tbuckley/cabot-search huggingface dataset:
Abstract 3658: Structure-guidedde novodesign of selective Mcl-1 Inhibitors: Synthesis, structural and biochemical characterization
Authors: Ahmed Mady, Lei Miao, Andrej Perdih, Chenzhong Liao, Naval Bajwa, Jeanne Stuckey, Zaneta Nikolovska-Coleska
Journal: Cancer Research (2015)

Abstract Myeloid cell leukemia-1 (Mcl-1) is a potent anti-apoptotic protein, member of the prosurvival Bcl-2 family. Amplification of the gene encoding the Mcl-1 protein is a common genetic aberration in human cancer. Overexpression of Mcl-1 is associated with high tumor grade, resistance to chemotherapy and poor prognosis in many types of cancers. Thus Mcl-1 is emerging as a critical survival factor in a broad range of human cancers and represents an attractive molecular target for development of a new class of cancer therapy. There is still need for developing BH3 mimetics that can efficiently and selectively target Mcl-1 protein. Employing de-novo structure-based drug-design, we have designed a new class of potent small-molecule Mcl-1 inhibitors based on the initial lead compound discovered by high-throughput screening. Analyzing the binding model of this compound with Mcl-1 through computational docking supported by HSQC NMR studies, and using the structural information, we have designed and optimized a class of small-molecule inhibitors of Mcl-1 using a 2-(phenylsulfonamido) benzoic acid as a scaffold to reproduce the key interactions with Mcl-1 such as the conserved hydrogen bond between the aspartate in pro-apoptotic proteins and Arg263 in Mcl-1. Several co-crystal structures of this class inhibitors in complex with Mcl-1 have provided a basis for their further optimization which ultimately led to the discovery of ligands with low-nanomolar potency (Ki = 8 nM) and selectivity for Mcl-1. These compounds bind in the canonical BH3 binding groove. Interestingly, depending on the particular substitution pattern in the core scaffold, a “flip’ binding mode was observed where the substituents bind in a reverse orientation. These findings were confirmed by X-ray crystallography. The most potent compounds were further biologically characterized with a series of complementary biochemical and functional assays. Citation Format: Ahmed Mady, Lei Miao, Andrej Perdih, Chenzhong Liao, Naval Bajwa, Jeanne Stuckey, Zaneta Nikolovska-Coleska. Structure-guided de novo design of selective Mcl-1 Inhibitors: Synthesis, structural and biochemical characterization. [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 3658. doi:10.1158/1538-7445.AM2015-3658
Continuous Culture of Human Melanoma Cells in Protein-Free Medium: Establishment and Partial Characterization
Authors: M Urade, S Hamada, M Sugi, K Watatani, T Miyazaki
Journal: JNCI Journal of the National Cancer Institute (1984)

Human melanoma cells (MEC) continuously grown in protein-free RPMI-1640 medium were established. These cultured cells, designated "sf-MEC," grow well in suspension and have been successfully subcultured more than 100 passages for 30 months with complete loss of serum requirement for their growth. Although sf-MEC as well as MEC had a moderate number of mature melanosomes in the cytoplasm, the tumorigenicity in nude mice was lower in sf-MEC than in MEC. In the tumor tissue formed by sf-MEC but not by MEC, a few immature melanosomes and an increased C-type-like virus production were detected. Furthermore, conditioned medium of sf-MEC stimulated DNA synthesis in both normal and transformed cells, including MEC and sf-MEC. Addition of the conditioned medium of sf-MEC in its cell growth assay caused a twofold to eighteenfold increase in cell number as compared to that for the control.
GP is suspended after prescribing zopiclone for patient to give to neighbours
Authors: Clare Dyer
Journal: BMJ (2016)

A GP who prescribed 28 zopiclone sleeping pills to an elderly patient to push through the letterbox of neighbours who allegedly played music and sang late into the night has been suspended from the medical register for three months.

