tbuckley/cabot-search huggingface dataset:
Abstract 1963: Analysis of aryl substitution and intramolecular ligand H-bonding in selective inhibitors of the MEK5/ERK5 cascade
Authors: Patrick T. Flaherty, Jane C. Cavanaugh, Mohit Gupta, Colin Vechery, Suravi Chakrabarty, Darlene Monlish, Thomas Wright
Journal: Cancer Research (2015)

Abstract Mitogen Activated Protein Kinase (MAPK) pathways initiate with external signaling, proceed through a sequence of protein kinases, and alter cell proliferation, growth, and survival. MAPK pathways proceed through a well-ordered sequence but are interconnected and modified by the cell's internal needs. The MEK-catalyzed phosphorylation of its target ERK represents the most selective interaction of MAPK signaling cascades. The type III MEK1/2 inhibitor, Mekinist, was recently approved by the FDA for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations. This success suggests inhibitors of other MEK/ERK cascades may be reasonable strategies for anti-cancer therapeutic strategies. Despite the likely involvement of MEK5 phosphorylation of ERK5 in early and triple negative breast cancers, prostate cancer, and renal cancer, little work has been focused on developing selective MEK5 inhibitors. We have previously described an initial series of anthranilic acid derivatives structurally derived from the known non-selective MEK inhibitor PD0325901. To explore structural requirements for selective inhibition of MEK5 versus MEK1/2, aryl substitution and the role of proposed internal hydrogen bonding of the ligand were examined with novel compounds. These were tested at 10 μM in MDB-MB-213 cells subsequently treated with EGF to induce MEK1/2 and MEK5 phosphorylation. Western blot analysis following electrophoresis using IR-tagged antibodies raised against pERK1/2, pERK5, ERK1/2, or ERK5 permitted determination of total and relative inhibition of MEK-mediated generation of pERK. Incubation with PD0325901 resulted in full suppression of both pERK1/2 and pERK5. For the aryl substitutions examined, omission of the halogens on the pendant phenyl group (SC-1-181) abolished MEK1/2 inhibition(0% decrease in pERK1/2) yet retained good MEK5 inhibition (82% decrease in pERK5). Disruption of an internal nitrogen-acyl hydrogen bond preferentially decreased MEK5 inhibition (SC-2-32: 40% and 16% decrease in pERK5 and pERK1/2 respectively). This establishes early evidence of significant variation in specificity of MEK type III binding sites that may be exploited as pharmacological tools and possibly as therapeutic agents for cancers overexpressing MEK5. Citation Format: Patrick T. Flaherty, Jane C. Cavanaugh, Mohit Gupta, Colin Vechery, Suravi Chakrabarty, Darlene Monlish, Thomas Wright. Analysis of aryl substitution and intramolecular ligand H-bonding in selective inhibitors of the MEK5/ERK5 cascade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1963. doi:10.1158/1538-7445.AM2015-1963
Results of a Sarcoma Alliance for Research through Collaboration (SARC) phase II trial of dasatinib in previously treated, high-grade, advanced sarcoma.
Authors: S. Schuetze, K. Wathen, E. Choy, B. L. Samuels, K. N. Ganjoo, A. P. Staddon, M. von Mehren, W. A. Chow, J. C. Trent, L. H. Baker
Journal: Journal of Clinical Oncology (2010)

