tbuckley/cabot-search huggingface dataset:
Anti-myeloma activity of the novel ADCC-optimized human CD54 (ICAM-1) antibody MSH-TP15e.
Authors: Katja Klausz, Michael Cieker, Renate Burger, Christian Kellner, Andreas Guenther, Matthias Peipp, Martin Gramatzki
Journal: Journal of Clinical Oncology (2016)

e14009 Background: Monoclonal antibodies directed against different target antigens have proven efficacy in cancer therapy. Recently, daratumumab and elotuzumab became the first antibodies approved for the treatment of multiple myeloma (MM). Due to the substantial number of patients still in need for long-term disease control, the investigation of additional target structures and potent molecule formats for antibody-based therapy of MM remains important. Methods: Human synthetic phage display libraries were screened with a cellular screening strategy and one clone was selected based on its favorable binding characteristics to various MM cell lines and patient-derived CD138-positive malignant plasma cells. CD54/ICAM-1 was identified as target antigen. Fully human IgG1 antibody variants with mutations in the Fc domain enhancing selected effector functions were generated and analyzed for their capacity to kill MM cells in vitro and in the INA-6 myeloma xenograft model. Results: MSH-TP15 did not directly induce apoptosis or inhibit proliferation of myeloma cells. However, the Fc-engineered antibody variant MSH-TP15e significantly triggered ADCC against various MM cell lines and freshly isolated patient myeloma cells. The recruitment of human NK cells was crucial for the observed effects. Importantly, MSH-TP15e completely prevented tumor engraftment in the INA-6 xenograft model. To unravel this strong anti-tumor mechanism of action, the MSH-TP15 antibody variants (wild-type IgG1, Fc-engineered, Fc knock-out) will be compared side-by-side. Conclusions: The novel ADCC-optimized human IgG1 antibody MSH-TP15e directed against CD54 exerts potent anti-myeloma activity by effectively recruiting human NK cells for tumor cell lysis. Therefore, this interesting antibody will be further evaluated for MM immunotherapy.
First WHO antimicrobial surveillance data reveal high levels of resistance globally
Authors: Susan Mayor
Journal: BMJ (2018)

The first data from the World Health Organization Global Antimicrobial Surveillance System (GLASS) have reported high rates of resistance to antibiotics commonly used to treat serious bacterial infections in many countries across the world.1

“The report confirms the serious situation of antimicrobial resistance (AMR) worldwide,” said Marc Sprenger, director of WHO’s Antimicrobial Resistance Secretariat.

WHO launched the first global collaborative effort to standardise surveillance of AMR in October 2015 as part of efforts to improve the evidence base for this growing global health threat.

Sprenger explained, “Some …
Neonatal Systemic AAV-Mediated Gene Delivery of GDF11 Inhibits Skeletal Muscle Growth
Authors: Quan Jin, Chunping Qiao, Jianbin Li, Juan Li, Xiao Xiao
Journal: Molecular Therapy (2018)

Growth and differentiation factor 11 (GDF11; BMP11) is a circulating cytokine in the transforming growth factor beta (TGF-β) superfamily. Treatment with recombinant GDF11 (rGDF11) protein has previously been shown to reverse skeletal muscle dysfunction in aged mice. However, the actions of GDF11 in skeletal muscle are still not fully understood. Because GDF11 activates the TGF-β-SMAD2/3 pathway, we hypothesized that GDF11 overexpression would inhibit skeletal muscle growth. To test this hypothesis, we generated recombinant adeno-associated virus serotype 9 (AAV9) vectors harboring the gene for either human GDF11 (AAV9-GDF11) or human IgG1 Fc-fused GDF11 propeptide (AAV9-GDF11Pro-Fc-1) to study the effects of GDF11 overexpression or blockade on skeletal muscle growth and function in vivo. After intravenous administration of AAV9-GDF11 into neonatal C57BL/6J mice, we observed sustained limb muscle growth inhibition along with reductions in forelimb grip strength and treadmill running endurance at 16 weeks. Conversely, treatment with AAV9-GDF11Pro-Fc-1 led to increased limb muscle mass and forelimb grip strength after 28 weeks, although a difference in the total body mass/muscle mass ratio was not observed between treatment and control groups. In sum, our results suggest GDF11 overexpression has an inhibitory effect on skeletal muscle growth.
Cell cycle checkpoint profiling in soft tissue sarcoma
Authors: Laura A. Lambert, Kelly K. Hunt, Khandan Keyomarsi
Journal: Cancer Research (2006)