The Medical Practitioners Tribunal Service also found that Alexander Munro, 67, had failed to properly examine the 84 year old woman, referred to as Patient A, for signs or symptoms of …
Abstract 14037: The Additive Effects of Tricuspid Regurgitation and Pressure Overload in Pulmonary Hypertension on Three-Dimensional Right Ventricular Mechanics and Patient Outcomes
Authors: Keiko Ryo, Akiko Goda, Antonia Delgado-Montero, Bhupendar Tayal, Marc A Simon, Michael A Mathier, John Gorcsan
Journal: Circulation (2014)

Introduction: Pulmonary hypertension (PH) results in chronic right ventricular (RV) pressure overload and variable degrees of tricuspid regurgitation (TR). The combined effects of RV pressure and volume overload on PH patient outcomes are unclear.

Methods: We studied 93 PH patients with invasive hemodynamics and 3D echo imaging (Toshiba Corp.) measuring RV end-diastolic and end-systolic volume index (EDVI, ESVI), and RV ejection fraction (EF). TR was graded (0=none, 1=mild, 2=moderate, 3=severe), PH patients were divided in 4 groups based on the mean pulmonary artery pressure (mPAP) and TR severity (≤ moderate was defined as significant TR+). Outcome analysis over 6 months was the combined end-point of first PH hospitalization, all-cause mortality, lung transplantation or pulmonary endarterectomy.

Results: Of the 93 PH patients, there were 40 (43%) with significant TR+. 3D RV EDVI was larger in patients with significant TR+ than others (129 ml/m2* vs. 93 ml/m2, *p<0.001). RV EF was 30±9%* in patients with significant TR+ vs. 36±9% in those without significant TR (p=0.003). In patients with significant TR+, 19 (48%) had mPAP ≤ 45mmHg and 21 (52%) had mPAP < 45mmHg. Kaplan-Mayer analysis showed that the subgroup of patients with both significant TR+ and mPAP ≤ 45mmHg had the worst prognosis, and TR+ was additive to high mPAP (Log rank p < 0.01).

Conclusion: 3D echocardiographic RV analysis of PH patients with invasive hemodynamics demonstrated that there are additive effects of pressure overload and volume overload by TR on RV mechanics which were strongly related to the outcomes, and of clinical importance.

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Liberalising agricultural policy for sugar in Europe risks damaging public health
Authors: Emilie K Aguirre, Oliver T Mytton, Pablo Monsivais
Journal: BMJ (2015)

2][3][4] Recent research estimates consumption of sugar sweetened beverages will cause about 80 000 excess cases of type 2 diabetes in the UK over 10 years. 1 In early 2015, the World Health Organization recommended intake of free sugars should be less than 10% of daily calories, and preferably below 5%. 5 In July, the UK Scientific Advisory Committee on Nutrition halved its recommendation for free sugars to no more than 5% of daily calories. 6etary sugars (non-milk extrinsic sugars) made up about 15% and 12% of dietary calories among UK children and adults, respectively, in 2012. 7[10] Earlier this year, Public Health England proposed a series of evidence informed measures to reduce sugar consumption. 11So far, relatively little attention has been given to important structural factors, including in agriculture, which influence sugar consumption in the UK. 12-143][14][15][16][17][18][19] The European common agricultural policy has historically protected the European sucrose (sugar beet) industry through interventions that have kept commodity prices high and prevented foreign imports.For the past decade, the EU has been phasing out these protections ("liberalisation").This process will be nearly complete by 2017.We describe the effect liberalisation may have on the production, price, and addition of sugars to processed foods.
Activity of azacitidine in chronic myelomonocytic leukemia.
Authors: R. B. Costa
Journal: Journal of Clinical Oncology (2010)

