tbuckley/cabot-search huggingface dataset:
Preliminary results of randomized phase III study comparing efficacy and safety of first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM) in Chinese advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR-activating mutations (OPTIMAL).
Authors: C. Zhou, Y. Wu, G. Chen, J. Feng, X. Liu, C. Wang, S. Zhang, J. Wang, S. Zhou, S. Ren
Journal: Journal of Clinical Oncology (2010)

7575 Background: Phase II study showed first-line erlotinib (Erl) produced promising efficacy in advance NSCLC pts with EGFR Muts. This phase III trial compared PFS and safety of first-line Erl versus chemotherapy (chemo) in EGFR Mut pts with advanced NSCLC. Methods: Chemonaive NSCLC pts (stage IIIB or IV) with ECOG PS of 0-2, measurable disease and EGFR exon 19 or L858R Muts were eligible. Direct sequencing was used to detect EGFR Muts. The pts were randomized to receive Erl 150 mg/d up to PD or intolerable toxicities or to receive GEM (1,000 mg/m2 d1+d8) plus CBDCA (AUC=5, d1) up to 4 cycles. First endpoint was PFS and second endpoints included OS, safety, and QoL. Results: 549 pts were screened, 186 were found to have EGFR Muts (34.3%) and 165 pts were randomized. Safety was evaluable in 155 pts. One pt in Erl arm was not eligible but received 1 cycle of Erl. 10 pts in chemo arm withdrew informed consent and did not receive chemo. Demographic characteristics were comparable (Erl vs chemo), age 56.5 vs 58.8; M/F 41.5%/58.5% vs 40.3%/59.7%, adenocarcinoma /nonadenocarcinoma 87.8%/12.2% vs. 86.1%/13.9%, non-/ex-/current smokers 72%/7.3%/20.7% vs. 66.7%/8.3%/25%, EGFR exons 19/21 Muts 53.7%/46.3% vs. 54.2%/45.8%. Median follow-up time was 4.1 months and PFS in Erl arm is not mature yet. Dose reduction was reported in 4 cases in Erl arm (4.9%) and 18 cases in chemo arm (25.0%) (p<0.001) and dose reduction or interruption of GEM on day 8 was seen in 41.7% of pts. The Table lists the most common adverse events. There was no toxic death or ILD. Conclusions: First-line erlotinib is better tolerated and no new safety signals are found. Efficacy of the study is being followed up and will be reported at the Meeting. Adverse events Adverse events Erlotinib (N = 83) (%) Chemotherapy (N = 72) (%) All AE 75.9 Grades 3-4 8.4 All AE 88.9 Grades 3-4 56.9 Drug-related AE 63.9 NA 86.1 NA SAE 6.0 NA 6.9 NA Anemia 2.4 0 55.6 5.6 Neutropenia 3.6 0 56.9 37.5 Thrombocytopenia 1.2 0 56.9 36.1 Alanine aminotransferase increased 8.4 1.2 11.1 1.4 Skin rash 59 1.2 19.4 0 Vomiting 1.2 0 33.3 0 Diarrhea 20.5 1.2 2.8 0 Retinal detachment 1.2 1.2 0 0 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche
114. A Novel Adeno-Associated Virus Serotype (AAV)-8 Capsid Mutant Improves Human Coagulation Factor IX Expression In Vivo
Journal: Molecular Therapy (2013)

