tbuckley/cabot-search huggingface dataset:
CNS Target Identification and Validation: Avoiding the Valley of Death or Naive Optimism?
Authors: P.H. Hutson, J.A. Clark, A.J. Cross
Journal: The Annual Review of Pharmacology and Toxicology (2016)

There are many challenges along the path to the approval of new drugs to treat CNS disorders, one of the greatest areas of unmet medical need with a large societal burden and health-care impact. Unfortunately, over the past two decades, few CNS drug approvals have succeeded, leading many pharmaceutical companies to deprioritize this therapeutic area. The reasons for the failures in CNS drug discovery are likely to be multifactorial. However, selecting the most biologically plausible molecular targets that are relevant to the disorder is a critical first step to improve the probability of success. In this review, we outline previous methods for identifying and validating novel targets for CNS drug discovery, and, cognizant of previous failures, we discuss potential new strategies that may improve the probability of success of developing novel treatments for CNS disorders.
Abstract 15685: Copper Transport Protein Antioxidant-1 Mediates Vascular Remodeling via Promoting Macrophage Infiltration and Copper- and Rac1-dependent Vascular Migration
Authors: Takashi Kohno, Norifumi Urao, Takashi Ashino, Sudhahar Varadarajan, Ronald D McKinney, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation (2012)

Vascular smooth muscle cell (VSMC) migration and inflammation are critically important in neointimal formation following vascular injury and atherosclerosis lesion formation. Copper (Cu) chelator inhibits neointimal formation with unknown mechanism. We previously demonstrated that Cu chaperone antioxidant-1 (Atox1) is involved in Cu-induced cell growth and that Cu transporter ATP7A, which obtains Cu from Atox1, is involved in VSMC migration. However, the role of Atox1 in neointimal formation after injury is unknown. In vivo, Atox1 is ubiquitously expressed in VSMCs and endothelial cells of noninjured vessels in wild type (WT) mice. Following wire injury, Atox1 expression is upregulated in injured vessels, and its expression is colocalized with ATP7A (+) cells, mainly in CD45 (+) inflammatory cells at day 3 and 7, and in neointimal α-smooth muscle actin (α-SMA) (+) VSMCs at day 14. Atox1 KO mice show significant inhibition of neointimal formation (I/M ratio: 53%) and fibrosis (34%) at day 21 compared to WT mice, which is associated with decreased α-SMA (+) cells infiltration within neointima at day 14. Mechanistically, in cultured VSMC, siRNAs for Atox1 or ATP7A inhibit VSMC migration induced by platelet-derived growth factor (PDGF) (77% and 70%) or wound scratch (63% and 60%). PDGF promotes Atox1 binding to ATP7A within 5 min via Cu-dependent manner, which in turn recruits Rac1 to the Atox1/ATP7A complex. Functional significance of this complex is demonstrated that Atox1 siRNA inhibits PDGF-induced ATP7A and Rac1 translocation to the leading edge, thereby inhibiting Cu- and Rac1-dependent lamellipodia formation. Furthermore, Atox1 KO mice show decreased perivascular macrophage infiltration at day 7 and 14 (56% and 57%). This result is further confirmed that thioglycollate-induced peritoneal macrophage recruitment is reduced in Atox1 KO mice (62%), suggesting that Atox1 also mediates macrophage recruitment in inflammatory conditions. In summary, Atox1 is involved in neointimal formation after vascular injury, through promoting VSMC migration and inflammation in injured vessels. Our results will provide new insight into Atox1 as a potential therapeutic target for the crucial events in inflammation and VSMC migration-related vascular diseases.
A baby with low Apgar scores at birth: Table 1
Authors: Sagarika Ray
Journal: BMJ (2016)

A baby girl, weighing 3510 g (50th centile), was born at 41+1 weeks’ gestation. The mother had presented in labour and initial assessment identified placental abruption and breech presentation. At emergency caesarean, the infant was found to be in the abdominal cavity after maternal uterine rupture. At initial assessment the baby was floppy and pale, with no respiratory effort and an inaudible heart rate. She was intubated at 45 seconds and a heart rate of 70 beats/min was first heard at 1 minute; this subsequently improved.