6574 Background: Hypomethylating drugs are active in the myelodysplastic syndrome (MDS). Two of these drugs, azacitidine and decitabine, have received FDA approval for the treatment of MDS and chronic myelomonocytic leukemia (CMML). However, phase II and III studies assessing these agents in MDS patients included only a small number of patients with CMML. The objective of this report is to evaluate the efficacy and safety of azacitidine in the treatment of CMML. Methods: The records of 38 patients diagnosed with CMML and treated with azacitidine at our institution were reviewed. Azacitidine was administered at 75 mg/m2/day for 7 days or 100 mg/m2/day for 5 days every 4 weeks. Patients who received at least one cycle of the drug were considered evaluable for response. Patient characteristics are described in the Table. Results: Response was assessed by the modified International Working Group (IWG) criteria. The overall response rate was 42% (15/36): complete response (CR) rate was 11% (4/36); partial response (PR) rate was 3% (1/36); hematologic improvement (HI) was 27.7% (10/36). The median overall survival was 12 months. The median overall survival was 13 months for responders and 9 months for nonresponders (p =0.021). Treatment was generally well tolerated. Most common side effects were cytopenia, fatigue, and site irritation. One out of two patients had complete resolution of monocytic skin infiltration. Conclusions: Azacitidine is active in the treatment of CMML. The therapy-associated toxicity is acceptable. Our results support further investigation of azacitidine in this setting, particularly in combination with other agents. Parameter Category No. (%) Age Median age 70.5 years Sex Female 7 (19.4) Splenomegaly Yes 10 (27.7) WBC × 109/L ≤ 13 11 (30.5) > 13 25 (69.4) Cytogenetics Good 19 (52.7) (IPSS) Intermediate 13 (36.1) Poor 3 (8.3) Not performed 1 (2.7) % marrow blasts < 10 26 (72.2) ≥ 10 9 (25) Not known 1 (2.7) Duration of disease < 6 25 (69.4) 6-12 5 (13.8) >12 6 (16.6) Prior therapy for CMML None 16 (44.4) Hydroxyurea 11 (30.5) G-CSF 3 (8.3) Erythropoetin 4 (11.1) Others 7 (19.4) Secondary CMML Yes 3 (8.3) Skin involvement Yes 2 (5.5) Abbreviations: IPSS, International Prognostic Scoring System; CMML, chronic myelomonocytic leukemia. No significant financial relationships to disclose.
Phase I study utilizing an intravenous busulfan test dose to prospectively target and determine the maximum tolerated systemic exposure (MTSE) of a continuous intravenous infusion
Authors: C. M. Walko, T. C. Shea, K. Rao, D. Gabriel, J. Serody, T. Comeau, A. Gilman, C. Krasnov, C. M. Lindley
Journal: Journal of Clinical Oncology (2006)

16502 Background: Busulfan systemic concentration has correlated with toxicity and efficacy. We previously demonstrated that administration of intravenous high-dose busulfan (HD-Bu) as a 90 hour continuous infusion (CIV) has efficacy, safety, and mean daily area under the concentration curves (AUC) comparable to intermittent dosing regimens and that it is possible to use a test dose of busulfan to predict the systemic exposure with less than 10% variability. The objective of this study is to identify the MTSE of CIV HD-Bu utilizing a test dose for AUC targeting. Methods: Prior to HD-Bu, patients received a single test dose of Bu (0.8 mg/kg) by two hour infusion with blood concentrations obtained at 0, 2.5, 4, 5, and 6 hours. Serum concentrations were analyzed using GC-MS. Non-compartmental PK analysis was used to determine clearance using WIN-NONLIN software. The systemic clearance (dose/AUC) of the test dose was used to predict the 90 hour CIV dose of Bu needed to achieve the desired AUC. On days -7 to -3, the treatment dose was administered and blood samples were collected at 0, 12, 16, 18, 48, 60, 72, and 89.5 hours to verify that the desired AUC was reached. Dose adjustments were made after 18 hours if necessary. A blood sample was obtained for evaluation of polymorphisms in genes associated with busulfan metabolism and transport. Results: Five patients (4 MUD, 1 matched-sibling donor) were enrolled at the 24 hour Bu target AUC of 4800 uM*min ± 15%. One patient was not able to be evaluated due to errors in PK acquisition. 3 of the 4 patients required CIV doses different than that based on weight alone (i.e. 12.8 mg/kg). All 4 patients had AUCs within the desired range (mean 24 hour busulfan AUC of 4708 uM*min) with a mean bias and precision of −1.9% and 8.7%, respectively. No adjustments were required after 18 hours. No grade 3 or greater chemotherapy related toxicity has been identified. Conclusions: The systemic clearance determined by a busulfan test dose may be used to prospectively target the desired AUC of a 90 hour CIV. Enrollment on this Phase I study will continue beyond the first dose level which is at the upper limit of the normal range (4800 uM*min). No significant financial relationships to disclose.
Cognitive outcome following tricyclic and electroconvulsive treatment of major depression in the elderly
Authors: A Stoudemire, C D Hill, R Morris, D Martino-Saltzman, H Markwalter, B Lewison
Journal: American Journal of Psychiatry (1991)

