tbuckley/cabot-search huggingface dataset:
Mitogen-activated protein kinase phosphatase-1 (MKP-1) as a biomarker of resistance to cetuximab in colorectal cancer patients.
Authors: M. Iglesias, F. G. Rojo, A. Martinez-Fernandez, M. Arumí, B. Bellosillo, A. Rovira, J. Bellmunt, J. Albanell, C. Montagut
Journal: Journal of Clinical Oncology (2010)

e14018 Background: The validation of KRAS mutations as a negative marker of response to the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab has meant a seminal advance towards treatment individualization of colorectal cancer (CRC) patients. However, since KRAS wild-type status does not guarantee response to anti-EGFR antibodies, identification of other biomarkers of response is urgently needed. We hypothesized that MKP-1, a phosphatase that inactivates phospho-MAPKs including the EGFR downstream protein ERK, could be a mediator of resistance to anti-EGFR antibodies. Methods: Tumor specimens from 48 metastatic CRC patients treated with cetuximab-based chemotherapy were evaluated for KRAS and BRAF mutational status as well as MKP-1 expression as assessed by immunohistochemistry. Results: As expected, clinical benefit was confined to wild-type KRAS and BRAF patients. MKP-1 was overexpressed in 16 patients (33%) and was not associated with patient baseline clinical characteristics or KRAS mutational status. All patients with BRAF mutations (n = 3) had MKP-1 overexpression. Among KRAS wild-type patients, MKP-1 overexpressors had a 7% response rate while patients non- overexpressing MKP-1 had a 44% response rate (p = 0.03). Moreover median time to progression was significantly longer in MKP-1 non-overexpressing patients (32 vs. 13 weeks, p = 0.009). Conclusions: These results support the concept of MKP-1 as a promising marker of resistance to cetuximab-based treatment in colorectal cancer patients with KRAS wild-type status. No significant financial relationships to disclose.
Abstract 16523: Prevalence of Major Geriatric Syndromes in Older Patients Hospitalized for Acute Cardiac Conditions in a Cardiology Unit and Influence in 1-Year Outcomes
Authors: Elisabet Sanchez, Maria T Vidan, Jose Antonio Serra, Francisco Fernandez-Aviles, Hector Bueno
Journal: Circulation (2010)

Background: Geriatric syndromes are prevalent multi-factorial conditions seen in elderly patients that increase their vulnerability, and influence their treatment and prognosis. The aim of the stud...
Abstract 18304: Clinical Impact of Initial Reduction of Low-density Lipoprotein Cholesterol Level on Long-term Outcome of Acute Myocardial Infarction in the Statin Era
Authors: Takashi Miura, Atsushi Izawa, Hirohiko Motoki, Yusuke Miyashita, Yuichiro Kashima, Takeshi Tomita, Takeshi Tomita, Jun Koyama, Uichi Ikeda
Journal: Circulation (2014)

Background: In terms of secondary prevention of acute myocardial infarction (AMI), optimal period for achievement of target percent reduction of LDL-C level has not yet been well established. Methods: The Assessment of Lipophilic vs. Hydrophilic Statin Therapy in AMI (ALPS-AMI) study enrolled a total of 508 patients (mean age, 66.0±11.6 years, 80.6% male) hospitalized for AMI. Of these patients, 248 patients achieved percent reduction of LDL-C ≧ 30% until 8 week after randomization, 204 patients achieved at 4 week (early reduction group), 44 patients achieved at 8week (late reduction group). The two groups were identified prospectively and analyzed with regard to the composite end point (MACE: all-cause death, myocardial infarction, stroke). We evaluated long term clinical outcomes of AMI patients after PCI in terms of the period for achievement of target percent reductions in LDL-C. Results: MACE were significantly higher in the late reduction group compared to early reduction group (20.5% vs. 3.9 %, P&lt;0.0001). The incidence of cardiac death were[[Unable to Display Character: &amp;#8195;]]significantly higher in the late reduction group than early reduction group (6.8% vs. 0.5%, P=0.003). In multivariate Cox proportional hazards analysis, percent reduction level of LDL-C during initial 4 week (HR, 0.93; 95% CI: 0.89-0.96, P&lt;0.0001) and baseline LDL-C level (HR, 0.98; 95% CI: 0.96-0.99, P=0.038) predicted adverse events after adjustment for age. Conclusions: The earlier reduction of LDL-C level is important for the patients with AMI in terms of reduction of ischemic events. We should reduce LDL-C level to target percent reductions for at least moderate-intensity statin therapy as early as 4 weeks after primary PCI in patients with AMI.
BIOSYNTHESIS OF ADRENALINE AND NORADRENALINE
Authors: Norman Kirshner
Journal: Pharmacological Reviews (1959)

