tbuckley/cabot-search huggingface dataset:
Abstract 2437: Crystal structures of CARM1 bound to sinefungin and diverse peptide substrates
Authors: Ann Boriack-Sjodin, Lei Jin, Suzanne L. Jacques, Allison Drew, Margaret Porter Scott, Scott Ribich, Oscar Moradei
Journal: Cancer Research (2015)

Abstract Co-activator-associated arginine methyltransferase 1 (CARM1) is a protein arginine N-methyltransferase (PRMT) enzyme that has been implicated in a variety of cancers including AML (1) and breast (2), prostate (3), lung (4) and colorectal (5) carcinomas. CARM1 is known to methylate H3 histones and non-histone substrates including p300/CBP, AIB1/SRC-3 and PABP1 (6). To date, several crystal structures of CARM1 have been solved, including structures with small molecule inhibitors (7), but no ternary structures with nucleotide and peptide substrate have been reported. Here, the crystal structures of human CARM1 with the SAM mimic sinefungin (SFG) and three different peptide sequences from histone H3 and PAPB1 are presented, and both non-methylated and singly-methylated arginine residues are exemplified. Extensive interactions are seen with residues Glu266, Glu257, and His414 and the substrate arginine side chain. Two key hydrogen bonds are made by the side chain of Asn161 with the backbone carbonyl of the P’1 peptide residue and the backbone NH of the P’3 peptide residue. The carbonyl of the P1 peptide residue engages the protein through water mediated hydrogen bonds. These structures show how the CARM1 binding site is capable of accommodating a variety of peptide sequences. Comparisons to known CARM1 complexes with small molecules provide additional insights into inhibitor design. 1. Vu, L. P. et al, PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Rep 2013, 5 (6), 1625-38. 2. Al-Dhaheri, M. et al, CARM1 is an important determinant of ERalpha-dependent breast cancer cell differentiation and proliferation in breast cancer cells. Cancer Res 2011, 71 (6), 2118-28. 3. Kim, Y. R. et al, Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer 2010, 10, 197. 4. Elakoum, R. et al, CARM1 and PRMT1 are dysregulated in lung cancer without hierarchical features. Biochimie 2014, 97, 210-8. 5. Ou, C. Y. et al, A coactivator role of CARM1 in the dysregulation of beta-catenin activity in colorectal cancer cell growth and gene expression. Mol Cancer Res 2011, 9 (5), 660-70. 6. Bedford M.T.; Clarke S.G. Protein arginine methylation in mammals: who, what, and why. Mol Cell 2009, 33, 1-13. 7. Sack, J.S et al, Structural basis for CARM1 inhibition by indole and pyrazole inhibitors. Biochem J 2011, 436, 331-9. Citation Format: Ann Boriack-Sjodin, Lei Jin, Suzanne L. Jacques, Allison Drew, Margaret Porter Scott, Scott Ribich, Oscar Moradei. Crystal structures of CARM1 bound to sinefungin and diverse peptide substrates. [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 2437. doi:10.1158/1538-7445.AM2015-2437
A retrospective analysis of clinical outcomes in patients treated for malignant mixed mesodermal tumors of the ovary and uterus with an evaluation of molecular marker expression
Authors: D. R. Crotzer, J. K. Wolf, R. R. Broaddus, L. M. Ramondetta
Journal: Journal of Clinical Oncology (2005)

