tbuckley/cabot-search huggingface dataset:
EXTH-51. GENETICALLY STABLE POLIOVIRUS VECTOR PLATFORM FOR DIPG IMMUNOTHERAPY
Authors: Matthias Gromeier, Mubeen Mosaheb, Elena Dobrikova, Michael Brown, Darell Bigner, David Ashley
Journal: Neuro-Oncology (2019)

Abstract Options for the immunotherapy of diffuse intrinsic pontine glioma (DIPG), due to its anatomical location and inherent therapy resistance, are limited. The histone 3.3(K27M) mutation in ~80% of such tumors offers a unique opportunity for immunotherapy intervention, as it defines a high affinity, HLA-A2-restricted tumor neoantigen that spontaneously elicits CD8+ T cell responses in DIPG patients. Immunizing against the H3.3(K27M) signature in the clinic has been challenging, as conventional approaches (i.e. peptide-conjugates administered with adjuvants) lack the costimulatory signals known to drive CD8+ effector T cell responses. Therefore, we built on a viral vector approach for engaging innate immune responses to virus infection specifically in antigen presenting cells. Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. We devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in syngeneic rodent tumor models. We are preparing a prototype PVSRIPO-derived vector delivering the H3.3(K27M) signature for clinical investigation.
Myelography and Myography
Authors: Parviz Kambin
Journal: JAMA (1963)

<h3>To the Editor:</h3> —As is evident from the title of the paper, the authors are not trying to discuss the clinical use and validity of the electromyography in radiculopathy per se. Most of our readers, who have read the paper thoroughly, have noticed that we are discussing only the root-compression syndrome which is produced by a herniated intervertebral disk. Clinically, all of these patients had a typical symptom and findings of root compression, which did not respond to conservative treatment and because of which they were scheduled for surgery. Just prior to surgical intervention, electromyography and myelography were done for detection of the level of the compression, so it becomes obvious that we did not have to use electromyography for screening purposes in these patients. In this paper, the authors were concerned with electromyographic determination of the exact level of compression, which is of concern to the surgeon before he
Human Leukocyte Antigen Matched Unrelated Donors for Patients with Sickle Cell Disease According to Geographic Origin: Results of International Donor Searches
Authors: Karina Tozatto-Maio, Margareth Afonso Torres, Neifi Hassan Saloum Degaide, Juliana Fernandes Cardoso, Fernanda Volt, Ana Cristina Silva Pinto, Danielli Oliveira, Hanadi Elayoubi, Simone Kashima, Pascale Loiseau, Hendrik Veelken, Alina Ferster, Barbara Cappelli, Evandra Strazza Rodrigues, Graziana M. Scigliuolo, Chantal Kenzey, Annalisa Ruggeri, Vanderson Rocha, Renato Cunha, Belinda Pinto Simões, Ryad Tamouza, Eliane Gluckman
Journal: Blood (2019)
ATIM-22. PHASE I TRIAL OF DRUG RESISTANT IMMUNOTHERAPY: A FIRST-IN-CLASS COMBINATION OF MGMT-MODIFIEDγδ T CELLS AND TEMOZOLOMIDE CHEMOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME
Authors: Lawrence Lamb, James Markert, G Yancey Gillespie, Melissa Beelen, Catherine Langford, Larisa Pereboeva, Samantha Youngblood, Louis Nabors
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Alkylating agents such as Temozolomide (TMZ) significantly upregulate stress-induced NKG2D ligands targeted by innate immune effector cells. Genetic modification of γδT cells with an MGMT-expressing lentivector abrogates TMZ-induced lymphodepletion allowing simultaneous chemotherapy and γδT cell therapy in a process we have termed Drug Resistant Immunotherapy (DRI) resulting in a significant improvement in long-term survival in patient-derived xenograft (PDXT) models of primary and recurrent GBM. We have now initiated a Phase I clinical trial of DRI in primary GBM (BB-IND-17928) to determine the safety of this approach. METHODS Effector γδT cells are manufactured from a fractional apheresis product obtained immediately prior to post-resection chemo/radiotherapy. Cultures are propagated in a Miltenyi Prodigy® bioreactor using media containing Zoledronic Acid and rhIL-12, transduced with a P140K-MGMT lentivector, maintained for up to 14 days, harvested, and cryopreserved. At the initiation of maintenance TMZ therapy, patients receive 150mg/m2 intravenous TMZ and 1 x 107 γδT cells delivered through a Rickham reservoir inserted into the tumor cavity at primary resection. Treatment frequency escalates from one to three 28-day cycles in a standard 3 x 3 design. RESULTS Closed system manufacturing in the Prodigy bioreactor produced 4.5 – 11.9 x 108 γδT cells (44–103 fold expansion) from the apheresis starting material (0.6–1.9% γδT cells) with vector copy numbers of 0.9 - 2.1 copies/cell and in vitro cytotoxicity against K562 44.3% - 77.9% at E:T 40:1. Products were successfully cryopreserved and retained in vivo potency against GBM PDXT in mice over single-agent TMZ (p= 0.0286). All cell products met sterility and identity criteria. CONCLUSIONS These findings show that genetically modified γδT cells can be manufactured to clinical scale under GMP compliance in an automated bioreactor and cryopreserved to produce multiple doses of functionally-competent γδT cells. Patient accrual will initiate in 2019.
Anticoagulant Therapy in Acute Myocardial Infarction
Authors: Richard J. Jones
Journal: JAMA (1979)

