tbuckley/cabot-search huggingface dataset:
Immunoconjugates comprised of drugs with impaired cellular permeability: A new approach to targeted therapy
Authors: Peter Senter, Svetlana Doronina, Brian Mendelsohn, Brian Toki, Steven Alley, Damon Meyer, Kevin Hamblett, Joseph Francisco, Charles Cerveny, Alan Wahl
Journal: Cancer Research (2004)

623  A great deal of interest has surrounded the use of monoclonal antibodies (mAbs) for the selective delivery of cytotoxic agents to tumor cells. Although the approach is conceptually appealing, several limitations have been identified, including the physiological barriers to mAb extravasation and intratumoral penetration, conjugate immunogenicity, non-specific conjugate uptake, low drug potency, and inefficient release of active drug. In previous work (Doronina, et al. Nature Biotech. 7, 778-784, 2003; Francisco, et al. Blood, 102, 1458-1465, 2003), we addressed some of these issues in developing cAC10-valine-citrulline-MMAE, a cathepsin B cleavable conjugate that delivers the highly potent antimitotic agent monomethyl auristatin E (MMAE) inside CD30 positive tumor cells recognized by the chimeric mAb, cAC10. One of the advantages in using MMAE as the drug component, is that being totally synthetic, it is amenable to extensive modification. Here, we describe novel analogues of MMAE that are designed for enhanced efficacy and lower toxicity. MMAF is an acidic form of MMAE that has reduced cytotoxic activity compared to MMAE, most likely due to impaired intracellular uptake. MMAF is significantly less potent than MMAE on a diverse panel of tumor cell lines, and has a >6-fold increased MTD in mice. However, mAb-valine-citrulline-MMAF conjugates are >10 times more potent than corresponding MMAE conjugates, presumably due to intracellular drug entrapment. Further evidence that this mechanism of enhanced potency stems from the finding that mAb-valine-citrulline-MMAF conjugates are as much as 400-fold more potent on antigen positive cells than the free MMAF drug. A phenylenediamine adduct of the auristatin acid, AFP, was also found to be highly potent when linked to mAbs through the cathepsin cleavable valine-citrulline linker. Upon intracellular uptake the mAb-valine-citrulline-AFP conjugates are subject to hydrolysis of the phenylenediamine unit, leading to the release of active AF. These new conjugates, comprised of an active drug that has impaired cellular permeability, are highly active and potent. Treatment of mice with low and well-tolerated doses of these conjugates leads to cures and regressions of established carcinoma and hematologic tumor xenografts. The results illustrate how mAbs can be used to enhance the potency of relatively impermeable drugs through active intracellular delivery.
The antitumor activity of alternating electric fields (TTFields) in combination with immune checkpoint inhibitors.
Authors: Moshe Giladi, Tali Voloshin, Anna Shteingauz, Mijal Munster, Roni Blat, Yaara Porat, Rosa S. Schneiderman, Shay Cahal, Aviran Itzhaki, Eilon Kirson, Uri Weinberg, Yoram Palti
Journal: Journal of Clinical Oncology (2016)