The metabolic pathway for the formation of adrenaline and noradrenaline has been established, but much remains to be done on the individual reactions. Only two of the reactions in the sequence, the decarboxylation of DOPA and the N-methylation of noradrenaline, have been demonstrated with any clarity of detail. The oxidation of phenylalanine to tyrosine has been studied in other tissues and it is highly probable that the same system applies to the adrenal medulla. The formation of DOPA from tyrosine has been found to be catalyzed by tyrosinase both in invertebrates and in mammalian tissues and it is likely that this enzyme may also be found in the adrenal medulla. The reaction in which noradrenaline is formed from hydroxytyramine is the least understood of the entire sequence. Initial studies indicate that this reaction is complex but show promise of elucidation.
Abstract 10833: Comprehensive Quantitative Epigenome Mapping Reveals the Differential Induction of Histone H3 Lysine 4 Trimethylation Marks in Pressure-overloaded Murine Hearts
Authors: Shuichiro Higo, Yoshihiro Asano, Seiji Takashima, Masafumi Kitakaze, Issei Komuro
Journal: Circulation (2012)

Background Although recent findings have revealed that environmental stimuli alter both transcriptional and epigenetic states, it remains uncertain whether both transcriptional changes and active e...
A Synthesis is Emerging between Biodiversity–Ecosystem Function and Ecological Resilience Research: Reply to Mori
Authors: Tom H. Oliver, Matthew S. Heard, Nick J.B. Isaac, David B. Roy, Deborah Procter, Felix Eigenbrod, Rob Freckleton, Andy Hector, C. David L. Orme, Owen L. Petchey, Vânia Proença, David Raffaelli, K. Blake Suttle, Georgina M. Mace, Berta Martín-López, Ben A. Woodcock, James M. Bullock
Journal: Trends in Ecology & Evolution (2016)
Fasting glucose and triglycerides as biomarkers of mTOR inhibition, evidence of a categorical response.
Authors: A. S. Nallari, T. Karrison, G. L. Rosner, M. R. Levine, L. Sit, K. Wu, W. M. Stadler, M. J. Ratain, E. E. Cohen, M. L. Maitland
Journal: Journal of Clinical Oncology (2010)

3091 Background: Hyperglycemia and hypertriglyceridemia are mechanism-based toxicities of mammalian target of rapamycin (mTOR) inhibitors, but have not been intensively studied as potential pharmacodynamic biomarkers. Methods: Changes in fasting serum glucose and triglyceride concentrations were determined in 127 patients (pts) before, and 4 weeks after treatment with the mTOR inhibitor sirolimus/rapamycin (S). Pts were enrolled in three different trials of S administered to achieve AUC of 1,000-6,000 ng-hr/ml. Results: Of these pts (67 male; 60 female; median age 62 y [range of 27-82], 72 had fasting measures for both glucose and triglycerides. Twelve pts had Type II diabetes. Mean/median change: in glucose = 17/8 mg/dL (SD=32, 95% CI 10-25, p< 0.0001), in triglycerides = 51/31 mg/dL (SD= 76, 95% CI 33-69, p< 0.0001) (p values for paired T-test). Changes were not associated with sex, S dose, baseline triglycerides, or use of lipid lowering agents. Change in glucose was significantly associated with a history of diabetes (larger increases in pts with a history, p<0.001) and baseline glucose levels (smaller increases in pts with higher baseline levels, p= 0.002). The Table features a striking observation. Of 72 pts, only 7 had no increase in glucose or triglyceride concentrations, and 9 had S- related increases in both glucose(>20 mg/dL) and triglycerides(>50 mg/dL). Meanwhile, 17 pts increased triglycerides of >50 mg/dL and 14 increased glucose of > 20 mg/dL without a change in the other marker. There was no evidence for association between changes in glucose and triglycerides (p = 0.72 by McNemar's test). Conclusions: Fasting blood glucose and triglyceride changes might be independent effects of mTOR inhibition. This would explain the absence of correlation between glucose and triglyceride changes and, excepting history of diabetes and changes in glucose, lack of association with clinically relevant covariates. These data suggest a new approach for developing these inexpensive validated laboratory measurements for qualification as clinically useful pharmacodynamic markers of mTOR inhibition. Δ glucose≤ 20 mg/dL Δglucose>20 mg/dL Δtriglycerides ≤ 50 mg/dL 32 14 Δtriglycerides > 50 mg/dL 17 9 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories, Amgen, Astellas Pharma, Biomarin, Daiichi Sankyo, Gilead, Millennium, Novartis, Pfizer, Takeda, Wyeth Actelion, Bayer, Bristol-Myers Squibb, EMD Serono, Genentech, Gilead, Lilly, Novartis, Pfizer, Roche patent pending for use of sorafenib in pulmonary hypertension
Regulation of proliferation in endometrial carcinoma cell line by the epidermal growth factor receptor and estrogen receptor beta.
Authors: J. H. Farley, M. Clark, T. J. Wu
Journal: Journal of Clinical Oncology (2010)