At 10 minutes of age, she remained ventilated and Apgar scores were 2 at 1 minute, 4 at 5 minutes, 4 at 10 minutes. Venous cord gas showed pH 6.6, partial pressure of carbon dioxide 20.1 kPa, base excess −25 mmol/L, bicarbonate 15.5 mmol/L. Passive cooling was started by switching off the resuscitaire’s overhead warmer.

On admission to the neonatal unit, ventilator settings were on a time cycled pressure limited mode of pressure control-assist control (PC-AC), peak inspiratory pressure 16, peak expiratory pressure 5, inspiratory time 0.4 seconds, fractional index of oxygen 0.25, ventilator rate 40 breaths/min (all breaths delivered by the ventilator owing to lack of regular spontaneous breaths by the infant). Observations included: temperature 34.8°C (axilla) and 34.4°C (rectal), heart rate 179 beats/min, respiratory rate 60 breaths/min, non-invasive blood pressure 70/30 mm Hg (mean 44), oxygen saturations 97%. Clinical examination showed generalised hypotonia with some limb movements in response to handling and no obvious clinical seizure activity at the time of admission.

1.  What is the most likely diagnosis?

2.  What further management is needed at this stage?

3.  What other relevant investigation is useful at this stage?

4.  What are the prognostic indicators?

5.  What are the long term outcomes of this condition?

### 1. What is the most likely diagnosis?

#### Short answer

Hypoxic ischaemic encephalopathy (HIE).

#### Discussion

The diagnosis of HIE is based on the Apgar …
Plasma IL-6 and HPA-axis function in depression and anxiety in patients with cancer
Authors: C. F. Jehn, D. M. Kühnhardt, K. Possinger, B. Flath
Journal: Journal of Clinical Oncology (2005)

8033 Background: Compelling evidence suggests that proinflammatory cytokines (IL-6) and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by increased levels of cortisol, play a role in the ethiology of depression. Patients (pts) with cancer show elevated prevalence rates for depression and anxiety. The objective of this study was to investigate the association of neuro-immune system abnormalities with affective disorders in pts with cancer. Methods: Depression and anxiety were assessed in 93 patients with metastatic cancer by the Hospital Anxiety and Depression Scale (HADS) and diagnosis was established according to DSM-IV criteria. A HADS-score of >11 was considered significant for the diagnosis of depression or anxiety disorder. PTS with scores 8–10 were classified as intermediate and excluded form the statistical analysis. Plasma concentrations of interleukin (IL-6) were measured in addition to cortisol levels at 8 am and 8 pm. In the statistical analysis the Mann-Whitney test was applied. Results: Pts characteristics (n=93): median age 60 y (25–85); 80,6% Females, 19,4% males. 33,3% of pts had depression, 29% of pts had anxiety disorder. Depression was associated with a significant higher median IL-6 level (19,4 vs. 2,4 pg/ml; p<0,001), 8 am cortisol plasma level (505,5 vs. 419 mmol/l; p=0,049), 8 pm cortisol level (431 vs. 155 mmol/l; p=0,002) and a reduced relative decrease of diurnal (8am-8pm) cortisol levels (15,7% vs. 50,8%; p=0,004), than the non-depression group. Associations for anxiety vs. non-anxiety pts group: median IL-6 level (14,6 vs. 2,9 pg/ml; p=0,01), 8 am cortisol plasma level (558,5 vs. 370 mmol/l), 8 pm cortisol level (530 vs. 159 mmol/l; p=0,012) and a reduced relative decrease of diurnal cortisol levels (2,9% vs. 44,5%; p=0,042). Conclusions: In cancer pts depression and anxiety is associated with increased plasma IL-6 concentrations. These pts show a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by increased levels of cortisol and a reduced relative decrease of diurnal cortisol levels. Increased plasma IL-6 and dysregulation of the HPA axis seem to be involved in the pathogenesis of depression and anxiety in cancer. No significant financial relationships to disclose.
Hypomagnesemia in patients with stage IV colorectal cancer treated with cetuximab as a single agent
Authors: E. J. Carson, A. M. Novak, P. J. Stella
Journal: Journal of Clinical Oncology (2005)