This study sought to ascertain the affective and cognitive outcome after tricyclic and electroconvulsive treatment of elderly medical-psychiatric patients meeting diagnostic criteria for major depression, some of whom had normal cognitive functioning and some of whom were cognitively impaired before treatment.Patients who met criteria for major depression on the basis of a structured diagnostic interview and who scored 17 or more on the Hamilton Rating Scale for Depression were evaluated with the Mattis Dementia Rating Scale. The patients were then treated in a nonrandom manner with either tricyclic antidepressants or ECT (followed by tricyclic maintenance therapy). The majority of the patients treated with ECT had not responded previously to tricyclics. Follow-up psychometric testing was repeated in 6 months.Among the patients with normal pretreatment cognitive functioning, cognition was generally stable. Among the patients with pretreatment cognitive impairment, a substantial number--including those receiving ECT--demonstrated improvement in cognition. While the majority of patients improved with respect to both their affective and cognitive states, certain treatment-refractory subgroups were nevertheless identified.The data suggest that cognitive dysfunction associated with depression may improve after treatment in a substantial number of elderly patients, including those receiving ECT. Relapse rates, however, may be relatively high, and residual symptoms may persist, which emphasizes the need for optimal initial and long-term antidepressant strategies for this population.
Phase III randomised trial of doxorubicin (A) and docetaxel (D) versus A and cyclophosphamide (C) as primary medical therapy (PMT) in women with breast cancer
Authors: T. R. J. Evans, A. Yellowlees, E. Foster, H. Earl, D. A. Cameron, A. W. Hutcheon, R. E. Coleman, J. Crown, R. C. Leonard, J. L. Mansi
Journal: Journal of Clinical Oncology (2004)

521 Background: Use of PMT as pre-operative therapy for large primary, or locally advanced inoperable, breast cancer (BC)is increasing. Such regimens usually contain A,in combination with C (AC). D is among the most active single agents in metastatic BC and is increasingly used with A in advanced BC. Methods: Patients suitable for PMT (n=363) were randomised to receive up to 6 cycles of either (a) A (50mg/m2) and D (75mg/m2) i/v every 3 weeks, or (b) A (60mg/m2) and C (600mg/m2) i/v every 3 weeks. Patients with operable disease after completing chemotherapy had surgery followed by radiotherapy if indicated, and tamoxifen if ER+. We compared the response rates (clinical and pathological), relapse-free survival (RFS) after subsequent surgery, and overall survival (OS) of patients treated with AC and AD as PMT. Results: Patients with locally advanced inoperable (8%), inflammatory (15%) or large, operable (77%) primary BC, and with no evidence of metastatic disease, were randomised to AC (n=180) or AD (n=183). Clinical response rates (CR+PR) were 61% and 71% for AC and AD respectively (p=0.06). 7 patients treated with AC (4%) and 8 with AD (4%) received less than the planned 6 cycles of chemotherapy due to disease progression, with 14 patients (AC=8, AD=6) withdrawn early due to toxicity despite dose modifications. Pathological involvement of axillary LNs was present at surgery in 61% treated with AC and 66% with AD (p=0.28). Pathological CR rates for AC and AD were 24% and 21% respectively (p=0.61). No significant difference exists yet between the 2 groups for number of relapses. The median RFS and OS have not yet been reached with a median follow-up of 32 months. Conclusions: Both AC and AD are tolerated as PMT in primary BC. There is a trend to a superior clinical response rate with AD compared to AC, which does not reach statistical significance. There is no evidence of differences in the pathological CR rates or axillary LN involvement. In contrast to the positive results reported for sequential D following AC as PMT, our data do not suggest a benefit for simultaneous AD over AC. Updated analyses will be presented at conference. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis
Pathogenesis of Marek's Disease: Early Distribution of Virus and Viral Antigens in Infected Chickens23
Authors: Hans K. Adldinger, Bruce W. Calnek
Journal: JNCI Journal of the National Cancer Institute (1973)