In 1948 the American Heart Association officially endorsed anticoagulation for patients sustaining an acute myocardial infarction. Its large cooperative, randomized, clinical trial was criticized because the randomization was not blind, and a possible bias was suggested by the enthusiasm of the cooperating investigators. Subsequent studies have not always supported the findings of that trial, and there is now a massive literature on the debate over the efficacy of this treatment in the acute infarct. Despite continuing arguments pro and con, the substantial proportion of physicians who accept the evidence in favor of coumarin derivatives has continued to pursue that therapy during the years so that in most of the large medical centers of this country it is possible to examine the results of their use in a large number of patients with myocardial infarction. This has been done in the report by Szklo et al in this issue ofThe
EXTH-07. OPTIMIZATION OF TARGETING ELTD1 IN GLIOBLASTOMA USING A MOLECULAR TARGETING APPROACH
Authors: Nataliya Smith, Debra Sauders, Rheal Towner, Michelle Zalles
Journal: Neuro-Oncology (2019)

Abstract The standard of care for glioblastoma multiform (GBM), an aggressive form of cancer, has not significantly increased the prognosis for patients. ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain containing protein 1), a biomarker for angiogenesis, was found to be highly expressed in human high-grade gliomas. Novel treatments targeting ELTD1 with polyclonal (pAb) and monoclonal (mAb) antibodies were effective as a potential cancer therapy in a G55-xenograft mouse model. While our studies have demonstrated that the blood brain barrier (BBB) was leaky around the tumor region, other studies have shown that the BBB is not equally disrupted in GBM patients, therefore suggesting that the mAb may have difficulty crossing the BBB and infiltrating the tumor due to its size. To overcome these limitations, this study focused on the optimization of targeting ELTD1 by using an optimized svFc antibody fragment derived from our mAb against ELTD1. Immunocompromised mice were intracerebrally injected with human-G55 cells. Morphological MRI was used to monitor and calculate tumor volumes. Treatments using IgG, anti-ELDT1 mAb or fragment upon tumor detection. Vascular perfusion images were obtained to examine vascular alterations. Molecular targeting imaging (mtMRI) was conducted to assess the binding specificity of our antibodies against the tumor region. Targeting ELTD1 with varying antibodies (anti-ELTD1 mAb and scFv fragment) resulted in increased survival and decreased tumor volumes in a G55 xenograft GBM mouse model. Additionally, through the use of mtMRI, we determined altered levels of binding specificity against the tumor region using three different anti-ELTD1 attached probes (monoclonal and scFv fragment antibodies). Our data suggest that the optimization of an anti-ELTD1 therapy could be used to better target angiogenesis in glioblastomas.
TMOD-11. CHARACTERISATION OF THE POST-SURGICAL INVASIVE TUMOUR NICHE USING ASTROCYTE-GLIOBLASTOMA ORGANOIDS AND DECELLULARISED HUMAN BRAIN
Authors: Mohammed Diksin, Jonathan Rowlinson, Alexander Kondrashov, Chris Denning, Jaime Hughes, Tim Constantin-Teodosiu, Wei Cui, David Scurr, Omar Ahmad, Christopher Gell, David Onion, Nicola Croxall, Stuart Smith, Ruman Rahman
