’la by echo (a measure highly correlated to left atrial pressure). In contrast, ONX 0914 (5 mg/kg) significantly decreased the β5 i: β5 active site ratio (P   Conclusions:  After MI, non-selective Prot inhibition is detrimental, while selective inhibition of the iProt is highly protective. Inhibition of the iProt may prevent amplification of the inflammatory response to myocardial injury. These data establish the iProt as a viable target for intervention after MI, and possibly in other cardiac diseases associated with acute or chronic inflammation.
Clonal Evolution In Patients With Chronic Lymphocytic Leukemia (CLL) Developing Resistance To BTK Inhibition
Authors: Jan A. Burger, Dan Landau, Julia Hoellenriegel, Carrie Sougnez, Matthias Schlesner, Naveed Ishaque, Benedikt Brors, Michael J. Keating, William G. Wierda, Kristian Cibulskis, Hagop M. Kantarjian, Susan M. O'Brien, Donna S. Neuberg, Thorsten Zenz, Gad Getz, Catherine J Wu
Journal: Blood (2013)
Post-therapeutic changes in the molecular profile of glioblastomas
Authors: C. Horbinski, A. Mintz, J. Engh, F. Lieberman, R. L. Hamilton, D. M. Park
Journal: Journal of Clinical Oncology (2009)

2026 Background: Glioblastoma multiforme is the most common and malignant primary brain tumor in adults. Despite aggressive surgery, radiation, and chemotherapy, average survival time after diagnosis is about 1 year. This may be partly due to development of resistance to adjuvant therapies. While the molecular alterations in pretreated glioblastomas have been the subject of much research in recent years, changes in their genetic profile after adjuvant therapy are largely unknown. Methods: Herein we describe a cohort of over 40 glioblastomas with characterization of key genetic loci (EGFR, p53, 1p, 19q, 9p, 10q, 17p) using fluorescence in situ hybridization, PCR-based loss of heterozygosity (LOH) analysis, and immunohistochemistry on formalin-fixed, paraffin-embedded tissues. Analyses were performed on tumor tissue obtained at initial diagnosis and at first recurrence. Treatment regimen during the interval consisted of external beam radiation therapy and temozolomide, an alkylating chemotherapeutic agent. Results: About 50% showed large increases or decreases in hyperploidy of chromosomes 1, 7, 9, and/or 19 after therapy. Over 70% showed changes in LOH patterns on 1p, 19q, 9p, 10q, and/or 17p. 24% of previously non-EGFR-amplified tumors acquired low-grade amplification (less than 10 copies/chromosome 7 CEP signal) after treatment, and 16% of EGFR-amplified tumors lost amplification after treatment. Conclusions: Our results suggest that the molecular profile of these tumors is dynamic and that certain key alterations, including acquisition of low-level EGFR amplification in previously EGFR-negative tumors, occurs in a subset of cases. Such alterations may contribute to therapy resistance as the glioma evolves in a changing microenvironment. No significant financial relationships to disclose.
Expression of myeloid-associated and lymphoid-associated cell-surface antigens in acute myeloid leukemia of childhood: a Pediatric Oncology Group study.
Authors: S J Kuerbitz, C I Civin, J P Krischer, Y Ravindranath, C P Steuber, H J Weinstein, N Winick, A H Ragab, M V Gresik, W M Crist
Journal: Journal of Clinical Oncology (1992)

