tbuckley/cabot-search huggingface dataset:
Antibody-mediated neutralization of Sema4D reduces tumor angiogenesis and growth in vivo.
Authors: T. Fisher, Alan Jonason, Sebold Torno, Holm Bussler, Ji Li, Elizabeth E. Evans, Raymond Watkins, Maurice Zauderer, John E Leonard, Ernest S. Smith
Journal: Journal of Clinical Oncology (2010)

e13154 Background: It has been demonstrated that semaphorin 4D (Sema4D; CD100) is a potent pro-angiogenic molecule. Sema4D binding to its receptor plexin-B1 (Plex-B1) on endothelial cells transactivates c-Met and promotes formation of new blood vessels and tumor growth in vivo. Sema4D is overexpressed in a wide array of tumor types, and is also produced by inflammatory cells present in the tumor microenvironment. It has recently been demonstrated that in an environment lacking Sema4D, the ability of mouse breast cancer cells to originate tumor masses and metastases is severely impaired, and that Sema4D produced by tumor-associated macrophages is required for tumor angiogenesis and growth. In addition to its effects on endothelial cells, Sema4D binding to Plex-B1 on tumor cells results in c-Met transactivation and migration of tumor cells. It has been further reported that overexpression of Plex-B1 and Met in breast and ovarian cancers is a negative prognostic factor. Tumors coexpressing Plex-B1 and Met were characterized by worse grading and a higher incidence of lymph node metastases. Collectively, these results suggest that expression of Sema4D, either by tumor cells or by tumor associated macrophages, may represent a widely used strategy by tumors to induce angiogenesis and that expression of the Sema4D receptor in tumors may further induce tumor invasion, thereby enhancing their growth, survival, and metastatic potential. Antibody neutralization of Sema4D (CD100) thus may represent a new therapeutic strategy for cancer treatment. Methods: We selected a high affinity human IgG4 antibody that is specific for both mouse and human Sema4D, and utilized several in vitro functional assays to demonstrate that this antibody blocks Sema4D – Plex-B1 interactions. Results: Using both transplanted and orthotopic tumor models we demonstrated that antibody mediated Sema4D neutralization in vivo inhibits tumor growth and tumor angiogenesis. Conclusions: This human antibody is currently in IND-directed toxicology testing and we anticipate the initiation of human clinical studies in 2H 2010. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Vaccinex, Inc. Vaccinex, Inc.
Prenatal and Perinatal Risk Factors and the Promise of Birth Cohort Studies
Authors: Thomas V. Fernandez, James F. Leckman
Journal: JAMA Psychiatry (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Phase I, pharmacokinetic (PK), pharmacodynamic study of paricalcitol [19-nor-1 alpha, 25-(OH)2 D2] in combination with gemcitabine [2’,2’ difluorodeoxycytidine] in patients with advanced malignancies
Authors: D. Trump, M. Javle, J. Muindi, L. Pendyala, W. Yu, N. Ramnath, M. Ross, M. Fakih, R. Iyer, C. Johnson
Journal: Journal of Clinical Oncology (2006)