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma therapeutic challenges are in considerable part due to myriad survival mechanisms which allow malignant cells to repurpose signalling pathways within discreet microenvironments. These Darwinian adaptations facilitate invasion into brain parenchyma and perivascular space. We hypothesised that pre-clinical modelling of glioma invasion by recapitulating early events occurring immediately after surgery at the glioblastoma invasive margin, could reveal the cross-talk between malignant cells and surrounding healthy astrocytes. We first generated transgenic H1-derived neural stem cells using CRISPR/Cas9-mediated knock-in of the YFP reporter gene under the control of the GFAP promoter at the AAVS1 safe harbour locus. Reproducible ultrahigh-throughput AggreWells™ (7200 mini-wells per plate) were used to create astrocyte-glioblastoma organoids, which we term ‘Gliomasphere Matrices’. YFP-labelled astrocytes were co-cultured with 10 treatment-naïve patient-derived cell lines isolated from the 5-aminolevulinic (5ALA)-determined glioblastoma invasive margin. Co-cultures were seeded upon a sequentially constructed, time-of-flight secondary ion mass spectrometry (ToF-SIMS)-characterised decellularised human brain extract. YFP-astrocytes were purified from each of the 10 Gliomasphere Matrices using fluorescence-activated cell sorting (FACS) after 6- and 10-days co-culture. RNA-sequencing of the putatively reprogrammed YFP-astrocytes showed the characteristic expression of canonical key regulators of multiple malignant diseases including high-grade glioma such as SND1 and EFNB2 in addition to the identification of a single novel marker located at chromosome 1 (C1orf61), highly expressed in malignant glioma when compared to somatic cancers according to TCGA RNA-sequencing data. Differentiated YFP-astrocytes also overexpressed IFITM2 and IFITM10, known to be involved in priming resistance against pathogenic microorganisms. This ultimately suggests a fluctuating state between malignant transformation imposed by the highly infiltrative glioma cells and the counter-action of the normal astrocytes to these deleterious invasive cells. This multi-faceted model offers a unique opportunity to recapitulate early molecular cross-talk which facilitates glioblastoma recurrence and may be utilised for high-throughput drug screening.
Recent updates on CAR T clinical trials for multiple myeloma
Authors: Quande Lin, Juanjuan Zhao, Yongping Song, Delong Liu
Journal: Molecular Cancer (2019)

Abstract Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies have dramatically changed the natural history of multiple myeloma (MM). However, most patients eventually suffer a relapse and succumb to the disease. Chimeric antigen receptor (CAR) engineered T cells targeting B cell maturation antigen (BCMA), CD138, CS1 glycoprotein antigen (SLAMF7) and light chains are in active development for therapy of refractory /relapsed (RR) MM. CD19- targeted CAR T cells in conjunction with autologous stem cell transplantation also showed activity in RRMM. Dual- target CAR T cells are in clinical trials for RRMM. This review summarized the recent updates of ongoing CAR T clinical trials for multiple myeloma.
Induction Related Mortality in Acute Myeloid Leukemia: Multivariate Model of Predictive Score from the Indian Acute Leukemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC)
Authors: Smita Kayal, Manju Sengar, Hasmukh Jain, Avinash Bonda, Biju George, Uday Prakash Kulkarni, Poonkuzhali Balasubramanian, Dinesh Bhurani, Rayaz Ahmed, Dubashi Biswajit, Jayachandran PK, Ankit Batra, Suman Kumar, Kundan Mishra, Jina Bhattacharyya, Chepsy C Philip, Maitreyee Bhattacharyya, Lokanatha Dasappa, K Govind Babu, Smitha Carol Saldanha, Atul Sharma, Jeyaseelan Lakshmanan, Jothilakshmi Durairaj, Vishnu Vardhan Rudravaram, Vikram Mathews, Rajan Kapoor
Journal: Blood (2019)
Extent of the problem
Authors: A. Taylor
Journal: BMJ (2003)

One in six couples have an unwanted delay in conception. Roughly half of these couples will conceive either spontaneously or with relatively simple advice or treatment. The other half remain subfertile and need more complex treatment, such as in vitro fertilisation and other assisted conception techniques; about half of these will have primary subfertility.