10009 Background: Advanced high grade sarcomas resistant to standard chemotherapy are usually rapidly fatal. Few drugs with antisarcoma activity are available. Molecular studies of sarcomas suggest that SRC and downstream focal-adhesion kinase are active in sarcoma and may contribute to malignant phenotype. Dasatinib is an orally-administered kinase inhibitor of SRC-family of kinases that exhibited anti-sarcoma activity in preclinical models. SARC undertook a phase II study of dasatinib in advanced sarcoma. Results of patients (pts) treated for high grade subtypes are presented. Methods: An open-label, single-arm study of dasatinib was conducted for pts with incurable sarcoma including 7 histologic subtypes of high grade sarcoma. A Bayesian hierarchical model was used to “borrow strength” statistically across the subtypes. Dasatinib 100 mg bid was initially administered but was reduced to a starting dose of 70 mg bid because of toxicity. Primary endpoint was objective response within or stable disease at 6 months (CBR) per Choi criteria, and disease was imaged every 2 months. For each subtype, if there was < 1% chance the CBR was > 25%, then accrual within that subtype was stopped. Results: 47 leiomyosarcoma (LMS), 42 undifferentiated pleomorphic sarcoma (UPS), 45 osteosarcoma (OS), 17 Ewing's, 14 malignant peripheral nerve sheath tumor, 13 rhabdomyosarcoma (RMS) and 11 liposarcoma (LPS) pts were evaluable for response. Accrual was discontinued early in Ewing's, RMS and LPS because of lack of activity. 8 pts with UPS, 6 LMS and 5 OS had response or stable disease. The probability that the CBR was >25% in UPS was 0.10 and in the other 6 subtypes was < 0.01. The most common adverse events (AEs) were constitutional, gastrointestinal and respiratory. 24% of pts had ≥ grade 3 AEs at least possibly related to dasatinib, and 29% required dose reduction due to toxicity. Conclusions: Dasatinib may have activity in UPS but appears inactive as a single agent in selected other subtypes of advanced high grade sarcoma. Archived tumor tissue will be used to explore the potential basis for activity in UPS. Dasatinib 70 mg bid is safe, but up to 1/3 pts required dose reduction for AEs. No significant financial relationships to disclose.
LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors
Authors: Ying Cheng, Kudakwashe Chikwava, Chao Wu, Haibing Zhang, Anchit Bhagat, Dehua Pei, John K. Choi, Wei Tong
Journal: Journal of Clinical Investigation (2016)

Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL commonly associated with alterations that affect the tyrosine kinase pathway, tumor suppressors, and lymphoid transcription factors. Loss-of-function mutations in the gene-encoding adaptor protein LNK (also known as SH2B3) are found in Ph-like ALLs; however, it is not clear how LNK regulates normal B cell development or promotes leukemogenesis. Here, we have shown that combined loss of Lnk and tumor suppressors Tp53 or Ink4a/Arf in mice triggers a highly aggressive and transplantable precursor B-ALL. Tp53–/–Lnk–/– B-ALLs displayed similar gene expression profiles to human Ph-like B-ALLs, supporting use of this model for preclinical and molecular studies. Preleukemic Tp53–/–Lnk–/– pro-B progenitors were hypersensitive to IL-7, exhibited marked self-renewal in vitro and in vivo, and were able to initiate B-ALL in transplant recipients. Mechanistically, we demonstrated that LNK regulates pro-B progenitor homeostasis by attenuating IL-7–stimuated JAK/STAT5 signaling via a direct interaction with phosphorylated JAK3. Moreover, JAK inhibitors were effective in prolonging survival of mice transplanted with Lnk–/–Tp53–/– leukemia. Additionally, synergistic administration of PI3K/mTOR and JAK inhibitors further abrogated leukemia development. Hence, our results suggest that LNK suppresses IL-7R/JAK/STAT signaling to restrict pro-/pre-B progenitor expansion and leukemia development, providing a pathogenic mechanism and a potential therapeutic approach for B-ALLs with LNK mutations.
Medical management of renal stones
Authors: Monica S C Morgan, Margaret S Pearle
Journal: BMJ (2016)