PURPOSE Although the expression of both myeloid- and lymphoid-associated cell-surface antigens in acute myeloid leukemia (AML) has been described, the clinical significance of such antigen expression remains unknown in the pediatric population. We sought to define an antibody panel for optimal diagnostic antigenic analysis and to test associations among antigen expression and a number of clinical features at presentation and prognosis in pediatric AML. PATIENTS AND METHODS We reviewed the extensive immunophenotypic analysis performed at the time of diagnosis on 132 assessable patients registered on a single Pediatric Oncology Group AML protocol between 1984 and 1988. RESULTS Eighty-eight percent of patients were identified by testing for expression of CD33 and CD13. Overall, 61% of patients expressed at least one lymphoid-associated antigen, most commonly CD4, CD7, or CD19. Expression of CD5, CD10, CD20, or CD22, commonly detected in T- or B-lineage pediatric acute lymphoid leukemia (ALL), was uncommon; coexpression of multiple lymphoid-associated antigens was also uncommon. Expression of the monocyte-associated antigen CD14 correlated with French-American-British (FAB) M4 or M5 morphology. Otherwise, no correlation between antigen expression and FAB classification was noted. None of the myeloid, lymphoid, natural-killer (NK), or progenitor-associated antigens were associated with significant differences in the likelihood of remission induction or event-free survival when expressor versus nonexpressor groups were compared. CONCLUSIONS The distribution of cell-surface antigen expression in pediatric acute leukemia usually permitted the discrimination of AML from ALL by using a limited panel of antibodies. Although the expression of lymphoid-associated antigens was common, such expression did not seem to be associated with an adverse prognosis in pediatric AML.
MiR-214-3p, a new fibromiR involved in the pathogenesis of idiopathic pulmonary fibrosis
Authors: Grégoire Savary, Matthieu Buscot, Edmone Dewaeles, Imène Sarah Henaoui, Stéphanie Quarré, Elisabeth Courcot, Christelle Cauffiez, Pascal Barbry, Michael Perrais, Bernard Mari, Nicolas Pottier
Journal: European Respiratory Journal (2014)

Recent evidence has unveiled a critical role of miRNAs in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). In particular, we established miR-199a-5p as a major regulator of lung fibroblast/myofibroblasts differentiation by targeting CAV1, a key player in TGFβ signaling (Lino Cardenas, CL et al . Plos Genetics 2013,9:2). Interestingly, miR-199a-5p belongs to the miR-199a/214 gene cluster encoded by the DNM3os (Dynamin 3 Opposite Strand) transcript. TGFβ stimulation of lung fibroblasts enhanced the expression of DNM3os and miR-199a/214, suggesting a transcriptional regulation of the whole cluster. In order to establish the role of this cluster in the pathogenesis of IPF, we focused on the contribution of miR-214 to fibrotic mechanisms.

First, we demonstrated that miR-214 overexpression was sufficient to induce lung fibroblast differentiation into myofibroblasts. Next, we addressed the importance of miR-214 in the molecular events underlying TGFβ signaling. Transcriptomic analysis of miR-214 overexpressing lung fibroblasts led us to identify miR-214 targets that are clearly involved in the non-canonical TGFβ pathway. Using similar approaches, we also reported that miR-214 was a potent regulator of the HGF/COX-2/PGE2 axis, which is crucial for lung epithelial repair.

Overall, we show here that the miR-199a/214 cluster functions as a key regulator of both canonic and non-canonic TGFβ pathways and as a critical actor of myofibroblast differentiation and epithelial-mesenchymal interactions. Finally, as aberrant lung expression of miR-199a and miR-214 has also been found in IPF patients, the inhibition of this cluster may represent a new effective therapeutic option for this devastating disease.
Clinical benefits of long-term use of sorafenib in Japanese patients with unresectable renal cell carcinoma (RCC)
Authors: S. Naito, T. Tsukamoto, M. Murai, K. Fukino, K. Nakajiima, H. Akaza
Journal: Journal of Clinical Oncology (2008)

16039 Background: Sorafenib has been approved for advanced renal cell carcinoma (RCC) worldwide, based on proven efficacy and tolerability in Phase III randomized control trial. Though sorafenib inhibits tumor growth and is given continuously, data of long-term use has been limited. Methods: Uncontrolled Phase II trial to evaluate efficacy and safety of sorafenib (400 mg bid, continuous) in Japanese patients (pts) with unresectable RCC (study 1) was conducted from Nov 2004 through Jan 2006. The result demonstrated the favorable profile of sorafenib, with partial response (PR) in 19 pts (14.7%) and stable disease (SD) in 93 pts (72.1%) out of 129 pts evaluable for efficacy (EAU 2007). To evaluate efficacy and tolerability of a long-term use of sorafenib, an extension study (study 2) followed study 1 has been conducted. Patients were transferred to study 2, if they remained on sorafenib at the end of study 1 without disease progression or intolerable toxicity. Results: Of 131 pts enrolled in study 1, 61 pts (PR: 19 pts, SD: 42 pts) were transferred to study 2. The median duration of sorafenib dosing is 589 days (84.1 weeks). Sixty-one pts out of 131 pts have survived over 30 months, and 2 year survival rate is 34 %. As of Nov 30 2007, the total duration of treatment ranged from 0.7 year (35 weeks) to 2.9 years (151 weeks) in pts enrolled in study 2. Twenty-one out of 61 pts (34.4 %) continued sorafenib for more than 2 years without PD or intolerable toxicity. Combined RR is19.4% (25 pts), with 6 pts out of 42 pts who achieved SD at the time of transfer experienced PR during long term use. Only 2 pts (3.3 %) discontinued sorafenib due to drug-related adverse events in study 2, while 13 pts (9.9 %) of 131 pts discontinued in study 1. No accumulated or unknown toxicity has been observed in study 2. Conclusions: Long-term use of sorafenib has been tolerated and benefited Japanese patients with unresectable RCC showing further tumor stabilization over longer duration of dosing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer
Expression of vascular cell adhesion molecule-1 in human renal allografts.
Authors: D M Briscoe, J S Pober, W E Harmon, R S Cotran
Journal: Journal of the American Society of Nephrology (1992)