12010 Background: Calcitriol+ gemcitabine (gem) combination results in synergistic anti-tumor effect in preclinical models. Cytidine deaminase (CDD) inactivates gem into 2’,2’-difluorodeoxyuridine (dFdU) and its overexpression may lead to gem resistance. Calcitriol decreases CDD activity in peripheral blood mononuclear cells (PBM). Paricalcitol is cytotoxic in vitro and synergistic with several chemotherapeutic agents, including gem. We are conducting a phase I study of paricalcitol + fixed-dose gem. Objectives: The primary aim is to determine maximum tolerated dose (MTD) of the combination in patients (pts) with advanced cancer. Secondary aims are to evaluate toxicity, the effect of paricalcitol on gem PK, CDD activity in PBM and clinical outcome. Methods: Each cycle is 4 weeks: Gem 800 mg/m 2 (over 80 min) weekly × 3, starting day 1; paricalcitol weekly, 24 h prior to gem, starting day 7. Standard 3+3 dose-escalation schema is used. Planned paricalcitol doses are 0.24, 0.72, 1.20, 1.8, 2.4 μg/kg, and 25% increments till MTD. Gem PK and CDD activity (PBM) are studied on days 1 and 8. Paricalcitol PK studies are obtained on day 7. Results: Fourteen pts with the following cancers: pancreatic (n=3), colon (n=3), lung (n=5), esophageal (n=1), bladder (n=1) and unknown primary (n=1) have been enrolled. No dose limiting toxicities have occurred. Median of 2 cycles were delivered (range 1–9). Grade 3 toxicities: anemia (n=3 pts), neutropenia (n=5), thrombocytopenia (n=3), thrombosis (n=2), anorexia (n=1), hypophosphatemia (n=1), dehydration (n=1), syncope (n=1), pneumonia (n=1) and chills (n=1). Grade 4 toxicities: anemia (n=1) and neutropenia (n=1). Hypercalcemia (&gt; grade 1) did not occur. Stable disease occurred in 2 and progressive disease in 3. Conclusions: MTD was not reached at 1.8 μg/kg of paricalcitol with gem 800 mg/m 2 /week. Dose escalation is ongoing. PK data will be presented at meeting. Supported by NIH grants CA67267 and CA85142. [Table: see text]
Landscape of Genomic Alterations in Pituitary Adenomas
Authors: Wenya Linda Bi, Peleg Horowitz, Noah F. Greenwald, Malak Abedalthagafi, Pankaj K. Agarwalla, Wiliam J. Gibson, Yu Mei, Steven E. Schumacher, Uri Ben-David, Aaron Chevalier, Scott Carter, Grace Tiao, Priscilla K. Brastianos, Azra H. Ligon, Matthew Ducar, Laura MacConaill, Edward R. Laws, Sandro Santagata, Rameen Beroukhim, Ian F. Dunn
Journal: Clinical Cancer Research (2016)

Purpose: Pituitary adenomas are the second most common primary brain tumor, yet their genetic profiles are incompletely understood.Experimental Design: We performed whole-exome sequencing of 42 pituitary macroadenomas and matched normal DNA. These adenomas included hormonally active and inactive tumors, ones with typical or atypical histology, and ones that were primary or recurrent.Results: We identified mutations, insertions/deletions, and copy-number alterations. Nearly one-third of samples (29%) had chromosome arm-level copy-number alterations across large fractions of the genome. Despite such widespread genomic disruption, these tumors had few focal events, which is unusual among highly disrupted cancers. The other 71% of tumors formed a distinct molecular class, with somatic copy number alterations involving less than 6% of the genome. Among the highly disrupted group, 75% were functional adenomas or atypical null-cell adenomas, whereas 87% of the less-disrupted group were nonfunctional adenomas. We confirmed this association between functional subtype and disruption in a validation dataset of 87 pituitary adenomas. Analysis of previously published expression data from an additional 50 adenomas showed that arm-level alterations significantly impacted transcript levels, and that the disrupted samples were characterized by expression changes associated with poor outcome in other cancers. Arm-level losses of chromosomes 1, 2, 11, and 18 were significantly recurrent. No significantly recurrent mutations were identified, suggesting no genes are altered by exonic mutations across large fractions of pituitary macroadenomas.Conclusions: These data indicate that sporadic pituitary adenomas have distinct copy-number profiles that associate with hormonal and histologic subtypes and influence gene expression. Clin Cancer Res; 23(7); 1841-51. ©2016 AACR.
Prognosis of advanced hepatocellular carcinoma (HCC) in patients undergoing surgery combined with peri- or postoperative treatment with sorafenib.
Authors: Liqun Wu, Xufeng Pang, Jingyu Cao, Zusen Wang
Journal: Journal of Clinical Oncology (2014)