Recombinant AAV-8 vectors have shown significant promise for hepatic gene therapy of hemophilia B. However, the theme of AAV vector dose dependent immunotoxicity seen with AAV2 vectors earlier seem to re-emerge with AAV8 vectors as well. It is therefore important to develop novel AAV8 vectors that provide enhanced gene expression at significantly less vector doses. We hypothesized that AAV8 during its intracellular trafficking, are targeted for destruction in the cytoplasm by the host-cellular kinase/ubiquitination/proteasomal degradation machinery and modification of specific serine/threonine kinase or ubiquitination targets on AAV8 capsid (Fig.1A) may improve its transduction efficiency. To test this, point mutations at specific serine (S)/threonine (T) > alanine (A) or lysine (K)>arginine (R) residues were generated on AAV8 capsid. scAAV8-EGFP vectors containing the wild-type (WT) and each one of the 5 S/T/K-mutant(S276A, S501A, S671A, T251A and K137R) capsids were evaluated for their liver transduction efficiency at a dose of 5 X 1010 vgs/ animal in C57BL/6 mice in vivo. The best performing mutant was found to be the K137R vector in terms of either the gene expression (46-fold) or the vector copy numbers in the hepatocytes (22-fold) compared to WT-AAV8 (Fig.1B). The K137R-AAV8 vector that showed significantly decreased ubiquitination of the viral capsid had reduced activation of markers of innate immune response [IL-6, IL-12, tumor necrosis factor α, Kupffer cells and TLR-9]. In addition, animals injected with the K137R mutant also demonstrated decreased (2-fold) levels of cross-neutralizing antibodies when compared to animals that received the WT-AAV8 vector. To study further the utility of the novel AAV8-K137R mutant in a therapeutic setting, we delivered human coagulation factor IX (h.FIX) under the control of liver specific promoters (LP1 or hAAT) at two different doses (2.5x10^10 and 1x10^11 vgs per mouse) in 8-12 weeks old male C57BL/6 mice. As can be seen in Fig.1C/D, the circulating levels of h.FIX were higher in all the K137R-AAV8 treated groups as compared to the WT-AAV8 treated groups either at 2 weeks (62% vs 37% for hAAT constructs and 47% vs 21% for LP1 constructs) or 4 weeks (78% vs 56% for hAAT constructs and 64% vs 30% for LP1 constructs) post hepatic gene transfer. These studies demonstrate the feasibility of the use of this novel vector for potential gene therapy of hemophilia B.
AB0890 Is There a Relationship Between Vitamin D and Schizophrenia?
Authors: D. Grados, J. Salavert, N. Ramiro, M. Carriόn, N. Ramírez, A. Erra
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Studies suggest a neuroprotective role for vitamin D. Its deficit has been linked with various psychiatric disorders such as schizophrenia (1). Increase in the prevalence of schizophrenia has been associated with high latitudes, winter/spring births, migration, urbanicity and cold climates (2,3). Vitamin D deficiency could be an important environmental risk factor, linking all of the previously exposed. <h3>Objectives</h3> We aimed to determine whether patients with a first psychotic episode had low levels of vitamin D compared to controls, considering their final diagnoses (schizophrenia vs other psychoses). <h3>Methods</h3> Cross-sectional study in an acute inpatient psychiatric unit. Vitamin D (25-hydroxyvitamin D) was determined by direct competitive chemiluminescence immunoassay. Vitamin D levels (ng/ml) were considered optimum &gt;30, insufficient 20–30 and deficient &lt;20 (4). Final diagnosis was obtained from the outpatient mental health service after a 6 month follow-up. <h3>Results</h3> We analyzed 27 patients with first-episode psychosis (13 with final diagnosis of schizophrenia and 14 of other psychoses) and 17 healthy controls, with no differences in mean age between the three groups (χ<sup>2</sup> (2)=5.20, p&gt;0.05). Schizophrenic patients showed deficient average values (ng/ml) of vitamin D (mean 12.87, range 6-24.9). Vitamin D levels in the other psychoses patient group were higher but also deficient (mean 15.74, range 6-34.6). Controls presented higher levels of vitamin D, but still insufficient (mean 21.45, range 11.20-33.5). Vitamin D levels in the schizophrenia group were significantly lower compared to controls (CI 1.8 – 15.4; p&lt;0.009). No other significant differences were found between groups. <h3>Conclusions</h3> We observed deficient vitamin D levels in all the patients studied, being significantly lower for schizophrenic patients. Future studies are required to further examine this association in schizophrenia because vitamin D deficiency may be an easily modifiable risk factor by means of a cheap and save public health intervention. <h3>References</h3> Belvederi Murri, M., Respino, M., et al. 2013 Vitamin D and psychosis: mini meta-analysis. Schizophr Res 150, 235-239. McGrath, J. J., Eyles, D.W., et al. 2010 Neonatal vitamin D status and risk of schizophrenia: a populationbased case-control study. Arch Gen Psychiatry 67, 889-94. McGrath, J. J., Burne, T.H., et al. 2010 Developmental vitamin D deficiency and risk of schizophrenia: a 10-year update. Schizophr Bull 36, 1073-8. Holick, M.F. 2007 Vitamin D deficiency. N Engl J Med 357, 266-81. <h3>Disclosure of Interest</h3> None declared
FAST-ACT: A phase II randomized double-blind trial of sequential erlotinib and chemotherapy as first-line treatment in patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: J. S. Lee, J. Ignacio, C. Yu, C. Zhou, Y. Wu, Y. Chen, L. Zhang, K. Jin, M. Johnston, T. S. Mok
Journal: Journal of Clinical Oncology (2008)