5107 Background: The purpose of this study was to compare molecular marker expression and clinical outcomes in patients treated for malignant mixed mesodermal tumor (MMMT) of the ovary with previously published findings in MMMT of the uterus. Methods: Following IRB approval, the records of patients treated for MMMT of the ovary between 1990 and 2001 were reviewed retrospectively. Clinical data was abstracted from these records to determine progression-free interval (PFI) and overall survival (OS). Available tissue specimens were stained for estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, C-kit, Abl, and platelet derived growth factor-b (PDGFR-b). The results were compared to published data on patients with MMMT of the uterus from our institution. Statistical significance was determined by a Chi-square test. Results: 22 patients were identified. 14 patients were treated with a regimen of cisplatin/ifosfamide. Median age at diagnosis was 58 (range 46–68). Median PFI was 10.5 months (range 0–94). Median OS was 20 months (range 10–94). In comparable patients with MMMT of the uterus treated with cisplatin/ifosfamide, median PFI was 23.5 months for patients without measurable disease. 16 cases of MMMT of the ovary with tissue specimens were available for staining. The results are shown in the table below. For ER, PR, c-Kit, HER-2/neu, and PDGFR-b, positivity was not statistically different between the uterine and ovarian specimens; positivity for Abl was significantly different between the ovarian and uterine samples. Conclusions: MMMTs of the ovary and uterus remain rare and aggressive neoplasms with a poor prognosis. Although the numbers are small, positivity for ER, Abl, PDGFR and HER-2/neu suggests that molecular therapies directed at these receptors may have some utility in the treatment of these rare and aggressive neoplasms. No significant financial relationships to disclose.
The take-home message: patients prefer consultation audiotapes to summary letters.
Authors: M H Tattersall, P N Butow, A M Griffin, S M Dunn
Journal: Journal of Clinical Oncology (1994)

PURPOSE Despite reports of poor patient understanding and recall after cancer consultations, few doctors provide communication aids. We conducted a randomized trial comparing an audiotape of the consultation versus individualized summary letters to patients after their first consultation with a medical oncologist. METHODS One hundred eighty-two cancer patients were randomized to receive either (1) the audiotape followed 7 to 10 days later by the letter or (2) the letter followed by the audiotape. Outcome measures included patient recall, anxiety and depression, satisfaction with and use of the communication aids, and patient preferences for six communication options. Demographic and disease variables and information and involvement preferences were documented. RESULTS Eighty percent of patients wanted all information and 72% wanted to participate in treatment decisions. Patients listened to the tape on average 2.3 times and read the letter 2.8 times over 4 weeks, and 90% showed the tape or letter to a friend, relative, or doctor. Satisfaction with the tape and letter were uniformly high and they did not differentially affect recall, anxiety, or depression. When asked to rank six communication options, 46% of patients gave the highest rank to the tape and 21% to the letter. CONCLUSION Patients use audiotapes of their cancer consultation and individualized letters to review the information given and communicate information to relatives and friends. They prefer audiotapes to letters. Clinicians should consider installing audiotape-recording facilities that could be used to tape new-patient consultations.
RISUS study: Rugby Injury Surveillance in Ulster Schools
Authors: H A P Archbold, A T Rankin, M Webb, R Nicholas, N W A Eames, R K Wilson, L A Henderson, G J Heyes, C M Bleakley
Journal: British Journal of Sports Medicine (2015)

To examine injury patterns in adolescent rugby players and determine factors associated with injury risk.Prospective injury surveillance study.N=28 Grammar Schools in Ulster, Ireland (2014-2015 playing season).825 adolescent rugby players, across in 28 school first XV rugby squads; mean age 16.9 years.Injuries were classified by body part and diagnosis, and injury incidence using injuries per 1000 match hours of exposure. HRs for injury were calculated through Cox proportional hazard regression after correction for influential covariates.A total of n=426 injuries were reported across the playing season. Over 50% of injuries occurred in the tackle situation or during collisions (270/426), with few reported during set plays. The 3 most common injury sites were head/face (n=102, 23.9%), clavicle/shoulder (n=65, 15.3%) and the knee (n=56, 13.1%). Sprain (n=133, 31.2%), concussion (n=81, 19%) and muscle injury (n=65, 15.3%) were the most common diagnoses. Injury incidence is calculated at 29.06 injuries per 1000 match hours. There were no catastrophic injuries. A large percentage of injuries (208/424) resulted in absence from play for more than 28 days. Concussion carried the most significant time out from play (n=33; 15.9%), followed by dislocations of the shoulder (n=22; 10.6%), knee sprains (n=19, 9.1%), ankle sprains (n=14, 6.7%), hand/finger/thumb (n=11; 5.3%). 36.8% of participants in the study (304/825) suffered at least one injury during the playing season. Multivariate models found higher risk of injury (adjusted HR (AHR); 95% CI) with: higher age (AHR 1.45; 1.14 to 1.83), heavier weight (AHR 1.32; 1.04 to 1.69), playing representative rugby (AHR 1.42; 1.06 to 1.90) and undertaking regular strength training (AHR 1.65; 1.11 to 2.46). Playing for a lower ranked team (AHR 0.67; 0.49 to 0.90) and wearing a mouthguard (AHR 0.70; 0.54 to 0.92) were associated with lower risk of injury.There was a high incidence of severe injuries, with concussion, ankle and knee ligament injuries and upper limb fractures/dislocations causing greatest time loss. Players were compliant with current graduated return-to-play regulations following concussion. Physical stature and levels of competition were important risk factors and there was limited evidence for protective equipment.
춘계학술대회 : 포스터전시 ; 간경화 환자의 간기능에 있어서 분지형 아미노산의 효과
Authors: 편래현, 고광현, 황성규, 임규성, 박필원, 홍성표
Journal: Clinical and Molecular Hepatology (2005)