Most couples presenting with a fertility problem do not have absolute infertility (that is, no chance of conception), but rather relative subfertility with a reduced chance of conception because of one or more factors in either or both partners. Most couples with subfertility will conceive spontaneously or will be amenable to treatment, so that only 4% remain involuntarily childless. As each couple has a substantial chance of conceiving without treatment, relating the potential benefit of treatment to their chances of conceiving naturally is important to give a realistic appraisal of the added benefit offered by treatment options.

Conception is most likely to occur in the first month of trying (about a 30% conception rate). The chance then falls steadily to about 5% by the end of the first year. Cumulative conception rates are around 75% after six months, 90% after a year, and 95% at two years. Subfertility is defined as a failure to conceive after one year of unprotected regular sexual intercourse. It is usually investigated after a year, although for some couples it may be appropriate to start investigations sooner. The likelihood of spontaneous conception is affected by age, previous pregnancy, duration of subfertility, timing of intercourse during the natural cycle, extremes of body mass, and pathology present. A reasonably high spontaneous pregnancy rate still occurs even after the first year of trying.

### Age

A strong association exists between subfertility and increasing female age. The reduction in fertility is greatest in women in their late …
Incidence of Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Including CNS Relapse in a Population-Based Cohort of 4205 Patients in Sweden
Authors: Sara Harrysson, Sandra Eloranta, Sara Ekberg, Gunilla Enblad, Mats Jerkeman, Sverker Hasselblom, Björn E Wahlin, Per-Ola Andersson, Karin E. Smedby
Journal: Blood (2019)
RTHP-40. EFFECT OF RIND-BASED DOSIMETRIC TECHNIQUES FOR SCALP DOSE REDUCTION IN BRAIN IRRADIATION
Authors: Diana No, Diana Julie, Jonathan Knisely
Journal: Neuro-Oncology (2019)

Abstract OBJECTIVE Radiation-induced alopecia is an unwanted side effect causing permanent cosmetic distress if hair regrowth does not occur. Rind-based techniques can effectively control dosimetric spread. We evaluated this technique to reduce scalp dose and alopecia while maintaining tumor coverage. METHODS Ten consecutive brain tumor plans were retrospectively evaluated. All planning tumor volume (PTV) margins were ≤ 15.0mm from the skin surface. Departmental guidelines for fractionation were followed, with minimum 95% PTV coverage receiving 100% dose. Fractionation variation was accounted for with biologically effective dose calculation (alpha/beta=2). Rind structures encompassed 5mm depth from scalp surface; upper dose limits were customized to minimum values without PTV coverage compromise. Standard comparative plans using identical criteria, without rind structures, were calculated. Scalp dose evaluation was defined for tissue from skin to 5mm depth. Paired T-tests were used for comparative evaluation. RESULTS Median age: 58 (range 27–85); 70% female (n=7). Histologies included gliomas (n=7) and meningiomas (n=3). Median PTV distance to skin surface: 13.5mm (range 8.0–15.0). Median PTV minimum and mean dose for rind-based plans: 88.63% (range 73.14–95.2) and 104.39% (range 102.07–107.38) of prescription and 90.90% (range 68.64–98.21) and 103.02% (range 101.91–107.04) for standard plans, respectively. Statistically significant reduction in scalp maximum and mean dose of 19.65% (p=2.72E-06) and 0.48% (p=0.007), respectively, was seen with rind-based planning. Scalp volume receiving 1000cGy-equivalent increased 6.7cc using rind-based techniques, although insignificant (p=0.33). Volume receiving 1500cGy-equivalent was significantly reduced 3.88cc (p=0.03) using rind-based techniques. With median 28.5 day follow-up, of 5 patients treated using rind-based techniques, 40% (n=2) exhibited acute alopecia compared to 100% of those treated with standard plans. CONCLUSION Rind-based dosimetric techniques exhibit significant reduction of scalp dose in brain irradiation. 60% of patients treated using this technique experienced no alopecia, versus 0% receiving standard treatment. Further investigation is warranted to better evaluate correlation.
Loop Ileostomy a Viable Alternative for <i>Clostridium difficile</i> Colitis?
Authors: Chelsia Zhen Lyn Ng, Carol Chin Yee Ng, Dean Owyang
Journal: JAMA Surgery (2019)