e14570 Background: Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via application of low intensity, intermediate frequency, alternating electric fields. This therapy is approved for the treatment of patients with glioblastoma. Previous investigations have shown that some of the outcomes of mitosis under TTFields application include abnormal chromosome segregation and ER stress which trigger different forms of cell death. In this study we evaluated whether TTFields induced cancer cell death can be perceived as immunogenic by the immune system, and explored the possibility of combining TTFields with immune-modulating drugs. Methods: Murine Lewis lung carcinoma (LLC) and ovarian surface epithelial (MOSE) cells were treated with TTFields using the inovitro system. The exposure of calreticulin (CRT) on the surface of treated cells was evaluated using flow cytometry. HMGB1 secretion was measured using ELISA assay. For in-vivo experiments, mice were implanted with LLC cells, and treated with TTFields, anti-PD-1 or combination of the two modalities. Changes in tumor volume were monitored and flow cytometry analysis was performed for phenotypic characterization of tumor infiltrating immune cells. Results: We demonstrate that application of TTFields leads to surface exposure of CRT and also promotes release of HMGB1. In vivo, the combined treatment of TTFields and anti-PD-1 led to a significant decrease in tumor volume compared to control group and to animals treated with anti-PD-1 alone. Significant increase in CD45+ tumor infiltrating cells was observed in the TTFields+anti-PD-1 combination treatment group. This cell population demonstrated a significant upregulation of PD-L1 expression on the cell surface. Specifically, this upregulation was observed in both F4/80+CD11b+ cells and CD11c+ cells whereas no effect on the infiltration pattern of these immune cell populations was noted. Conclusions: Our results demonstrate that TTFields application potentiates immunogenic cell death in cancer cells and that combining TTFields with specific immunotherapies such as anti-PD-1 might achieve tumor control by further enhancing antitumor immunity.
Cognitive Function After Testosterone Treatment
Authors: Ralph N. Martins, Malcolm Carruthers, Hamid R. Sohrabi
Journal: JAMA (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 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
Interpreting iron studies
Authors: Alison U Kelly, Stephen T McSorley, Prinesh Patel, Dinesh Talwar
Journal: BMJ (2017)

#### What you need to know A 63 year old woman visits her doctor with a three month history of fatigue and generalised joint pains. Her medical history is unremarkable and she reports no recent stress, infection, or weight loss. There are no abnormalities on clinical examination. Haemoglobin, creatinine, and electrolytes, liver enzymes, glucose, inflammatory markers, and thyroid function tests are normal. Ferritin, iron, transferrin, and transferrin saturation are also requested. This article discusses some situations in which ferritin and iron studies might be helpful and how to avoid common pitfalls in their interpretation. The doctor in this case requested iron studies to investigate the possibility of iron overload and to screen for haemochromatosis. Iron studies are also commonly indicated in clinical practice to investigate iron deficiency, or to monitor response to treatment for these conditions (box 1). #### Box 1: Suggested indications for iron studies Investigation of
MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway
Authors: Qiuran Xu, Xin Liu, Zhikui Liu, Zhenyu Zhou, Yufeng Wang, Jianfeng Tu, Lijie Li, Hangxing Bao, Liu Yang, Kangsheng Tu
Journal: Molecular Cancer (2017)

Increasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC). Underexpression of miR-1296 is recently reported to promote growth and metastasis of human cancers. However, the expression and role of miR-1296 in HCC remain unknown.The levels of miR-1296 in HCC tissues and cells were detected by qRT-PCR. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. Transwell assays were performed to determine migration and invasion of HCC cells. A lung metastasis mouse model was used to evaluated metastasis of HCC in vivo. The putative targets of miR-1296 were disclosed by public databases and a dual-luciferase reporter assay.We found that the expression of miR-1296 was reduced in HCC tissues and cell lines, and it was associated with metastasis and recurrence of HCC. Notably, miR-1296 overexpression inhibited migration, invasion and EMT progress of HCCLM3 cells, while miR-1296 loss facilitated these biological behaviors of Hep3B cells in vitro and in vivo. In addition, miR-1296 inversely regulated SRPK1 abundance by directly binding to its 3'-UTR, which subsequently resulted in suppression of p-AKT. Either SRPK1 re-expression or PI3K/AKT pathway activation, at least partially, abolished the effects of miR-1296 on migration, invasion and EMT progress of HCC cells. Furthermore, miR-1296 and SRPK1 expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the underexpression of miR-1296 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by miR-1296.Underexpression of miR-1296 potentially serves as a prognostic biomarker in HCC. Hypoxia-induced miR-1296 loss promotes metastasis and EMT of HCC cells probably by targeting SRPK1/AKT pathway.
Macrophages with cellular backpacks for targeted drug delivery to the brain
Authors: Natalia L. Klyachko, Roberta Polak, Matthew J. Haney, Yuling Zhao, Reginaldo J. Gomes Neto, Michael C. Hill, Alexander V. Kabanov, Robert E. Cohen, Michael F. Rubner, Elena V. Batrakova
Journal: Biomaterials (2017)
A randomized, placebo-controlled, double-blinded, crossover trial of pioglitazone for severe asthma
Authors: Maryann Kaler, Amisha V. Barochia, Nargues A. Weir, Rosemarie A. Cuento, Mario Stylianou, Mark J. Roth, Armando C. Filie, Ellen C. Vaughey, Steven D. Nathan, Stewart J. Levine
Journal: Journal of Allergy and Clinical Immunology (2017)
Effect of Abdominal Ultrasound on Clinical Care, Outcomes, and Resource Use Among Children With Blunt Torso Trauma
Authors: James F. Holmes, Kenneth M. Kelley, Sandra L. Wootton-Gorges, Garth H. Utter, Lisa P. Abramson, John S. Rose, Daniel J. Tancredi, Nathan Kuppermann
Journal: JAMA (2017)

