tbuckley/cabot-search huggingface dataset:
HA22 (R490A) is a recombinant immunotoxin with increased anti-tumor activity and therapeutic index
Authors: Sookhee Bang, Robert J. Kreitman, David Fitzgerald, Ira Pastan
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

622 

RFB4 (dsFv)-PE38 (BL22) is a recombinant immunotoxin containing an anti-CD22 variable domain (Fv) fused to a 38-kDa form of Pseudomonas exotoxin A (PE). BL22 has been evaluated in a Phase I clinical trial at the National Cancer Institute in patients with hematological malignancies. BL22 is able to induce a high complete remission rate in patients with purine analogue-resistant HCL. This finding establishes the concept that immunotoxins can produce clinical benefit to patients with advanced malignancies. Our laboratory recently made a mutant immunotoxin, HA22, with improved affinity and cytotoxic activity using a combination of phage display and hot spot mutagenesis techniques. HA22 is derived from BL22 and has three mutations in the heavy chain CDR3 that result in its increased activity. Previous studies using native PE showed that destruction of a protease sensitive site in domain 3 by deleting arginine 490 increased the half-life of PE in the circulation of mice. Several factors are thought to control the lifetime of proteins in the circulation and inactivation or degradation of proteins by proteolysis could be one of them. We have now extended these studies to immunotoxins. For this purpose we have chosen HA22 and made a new mutant in which arginine 490 is changed to alanine. We chose to mutate R490 to A rather than delete it to diminish possible changes in protein structure. We found that HA22 (R490A) is ∼2-fold more active than HA22 on several CD22-positive cell lines. Surprisingly, the plasma half-life of HA22 (490A) was not increased. It was 18.8 min compared to a half -life of 21.9 min for HA22. When injected into mice HA22 and HA22 (R490A) had very similar toxicities with an LD50 of about 1.3 mg/kg for each. However, HA22 (R490A) had a more potent anti-tumor activity than HA22 against CA46 tumors in mice reflecting its increased cytotoxic activity in cell culture. These studies show that protein engineering can be used to increase the efficacy of recombinant immunotoxins. Furthermore because HA22 (490A) has increased anti-tumor activity and not increased animal toxicity, immunotoxins with this mutation are better candidates for clinical development.
Abstract 104: Vasonatrin Peptide Inhibits Endoplasmic Reticulum Stress and Attenuates Myocardial Ischemia/reperfusion Injury in Diabetic Rats
Authors: Haifeng Zhang, Wenjuan Xing, Feng Gao
Journal: Circulation Research (2015)

Aims: Diabetes mellitus (DM) increases morbidity/mortality of ischemic heart disease. Although the ability of the natriuretic peptides to modulate cardiac function and cell proliferation has been recognized, their effects on myocardial ischemia/reperfusion (MI/R) injury is still unclear. This study was to investigate the effects of the artificial synthetic natriuretic peptide — vasonatrin peptide (VNP) on MI/R injury in diabetic rats, and underlying mechanisms. Method: The high-fat diet-fed streptozotocin induced diabetic rats were subjected to MI/R (30 min/4 h) and VNP treatment (100 μg/kg, i.v., 10 min before R). In vitro study was performed using H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R, 3 h/6 h) and incubated with or without VNP (10 -8 mol/L). Result: The diabetic state aggravated MI/R injury and showed more severe myocardial functional impairment than normal state. VNP treatment (100 μg/kg, i.v., 10 min before R) significantly improved ± LV d P /dt max and LVSP, and decreased infarct size, apoptosis index, caspase-3 activity, serum CK and LDH levels (n=8, P &lt;0.05). Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing GRP78 and CHOP, and consequently increased Akt and ERK1/2 expression and phosphorylation levels (n=3, P &lt;0.05). These effects were mimicked by 8-Br-cGMP (1 mg/kg, i.p., 20 min before R), a cGMP analogue, whereas inhibited by KT-5823 (0.5 mg/kg, i.p.), the selective inhibitor of PKG ( P &lt;0.05). Pretreated DM rats with TUDCA (50 mg/kg, i.p.), an inhibitor of ER stress, couldn’t further promote the VNP’s cardioprotective effect. Additionally, gene knockdown of PKG1α with siRNA blunted VNP’s inhibition of ER stress and apoptosis, while overexpression of PKG1α resulted in significant decreased ER stress and apoptosis in H/R H9c2 cardiomyocytes (n=6, P &lt;0.05). Conclusion: We demonstrated that VNP protects diabetic heart against MI/R injury by inhibiting ER stress via cGMP-PKG signaling pathway.
Genomic profiling to distinguish poorly differentiated neuroendocrine carcinomas arising in different sites.
Authors: Emily K. Bergsland, Ritu Roy, Phil Stephens, Jeffrey S. Ross, Mark Bailey, Adam Olshen
Journal: Journal of Clinical Oncology (2016)