377 Background: Liver resection/transplantation are effective therapies for primary hepatocellular carcinoma (HCC), but high relapse rates can significantly impact long term survival, especially for patients with advanced disease. The objective of this study was to investigate the effects of surgery plus sorafenib on the prognosis of patients with advanced HCC. Methods: 36 male and 2 female patients of mean age 52.6 (range 36-65) years and an ECOG performance status score 0-1 (n=26) or 2 (n=12), received surgical therapy (28 liver resection and 10 liver transplantation) plus sorafenib for treatment of HCC with a high risk of relapse (n=3) or had relapsed. Sorafenib was administered orally 400 mg once or twice daily, and the dose was reduced or the treatment temporarily discontinued if a grade 3 or worse adverse event occurred. Treatment duration was &gt;3 months and patients were evaluated every 4 weeks. The main endpoints were overall survival (OS) and time to progression (TTP). Results: Median follow-up time was 12.9 (range 4-59) months. Kaplan-Meier analysis demonstrated that median OS was 17 months (95%CI: 11.6-22.4), median TTP was 15 months (95%CI: 11.6-18.4). During follow-up, 20 patients died (18 from disease progression, 1 from a lung infection, and 1 accidently). Univariate analysis demonstrated that serum ALT &gt;60 U/L at the beginning of treatment, Child-Pugh grade B, ECOG performance status score 2, tumor cell embolism in blood vessels, tumor volume ≥3 liver segments, and a tumor involving 2 vital organs were important factors affecting OS. The median OS of patients with a tumor volume ≥3 liver segments vs. patients with tumor volume &lt;3 liver segments was 8 vs. 28 months (log-rank test, p&lt;0.001), and median TTP was 5 vs. 24 months (p&lt;0.001). Conclusions: Surgical resection in combination with sorafenib helped prolong OS and TTP in patients with advanced or relapsed HCC. OS for patients treated with sorafenib peri-operatively was longer than that for patients who received therapy after a relapse had occurred. Decreasing tumor burden and administering sorafenib as early as possible are helpful strategies to improve prognosis in patients with HCC.
Therapeutic hypothermia has no benefit for in-hospital cardiac arrest, study finds
Authors: Michael McCarthy
Journal: BMJ (2016)

Therapeutic hypothermia for cardiac arrests that occur in hospital was not associated with improved survival or neurological outcome compared with usual care, a retrospective US study, published in JAMA , has found.1

Therapeutic hypothermia, or targeted temperature management, is currently recommended in the US for comatose patients after out-of-hospital and in-hospital cardiac arrests. The procedure involves maintaining patients’ core temperature between 32°C and 36°C for at least 24 hours after …
Proteosome Inhibitor Treatment Down-Regulates S-Phase Kinase-Associated Protein 2 Causing Inhibition of Proliferation and Induces Apoptosis in Primary Effusion Lymphoma.
Authors: Azhar R. Hussain, Naif A. Al-Jomah, Mehar Sultana, Manugaran S. Pulicat, Khawla S. Al-Kuraya, Shahab Uddin
Journal: Blood (2006)
Intubation During Pediatric CPR
Authors: Allan R. deCaen, Gonzalo Garcia Guerra, Ian Maconochie
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma
Authors: Meletios A. Dimopoulos, Albert Oriol, Hareth Nahi, Jesus San-Miguel, Nizar J. Bahlis, Saad Z. Usmani, Neil Rabin, Robert Z. Orlowski, Mieczyslaw Komarnicki, Kenshi Suzuki, Torben Plesner, Sung-Soo Yoon, Dina Ben Yehuda, Paul G. Richardson, Hartmut Goldschmidt, Donna Reece, Steen Lisby, Nushmia Z. Khokhar, Lisa O’Rourke, Christopher Chiu, Xiang Qin, Mary Guckert, Tahamtan Ahmadi, Philippe Moreau
Journal: New England Journal of Medicine (2016)

Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1–2 study involving patients with relapsed or refractory multiple myeloma.
Association of methylation of homologous repair genes with expression of immune checkpoints in squamous cell carcinoma of head and neck, lung and cervix.
Authors: Damian Tobias Rieke, Sebastian Ochsenreither, Frederick Klauschen, Inge Tinhofer, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2016)