The prevalence of kidney stones is increasing in industrialized nations, resulting in a corresponding rise in economic burden. Nephrolithiasis is now recognized as both a chronic and systemic condition, which further underscores the impact of the disease. Diet and environment play an important role in stone disease, presumably by modulating urine composition. Dietary modification as a preventive treatment to decrease lithogenic risk factors and prevent stone recurrence has gained interest because of its potential to be safer and more economical than drug treatment. However, not all abnormalities are likely to be amenable to dietary therapy, and in some cases drugs are necessary to reduce the risk of stone formation. Unfortunately, no new drugs have been developed for stone prevention since the 1980s when potassium citrate was introduced, perhaps because the long observation period needed to demonstrate efficacy discourages investigators from embarking on clinical trials. Nonetheless, effective established treatment regimens are currently available for stone prevention.
Serum Levels of Tryptase Suggest That Mast Cells Might Have an Antiinflammatory Role in Rheumatoid Arthritis: Comment on the Article by Rivellese et al
Authors: Maurizio Rossini, Ombretta Viapiana, Giovanna Zanoni, Gaia Tripi, Luca Idolazzi, Elena Fracassi, Giovanni Adami, Silvano Adami, Davide Gatti
Journal: Arthritis & Rheumatology (2015)
Forssman Antigen Content of Guinea Pig Hepatomas Induced by Diethylnitrosamine: A Quantitative Approach to the Search for Tumor-Specific Antibodies
Authors: Crile Crisler, Herbert J. Rapp, Ronald M. Weintraub, Tibor Borsos
Journal: JNCI Journal of the National Cancer Institute (1966)

The Forssman antigen content of diethylnitrosamine-induced guinea pig hepatomas was found to be greater than that of either autogenous or allogeneic guinea pig liver. The autogenous normal liver was obtained from guinea pigs before tumor induction, and comparison of normal and neoplastic tissues was based on the capacity of these tissues to inhibit (absorb) the hemolytic activity of rabbit antitumor serum. A method is presented for distinguishing quantitative from qualitative antigenic differences in the search for tumor-specific antigens. The results of these experiments indicate that, in the absence of strict quantitation, quantitative differences may be mistaken for qualitative differences.
Hospitals and GPs are offered incentives to reduce antibiotic prescribing
Authors: Jacqui Wise
Journal: BMJ (2016)

GPs and hospitals in England will be given incentives to reduce the number of antibiotics they prescribe, in an effort to tackle the growing problem of antibiotic resistance.

NHS England announced that, from April 2016, clinical commissioning groups (CCGs) will receive extra funding if they reduce the number of antibiotics prescribed in primary care either by 4% or down to the average performance level of 2013-14. The incentive is part …
The Neo-Bioscore Update for Staging Breast Cancer Treated With Neoadjuvant Chemotherapy
Authors: Elizabeth A. Mittendorf, Jose Vila, Susan L. Tucker, Mariana Chavez-MacGregor, Benjamin D. Smith, W. Fraser Symmans, Aysegul A. Sahin, Gabriel N. Hortobagyi, Kelly K. Hunt
Journal: JAMA Oncology (2016)

We previously described and validated a breast cancer staging system (CPS+EG, clinical-pathologic scoring system incorporating estrogen receptor-negative disease and nuclear grade 3 tumor pathology) for assessing prognosis after neoadjuvant chemotherapy using pretreatment clinical stage, posttreatment pathologic stage, estrogen receptor (ER) status, and grade. Development of the CPS+EG staging system predated routine administration of trastuzumab in patients with ERBB2-positive disease (formerly HER2 or HER2/neu).To validate the CPS+EG staging system using the new definition of ER positivity (≥1%) and to develop an updated staging system (Neo-Bioscore) that incorporates ERBB2 status into the previously developed CPS+EG.Retrospective review of data collected prospectively from January 2005 through December 2012 on patients with breast cancer treated with neoadjuvant chemotherapy at The University of Texas MD Anderson Cancer Center.Prognostic scores were computed using 2 versions of the CPS+EG staging system, one with ER considered positive if it measured 10% or higher, the other with ER considered positive if it measured 1% or higher. Fits of the Cox proportional hazards model for the 2 sets of prognostic scores were compared using the Akaike Information Criterion (AIC). Status of ERBB2 was added to the model, and the likelihood ratio test was used to determine improvement in fit.A total of 2377 patients were included; all were women (median age, 50 years [range, 21-87 years]); ER status was less than 1% in 28.9%, 1% to 9% in 8.3%, and 10% or higher in 62.8%; 591 patients were ERBB2 positive. Median follow-up was 4.2 years (range, 0.5-11.7 years). Five-year disease-specific survival was 89% (95% CI, 87%-90%). Using 1% or higher as the cutoff for ER positivity, 5-year disease-specific survival estimates determined using the CPS+EG stage ranged from 52% to 98%, thereby validating our previous finding that the CPS+EG score facilitates more refined categorization into prognostic subgroups than clinical or final pathologic stage alone. The AIC value for this model was 3333.06, while for a model using 10% or higher as the cutoff for ER positivity, it was 3333.38, indicating that the model fits were nearly identical. The improvement in fit of the model when ERBB2 status was added was highly significant, with 5-year disease-specific survival estimates ranging from 48% to 99% (P < .001). Incorporating ERBB2 into the staging system defined the Neo-Bioscore, which provided improved stratification of patients with respect to prognosis.The Neo-Bioscore improves our previously validated staging system and allows its application in ERBB2-positive patients. We recommend that treatment response and biologic markers be incorporated into the American Joint Committee on Cancer staging system.
PD-L1 Testing and Lack of Benefit to Guide Treatment With Immune Checkpoint Inhibitors in Patients With Non–Small-Cell Lung Cancer
Authors: Nathan A. Pennell
Journal: JAMA Oncology (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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Oncology journal
Impact of gene expression of orotate phosphoribosyl transferase for complete response to chemoradiotherapy in patients with squamous cell carcinoma of the esophagus
Authors: T. Kajiwara, T. Nishina, I. Hyodo, T. Moriwaki, S. Endo, J. Nasu, S. Hori, H. Iguchi, Y. Hiasa, M. Onji
Journal: Journal of Clinical Oncology (2007)