The expression of vascular cell adhesion molecule-1 (VCAM-1) in 11 human renal allograft biopsies and 3 normal kidney specimens was investigated by immunocytochemistry. VCAM-1 expression was correlated with the degree of CD3+ T cell infiltration and the clinicopathologic diagnosis of acute rejection. CD3+ infiltrates were seen in all biopsies with rejection, but not in normal biopsies or one with acute tubular necrosis, and were accompanied by CD68+ monocyte/macrophage infiltrates. In normal biopsies, VCAM-1 was present on occasional tubules, where its expression was patchy and restricted to the basolateral surface of cells with slight cytoplasmic staining. The total number of tubules expressing VCAM-1 significantly increased in specimens infiltrated with CD3+ T cells. Moreover, in these infiltrated biopsy specimens, VCAM-1 was present throughout the cytoplasm of tubular cells concentrated on the basolateral surface. VCAM-1 was also observed on vascular endothelial cells where its expression correlated with the degree of CD3+ infiltrate. Mean scores (0 to 3+) for endothelial VCAM-1 expression increased from 0 (CD3+ score, 0) to a mean score of 2.25 in association with CD3+ T cell infiltrates (CD3+ score, 3). Endothelial VCAM-1 was predominantly on vessels in areas of infiltrate, including peritubular capillaries, venules, and arterioles, but was notably absent on glomerular endothelium. VCAM-1 also stained mesangial cells in an occasional CD3+ infiltrated specimen. It was concluded that the expression of VCAM-1 is increased on renal tubules and renovascular endothelium in rejecting renal allografts in association with CD3+ infiltrates.(ABSTRACT TRUNCATED AT 250 WORDS)
Factors impacting oncologic outcomes after sublobar pulmonary resection: Results from ACOSOG Z4032 (Alliance), a randomized trial for high-risk operable non-small cell lung cancer (NSCLC).
Authors: Michael S Kent, Rodney Jerome Landreneau, Sumithra J. Mandrekar, Francis C Nichols, Thomas A. DiPetrillo, Bryan F Meyers, Dwight Earl Heron, Joe B. Putnam, David R Jones, Sandra Lynne Starnes, Benedict Daly, Angelina D. Tan, Hiran Chrishantha Fernando
Journal: Journal of Clinical Oncology (2013)

7524 Background: A multicenter study (Z4032) compared sublobar resection (SR) to sublobar resection with brachytherapy (SRB) for stage I NSCLC. Local recurrence (LR) and overall survival (OS) rates at 3-years (3-yr) were similar between arms (see abstract 113613). This analysis combines arms, and evaluates the effect of factors previously reported to impact oncological outcomes after SR. Methods: 213 patients (pts) were evaluable for analysis. LR was defined as recurrence at the staple line (local progression), same lobe away from the staple line, or within hilar nodes. Factors assessed for impact on 3-yr outcomes were: resection type (wedge/segmentectomy), margin size (&lt;1cm /≥1cm), margin:tumor ratio (&lt;1/ ≥1), tumor size (≤2cm/&gt;2cm) and staple line cytology (+/-). Results: LR occurred in 27/213 (12.6%) pts and included local progression in 12/213 (5.6%). OS rate at 3-yr was 152/213 (71.4%). Trends favored the use of segmentectomy, margin:tumor ratio≥1, tumor size ≤2cm and negative staple line cytology; no factor reached statistical significance at 3-yr. The only factor significantly (p=0.02) associated with decreased 3-yr LR was margin size ≥1cm (8.3%) compared to margin&lt;1cm (19.3%). Conclusions: SR is a good option for high-risk pts with NSCLC. The 3-yr OS rate of 71.4% and local progression rate of 5.6% are useful benchmarks to compare to other therapies. A resection margin of at least 1 cm is desirable. Clinical trial information: NCT00107172. [Table: see text]
Neoadjuvant treatment for rectal cancer in fit and vulnerable patients older than 70 years
Authors: M. L. Friso, L. M. Pasetto, U. Basso, S. Pucciarelli, M. Rugge, M. Agostini, S. Serpentini, A. Favaretto, D. Nitti, S. Monfardini
Journal: Journal of Clinical Oncology (2006)