3655 Background: Cetuximab (Erbitux, Bristol-Myers Squibb, Princeton, NJ), a humanized monoclonal antibody directed against the extracellular component of the epidermal growth factor receptor (EGFR, Her-1), is now approved for treatment of stage IV colorectal cancer in the United States and is under investigation for a number of other uses. Our institution participated in two trials evaluating cetuximab as monotherapy in pretreated stage IV colorectal cancer patients. All patients had previously received therapy with oxaliplatin. Methods: 60 patients were enrolled between October 2002 and February 2004. A magnesium level was checked in one of the early patients (patient number 3) after 5.5 months of treatment and was found to be 0.9 mg/dL (normal 1.7–2.5). Extensive evaluation of that patient revealed no other concurrent process that might have contributed to hypomagnesemia. We checked magnesium levels in all 48 patients who were subsequently enrolled, and baseline magnesium levels were normal in 46 of them. Results: 34 of the 46 patients with normal baseline magnesium levels had magnesium levels checked while on therapy, and 22 of those 34 (65%) developed hypomagnesemia at a median of 8 weeks (range 2–28 weeks). The lowest magnesium level measured was 0.5 mg/dL. Patients were treated with oral or IV magnesium supplementation. No dysrhythmias or other serious complications of hypomagnesemia were seen; diarrhea attributable to oral magnesium supplementation was common but relatively minor. Conclusions: Therapy with cetuximab may be associated with hypomagnesemia, at least in patients already treated with oxaliplatin. To our knowledge, hypomagnesemia has not previously been reported as an adverse effect of any monoclonal antibody therapy or of any therapy directed against EGFR. Monitoring of magnesium levels and of possible consequences of hypomagnesemia in the current trials of cetuximab should be considered. Duration of therapy may be correlated with the risk of developing hypomagnesemia. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb
The Clinical and Genetic Features of Dyskeratosis Congenita, Cryptic Dyskeratosis Congenita, and Hoyeraal-Hreidarsson Syndrome in Japan
Authors: Hiroki Yamaguchi, Hirotoshi Sakaguchi, Kenichi Yoshida, Miharu Yabe, Hiromasa Yabe, Yusuke Okuno, Hideki Muramatsu, Shunsuke Yui, Koiti Inokuchi, Etsuro Ito, Seishi Ogawa, Seiji Kojima
Journal: Blood (2014)
Ultrastructure of 1,2-Dimethylhydrazine-Induced Adenocarcinomas in Rat Colon2
Authors: David H. Barkla, Peter J. M. Tutton
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Ultrastructure of 1,2-Dimethylhydrazine-Induced Adenocarcinomas in Rat Colon Get access David H. Barkla, David H. Barkla 3Department of Anatomy, Monash University, Clayton, Victoria, 3168 Australia. Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter J. M. Tutton Peter J. M. Tutton 3Department of Anatomy, Monash University, Clayton, Victoria, 3168 Australia. 4We thank Professor G. C. Schofield for his continued encouragement and Ms. Jody Jameson, Ms. Fiona Christensen, and Ms. Christine Stevens for their excellent technical assistance. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 61, Issue 5, November 1978, Pages 1291–1299, https://doi.org/10.1093/jnci/61.5.1291 Published: 01 November 1978 Article history Received: 15 February 1978 Accepted: 09 June 1978 Published: 01 November 1978
Heterophil Forssman Glycoprotein and Adenovirus 12: Transformed Rat Cell Lines<xref ref-type="fn" rid="FN1">2</xref>
Authors: T Mori, E Mori, Y Shigyo, T Sudo, K Kano
Journal: JNCI Journal of the National Cancer Institute (1986)