The utility of the focused assessment with sonography for trauma (FAST) examination in children is unknown.To determine if the FAST examination during initial evaluation of injured children improves clinical care.A randomized clinical trial (April 2012-May 2015) that involved 975 hemodynamically stable children and adolescents younger than 18 years treated for blunt torso trauma at the University of California, Davis Medical Center, a level I trauma center.Patients were randomly assigned to a standard trauma evaluation with the FAST examination by the treating ED physician or a standard trauma evaluation alone.Coprimary outcomes were rate of abdominal computed tomographic (CT) scans in the ED, missed intra-abdominal injuries, ED length of stay, and hospital charges.Among the 925 patients who were randomized (mean [SD] age, 9.7 [5.3] years; 575 males [62%]), all completed the study. A total of 50 patients (5.4%, 95% CI, 4.0% to 7.1%) were diagnosed with intra-abdominal injuries, including 40 (80%; 95% CI, 66% to 90%) who had intraperitoneal fluid found on an abdominal CT scan, and 9 patients (0.97%; 95% CI, 0.44% to 1.8%) underwent laparotomy. The proportion of patients with abdominal CT scans was 241 of 460 (52.4%) in the FAST group and 254 of 465 (54.6%) in the standard care-only group (difference, -2.2%; 95% CI, -8.7% to 4.2%). One case of missed intra-abdominal injury occurred in a patient in the FAST group and none in the control group (difference, 0.2%; 95% CI, -0.6% to 1.2%). The mean ED length of stay was 6.03 hours in the FAST group and 6.07 hours in the standard care-only group (difference, -0.04 hours; 95% CI, -0.47 to 0.40 hours). Median hospital charges were $46 415 in the FAST group and $47 759 in the standard care-only group (difference, -$1180; 95% CI, -$6651 to $4291).Among hemodynamically stable children treated in an ED following blunt torso trauma, the use of FAST compared with standard care only did not improve clinical care, including use of resources; ED length of stay; missed intra-abdominal injuries; or hospital charges. These findings do not support the routine use of FAST in this setting.clinicaltrials.gov Identifier: NCT01540318.
ZFP521 regulates murine hematopoietic stem cell function and facilitates MLL-AF9 leukemogenesis in mouse and human cells
Authors: Brian S. Garrison, Adrian P. Rybak, Isabel Beerman, Balthasar Heesters, Francois E. Mercier, David T. Scadden, David Bryder, Roland Baron, Derrick J. Rossi
Journal: Blood (2017)
Changes in Hospital Quality Associated with Hospital Value-Based Purchasing
Authors: Andrew M. Ryan, Sam Krinsky, Kristin A. Maurer, Justin B. Dimick
Journal: New England Journal of Medicine (2017)