13586 Background: To evaluate the toxicity and feasibility of neoadjuvant 5FU continuous infusion or bolus in combination with pelvic radiotherapy (RT) in rectal cancer patients older than 70 years. Methods: From June 2000 to June 2005, 36 patients older than 70 years out of a total of 300 consecutive cases with histologically proven locally advanced rectal adenocarcinoma (≤ 12 cm from the anal verge) classified as either T3 or T4, N0 or N1–2 M0 disease, were examined. Comorbidities were evaluated according to Cumulative Illness Rating Scale-Geriatric (CIRS-G) and patients were deemed “fit” if they were otherwise healthy or had one or more comorbidities of only grade 1; “vulnerable” if had one or more comorbidities of grade 2. Results: Median age was 74 years (range, 70–82). 14 patients (5 healthy, 13.8%, and 9 with slight comorbidities, 25%) were fit and 22 (61.2%) were vulnerable. All the patients received the full course of RT, with a total dose of 50.4 Gy. The mean number of chemotherapy weeks was 5.34 (range, 2–6). 4 out 14 (28.6%) fit patients and 9 out 22 (40.9%) vulnerable patients had to interrupt chemotherapy prematurely because of toxicity (p=0.26). Vulnerable patients did not experience superior toxicity compared to fit patients (8/22 vulnerable and 6/14 fit patients developed toxicities of grade ≥ 2, p=0.69). With the exception of 2 fit and 2 vulnerable patients who were lost to follow up before surgery, 32 patients (88.9%) were operated. Thirty cases (12/14 fit patients, 85.7%, and 18/22 vulnerable patients, 81.8%) were radically resected without relevant postoperative complications. 13/20 vulnerable and 10/12 fit patients had a pathological downstaging of disease (p=0.24). Conclusions: Selected vulnerable elderly patients with rectal cancer can receive the same neoadjuvant chemoradiotherapy and undergo surgery as well as fit elderly patients since tolerability and response rate seem to be similar in both categories of patients. No significant financial relationships to disclose.
Survival of SLNB-positive melanoma patients with and without complete lymph node dissection: A multicenter, randomized DECOG trial.
Authors: Ulrike Leiter, Rudolf Stadler, Cornelia Mauch, Werner Hohenberger, Norbert Brockmeyer, Carola Berking, Cord Sunderkötter, Martin Kaatz, Klaus-Werner Schulte, Percy Lehmann, Thomas Vogt, Jens Ulrich, Rudolf Herbst, Wolfgang Gehring, Jan-Christoph Simon, Ulrike Keim, Claus Garbe
Journal: Journal of Clinical Oncology (2015)