4020 Background: Extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-NEC) occur in nearly any site. Traditionally treated like small cell lung carcinoma (SCLC), optimal therapy has not yet been defined. We examined genomic alterations in EP-NEC of different sites in comparison to SCLC and to each other. Methods: Genomic profiling was performed on 867 NEC, including 593 SCLC and 274 EP-NEC (pathologist-confirmed poorly differentiated morphology) arising in the gastrointestinal (GI) tract and pancreas: 123 pancreas, 92 colon, and 59 "other GI" (esophageal, stomach, small intestine). Hybridization-captured, adaptor ligation based libraries were used to a mean coverage depth of 600X for 192 cancer-related genes. All classes of genomic alterations were identified (copy number losses, amplifications, rearrangements, and short variant mutations). Results: There were 9 genes with alterations in > 15% of tumors in any group (Table 1). Only TP53 crossed the 15% threshold in every group; MEN1 and DAXX > 15% specific to pancreas, APC and KRAS > 15% specific to colon, and CCNE1 > 15% specific to "other GI". Every EP-NEC group had a lower rate of alteration for TP53 and RB1than SCLC. Conclusions: In this dataset, molecular alterations in GI tract and pancreas EP-NEC differ from SCLC and from each other. TP53 and RB1alterations are less common in EP-NEC and other genes more frequently altered than in SCLC. These findings suggest that optimal therapy for EP-NEC may be site-specific and different from SCLC. An in-depth analysis of site-specific alterations and targetable mutations will be presented. Correlation with histopathologic subtype is planned. Genes with alterations in > 15% of tumors in any group (% with alterations). Gene SCLC (N = 593) Pancreas (N = 123) Colon (N = 92) Other GI (N = 59) TP53 90%P,C,O 18%S,C,O 59%S,P 49%S,P RB1 67% P,C,O 10% S,C,O 34%S,P 29% S,P CDKN2A 3%P,O 21%S,C 5%P,O 25%S,C MEN1 1%P 33%S,C,O 3%P 2%P CDKN2B 1%P,O 16%S,C 1%P,O 19%S,C DAXX 0%P 20%S,C,O 0%P 0%P APC 2%C 3%C 47%S,P,O 8%C KRAS 4%C 7%C 37%S,P,O 3%C CCNE1 4%O 2%O 1%O 17%S,P,C S, P, C or O: Statistically significant difference compared to S= SCLC, P= Pancreas, C= colon, O= Other GI
Elective waiting times rise again after relaxation of targets
Authors: Adrian O’Dowd
Journal: BMJ (2017)

The number of patients waiting for elective treatment in England was 5% higher in April than in the same month in 2016, new data show.

Doctors’ leaders have expressed their concern over the performance data,1 which were released by NHS England on the same day as the UK general election results (9 June).