배경/목적: 간경화 환자에 있어서 경구형 분지형 아미노산(branched-chain amino acids)의 투여가 간기능에 어떠한 영향을 주는지 연구하였다. 대상 및 방법: 2001년 1월부터 2003년 7월까지 분지형 아미노산을 투여한 38명의 환자와 분지형 아미노산을 투여하지 않은 100명을 대상으로 간암의 발생빈도, 알부민, 빌리루빈, 프로트롬빈 시간, Child-Pugh score 등을 후향적 연구를 하였다. 결과: 분지형 아미노산을 투여한 환
EGFR mutations detected by high-resolution melting analysis (HRMA) as a predictor of response and survival in non-small cell lung cancer (NSCLC) patients treated with gefitinib
Authors: T. Takano, Y. Ohe, K. Furuta, K. Tsuta, K. Nomoto, Y. Matsuno, T. Fukui, I. Sekine, H. Kunitoh, T. Tamura
Journal: Journal of Clinical Oncology (2006)

7075 Background: Recent studies have shown that EGFR mutations, mainly deletions in exon 19 (DEL) and L858R, are associated with gefitinib sensitivity in patients (pts) with NSCLC. We established a new easy method, using high-resolution melting analysis (HRMA), for detecting DEL and L858R mutations even from small biopsy or cytology samples, and evaluated the significance of EGFR mutations in NSCLC on a larger scale. Methods: Among 364 advanced or recurrent NSCLC pts treated with gefitinib between Jul 2002 and Dec 2004, HRMA was performed in 207 pts from whom specimens were available. DNA extracted from the archival tissue or cytology samples not subjected to microdissection was analyzed to detect DEL and L858R using HR-1 (Idaho Technology), an HRMA device. To validate this method, the results were compared with direct sequencing data obtained from microdissected tumor cells from surgical specimens in 66 pts. Results: Tissue/cytology/both samples were analyzed in 91/77/39 pts. EGFR mutations were detected in 85 (41%; DEL/L858R: 49/36) of the 207 pts. In the comparison with direct sequencing, consistent results were obtained from all of the 66 tissue samples, while false negative results were obtained in 2 of the 28 cytology samples. EGFR mutations were seen more frequently in women (54% vs. 31%; P = .001), never-smokers (53% vs. 32%; P = .002), and pts with adenocarcinoma (44% vs. 11%; P = .007). CR/PR/SD/PD was observed in 2/64/11/8 pts with EGFR mutations and in 0/10/23/89 pts with wild-type EGFR. The response rate (78% vs. 8%), time to progression (median, 9.1 vs. 1.6 months) and overall survival (median, 19.9 vs. 9.1 months) were all significantly superior in pts with EGFR mutations (P &lt; .0001). Minor response and/or long SD (&gt;6 months) was observed more frequently in SD pts with EGFR mutations than in those with wild-type EGFR (91% vs. 26%; P &lt; .001). Among the pts with EGFR mutations, the response rate was significantly higher in the pts with DEL than in those with L858R (86% vs. 67%; P = .037). Conclusions: HRMA is a practical and precise method to detect DEL and L858R mutations. EGFR mutations strongly predict a better response and longer survival in NSCLC pts treated with gefitinib. No significant financial relationships to disclose.
Measurable or assessable disease in lung cancer trials: does it matter?
Authors: J R Jett, J Q Su, J E Krook, R M Goldberg, J W Kugler
Journal: Journal of Clinical Oncology (1994)