Immunobiological significance of Forssman (F) glycoprotein expressed on rat tumor cells derived from transfection of a fibroblast line with whole DNA (WY-3); EcoRI-C fragment, 0–16.5 map units (CY-1); and Accl-H fragment, 0–14.7 map units (HY-1) of adenovirus 12 was investigated. Culturing of F-positive WY-3 and CY-1 cells, but not F-negative HY-1 cells, with monoclonal rat F-antibody resulted in the blocking of their cell-cell adhesion and attachment to plastic surface and inhibition of their growth. Immunization of WY-3 or CY-1 tumor-bearing F344 rats with sheep red blood cells or purified F-antigen in adjuvants brought regression of the tumor in 13 of 19 rats. No such antitumor effect was observed in F-negative HY-1 tumor-bearing rats upon immunization with the F-antigens. Results of this study indicated that the membrane glycoprotein with F-epitope may playa role in lodgement of the tumor cells in vitro and serve as an in vivo target of specific immune effectors.
The Respiratory Epithelium. VI. Histogenesis of Lung Tumors Induced by Benzo[&lt;italic&gt;a&lt;/italic&gt;]pyrene-Ferric Oxide in the Hamster&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Becci, Peter J., McDowell, Elizabeth M., Trump, Benjamin F.
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article The Respiratory Epithelium. VI. Histogenesis of Lung Tumors Induced by Benzo[a]pyrene-Ferric Oxide in the Hamster Get access Peter J. Becci, Ph.D., Peter J. Becci, Ph.D. 4Department of Pathology, University of Maryland, School of Medicine, 31 S. Greene St., Baltimore, Md. 21201. Search for other works by this author on: Oxford Academic PubMed Google Scholar Elizabeth M. McDowell, B. Vet. Med., Ph.D., Elizabeth M. McDowell, B. Vet. Med., Ph.D. 4Department of Pathology, University of Maryland, School of Medicine, 31 S. Greene St., Baltimore, Md. 21201. Search for other works by this author on: Oxford Academic PubMed Google Scholar Benjamin F. Trump, M.D. Benjamin F. Trump, M.D. 6 4Department of Pathology, University of Maryland, School of Medicine, 31 S. Greene St., Baltimore, Md. 21201. 6Address reprint requests to Dr. Trump. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 61, Issue 2, August 1978, Pages 607–618, https://doi.org/10.1093/jnci/61.2.607 Published: 01 August 1978 Article history Received: 01 July 1977 Revision received: 24 February 1978 Accepted: 17 March 1978 Published: 01 August 1978
A proposal of pathological classification (pTNM) of patients with head and neck cancer according to capsular rupture (pN- RC)
Authors: O. Gallego, X. Leon, A. Lopez Pousa, N. Farre, M. Vega, M. Lopez, G. Carreras, G. Carreras, R. Marse, M. Quer, A. Barnadas
Journal: Journal of Clinical Oncology (2007)

16525 Background: Lymph node metastasis remains one of the most significant prognostic factors of head and neck squamous cell carcinoma survival. Several studies have demonstrated that capsular rupture (CR) significantly decreases survival in patients with a positive neck dissection. We proposed to investigate whether inclusion of CR in the pTNM improves the prognostic capacity of the classification. Methods: We reviewed 841 patients (p) who underwent neck dissection and had a minimum follow-up of two years. The Kaplan-Meier method was used to analyce survival according to presence of neck nodes with CR and number of nodes with CR. Results: We analyzed 841p (151 oral cavity, 97 oropharynx, 136 hypopharynx, 258 supraglotis, 151 glotis and 48 only node; T1, 208 T2, 336 T3, 164 T4; 349 N0, 174 N1, 242 T2 and 78 N3). Treatment was surgery in 220 p and surgery plus radiotherapy in 621p. We treated 465 p with induction chemotherapy. Five-year survival was: 87% for pN0 (n=34), 67.2% for pN1RC-negative (n=118), 74.6% for pN1RC-positive (n=24), 51.7% for pN2RC-negative (n=127), 39.8% for pN2RC-positive only one node (n=58), 17.4% for pN2RC-positive more than one node (n=93) and 21.7% for pN3 (n=72). Conclusions: These results indicate that including CR information in the pTNM improves prognostic capacity of the classification. We propose four pTNM categories: Category 0: pN0; category 1: pN1RC-negative or -positive; category 2: pN2RC-negative or pN2RC-positive only one node; category 3: pN2RC-positive more than one node or pN3. No significant financial relationships to disclose.
Rapid recruitment of CD14+ monocytes in experimentally induced allergic rhinitis in human subjects
Authors: Ibon Eguíluz-Gracia, Anthony Bosco, Ralph Dollner, Guro Reinholt Melum, Maria H. Lexberg, Anya C. Jones, Sinan Ahmed Dheyauldeen, Patrick G. Holt, Espen S. Bækkevold, Frode Lars Jahnsen
Journal: Journal of Allergy and Clinical Immunology (2016)
Physician-drug company conflict of interest.
Authors: W B Patterson, E J Emanuel
Journal: Journal of Clinical Oncology (1996)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1996.14.1.316 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 8558213 Physician-drug company conflict of interest. W B PattersonxW B PattersonSearch for articles by this author , E J EmanuelxE J EmanuelSearch for articles by this author Show More Dana-Farber Cancer Institute, Boston, MA 02115, USA. https://doi.org/10.1200/JCO.1996.14.1.316 First Page PDF © 1996 by American Society of Clinical OncologyKeywords: American College of PhysiciansAmerican Medical AssociationAmerican Society of Clinical OncologyHealth Care and Public HealthProfessional Patient Relationship... Show All
Gangliosides of Human Melanoma: GM2 and Tumorigenicity2
Authors: Tetsuya Tsuchida, Romaine E. Saxton, Reiko F. Irie
Journal: JNCI Journal of the National Cancer Institute (1987)