The data show that at the end of April 3.78 million people were on the waiting list for planned treatment in England, up from 3.6 million in the same month last year. Collectively, 89.9% of patients waiting to start treatment had waited more than the targeted 18 weeks, and thus the …
Modern allergy diagnostics in China: The past and present
Authors: Baoqing Sun, Wenting Luo, Heng Zhong, Guangqiao Zeng
Journal: European Respiratory Journal (2014)

Aims: Despite a variety of difficulties, allergy diagnostics in China wound its way of advancement over half a century. Here we presented a comprehensive review on the past and present of modern allergy diagnostics in China.

Methods: History of allergy research in China was reviewed, methods of modern allergy diagnostics were briefly introduced and the application of each method was discussed.

Results: After reviewed, nearly 300 hospitals or medical research institutes published manuscripts related to allergen detection. Prevalence of allergies in China is on the rise due to urbanization and westernization of life-style and social culture. Mainstay approaches for allergic tests commonly used in China include clinical history, skin prick test, detection of allergen-specific IgE with RAST and ELISA. New techniques, such as microarray, are also increasingly developed. Inadequate medical investment and the yet-to-improve techniques become the concerning development of allergy diagnostics in China.

![Figure][1] 



Prospect: In the future, the Chinese allergen atlas should be finished through multi-centre epidemiology survey. There is a large requirement of high-quality reagents for detecting allergens, new developing technology could be considered as imported. The national GMP of allergen detection reagents should be published and GLP of application of allergens in different diseases needs to be drafted, finally national guideline for allergic diseases will be drawn.

 [1]: pending:yes
Evaluation of Blunt Suture Needles in Preventing Percutaneous Injuries Among Health-Care Workers During Gynecologic Surgical Procedures— New York City, March 1993-June 1994
Journal: JAMA (1997)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Abstract 089: Response Gene To Complement 32 Is Involved In Glucose Metabolism Disorder In Endothelial Cells And Mediated By P53
Authors: Shuzhen Guo, Hongjian Lian, Wenjing Chuo, Xuanchao Feng
Journal: Circulation Research (2013)

Response gene to complement 32 (RGC-32) was considered as an apoptosis-promoting factor. To explore the novel functions of RGC-32, a DNA array analysis was performed in Human Microvascular Endothelial Cells (HMEC) treated with SiRNA, which showed that glucose metabolism was one of most dramatically changed biological process. qPCR analysis also proved that many glucose metabolism related genes were changed dramatically in RGC32 o/e HMEC, one of which was Insulin-like growth factor binding protein 4(IGFBP4). We propose that RGC-32 may be a potential factor involved in the cycle of endothelial glucose metabolism besides glucose induced apoptosis. Then we found that expression of RGC-32 was dramatically increased in mice hearts and adipose tissue after high fat diet treatment, as well as in HMEC after high glucose (30mM) treatment. In high fat diet treated endothelial specific RGC-32 transgenic mice (VE-Cad/RGC-32), decreases in area under the curve (AUC) of glucose tolerance test were observed when compared to their wild type littermates. Upregulated P53 and downregulated IGFBP4 mRNA expression level were also observed in the heart of VE-Cad/RGC-32 mice.Furthermore, we found that P53 was upregulated in RGC-32 o/e HMEC and blocking of p53 was able to decrease the RGC-32-related induction of apoptotic cells. We also observed that RGC-32 can not only decrease IGFBP4 but also reverse the decrease of IGFBP4 in high glucose or insulin condition. Interestingly, after treated the cells with pifithrin-a, a specific P53 inhibitor, decreased IGFBP4 by RGC-32 was rescued. These results demonstrate that RGC-32 may have some kind of connections with glucose metabolism besides its well-known apoptosis-promoting characters and P53 may be a mediator of RGC-32 related glucose metabolism disorder as well as apoptosis.These findings will provide some clues for novel insights into the functions of RGC-32.
Abstract 129: Inhibition of MEF2 By Atenolol Modifies the Transcriptome During Cardiac Hypertrophy to Improve Heart Function
Authors: Stephanie Wales, Sara Hashemi, Keith Dadson, Subat Tuerdi, Jian Zhao, Gary Sweeney, Jorg Grigull, John C McDermott
Journal: Circulation Research (2015)