Starting in fiscal year 2013, the Hospital Value-Based Purchasing (HVBP) program introduced quality performance-based adjustments of up to 1% to Medicare reimbursements for acute care hospitals.We evaluated whether quality improved more in acute care hospitals that were exposed to HVBP than in control hospitals (Critical Access Hospitals, which were not exposed to HVBP). The measures of quality were composite measures of clinical process and patient experience (measured in units of standard deviations, with a value of 1 indicating performance that was 1 standard deviation [SD] above the hospital mean) and 30-day risk-standardized mortality among patients who were admitted to the hospital for acute myocardial infarction, heart failure, or pneumonia. The changes in quality measures after the introduction of HVBP were assessed for matched samples of acute care hospitals (the number of hospitals included in the analyses ranged from 1364 for mortality among patients admitted for acute myocardial infarction to 2615 for mortality among patients admitted for pneumonia) and control hospitals (number of hospitals ranged from 31 to 617). Matching was based on preintervention performance with regard to the quality measures. We evaluated performance over the first 4 years of HVBP.Improvements in clinical-process and patient-experience measures were not significantly greater among hospitals exposed to HVBP than among control hospitals, with difference-in-differences estimates of 0.079 SD (95% confidence interval [CI], -0.140 to 0.299) for clinical process and -0.092 SD (95% CI, -0.307 to 0.122) for patient experience. HVBP was not associated with significant reductions in mortality among patients who were admitted for acute myocardial infarction (difference-in-differences estimate, -0.282 percentage points [95% CI, -1.715 to 1.152]) or heart failure (-0.212 percentage points [95% CI, -0.532 to 0.108]), but it was associated with a significant reduction in mortality among patients who were admitted for pneumonia (-0.431 percentage points [95% CI, -0.714 to -0.148]).In our study, HVBP was not associated with improvements in measures of clinical process or patient experience and was not associated with significant reductions in two of three mortality measures. (Funded by the National Institute on Aging.).
IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance
Authors: Pei-Yun Tsai, Bingkun Zhang, Wei-Qi He, Juan-Min Zha, Matthew A. Odenwald, Gurminder Singh, Atsushi Tamura, Le Shen, Anne Sailer, Sunil Yeruva, Wei-Ting Kuo, Yang-Xin Fu, Sachiko Tsukita, Jerrold R. Turner
Journal: Cell Host & Microbe (2017)
Evaluating guidelines across primary care-secondary care interface
Authors: N. Freemantle, J. Wood, J. Morrison, A. Leyland, J. Grimshaw
Journal: BMJ (2001)

Editor—Readers' ability to extract information from Morrison et al's study is impeded by errors in analysis and reporting.1 The trial evaluated clinical guidelines on the management of subfertility for doctors in general practice. The hope was that consequent improvements to procedure in primary care would affect processes in secondary care after referral, with more efficient management overall.

The subjects of the study were healthcare professionals, and the focus (the object of the intervention and the outcomes measured) was on their behaviour. All the results, however, are given as aggregated patient referrals, which does not respect the structure of the experiment.

Although one can compare case mix through aggregated patient characteristics (table 1), it is wrong to assess and report the effects of the intervention on this basis.2 The authors adjust for within practice correlation in their analysis, but at a level that is inappropriate. Two important consequences are the absence of information on variability between clinicians and inappropriate inflation of the sample size. Indeed, at a recent Medical Research Council meeting on cluster randomised trials it was acknowledged that using patients as the unit of analysis for trials in which the healthcare provider formed the natural subject is always incorrect.

Other concerns centre on the significant difference between the guideline and non-guideline groups in the number of appropriate investigations carried out in general practice, flagged as a “positive result” for the trial. Firstly, some confusion surrounds this statement. The paper refers to a “significantly higher mean number,” with means given in table 2. Alongside the means, however, is an odds ratio with confidence interval and significance (P=0.05). It is these latter figures that are given in the abstract, described as the binary outcome “all relevant investigations carried out,” though now with P=0.025 (presumably one sided).

Secondly, and fundamentally, this significant result stands in isolation among the outcomes measured. Naturally, it is efficient to measure several outcomes in a trial, summarising these with confidence intervals. However, if we ask essentially the same yes/no question several times in significance tests (here, whether guidelines modified doctors' behaviour) and get a single “yes” in reply, then multiplicity matters. The direct way through this is to pre-specify a single primary outcome to identify whether the trial is positive.3 As no such outcome is defined in the paper, the correct interpretation is that the trial is neutral. No post-hoc action can turn around this conclusion.

We frequently have just one opportunity to assess important questions of healthcare delivery in randomised controlled trials. These opportunities are wasted when studies are poorly designed and reported.
You've got mail
Authors: Douglas Kamerow
Journal: BMJ (2004)

The Internet changes everything, and health care is no exception. The Internet is already one of the leading sources of health information, both for patients and clinicians. Some day we will have fully integrated and secure electronic health records accessible to patients and authorized professionals anywhere there is Internet access, which by then will be everywhere.