Further evidence supported the earlier observation that the respiratory tract of the chicken is the natural entry for Marek's disease virus (MDV). After inhalation exposure to infectious feather material, a high incidence of infection was established in 2 strains of chickens free of MDV antibody. The results indicated that virions in the feather material were taken up by phagocytic alveolar cells of the lung. Evidence of virus replication was found at that site, but the cells prominent in the early stages of infection were in lymphoid tissues. During substantial virus replication in thymus, spleen, and bursa in the 1st week post exposure, a persistent infection of white blood cells developed. No evidence of an early cell-free period of viral presence in the host was found. The signs of infection subsided briefly in the 2d week post exposure, followed by a progressive lymphoproliferation and spread of the infection to an increasing number of tissue.
Phase Ib safety trial of CVX-060, an intravenous humanized monoclonal CovX body inhibiting angiopoietin 2 (Ang-2), with axitinib in patients with previously treated metastatic renal cell cancer (RCC).
Authors: Ashwin Gollerkeri, Michael S. Gordon, John M. Burke, Ralph Hauke, Jiri Tomasek, Donald A. Richards, Christopher DiSimone, Scott S. Tykodi, Amit R. Mehta, Charles Chen, Rachelle Perea, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2013)

2533 Background: PF-04856884 is a recombinant humanized monoclonal antibody fused to two Ang-2 binding peptides. Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factors (VEGFs) that is approved for patients (pts) with advanced renal cell cancer who failed 1 prior therapy. Metastatic RCC (mRCC) is an angiogenic tumor sensitive to VEGF tyrosine kinase inhibitors. Resistance to VEGF targeted therapy may be mediated by Ang-2. Methods: In Part I (safety lead in) of the study, the primary endpoint was treatment related dose limiting toxicities (DLT) in pts with mRCC who had received 1-3 prior treatments. Pts received PF-04856884 (15 mg/kg/week) plus axitinib (5 mg BID) for 4 week cycles (the recommended Phase II dose of each) and were assessed for DLT, PK, and potential predictive biomarkers (Ang-2 and VEGF-A). For Part II (Phase II portion), pts with mRCC who had received 1 prior anti-VEGF agent were to be randomized to PF-04856884 + axitinib or axitinib alone to assess median progression free survival. Results: Part I enrolled 18 pts with median age of 62.5 years (39-82), and ECOG performance status of 0-1. One pt had a DLT of Grade 4 pulmonary embolism (PE). Most common related AEs: anorexia in 10 pts (56%), diarrhea 8 (44%), fatigue 8 (44%), nausea 7 (39%), hypertension 6 (33%) and vomiting 6 (33%). Treatment-related thromboembolic events (TEEs) were observed: PE in 2 pts (11%), and cerebrovascular accident (CVA), presumed bowel ischemia, and possible cardiac chest pain in 1 pt (6%) each. One pt had Grade 2 venous thrombosis unrelated to either treatment. Due to the reported TEE, PF-04856884 was reduced to 10 mg/kg in pts remaining on study and enrollment to Part II was not initiated. No significant PK interaction was observed. Two pts had partial response (PR) and 1 pt had unconfirmed PR. Twelve pts (66%) remained on study ≥91 days with a median duration of 120 days (8-279). Anti-PF-04856884 antibody results are not available. Conclusions: Due to the higher than expected TEEs, alternate doses of PF-04856884 and/or disease settings are being considered. Clinical trial information: NCT01441414.
Abstract 060: Contribution of Immunodeficiency to Coronary Heart Disease: Cohort Study of HIV-infected and HIV-uninfected Kaiser Permanente Members
Authors: Daniel B Klein, Wendy A Leyden, Lanfang Xu, Chun R Chao, Michael A Horberg, William J Towner, Leo B Hurley, Charles P Quesenberry, Michael J Silverberg
Journal: Circulation (2012)