4566 Background: Chemoradiotherapy (CRT) is a potential alternative to surgery in patients with squamous cell carcinoma of the esophagus. Complete response (CR) to CRT is essential for a good prognosis and there is a need for a predictive method of CR in CRT. Methods: The pretreatment formalin-fixed, paraffin-embedded endoscopic tumor biopsy material was obtained from 41 patients treated with a definitive concurrent CRT (5-FU/CDDP and 60 Gy) for esophageal cancer (cStage II or III). cDNA was derived from tumor cells of biopsy specimens by the laser capture microdissection and analyzed to determine mRNA expression relative to an internal reference gene (β-actin) using fluorescence-based, real-time reverse transcription PCR. Gene expression levels of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, orotate phosphoribosyl transferase (OPRT), metylenetetrahydrofolate reductase, dihydrofolate reductase (DHFR), excision repair cross-complementing gene 1, vascular endothelial growth factor, epidermal growth factor receptor and matrix metalloproteinase 9 (MMP-9) were measured. Results: Median gene expression levels of OPRT and DHFR were significantly higher in CR patients (p=0.0206 and 0.0191, respectively). MMP-9 was significantly lower in CR patients (p=0.0436). When the median values of the gene expression levels were selected as the cutoff values, CR rate was significantly higher in the high OPRT group and high DHFR group (p=0.0104 and 0.0104, respectively). However, there was no statistical difference in CR rate between the low MMP-9 group and the high MMP-9 group. Multivariate analysis, including clinical stage and biomarkers, revealed that high OPRT gene expression was an independent predictive factor of CR (p=0.0329, relative risk=6.65, 95% confidence interval, 1.17–37.89%). Conclusions: The measurement of OPRT gene expression in tumor biopsies may be a predictive factor of CR to CRT in patients with squamous cell carcinoma of the esophagus. No significant financial relationships to disclose.
Inhibition of DNA Synthesis and Alteration of Cyclic Adenosine 3′ ,5′-Monophosphate Levels in RSa Cells by Human Leukocyte Interferon 2
Authors: Akira Fuse, Tsuguo Kuwata
Journal: JNCI Journal of the National Cancer Institute (1978)