8031 Background: Concurrent administration of EGFR TKIs and chemotherapy in 1st line failed to improve survival. Preclinical data suggested potential antagonism due to TKI-induced G1 arrest reducing cell cycle phase-dependent activity of chemotherapy, whereas sequential administration of EGFR-TKI following chemotherapy may improve efficacy [Gumerlock et al, ASCO 2003; Solit et al, Clin Can Res 2005]. Methods: All eligible pts with chemonaïve stage IIIB/IV NSCLC, performance status of 0/1 and adequate organ function were randomized to receive either erlotinib (E) 150mg/d or placebo (P) p.o. on d15–28 of 4-weekly chemotherapy cycles. Chemotherapy consisted of gemcitabine (G) 1250mg/m2 i.v. (d1, 8) plus either cisplatin (C) 75mg/m2 or carboplatin (C) 5xAUC (d1) for a maximum of 6 cycles. Responding pts continued to receive E or P until progression or unacceptable toxicity. The primary endpoint was non-progression rate (NPR: CR+PR+SD) at 8 wks using RECIST. Results: Between Aug 2006 and Apr 2007, 154 pts were enrolled from 7 countries. Median age was 57 years and 94% were Asian. Other baseline characteristics and efficacy results are shown in the table below. The median number of treatment cycles received was 6 vs 5 (GC-E vs GC-P). Rash-like events were noted in 66% of GC-E vs 35% of GC-P arm, and diarrhea was observed in 24% and 18% of pts, respectively. The most common grade 3–5 adverse events (GC-E vs GC-P) were neutropenia (20% vs 15%); anemia (8% vs 6%); thrombocytopenia (5% vs 5%); and vomiting (3% vs 8%). Overall safety profiles were similar between the two arms. A statistically significant improvement in PFS (p=0.005) was observed in the GC-E arm. Conclusions: 1st- line sequential administration of erlotinib with chemotherapy has demonstrated promising results. This treatment strategy warrants further investigation in advanced NSCLC. Baseline characteristics and efficacy results Characteristics (%) GC-E (n=76) GC-P (n=78) Male/Female 71/29 69/31 Never/Former/Current smoker 32/25/43 36/18/46 Adenocarcinoma/Others 67/33 67/33 Stage IIIB/IV 17/83 21/79 Efficacy NPR at 8 wks 80.3% 76.9% ORR (CR+PR) 36.8% 24.4% Median PFS * 7.2 mo 5.5 mo Median OS NR NR * HR=0.57 (95% CI 0.38; 0.84), p=0.005; NR=not reached Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche AstraZeneca, GlaxoSmithKline, Lilly, Pfizer, Roche Roche AstraZeneca, Eli Lilly, Pfizer, Roche AstraZeneca, Bayer, Lilly, Novartis, Roche AstraZeneca, Pfizer, Roche
<i>Waiting Room</i>
Authors: Jeanette M. Smith
Journal: JAMA (2016)

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Post-earthquake injuries treated at a field hospital - Haiti, 2010.
Authors: G. Hotz, E. Ginzburg, G. Wurm, V. DeGennaro, D. Andrews, S. Basavaraju, V. Coronado, L. Xu, T. Dulski, D. Moffett, J. Tappero, M. Selent
Journal: MMWR Morbidity and Mortality Weekly Report (2010)
Circulating Cell Death Biomarkers May Predict Survival in Human Lung Transplantation
Authors: Kohei Hashimoto, Rickvinder Besla, Ricardo Zamel, Stephen Juvet, Hyunhee Kim, Sassan Azad, Thomas K. Waddell, Marcelo Cypel, Mingyao Liu, Shaf Keshavjee
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Immediate graft performance after lung transplantation is associated with short- and long-term clinical outcomes. However, the biologic mechanism that determines outcomes is not fully understood.Objectives: To investigate the impact of cell death signals at 24 and 48 hours after lung transplantation on short- and long-term clinical outcomes.Methods: Plasma samples were collected pretransplantation and at 24 and 48 hours after transplant from 60 bilateral lung transplant recipients. Ten patients had primary graft dysfunction (PGD) grade 3 (PaO2/FiO2 ratio <200 or on extracorporeal membrane oxygenation support) at 72 hours after transplant (PGD group). The remaining 50 patients were defined as the control group. Levels of plasma M30 (signifying epithelial apoptosis), M65 (signifying epithelial apoptosis plus necrosis), and high-mobility group box 1 protein (HMGB-1; signifying necrosis of all cell types) were measured by ELISA and correlated with clinical outcomes. Survival analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. Prediction accuracy of markers was assessed by calculated area under the curve of receiver operating characteristic graph.Measurements and Main Results: The PGD group had significantly higher M30 and M65 levels at 24 and 48 hours after transplant compared with the control group. There was no significant difference in HMGB-1. Area under the curve for 1-year survival was 0.86, 0.93, and 0.51 for M30, M65, and HMGB-1 at 48 hours, respectively. Survival analysis showed that higher M30 and M65 levels at 24 and 48 hours were significantly associated with worse survival. M65 at 48 hours remained significant even after adjustment for PGD. HMGB-1 was not significantly associated with survival.Conclusions: Recipient plasma concentration of epithelial cell death markers (M30, M65) after lung transplantation is negatively correlated with early graft performance and long-term survival.
Poliomyelitis in Suburban Surrey
Authors: A. F. Huston, J. B. Morwood, G. J. Christofinis, W. Wood
Journal: BMJ (1956)