11543 Background: Immune checkpoints are an emerging treatment target. Microsatellite instability (MSI), mutational load and checkpoint expression are imperfect predictors of treatment efficacy. We here describe a link between DNA repair gene methylation and expression of immune checkpoints in tumor tissue. Methods: A list of DNA repair genes (179 genes) was established from literature. mRNA expression and methylation status was extracted from TCGA data. Correlation analysis of DNA repair gene methylation status and expression of immune checkpoint gene mRNA was performed (cbioportal.org) in HNSSC (279 samples) and validated in other cancer types. Statistical analysis was carried out in R. Results: In HNSCC, methylation of 15 DNA repair genes was identified to be positively correlated to expression of PD-L1 and CTLA4 expression (cutoff: Spearman coefficient r > 0.3). Subgroup analysis revealed statistically significant enrichment for the homologous recombination pathway (p = 0.003). Methylation of candidate genes was associated with reduced expression. Among candidate genes, RAD51B and XRCC3 methylation showed the highest correlation with PD-L1 (r = 0.471, r = 0.472) and CTLA4 (r = 0.525, r = 0.616) expression (p values < 2.2x10-16). Methylation of these DNA repair genes was associated with expression of other checkpoint (CD28, PD-1, TIM-3, LAG-3, VISTA, ICOS, BTLA), ligand (PD-L2, CD80/86), IFNg, MHC-class 1 and T-cell associated genes (FOXP3, CD8A). These findings could be reproduced in independent datasets of lung squamous and cervical carcinoma and, to various extents, also in non-squamous cancer histologies (e.g. melanoma, lung adenocarcinoma). Conclusions: We propose for the first time a link between DNA repair gene methylation and expression of immune checkpoints identified in HNSCC and validated for lung and cervical cancer with similar effects also seen in other cancer types. We hypothesize that homologous recombination deficiency (HRD) may be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype. Correlation of DNA repair gene methylation and clinical efficacy of checkpoint inhibitors should be investigated.
2012 Late-Breaking Basic Science Oral Session
Authors: Diederik W Kuster, Adriana Cardenas-Ospina, Lawson Miller, Christian Troidl, Holger M Nef, Christoph Liebetrau, Möllmann Helge, Karen S Pieper, Kenneth W Mahaffey, Neal S Kleiman, Bruno D Stuyvers, Ali J Marian, Sakthivel Sadayappan, Loyola Univ Chicago, Maywood, Memorial Univ, St John's, Canada, Kerckhoff Heart and Thorax Cntr, Bad Neuheim, Germany, Duke Univ Med Cntr, Durham, The Methodist DeBakey Heart and Vascular Cntr, Houston, Univ of Texas Health Sciences, Houston
Journal: Circulation Research (2012)
P1.49 (also presented as PD1.05): The Genomics of Young Emergent Lung Cancer
Authors: Barbara Gitlitz, Bonnie Addario, Alicia Sable-Hunt, Silvia Novello, Tiziana Vavala, Ruthia Chen, Marisa Bittoni, S. Lani Park, Mark Jennings, Geoffrey Oxnard
Journal: Journal of Thoracic Oncology (2016)
FGF2 Promotes Resistance To Quizartinib In Vitro, and FGF2 Increases In The Marrow Of Patients Prior To Resistance
Authors: Elie Traer, Nathalie Javidi-Sharifi, Anupriya Agarwal, Jennifer B Dunlap, Isabel English, Jacqueline Martinez, Tibor J. Kovacsovics, Jeffrey W. Tyner, Melissa Wong, Brian J. Druker
Journal: Blood (2013)
Progression to tuberculosis disease increases with multiple exposures
Authors: Robyn S. Lee, Jean-François Proulx, Dick Menzies, Marcel A. Behr
Journal: European Respiratory Journal (2016)

During a single year, a Canadian village had 34 individuals with microbiologically confirmed tuberculosis (TB) among 169 people with a new infection (20%). A contact investigation revealed multiple exposures for each person. We investigated whether the intensity of exposure might contribute to this extraordinary risk of disease. We carried out a case–control study using a public health database. Among those with a new infection, 34 had culture-confirmed TB (cases) and 118 did not progress to disease (controls). 17 patients with probable disease were excluded. Contact investigation data were utilised to tabulate the number of potential sources (total exposures). Generalised estimating equations with a logit link were used to identify associations between exposures and progression, and to investigate other potential risk factors. The median (interquartile range) number of total exposures was 15 (3–23) for cases and 3 (2–12) for controls (p=0.001). The adjusted OR for disease was 1.11 (95% CI 1.06–1.16) per additional exposure, corresponding to an OR of 3.4 for disease when comparing the medians of 15 versus 3 total exposures. This association increased when restricting to tuberculin skin test conversions. Increased exposure could be a marker of greater risk of progression to TB disease. Therefore, this risk may not be transportable across epidemiologic settings with variable exposure intensities.
Biological and clinical outcomes from a phase II placebo-controlled neoadjuvant study of anastrozole alone or with gefitinib in postmenopausal women with ER/PgR+ breast cancer (Study 223)
Authors: M. Dowsett, I. Smith, A. Skene, A. Llombart, J. Mayordomo, S. Detre, J. Salter, E. Beresford, P. Magill
Journal: Journal of Clinical Oncology (2006)