5087 Background: The epidermal growth factor receptor (EGFR) family can subvert the ability of estrogens to regulate the cell cycle in breast cancer cell lines. The purpose of this study is to determine the role of the EGFR, and estrogen receptor beta (ER-β) in regulating the growth of uterine cancer cells exposed to estrogen. Methods: We performed growth studies on ER positive Ishikawa cell lines. Ishikawa cell lines were treated in a dose-dependent manner (0- and 0.1- to 103-nM) with estradiol-17b (E2) to determine the ability of estrogen to regulate cellular growth. Cell lines were also treated with epidermal growth factor (EGF) as a positive control. A tetrazolium-based assay was used to determine the effect these compounds had on cell proliferation. EGFR, pEGFR, Akt, pAkt, and ER-β protein expression was measured by Western blot after EGF and E2 administration. Results: EGF and E2 exposure had proliferative effects on Ishikawa cell lines. EGF increased pEGFR expression up to 200% when compared to vehicle (VEH-treated cells) after 5 min, while EGFR expression was unchanged. pAkt expression was increased 20% by EGF exposure while Akt expression decreased by 40% when compared to vehicle after 5 min. EGF increased ER-β expression up to 60% when compared to vehicle after 15 min. E2 increased pEGFR expression up to 300% when compared to vehicle after 5 min, while EGFR expression decreased by 50%. Interestingly, pAkt expression was unchanged by E2 exposure while Akt expression decreased by 40% when compared to vehicle after 15 min. Finally, E2 exposure also increased ER-β expression up to 40% when compared to vehicle after 15 min. Conclusions: The results suggest that E2 may have a selective proliferative effect on endometrial cancer cells through activation of EGFR, and subsequent increase in ER-β rather than activation of the phosphatidylinositol 3-kinase (PI3-kinase) pathway. This apparent robust activation of EGFR by E2 on ER positive Ishikawa cell lines with lack of effect on PI3-kinase pathway could explain the observation that PTEN inactivation is an essential, necessary, early event in endometrial cancer carcinogenesis. No significant financial relationships to disclose.
S-adenosylmethionine treatment of depression: a controlled clinical trial
Authors: K M Bell, L Plon, W E Bunney, S G Potkin
Journal: American Journal of Psychiatry (1988)

The antidepressant properties of S-adenosylmethionine, an endogenous methyl donor, were studied in inpatients who met the DSM-III criteria for major depression. Nine patients given intravenous S-adenosylmethionine and nine given low oral doses of imipramine were compared in a double-blind design for 14 days. The S-adenosylmethionine produced superior results by the end of the first week of treatment. By the end of the second week, 66% of the S-adenosylmethionine patients had a clinically significant improvement in depressive symptoms, compared to 22% of the imipramine patients. Side effects appeared to be fewer with S-adenosylmethionine than with imipramine during the last 5 days of the study.
A pilot study of PLX3397, a selective colony-stimulating factor 1 receptor (CSF1R) kinase inhibitor, in pigmented villonodular synovitis (PVNS).
Authors: William D. Tap, Stephen Patrick Anthony, Bartosz Chmielowski, Arthur P. Staddon, Allen Lee Cohn, Geoffrey Shapiro, Igor Puzanov, Eunice L Kwak, Andrew J Wagner, Charles Peterfy, Henry H Hsu, Carolyn Gee, Paul S. Lin, Sandra Tong, Zev A. Wainberg
Journal: Journal of Clinical Oncology (2014)