ADRENALECTOMY FOR CEREBRAL METASTASES ftff= 629 monary metastases (Fig. 3).Treatment was immediately started with testosterone-propyl-propionate (100 mg.twice a week).In November a single attack of petit mal was reported.Early in December she became semiconscious
Pleiotropic activity of the novel cyclin-dependent kinase inhibitor RGB 286638 predicts therapeutic potential in multiple myeloma
Authors: D. Cirstea, T. Hideshima, S. Pozzi, S. Vallet, H. Ikeda, Y. Okawa, L. Santo, S. Meier-Ewert, K. C. Anderson, N. Raje
Journal: Journal of Clinical Oncology (2008)

14602 Background: Cyclin-dependent kinases (Cdk) regulate the cell cycle through interaction with various cyclins. Uncontrolled proliferation of cancer cells is predominantly a consequence of dysregulation of Cdks and/or their cyclin complexes as well as their inhibitors. Targeting Cdk therefore is a promising therapeutic strategy, and small molecule inhibitors have been developed. These agents are currently being studied in various tumor types. Deregulation of the cyclins, specifically the D cyclins, in multiple myeloma (MM) is well characterized, providing an opportunity to validate such Cdk inhibitors. RGB 286638 is a multi-targeted novel small molecule inhibitor that predicts broad cell cycle inhibitory effects via potent inhibition of cdk1, 2, 4, 5, 7, and 9. Methods: Growth inhibitory effect of RGB 286638 was assessed on MM cell lines and primary tumor cells from MM patients. Apoptosis and cell cycle profile were determined by Annexin/propidium iodide staining. Cell proliferation was measured by DNA synthesis. Western blotting was used to identify the molecular targets and delineate the mechanisms of cell death. Co-culture systems with patient derived bone marrow stromal cells (BMSCs) were used to recapitulate the in vivo host-tumor cell/BM interaction. Results: RGB 286638 triggered dose-dependent cytotoxicity in conventional drug-sensitive (MM1.S, RPMI 8226, U266, OPM2), -resistant (MM1.R, Dox-40, LR5) and primary tumor cells from MM patient. RGB 286638 induced G2/M arrest followed by increased sub-G1 phase. RGB 286638-induced cytotoxicity was mediated via apoptosis, evidenced by an increase of the Annexin V+PI+ fraction associated with early PARP and caspase cleavage. This was preceded by a dose and time-dependent inhibition of cdk1/cyclin B, cdk4, 6/Cyclin D1, D3, and cdk2/Cyclin E complexes associated with rapid downregulation of Rb phosphorylation. RGB 286638 was able to overcome the growth and survival advantage conferred by IL-6, IGF-1, and BMSCs. Conclusion: Our results indicated that RGB 286638 induces MM cell death involving inhibition of cdk/cyclin complexes and cell cycle progression. In vivo studies are ongoing providing the design of future clinical testing of RGB 286638 in MM. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis GPC Biotech Celgene, Millenium, Novartis
RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM).
Authors: Mark R. Gilbert, James Dignam, Minhee Won, Deborah T. Blumenthal, Michael A. Vogelbaum, Kenneth D. Aldape, Howard Colman, Arnab Chakravarti, Robert Jeraj, Terri S. Armstrong, Jeffrey Scott Wefel, Paul D. Brown, Kurt A. Jaeckle, David Schiff, James Norman Atkins, David Brachman, Maria Werner-Wasik, Ritsuko Komaki, Erik P. Sulman, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2013)