An increased synthesis of the ganglioside GM2 has been reported on transformed murine cells, human fetal tissues, and transformed melanocytes. This study was designed to investigate whether any correlation existed between GM2 expression and the tumorigenicity of human melanoma. Ten established human melanoma cell lines, 5 rich in GM2 (group A) and 5 poor in GM2 (group B), were selected on the basis of previous ganglioside analysis of 28 melanoma cell lines. Six athymic nude mice per cell line were given an sc injection of 106 human melanoma cells/mouse. Tumors were measured every 2–4 days. By day 36 after the injection, 28 of 30 mice (93%) in group A developed medium to large tumors, but only 1 of 30 (3%) in group B developed a small tumor (P<.005). The correlation of GM2 content of individual melanomas with tumor growth rate also was very high. GM2 content was expressed as nanomoles per gram wet weight of each melanoma. The area under the log values of tumor growth curves from day 0 to day 36, which represented tumor growth rate, tumor size, and latent period, was proportional to GM2 content, with a correlation coefficient of 0.927 and with P<.001. The same log relationship when tested with other gangliosides, GM3, GD3, and GD2, was not statistically significant. These results, combined with the fact that variations in GM2 content do not affect in vitro growth of human melanoma cells, suggest that GM2 expression may be directly related to the dedifferentiation or the tumorigenicity of human melanoma.
Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): DASISION 3-year follow-up.
Authors: Andreas Hochhaus, Neil P. Shah, Jorge E. Cortes, Michele Baccarani, M. Brigid Bradley-Garelik, David Dejardin, Hagop Kantarjian
Journal: Journal of Clinical Oncology (2012)

6504 Background: In the phase 3 DASISION trial of dasatinib v IM in patients (pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates of complete cytogenetic response (CCyR) and major molecular response (MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P=0.001, meeting the primary endpoint. Methods: Pts were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Results: Minimum 24-month follow-up (median 26.6 months) is reported here. 24-month molecular response rates were higher for dasatinib v IM: MMR (BCR-ABL ≤0.1%) 64% v 46%, P&lt;0.0001; MR 4 (BCR-ABL ≤0.01%) 29% v 19%, P=0.0053; MR 4.5 (BCR-ABL ≤0.0032%) 17% v 8%, P=0.0032. MMR rates were higher for dasatinib in all Hasford risk groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had maintained their MMR at 24 months, respectively. Pts receiving dasatinib v IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and 15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts receiving dasatinib (n=9; 3.5%) transformed to accelerated/blast phase v IM (n=15; 5.8%) on study or during follow-up after discontinuation. 24-month overall and progression-free survival were similar for dasatinib v IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few additional adverse events (AEs) were reported between 12 and 24 months in both arms, with grade 3/4 nonhematologic AE rates ≤1%. In each arm, 10 pts had a BCR-ABL mutation detected at time of discontinuation. For dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs (7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v &lt;1%), death (2% v &lt;1%), and other (4% v 8%). Few pts discontinued between 12 and 24 months for dasatinib (n=19; 7%) and IM (n=16; 6%). Conclusions: Updated data with minimum 36-month follow-up will be presented, including mutation analyses in pts who discontinued, progressed, or had suboptimal response. Pts receiving dasatinib had a lower transformation rate and higher molecular responses v pts receiving IM, supporting the use of dasatinib in newly diagnosed CML-CP.