10503^ Background: PLX3397 is a novel, oral small molecule that potently and selectively inhibits CSF1R, Kit, and Flt3 kinases. CSF1R and Kit regulate key components of both the tumor and its microenvironment (macrophages, osteoclasts, mast cells). PVNS is a rare proliferative neoplasm involving the synovium of joints or tendon sheaths. Tumors contain CSF1R-bearing macrophages recruited by local overexpression of CSF-1 due to a gene translocation. Methods: Patients (pts) with advanced PVNS were enrolled onto an expansion cohort of an ongoing single-arm, multicenter, clinical study. PLX3397 was given orally, 1000 mg daily (600 mg AM, 400 mg PM – 28 day cycles). MRI assessment by a central musculoskeletal radiologist blinded to chronology was performed every 2 cycles using a novel Tumor Volume Score (TVS) developed specifically for PVNS. Partial response (PR) was defined as ≥50% decrease in TVS compared to screening and progressive disease was ≥30% increase relative to lowest score. Patients remained on treatment until disease progression or intolerability. Results: 17 PVNS pts have been enrolled to date. Median exposure 166 days (range 23- 264). 59% pts were women; median age 46 yrs (range 22-80). Tumor locations: knees (12), ankles (2), feet (2), elbow (1). Of the 11 pts with evaluable MRI scans at this interim analysis, 7 pts (64%) achieved a PR and 4 pts (36%) had stable disease (SD). Mean tumor size reduction was 51% (range: -10% to -88%). Clinical improvements were seen in pain, stiffness, and overall function. Common AEs (>10%): fatigue, nausea, hair color changes, and diarrhea. Treatment-related AEs ≥Grade 3: anemia (1), hyponatremia (2), elevated ALT and AST (1), fatigue (1) and diarrhea (1). Conclusions: PLX3397 was well tolerated and demonstrated profound activity as measured by a novel response criterion in pts with advanced PVNS. PLX3397 warrants further study in a larger clinical trial. Clinical trial information: NCT01004861.Percent change in TVS compared to screening. Patient Cycle Best response 3 5 7 9 1 -64% -40% -68% -64% PR 2 -85% -85% -87% -88% PR 3 -50% -50% -50% -58% PR 4 -60% -75% - -83% PR 5 -13% -13% -13% - SD 6 -42% -50% -58% - PR 7 -5% -10% - - SD 8 -40% - - - SD 9 -43% -57% - - PR 10 -50% - - - PR 11 -39% - - - SD
Manufacturers failed to report infections from duodenoscopes, US investigation finds
Authors: Michael McCarthy
Journal: BMJ (2016)

Manufacturers of hard to clean duodenoscopes that spread potentially life threatening, antibiotic resistant bacterial infections to hundreds of patients in the United States and Europe failed to meet their legal obligations to report serious infections and deaths to federal regulators, says a US Senate committee report released on 13 January.1

The report, the result of a year long investigation by the Senate Health, Education, Labor, and Pensions Committee, also found that almost all the US hospitals where the infections occurred failed to properly inform health officials of the outbreaks. The investigators estimated that the outbreaks, which occurred in 2013 and 2014, were responsible for at least 250 deaths, considerably more than previous estimates.