515 Background: Gefitinib, an EGFR-tyrosine kinase inhibitor, reduces breast cancer cell growth and potentiates endocrine therapy in model systems. This double-blind multicentre study compared anastrozole 1 mg/day alone with anastrozole + gefitinib 250 mg/day as neoadjuvant therapy for breast cancer in a novel design aiming to assess additional benefit from gefitinib in individual patients. Methods: Postmenopausal women with stage I-IIIB breast cancer and ER and/or PgR+ tumours received anastrozole for 16 wks and were randomised (2:5:5 ratio) to: combination with gefitinib for 16 wks (AG); placebo for 2 wks then gefitinib for 14 wks (A:AG, to test for additional Ki67 suppression); placebo for 16 wks (A alone). Biopsies were taken at baseline, 2 and 16 wks. Primary comparison was change in Ki67 by 16 wks. Secondary comparison was objective tumour response rate (ORR) using UICC/WHO criteria at 16 wks. Results: 206 patients (pts) were randomised: (31 AG, 90 A:AG, 85 A alone); demography was well balanced between the groups. 109 pts were evaluable for Ki67: 59 AG + A:AG; 50 A alone. Change in Ki67 levels at 16 wks was not significantly different in those pts who received gefitinib + anastrozole versus anastrozole alone (p=0.257). The addition of gefitinib after 2 weeks of anastrozole did not further suppress Ki67 levels (p=0.164). 188 pts were evaluable for ORR (109 AG + A:AG; 79 A alone). The ORR was 48% in pts who received gefitinib + anastrozole and 61% in pts treated with anastrozole alone (p=0.067). Conclusions: Neither the biological nor the clinical activity of anastrozole was enhanced by the addition of gefitinib; although non-significant, both endpoints unexpectedly suggested a trend against the combination in this patient population. Molecular investigations of signal transduction pathways are underway to understand the significance of these findings. [Table: see text] [Table: see text]
A small RNA in neutrophils protects against acute-on-chronic alcoholic liver injury
Authors: Shaogui Wang, Wen-Xing Ding
Journal: Gut (2016)

Alcoholic liver disease (ALD) is a major cause of chronic liver injury worldwide.1 ,2 Clinically, jaundice and liver failure are hallmark presentations of patients with severe alcoholic hepatitis (AH) who typically have been drinking up to the time of admission or have stopped drinking within 4–6 weeks of their presentation of symptoms. The liver histology of AH has features of steatohepatitis, hepatic neutrophil infiltration, cholestasis and florid inflammation.3 Among patients with ALD, liver-related mortality is much higher in patients with AH than those with only simple steatosis.3 Current recommended treatments for AH include corticosteroids or pentoxifylline and nutritional supplements, but they only have moderate therapeutic effects.3

A major barrier preventing drug development against AH is our lack of understanding of the regulatory pathways involved in the pathogenesis of AH despite decades of research on ALD. One reason for this knowledge gap is a lack of proper animal models that reflect the exact pathogenesis of human ALD. The commonly used rodent models, including mice or rats administered with acute oral gavage, ad libitum oral alcohol in drinking water or chronic Lieber–DeCarli ethanol diet feeding, only show mild elevation of serum alanine aminotransferase (ALT) and increased hepatic levels of triglyceride (TG). These models only mimic early pathogenic changes in human ALD, and neutrophil infiltration in the liver is not evident. Dr Bin Gao's group recently developed a mouse model in which mice were fed with the Lieber–DeCarli ethanol diet for 10 days followed by an acute gavage of alcohol (hereafter referred to as Gao-binge model).4 Mice administered with Gao-binge have elevated serum ALT levels, increased hepatic TG, and more importantly, increased circulating and hepatic infiltrated neutrophils, making it possible to determine the mechanisms and role of neutrophils in AH. Indeed, using this Gao-binge model, Dr Gao's group demonstrated …