PURPOSE The goals of this study were to analyze and compare the major clinical response rates and survival of patients with either measurable or assessable disease status to treatment with systemic chemotherapy. PATIENTS AND METHODS All patients had stage IIIB or IV non-small-cell lung cancer (NSCLC) and were enrolled onto three consecutive phase III clinical trials. Patients were stratified by disease status (measurable or assessable) before randomization to systemic chemotherapy. The three trials were conducted in the setting of a multicenter cooperative oncology group. Composite data were obtained for the three trials. Major clinical responses, time to progression, and survival were analyzed and compared in patients with measurable or assessable disease using standard statistical methods. RESULTS Four hundred twenty-six patients were enrolled onto the three trials from June 1981 through August 1990. Measurable disease was present in 236 patients (55%) and assessable disease in 190 (45%). Each study was well balanced for the number of patients with measurable or assessable disease on either treatment regimen. A major clinical response was observed in 71 patients with measurable disease (30%; 95% confidence interval [CI], 24 to 36). Forty patients with assessable disease responded to treatment (21%; 95% CI, 16 to 28) (P = .04). The time to progression for all patients (P = .23) and for responders only (P = .10) was not significantly different based on disease status. Overall survival and survival of responders only was not significantly different, but patients with assessable disease tended to do better. Using multivariate analysis, sex and disease status had a borderline influence on the major response rate (P = .05). Performance score (PS) was the only factor that was significantly correlated with survival. CONCLUSION NSCLC patients with assessable disease have major clinical response rates, time to progression, and survival that are similar to those of NSCLC patients with measurable disease. This study supports the inclusion of patients with assessable-disease lung cancer in both phase II and III trials conducted in the cooperative group setting.
An Electron Microscope Study of Glycogen Formation in Novikoff Ascites-Hepatoma Cells<xref ref-type="fn" rid="FN2">2</xref>
Authors: S. Karasaki, V. N. Nigam
Journal: JNCI Journal of the National Cancer Institute (1969)

Electron microscopy of Novikoff ascites-hepatoma cells after their incubation with glucose revealed abundant “rosette”-shaped glycogen particles in the cytoplasm of the tumor cells.
Early HIV treatment to forestall drug resistance
Authors: Mark A Wainberg
Journal: The Lancet Infectious Diseases (2016)

In this issue, Ravindra Gupta and colleagues1 present compelling findings of the epidemiology of HIV drug resistance. Based on the results of a collaborative study termed TenoRes, the researchers clearly document that the prevalence of HIV drug resistance against the commonly used antiretroviral drug tenofovir is far higher than expected, especially in sub-Saharan Africa. This result is disconcerting because it had previously been thought that tenofovir might be less prone to development of drug resistance than other compounds.
A phase Ib study of oral panobinostat (LBH589) administered with 5-azacitidine (5-Aza) in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML).
Authors: O. G. Ottmann, P. Fenaux, M. Lübbert, D. J. DeAngelo, G. Garcia-Manero, K. N. Bhalla, M. A. Sekeres, F. Lüdicke, H. J. Weber, I. J. Winiger
Journal: Journal of Clinical Oncology (2010)