LBA9002 Background: Complete lymph node dissection (CLND) following positive sentinel node biopsy (SLNB) was evaluated in a randomized phase III trial. Methods: 1,258 patients with cutaneous melanoma of the trunk and extremities and with positive SLNB were evaluated. Of these, 483 (39%) agreed to randomization into the clinical trial. 241 patients underwent observation only, 242 received CLND. Both groups had a subsequent 3-years follow-up. Recurrence-free (RFS), distant metastases free (DMFS) and melanoma specific (MSS) survival were analyzed as endpoints. Results: Patient enrolment was performedfrom January 2006 to December 2014. In the intent to treat analysis, both groups did not differ significantly in distribution of age, gender, localization, ulceration, tumor thickness (median 2,4 mm in both groups), number of positive nodes, or tumor burden in the SN. The mean follow-up time was 34 months (SD ± 22.1). No significant treatment-related difference was seen in the 5-years RFS (P = 0.72), DMFS (P= 0 .76) and MSS (P = 0.86) in the overall study population. Conclusions: In this early analysis of trial results, no survival benefit was achieved by CLND in melanoma patients with positive SLNB. A subsequent analysis three years after inclusion of the last patient is planned.
VKORc1 Is Under-Expressed in Skeletal Muscle of Humans, Dogs and Mice: Potential Implications for Ectopic Coagulation Factor Expression in Pre-Clinical and Therapeutic Applications
Authors: Courtney T Connolly, Armida Faella, Timothy C. Nichols, Katherine A. High, Valder R. Arruda, Paris Margaritis
Journal: Blood (2014)
Induction of Carcinomas of the Colon and Rectum in Rats by Intrarectal Instillation of N-Methyl-N'-Nitro-N-Nitrosoguanidine2
Authors: B. T. So, N. E. Magadia, E. L. Wynder
Journal: JNCI Journal of the National Cancer Institute (1973)

Adenocarcinomas of the large intestine developed in 30 Sprague-Dawley rats after intrarectal administration of 2 mg N-methyl-N'-nitro-N-nitrosoguanidine/kg body weight twice weekly for 250 days. The tumors were often multiple, and there were 106 nodules in the 30 rats. Metastases were found in the liver, pancreas, and adrenals of 1 rat. In addition to the adenocarcinomas, 1 animal had a squamous cell carcinoma of the anus.
Because not all blows to the head are the same
Authors: É C Falvey, P McCrory
Journal: British Journal of Sports Medicine (2015)

This case illustrates a specific medical risk with this rule change where an amateur boxer suffered an acute subdural haematoma following an Amateur International Boxing Association (AIBA) sanctioned event.

Boxing, by its very nature, carries a risk of injury, particularly brain injury. Within amateur boxing, the AIBA is the international sporting federation that has the governance and medical oversight of all Olympic and international competition. AIBA has been mindful of boxers’ health and has instituted a number of rule changes over the past six decades that have been aimed at improving safety and reducing the injury risk for boxers.1 

AIBA has recently changed its rules to remove helmets and head protectors for international competition and is currently proposing similar rule changes for helmets not to be used at the 2016 Rio de Janeiro Summer Olympics Games. The removal of head protectors in amateur boxing has the potential to increase head and brain injury rates and it is prudent to consider the evidence for and against such a proposed change at this level of competition.2 

A critical issue in interpreting the available evidence about the use of headgear for preventing head injuries in sport over time is that headgear rules have coincided with other rule changes or implementation that could also have influenced head injury risk.1 Furthermore, the proposed rule changes may change the nature of the way amateur boxing is conducted, which in turn may result in more head impacts from both glove and head to head contact.

This case illustrates a specific medical risk with this rule change where an amateur boxer suffered an acute subdural haematoma following an AIBA sanctioned event.

A 22-year-old male boxer with 5 years senior international experience was competing in a multinational event in the 54 kg division. He won the competition having …
A phase II study of bevacizumab (BEV) plus erlotinib (ERL) in patients with gemcitabine (GEM)-refractory metastatic pancreatic cancer (MPC)
Authors: A. H. Ko, E. Dito, B. Schillinger, A. P. Venook, E. K. Bergsland, W. M. Korn, M. A. Tempero
Journal: Journal of Clinical Oncology (2008)

4516 ⌃
Control of Cell Growth. I. Estrogen-Dependent Growth In Vivo of a Rat Pituitary Tumor Cell Line23
Authors: Joseph M. Sorrentino, Willis L. Kirkland, David A. Sirbasku
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article Control of Cell Growth. I. Estrogen-Dependent Growth In Vivo of a Rat Pituitary Tumor Cell Line Get access Joseph M. Sorrentino, Joseph M. Sorrentino Search for other works by this author on: Oxford Academic PubMed Google Scholar Willis L. Kirkland, Willis L. Kirkland Search for other works by this author on: Oxford Academic PubMed Google Scholar David A. Sirbasku David A. Sirbasku 8 8Address reprint requests to Dr. Sirbasku. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 56, Issue 6, June 1976, Pages 1149–1154, https://doi.org/10.1093/jnci/56.6.1149 Published: 01 June 1976 Article history Received: 08 July 1975 Accepted: 10 December 1975 Published: 01 June 1976