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 Surgery 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 Surgery journal
Effect of Prior Therapy on the Efficacy and Safety of Oral Selinexor in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis of the Sadal Study
Authors: Federica Cavallo, George A Follows, Andre Goy, Joost Vermaat, Rene-Olivier Casasnovas, Orly Lavee, Marie Maerevoet, Josée M Zijlstra, Sameer Bakhshi, Reda Bouabdallah, Sylvain Choquet, Ronit Gurion, Brian T. Hill, Ulrich Jaeger, Juan-Manuel Sancho, Michael W. Schuster, Catherine Thieblemont, Fatima De la Cruz, Miklos Egyed, Sourav Mishra, Fritz Offner, Theodoros P. Vassilakopoulos, Krzysztof Warzocha, Daniel McCarthy, Xiwen Ma, Kelly Corona, Jean-Richard Saint-Martin, Anita Joshi, Jatin Shah, Eric Van Den Neste, Miguel A Canales, Nagesh Kalakonda
Journal: Blood (2019)
High Interpatient Variability in Molecular MRD Response to Consolidation Chemotherapy in Acute Myeloid Leukemia
Authors: Tracy Murphy, Jinfeng Zou, Ting Ting Wang, Yangqiao Zheng, Zhen Zhao, Roman M Shapiro, Vikas Gupta, Dawn Maze, Caroline J McNamara, Mark D. Minden, Aaron D Schimmer, Andre C. Schuh, Hassan Sibai, Karen W.L. Yee, Tracy L. Stockley, Philip Zuzarte, Carolina Bocanegra, Lawrence Heisler, Paul Krzyzanowski, Trevor Pugh, Scott Bratman, Steven M Chan
Journal: Blood (2019)
A Multisite Phase Ib Study of Pevonedistat, Azacitidine and Venetoclax (PAVE) for the Treatment of Subjects with Acute Myelogenous Leukemia (AML)
Authors: Guru Subramanian Guru Guru Murthy, Scott H. Kaufmann, Aniko Szabo, Arielle Baim, Ashish Anshu, Alexander Hinman, Laura C. Michaelis, Sameem Abedin, Karen-Sue B. Carlson, Lyndsey Runaas, Ehab L. Atallah
Journal: Blood (2019)
Urinary Extracellular Vesicles Carrying Klotho Improve the Recovery of Renal Function in an Acute Tubular Injury Model
Authors: Cristina Grange, Elli Papadimitriou, Veronica Dimuccio, Cecilia Pastorino, Jordi Molina, Ryan O’Kelly, Laura J. Niedernhofer, Paul D. Robbins, Giovanni Camussi, Benedetta Bussolati
Journal: Molecular Therapy (2019)

Acute kidney injury, defined by a rapid deterioration of renal function, is a common complication in hospitalized patients. Among the recent therapeutic options, the use of extracellular vesicles (EVs) is considered a promising strategy. Here we propose a possible therapeutic use of renal-derived EVs isolated from normal urine (urine-derived EVs [uEVs]) in a murine model of acute injury generated by glycerol injection. uEVs accelerated renal recovery, stimulating tubular cell proliferation, reducing the expression of inflammatory and injury markers, and restoring endogenous Klotho loss. When intravenously injected, labeled uEVs localized within injured kidneys and transferred their microRNA cargo. Moreover, uEVs contained the reno-protective Klotho molecule. Murine uEVs derived from Klotho null mice lost the reno-protective effect observed using murine EVs from wild-type mice. This was regained when Klotho-negative murine uEVs were reconstituted with recombinant Klotho. Similarly, ineffective fibroblast EVs acquired reno-protection when engineered with human recombinant Klotho. Our results reveal a novel potential use of uEVs as a new therapeutic strategy for acute kidney injury, highlighting the presence and role of the reno-protective factor Klotho.