Background: We compared CHD rates among HIV+ and HIV- patients in a large integrated care system, to explore the role of immunodeficiency in CHD. Methods: Kaiser Permanente (KP) California serves &gt;6 million members. Using previously described databases, we matched adult HIV+ members to HIV- members (1:10 ratio) on age, sex, medical center and year of start of follow-up. We searched hospitalization records to identify members with discharge diagnoses codes [MH1] ICD-9: 410x-411x, 413x-414x. The cohort was followed from first KP enrollment after 1996 until earliest recorded CHD event, death, KP disenrollment, or 12/31/2009. We stratified HIV+ members by antiretroviral therapy (ART) use, recent and lowest KP-recorded CD4, and compared rates with HIV- KP members. We obtained rate ratios (RRs) for any CHD diagnosis and MIs from Poisson regression models adjusting for age, sex, race, tobacco use, alcohol/drug abuse, obesity, diabetes, use of lipid lowering, and hypertension therapy. An additional analysis of only HIV+ individuals examined the effects of antiretroviral therapy use, recent HIV RNA, and recent and nadir CD4 on CHD.[MH2] Results: 22,081 HIV+ and 215,158 HIV- members contributed 101,044 pys and 1,265,819 pys respectively. HIV+ had 446 CHD events (including 280 MIs), corresponding to a rate of 451/100,000 py. HIV- had 3,926 CHD events (including 2,064 MIs), corresponding to a rate of 316 cases/100,000 py. The adjusted CHD RR for HIV status was 1.4 (95% CI: 1.3-1.6; p&lt;0.001), and the adjusted MI RR was 1.7 (95% CI: 1.5-1.9; p&lt;0.001). CHD RRs for HIV+ as stratified by ART use and CD4 level are shown in Table (with HIV- as reference). Table. Adjusted rate ratios * for CHD among HIV+ individuals by recent and lowest CD4 Recent CD4 Lowest KP CD4 RR (95% CI) p value RR (95% CI) p value ART+, CD4 ≥500 0.9 (0.7, 1.1) 0.218 0.8 (0.5, 1.2) 0.231 ART+, CD4 201-499 1.4 (1.2, 1.6) &lt;0.001 1.1 (0.9, 1.3) 0.300 ART+, CD4 ≤200 1.8 (1.4, 2.2) &lt;0.001 1.4 (1.3, 1.6) &lt;0.001 ART-, CD4 ≥500 1.3 (0.9, 1.9) 0.213 1.3 (0.8, 2.1) 0.363 ART-, CD4 201-499 1.1 (0.7, 1.7) 0.671 1.3 (0.9, 1.8) 0.182 ART-, CD4 ≤200 1.8 (0.9, 3.8) 0.113 1.1 (0.6, 2.2) 0.778 * HIV- as reference for all RRs Conclusions: Adjusting for traditional risk factors, HIV+ individuals have a statistically significant increased risk for cardiovascular complications. Aggressive attention to modifiable risk factors is particularly important. As increased CHD risk was not seen for patients with relatively preserved CD4, earlier initiation of ART may further reduce CHD [. l