Cardiac hypertrophy is a growth response of the adult heart that often results from increased mechanical loading due to high blood pressure and myocardial damage caused by ischemic heart disease. The β1 selective β-adrenergic antagonist, atenolol, is historically one of the most frequently prescribed of all medicines used to preserve heart function following myocardial damage. Transcription factor, myocyte enhancer factor 2 (MEF2), is required for early cardiac development and has also been implicated in cardiac hypertrophy. The effect of β-blockade on the gene program that is activated following cardiac hypertrophy as heart failure progresses is not fully understood. Here we show that treatment with atenolol leads to in vivo changes within the murine heart to reverse cardiac hypertrophy, and this is accompanied by repression of MEF2 activity. Cardiac hypertrophy was simulated using transverse aortic constriction (TAC) for four weeks in a transgenic MEF2-lacZ mouse model, followed by six weeks of vehicle (AT-) or atenolol treatment (AT+). Physiological responses in cardiac function, fibrosis, and cardiomyocyte size in TAC+AT+ mice were consistent with cardiac hypertrophy and demonstrated increased MEF2 activity compared to control (TAC-AT-). Atenolol treatment resulted in an overall improvement in cardiac function of TAC+ mice, showing a decrease in cardiomyocyte size, fibrosis and MEF2 activity. RNA was isolated from the left ventricle of the heart to determine changes in mRNA and lncRNA using RNA-seq. Atenolol reversed the expression of a specific subset of genes and lncRNA that become upregulated by TAC which corresponded to gene ontology terms related to metabolism and the immune system. Together, these data demonstrate that atenolol treatment during cardiac hypertrophy inhibits MEF2 activity and concomitantly leads to improved cardiac function. Thus, inhibition of MEF2 may be necessary to improve or reverse the effects of long-term heart failure.
Association of Interleukin 1 Beta Gene -511 Single Nucleotide Polymorphism with Eesophageal Cancer
Authors: K Azim, D Kelleher, J Reynolds, R McManus
Journal: Endoscopy (2004)

Aim: To estimate the distribution of IL-1B gene -511 C-T biallelic single nucleotide polymorphism (snp) in patients with cancer of the esophagus and a control population of Irish origin.
Abstract 18794: Systemic Heparin Use and Outcomes in Cardiac Arrest Patients Treated With Therapeutic Hypothermia Without Coronary Intervention
Authors: Michael N Young, Benjamin B Holmes, Meng Xu, Nyal Borges, Emily K Zern, William C Armstrong, John A McPherson
Journal: Circulation (2015)

Introduction: The effects of hypothermia on hemostatic function are complex and poorly understood. While cardiac arrest and CPR can elicit a pro-inflammatory, pro-coagulant state, hypothermia may alter platelet count, activation and aggregation. Hypothesis: We hypothesized that treatment with systemic heparin during therapeutic hypothermia (TH) is associated with improved neurologic outcomes. Methods: We conducted a retrospective study of 157 cardiac arrest survivors treated with TH at our institution from 2007-2014. A priori, we excluded TH patients (pts) presenting with an acute coronary syndrome requiring percutaneous coronary intervention, pulmonary embolus, venous thrombosis or need for mechanical circulatory support. We used a multivariable logistic regression model to examine the relationship between systemic heparin and neurologic outcome (Cerebral Performance Category score 1-2=good; 3-5=poor) as well as inpatient survival. We also performed a chi-square analysis for the secondary endpoint of major bleeding. Results: Mean age was 57.0 (+/- 16.2) years; 86 (54%) pts were male; and 75 (47.8%) pts had an initial rhythm of ventricular tachycardia or ventricular fibrillation. At discharge, 48 (30.6%) pts had a good neurologic outcome and 23 (14.7%) pts suffered from a major bleed. Systemic heparin was administered to 48 (30.6%) pts, and was neither associated with favorable neurologic outcome (OR 0.99, CI 0.39-2.56, p=0.991) nor inpatient survival (OR 1.28, CI 0.54-3.05, p=0.574). The risk of bleeding with heparin was 2.08 (CI 0.99-4.38, p=0.052). Conclusions: In our cohort, indiscriminate use of systemic heparin during TH post-cardiac arrest was not associated with improved neurologic outcomes. Conversely, a trend towards increased risk of major bleeding was noted.
Marketing Claims for Infant Formula Additives and Infant Formula—Reply
Authors: Helen K. Hughes, Michael M. Landa, Joshua M. Sharfstein
Journal: JAMA Pediatrics (2017)