“These outbreaks occurred despite the fact that the manufacturer of 85% of the duodenoscopes used in the United States, Olympus, was aware by early 2012 that its …
Hemangioendothelioma of the Lung
Journal: JAMA (1963)

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Intratumoral heterogeneity in glioblastoma: don't forget the peritumoral brain zone
Authors: Jean-Michel Lemée, Anne Clavreul, Philippe Menei
Journal: Neuro-Oncology (2015)

Glioblastoma (GB) is the most frequent and aggressive primary tumor of the central nervous system. Prognosis remains poor despite ongoing progress. In cases where the gadolinium-enhanced portion of the GB is completely resected, 90% of recurrences occur at the margin of surgical resection in the macroscopically normal peritumoral brain zone (PBZ). Intratumoral heterogeneity in GB is currently a hot topic in neuro-oncology, and the GB PBZ may be involved in this phenomenon. Indeed, this region, which possesses specific properties, has been less studied than the core of the GB tumor. The high rate of local recurrence in the PBZ and the limited success of targeted therapies against GB demonstrate the need for a better understanding of the PBZ. We present here a review of the literature on the GB PBZ, focusing on its radiological, cellular, and molecular characteristics. We discuss how intraoperative analysis of the PBZ is important for the optimization of surgical resection and the development of targeted therapies against GB.
Intralymphatic treatment of flagellin-ovalbumin mixture reduced allergic inflammation in murine model of allergic rhinitis
Authors: E. H. Kim, J. H. Kim, R. Samivel, J.-S. Bae, Y.-J. Chung, P.-S. Chung, S. E. Lee, J.-H. Mo
Journal: Allergy (2016)

Bacterial flagellin, a Toll-like receptor 5 agonist, is used as an adjuvant for immunomodulation. In this study, we aimed to evaluate the effect and its mechanism following intralymphatic administration of OVA-flagellin (FlaB) mixture in the mouse model of allergic rhinitis.BALB/c mice were sensitized with OVA and treated with an OVA-FlaB mixture via intranasal, sublingual, and intralymphatic routes to evaluate the effect of each treatment. Several parameters for allergic inflammation and its underlying mechanisms were then evaluated.Intralymphatic injection of the OVA-FlaB mixture reduced symptom scores, eosinophil infiltration in the nasal mucosa, and total and OVA-specific IgE levels more significantly than intranasal and sublingual administration. Systemic cytokine (IL-4, IL-5, IL-6, IL-17, and IFN-γ) production and local cytokine (IL-4 and IL-5) production were also reduced significantly after intralymphatic injection with OVA-FlaB. Double intralymphatic injection of the mixture was more effective than single injection. Moreover, the expression of innate cytokines such as IL-25 and IL-33 in nasal epithelial cells was reduced, and the expression of chemokines such as CCL24 (eotaxin-2), CXCL1, and CXCL2 was decreased in the nasal mucosa, suggesting the underlying mechanism for intralymphatic administration of the OVA-FlaB mixture.Intralymphatic administration of an OVA-FlaB mixture was more effective in alleviating allergic inflammation than intranasal and sublingual administration in a mouse model of allergic rhinitis. This effect may be attributed to the reduced expression of innate cytokines and chemokines. This treatment modality can be considered as a new therapeutic method and agent.
Diversity of Gene Expression in Hepatocellular Carcinoma Cells
Authors: Fan Zhang, Li Cui, Michael D. Kuo
Journal: Genomics Proteomics & Bioinformatics (2015)

Abstract Understanding tumor diversity has been a long-lasting and challenging question for researchers in the field of cancer heterogeneity or tumor evolution. Studies have reported that compared to normal cells, there is a higher genetic diversity in tumor cells, while higher genetic diversity is associated with higher progression risks of tumor. We thus hypothesized that tumor diversity also holds true at the gene expression level. To test this hypothesis, we used t-test to compare the means of Simpson’s diversity index for gene expression (SDIG) between tumor and non-tumor samples. We found that the mean SDIG in tumor tissues is significantly higher than that in the non-tumor or normal tissues (P &amp;lt; 0.05) for most datasets. We also combined microarrays and next-generation sequencing data for validation. This cross-platform and cross-experimental validation greatly increased the reliability of our results.
GP who orchestrated cigarette scam is struck off
Authors: Clare Dyer
Journal: BMJ (2016)

A GP who helped his girlfriend smuggle duty free cigarettes into the United Kingdom and falsely claimed to have won a medal for rescuing a child has been struck off the medical register.

Alan Pollock, 50, was given a two year suspended prison sentence at Lewes Crown Court in January 2015 after admitting running the cigarette scam between 2011 and 2013 with his …