Human leukocyte interferon inhibits the proliferation of the virus-transformed human embryonic cells RSa. Incorporation of [3H]thymidine (TdR) into an intracellular pool and the activity of TdR kinase were reduced in the interferon-treated RSa cell culture. High-degree (90%) inhibition of [3H]TdR incorporation was associated with concentrations of added interferon that produced more than a twofold increase in the intracellular cyclic AMP (cAMP) level, and low-degree inhibition was associated with smaller increases in cAMP. In the IFr cell culture, which is relatively resistant to the anticellular action of interferon, considerably less inhibition of TdR incorporation and a slight increase in cAMP were observed. Extracellularly added dibutyryl-cAMP inhibited the proliferation of both RSa and IFr cells to almost the same degree. A decrease in cAMP level and the initiation of DNA synthesis of G1-phase-arrested RSa cells by serum addition were prevented when cells were pretreated with interferon. These results indicated that intracellular cAMP may mediate the inhibitory effect of interferon on DNA synthesis and cell growth.
Retreatment with sofosbuvir and simeprevir of patients with hepatitis C virus genotype 1 or 4 who previously failed a daclatasvir‐containing regimen
Authors: Christophe Hézode, Stéphane Chevaliez, Giovanna Scoazec, Alexandre Soulier, Anne Varaut, Magali Bouvier‐Alias, Isaac Ruiz, Françoise Roudot‐Thoraval, Ariane Mallat, Cyrille Féray, Jean‐Michel Pawlotsky
Journal: Hepatology (2016)

Failure to achieve sustained virological response (SVR) with hepatitis C virus (HCV) direct‐acting antiviral‐based regimens is commonly associated with emergence of resistance‐associated variants (RAVs). To avoid cross‐resistance, recent guidelines recommend that patients who have failed on nonstructural protein 5A (NS5A) inhibitors should be retreated with sofosbuvir (SOF; NS5B inhibitor) combined with simeprevir (SIM; protease inhibitor [PI]); however, supporting evidence is lacking. This “real‐world” study comprised patients who had failed to achieve SVR on previous NS5A‐based therapy with daclatasvir (DCV) plus pegylated interferon (Peg‐IFN) and ribavirin (RBV), with (n = 3) or without (n = 13) asunaprevir (ASV; PI). All 16 patients were retreated for 12 weeks with SOF plus SIM, without RBV. Antiviral efficacy was evaluated using the primary endpoint of SVR12 (SVR 12 weeks post‐treatment); on‐treatment response was also assessed. Patients (N = 16; 13 male; mean age: 54 years [range, 43‐73]) were chronically infected with HCV genotype (GT) 1 (1a, n = 11; 1b, n = 3) or 4 (n = 2); they had advanced fibrosis or compensated cirrhosis (FibroScan, 9.6‐70 kPa; cirrhosis, n = 9); median baseline HCV‐RNA level was 1.38 × 10 6 IU/mL. No patient discontinued treatment because of adverse events or virological failure. All patients achieved HCV RNA below lower limit of quantification (&lt;12 IU/mL) by end of treatment (EOT) and 10 of 16 had a rapid response (week 4). SVR12 was achieved by 14 of 16 patients; the remaining 2 relapsed by 4 weeks post‐EOT (both were GT 1a infected with cirrhosis; 1 had previously failed DCV‐ASV plus Peg‐IFN and RBV). Presence of SIM RAVs/polymorphisms (R155K and Q80K) at study baseline did not predict retreatment failure. Conclusion: Our findings support the concept of retreating NS5A inhibitor failures with SOF combined with SIM. However, the most difficult‐to‐cure patients may need more than 12 weeks of treatment and/or the addition of RBV. (H epatology 2016;63:1809‐1816)
Human gamma interferon enhances release from phytohemagglutinin- stimulated T4+ lymphocytes of activities that stimulate colony formation by granulocyte-macrophage, erythroid, and multipotential progenitor cells
Authors: W Piacibello, L Lu, D Williams, M Aglietta, BY Rubin, S Cooper, M Wachter, F Gavosto, HE Broxmeyer
Journal: Blood (1986)
A First-In-Human Study Evaluating the Safety and Pharmacology of Mm-151, a Novel Oligoclonal Anti-Egfr Antibody Combination in Patients with Refractory Solid Tumors
Authors: W. Harb, C. Lieu, M. Beeram, L. Power, C. Sloss, J. Kearns, R. Nering, V. Moyo, B. Wolf, A.A. Adjei
Journal: Annals of Oncology (2014)