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 Pediatrics 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 Pediatrics journal
Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE (NCT00268476).
Authors: Nicholas D. James, Johann S. De Bono, Melissa Ruth Spears, Noel Clarke, Malcolm David Mason, David P. Dearnaley, Alastair W S Ritchie, J. Martin Russell, Clare Gilson, Robert J. Jones, Silke Gillessen, David Matheson, San Aung, Alison J. Birtle, Simon Chowdhury, Joanna Gale, Zafar Malik, Joe M. O'Sullivan, Mahesh K B Parmar, Matthew Robert Sydes
Journal: Journal of Clinical Oncology (2017)

LBA5003 Background: Abiraterone showed a survival advantage in men with castration-refractory prostate cancer. We assessed whether abiraterone would work earlier in the disease. STAMPEDE is a randomized controlled trial using a multi-arm multi-stage platform design. It recruits patients (pts) with high-risk locally advanced or metastatic PCa starting long-term ADT. We report the first comparative survival data. Methods: The standard-of-care (SOC) was ADT for 2+yrs; radiotherapy (RT) was mandated for men with N0M0 disease &amp; encouraged for N+M0. Stratified randomization allocated pts 1:1 to SOC or SOC+abiraterone 1000mg + prednisolone 5mg daily. Treatment duration depended on stage &amp; intent to give radical RT: pts not having RT or M1 disease, treatment continued until PSA, radiological &amp; clinical progression; otherwise treatment continued until the earlier of 2 years or all types of progression. The primary outcome measure was death from any cause. Comparison to control for survival had 90% power at 2.5% 1-sided alpha for hazard ratio (HR) of 0.75, requiring ~267 control arm deaths, accounting for 3 intermediate lack-of-benefit analyses on failure-free survival (FFS). Analyses used Cox proportional hazards &amp; flexible parametric models, adjusted for stratification factors. Results: 1,917 pts were contemporaneously randomized to these arms (Nov 2011- Jan 2014). Groups were balanced: median age 67yrs; 52% metastatic, 20% N+/X M0, 28% N0M0; 95% newly-diagnosed; median PSA 53ng/ml. Median follow-up was 40m. There were 262 control arm deaths (82% PCa). The adjusted HR = 0.63 (95% CI 0.52-0.76; p=0.115x10 -7 ; 184 deaths) for SOC+Abi vs SOC, with 3yr OS improved from 76% to 83%. There were 535 control arm FFS events; the adjusted HR = 0.29 (95% CI 0.25-0.34; p = 0.377x10 -63 , 248 FFS events) for SOC+Abi vs SOC. Grade 3 &amp; 4 adverse events were seen in 29% &amp; 3% SOC, 41% &amp; 5% SOC+Abi; Grade 5: 3 &amp; 9 (1 &amp; 2 related). Conclusions: The results show a clinically &amp; statistically significant effect on overall survival &amp; failure-free survival from adding abiraterone at start of ADT with a manageable increase in toxicity. ADT (+/- RT) + abiraterone is a new standard of care for this group. Clinical trial information: NCT00268476.