TPS282 Background: The demethylating agent 5-Aza is an integral therapy in MDS and AML, in which epigenetic modifications contributing to disease are well-documented. Despite an overall survival benefit, better and earlier responses are needed. Combination of a demethylating agent and a deacetylase inhibitor (DACi) is a rational strategy to reverse aberrant epigenetic alterations and the malignant phenotype. Preclinical data indicate that sequential treatment with demethylating agents and DACi targets multiple mechanisms to synergistically de-repress silenced genes and exert antileukemic activity. Panobinostat (PAN; LBH589) is a potent pan-DACi that has demonstrated antileukemic activity in patients (pts) with AML and MDS. This phase Ib, open-label, multicenter, dose-finding study comprises 2 phases: a dose-escalation phase to determine the maximum tolerated dose (MTD) of PAN in combination with standard dose 5-Aza, and a subsequent expansion phase to further evaluate safety, tolerability, and antileukemic activity (FPFV Dec 2, 2009). Other objectives include assessment of gene expression and methylation status in peripheral blood cells before and during therapy. Methods: Adult pts with IPSS INT-2 or high-risk MDS, CMML, or AML with multi-lineage dysplasia and ≤30% marrow blasts who are candidates for therapy with 5-Aza and have not received epigenetic therapy are eligible. Oral PAN is administered on Days (D) 3, 5, 8, 10, 12, and 15 of a 28-D cycle, starting at 20 mg and guided by a Bayesian logistic regression model with overdose control, in combination with 5-Aza (75 mg/m2 sc D 1–7). At least 3 pts are required per dose cohort and ≥9 evaluable pts are required to declare MTD. An additional 11 pts will be enrolled at MTD for the dose-expansion phase. Treatment is continued until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint is incidence of dose-limiting toxicity. Secondary endpoints include type, duration, frequency, and relatedness of adverse events. Exploratory endpoints include clinical response and hematologic improvement according to IWG criteria. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Celgene, Novartis Novartis Bristol-Myers Squibb, Celgene, Cepahlon, Johnson & Johnson, Merck, Novartis, Roche Bristol-Myers Squibb, Celgene, Novartis Novartis
Recombinant Human Thrombopoietin and Rituximab vs Rituximab Monotherapy in Corticosteroid-Resistant Primary Immune Thrombocytopenia: a Multicenter Randomized Controlled Study
Authors: Miao Xu, Ping Qin, Xiaoyuan Dong, Jie Li, Haiyan Zhang, Xin Wang, Yuesheng Meng, Chenglu Yuan, Hongguo Zhao, Jun Peng, Ming Hou
Journal: Blood (2013)
Recent horizontal transfer of a mariner transposable element among and between Diptera and Neuroptera.
Authors: H M Robertson, D J Lampe
Journal: Molecular Biology and Evolution (1995)

Transposable elements of the mariner family are widespread among insects and other invertebrates, and initial analyses of their relationships indicated frequent occurrence of horizontal transfers between hosts. A specific PCR assay was used to screen for additional members of the irritans subfamily of mariners in more than 400 arthropod species. Phylogenetic analysis of cloned PCR fragments indicated that relatively recent horizontal transfers had occurred into the lineages of a fruit fly Drosophila ananassae, the horn fly Haematobia irritans, the African malaria vector mosquito Anopheles gambiae, and a green lacewing Chrysoperla plorabunda. Genomic dot-blot analysis revealed that the copy number in these species varies widely, from about 17,000 copies in the horn fly to three copies in D. ananassae. Multiple copies were sequenced from genomic clones from each of these species and four others with related elements. These sequences confirmed the PCR results, revealing extremely similar elements in each of these four species (greater than 88% DNA and 95% amino acid identity). In particular, the consensus sequence of the transposase gene of the horn fly elements differs by just two base pairs out of 1,044 from that of the lacewing elements. The mosquito lineage has diverged from the other Diptera for over 200 Myr, and the neuropteran last shared a common ancestor with them more than 265 Myr ago, so this high similarity implies that these transposons recently transferred horizontally into each lineage. Their presence in only the closest relatives in at least the lacewing lineage supports this hypothesis. Such horizontal transfers provide an explanation for the evolutionary persistence and widespread distribution of mariner transposons. We propose that the ability to transfer horizontally to new hosts before extinction by mutation in the current host constitutes the primary selective constraint maintaining the sequence conservation of mariners and perhaps other DNA-mediated elements.
Current exposure to pollution has greater health impact than former exposure, study shows
Authors: Ingrid Torjesen
Journal: BMJ (2016)

The health risks of exposure to pollution follow a similar pattern to those from exposure to tobacco smoke, a study has found. It also noted a marked acute rise in risk from living in a polluted area, which then tails off if someone moves to a place with cleaner air.1

The study, published in Thorax , also said that, while overall pollution levels seemed to be dropping in the United Kingdom, the pollution itself seemed to be more toxic now.

Researchers from Imperial College London used historical pollution monitoring data on black smoke and sulphur dioxide taken in 1971, 1981, and 1991, as well as PM10 levels (fine particulates of ≤10 micrometers in diameter) taken in 2001, to estimate the level of exposure of 367 658 people at those four specific times, according to where they were living …