1 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
P-162 Interim Results of IMMU-132 (Sacituzumab Govitecan), an Anti-Trop-2 Antibody-Drug Conjugate (ADC), in Patients (pts) with Metastatic Gastrointestinal (GI) Cancers
Authors: A. Ocean, A. Starodub, W. Messersmith, V. Picozzi, M. Guarino, S. Thomas, A. Bardia, M. Shah, S. Govindan, P. Maliakal, W. Wegener, R. Sharkey, F. Wilhelm, D. Goldenberg
Journal: Annals of Oncology (2015)
Stimulation of Appetite and Growth in the Tumor-Bearing Rat by a Variety of Tissues
Authors: Florence K. Millar, Robin H. Brooks, Julius White
Journal: JNCI Journal of the National Cancer Institute (1959)

Sprague-Dawley rats bearing the Walker carcinosarcoma 256 subcutaneously and maintained on a 25 percent casein diet (C-25) were transferred, after weight loss, to a variety of diets in which lyophilized tumor tissue (rat, mouse, or human) or normal rat tissue (liver or muscle) replaced casein. Under these conditions, animals ingesting the tumor diets showed variable weight gains. A diet (RNH) containing tissue of the Novikoff rat hepatoma was similar to diet T-24 in producing large weight gains and increases in food intake. Diets containing defatted human tumor and defatted Walker 256 tumor gave equal growth response. Animals transferred to normal muscle or liver diets showed average increases of 2 to 3 gm. per day, considerably less than animals transferred to T-24, which averaged 11 gm. per day. Tumor-bearing rats on C-25 similarly transferred, after weight loss, to a 20 percent casein diet (C-20), or allowed to remain on C-25, showed a smaller positive response than rats transferred to T-24. Rats bearing the Novikoff hepatoma subcutaneously were transferred to T-24 after weight loss on C-25, and weight-loss reversal was observed whenever the diet was acceptable. RNH, T-24, and C-20 were compared for their effect on body-weight change and tumor size in Novikoff hepatoma-bearing rats fed these diets during the period of tumor growth. Both tumor diets produced far greater increase in total body weight and in carcass-weight change than C-20 did. Tumor weight was greater for rats on the T-24 diet than for those on C-20, but was intermediate for rats on RNH, showing greater variability.
Abstract 17242: Role Reversal of Oxidants in Coronary Endothelium: Short-term vs Long-term Exposure
Authors: Ruhul Abid, Ehtesham Shafique, Yuhong Liu, Jun Feng, Laura E Benjamin, Elizabeth Harrington, Frank W Sellke
Journal: Circulation (2014)

Introduction: Increase in reactive oxygen species (ROS) is often associated with vascular pathophysiological conditions. Our recent findings demonstrated that whereas short-term (4 weeks) increase in NADPH oxidase-derived endothelium (EC)-specific ROS improved coronary endothelial function, long-term (16 plus weeks) increase in ROS had adverse effects.

Hypothesis: We tested the hypothesis that short-term (four to eight weeks) increase in EC-ROS induces AMPK-FOXO1-mediated expression of SOD2 and thus exert protective effects on EC mitochondria; whereas long-term (16 to 20 weeks) increase in EC-ROS results in nitrotyration and inactivation of MnSOD leading to mitochondrial membrane potential loss and mitophagy leading to oxidative damage to EC.

Methods: Our binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) induces 1.8±0.42-fold increase in NADPH oxidase-derived ROS in endothelium. Using these animals, we have examined the effects of short-term vs. the long-term effects of ROS on EC signaling, mitochondrial activity, EC proliferation, and coronary endothelial function (microvessel reactivity).

Results: We demonstrate that whereas EC-dependent coronary vasodilation was significantly increased after short-term increase in ROS, coronary vasodilation was drastically reduced after long-term increase in EC-ROS in Tet-OFF Nox2 mice compared to the control littermates. Using EC isolated from mouse heart, we demonstrate that, whereas Nox2-derived both short-term and long-term increase in ROS increased activation of AMPK and eNOS, and nitric oxide (NO) synthesis, long-term increase in ROS abrogated these positive effects due to increased peroxynitrite levels and nitrotyration of MnSOD. We also show that long-term ROS increase results in mitochondrial membrane potential loss, reduction in mitochondrial content and EC proliferation.

Conclusion: This study demonstrates that whereas short-term increase in ROS is beneficial for EC function, long-term increase in ROS results in EC mitochondrial damage, reduction in EC proliferation, and inhibition of endothelial function. Ongoing LAD ligation studies are being carried out in the lab to examine the effects of endothelial ROS on myocardial preservation.