One of our challenges right now, however, is figuring out the role of email in the clinical relationship. Most patients have access to email, and virtually all doctors do. …
Refined Graft-Versus-Host Disease-Free, Relapse-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate and Unfavorable Prognosis Acute Myeloid Leukemia Ttransplanted in First Complete Remission from HLA-Identical Related or Unrelated Donors: A Retrospective Study on Behalf of the ALWP of the EBMT
Authors: Giorgia Battipaglia, Annalisa Ruggeri, Myriam Labopin, Liisa Volin, Didier Blaise, Gerard Socié, Noel Milpied, Jan J. Cornelissen, Ardeshir Ghavamzadeh, Anne Huynh, Wu Depei, Ibrahim Yakoub-Agha, Johan Maertens, Patrice Chevallier, Mohamad Mohty, Arnon Nagler
Journal: Blood (2016)
Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity
Authors: Yong Teng, Yafei Cai, Wenhu Pi, Lixia Gao, Chloe Shay
Journal: Journal of Hematology & Oncology (2017)

Abnormalities of tubulin polymerization and microtubule assembly are often seen in cancer, which make them very suitable targets for the development of therapeutic approach against rapidly dividing and aggressive cancer cells. CYT997 is a novel microtubule-disrupting agent with anticancer activity in multiple cancer types including prostate cancer. However, the molecular mechanisms of action of CYT997 in prostate cancer have not been well characterized. Src knockdown cells were achieved by lentiviral-mediated interference. The drug effects on cell proliferation were measured by MTS. The drug effects on cell viability and death were determined by Cell Titer-Glo® Luminescent cell viability kit and flow cytometry with Zombie Aqua™ staining. The drug effects on apoptosis were assessed by Cell Death Detection Elisa kit and Western blot with a cleaved PARP antibody. The drug effects on cell invasion were examined by Matrigel-coated Boyden chambers. Oxidative stress was detected by DCFH-DA staining and electrochemical biosensor. Mouse models generated by subcutaneous or intracardiac injection were used to investigate the in vivo drug efficacy in tumor growth and metastasis. CYT997 effectively inhibited proliferation, survival, and invasion of prostate cancer cells via blocking multiple oncogenic signaling cascades but not the Src pathway. Inhibition of Src expression by small hairpin RNA or inactivation of Src by dasatinib increased the CYT997-induced cytotoxicity of in vitro. Moreover, the combination of dasatinib and CYT997 exhibited a superior inhibitory effect on tumor growth and metastasis compared with either of the drugs alone. Our findings demonstrate that blockage of Src augments the anticancer effect of CYT997 on prostate cancer and suggest that co-treatment of dasatinib and CYT997 may represent an effective therapeutic regimen for limiting prostate cancer.
New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31stAnnual Meeting of the Society for Immunotherapy of Cancer, 2016
Authors: Prasad S. Adusumilli, Edward Cha, Mark Cornfeld, Thomas Davis, Adi Diab, Thomas W. Dubensky, Elizabeth Evans, Jane L. Grogan, Bryan A. Irving, Rom S. Leidner, Shane A. Olwill, Patrick Soon-Shiong, Frederic Triebel, David Tuck, Adrian Bot, Roger D. Dansey, Charles G. Drake, Gordon J. Freeman, Ramy Ibrahim, Salil Patel, Daniel S. Chen
Journal: Journal for ImmunoTherapy of Cancer (2017)

This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.
Case 18-2017 — An 11-Year-Old Girl with Difficulty Eating after a Choking Incident
Authors: Jennifer J. Thomas, Kathryn S. Brigham, Sarah T. Sally, Eric P. Hazen, Kamryn T. Eddy
Journal: New England Journal of Medicine (2017)

An 11-year-old girl presented with difficulty eating and weight loss after a choking incident that had occurred 14 days earlier. She had always been a selective eater, but fear of choking led her to consume only a liquid diet. A diagnosis and management decisions were made.