3214   Introduction: Soft tissue sarcomas (STS) are a rare, heterogenous group of mesenchymal tumors that are often chemoresistant. Both their rarity and heterogeneity make it extremely difficult to develop an optimal therapeutic strategy. Despite their histological heterogeneity, by definition, all STS, like all neoplastic cells, possess some form of cell cycle deregulation. In epithelial malignancies, such deregulation has been associated with prognosis and responsiveness to different types of chemotherapy. However, little is known about the role of cell cycle deregulation in STS. This study profiles the G1/S and G2/M cell cycle checkpoint regulators and their relationship with the growth characteristics of various STS cell lines. Methods: Western blot analysis was used to assess cell cycle protein expression in 1 fibroblast and 3 STS cell lines. Doubling times were determined by growth curve analysis. Cdk2 activity was assessed by H1 histone kinase. Results: Growth rates ranged from 25 hrs (HT1080) to 66 hrs (AR04). With the exception of AR04 in which low levels of Cdk2 and the phosphorylated form of Cdk1 were observed, protein expression of both the G1/S and G2/M cyclins and Cdks were similar in all 4 cell lines (Table 1). The negative checkpoint regulators were variably expressed. Cdk2 kinase function differed across the cell lines with the greatest function seen in the most rapidly dividing cell line. Conclusion: These data suggest biologically significant differential regulation of the G1/S and G2/M checkpoints within these STS cell lines. As in epithelial malignancies, cell cycle deregulation may contribute to response to chemotherapy in STS. Determination of the mechanisms of cell cycle checkpoint deregulation in STS is necessary for the potential development of cell cycle-based methods of chemotherapy selection.
Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study
Authors: Emma Guttman-Yassky, Jonathan I. Silverberg, Osamu Nemoto, Seth B. Forman, August Wilke, Randy Prescilla, Amparo de la Peña, Fabio P. Nunes, Jonathan Janes, Margaret Gamalo, David Donley, Jim Paik, Amy M. DeLozier, Brian J. Nickoloff, Eric L. Simpson
Journal: Journal of the American Academy of Dermatology (2018)
Low-Dose Anti-Thymocyte Globulin for Graft-Versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplant
Authors: Adam Bryant, Ranjeeta Mallick, Lothar B. Huebsch, David S. Allan, Harold Atkins, Grizel Anstee, Isabelle Bence-Bruckler, Linda Hamelin, Michael Hodgins, Mitchell Sabloff, Nicholas Scrivens, Dawn C. Maze, Christopher N. Bredeson, Natasha Kekre
Journal: Blood (2016)
Duration of Anti–Programmed Death-1 Therapy in Advanced Melanoma: How Much of a Good Thing Is Enough?
Authors: Nikhil I. Khushalani
Journal: Journal of Clinical Oncology (2018)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 53-year-old healthy man presented with recurrent in-transit melanoma of the right lower extremity. Eight years prior he had undergone wide local excision and sentinel lymph node biopsy for invasive melanoma of the anteromedial aspect of the distal right thigh. Pathology revealed an ulcerated melanoma, Breslow depth 3.5 mm, and with one involved micrometastatic inguinal lymph node. Staging studies did not demonstrate distant metastases. Superficial inguinal node dissection was performed and did not identify any additional metastatic nodes of 14 retrieved for a final pathologic staging of T3bN1aM0 (stage IIIB) cutaneous melanoma. He received 12 months of adjuvant high-dose interferon alfa-2b. Two years later, he developed a 1.2-cm subcutaneous focus of in-transit recurrence approximately 4 cm proximal to the original melanoma site in the right thigh, which was treated with surgical resection followed by adjuvant radiotherapy. Over the next 4 years, he underwent six additional surgeries for isolated in-transit recurrences affecting the same limb. He was referred for therapeutic options at the time of his latest in-transit recurrence. Examination revealed three palpable subcutaneous nodules in the right thigh in the setting of lymphedema. A core biopsy confirmed recurrent melanoma (Fig 1). Whole-body fluorodeoxyglucose positron emission tomography imaging revealed at least 17 hypermetabolic cutaneous and subcutaneous nodules in the right thigh, four fluorodeoxyglucose-avid nodules below the right knee, but no distant metastases (Fig 2A). Brain magnetic resonance imaging was normal. His serum chemistry profile, including lactate dehydrogenase, was normal. Molecular analysis demonstrated presence of BRAF V600E mutation in the tumor. After multidisciplinary evaluation, an isolated limb infusion procedure of the right lower extremity was not believed to be feasible, secondary to the proximal extent of the recurrence. Therapy was initiated with pembrolizumab at 2 mg/kg intravenously every 3 weeks.
Abstract 18288: Clinical Outcome and Long-term Follow-up in Patients With Angina in the Absence of Obstructive Coronary Artery Disease
Authors: Vedant S Pargaonkar, Yuhei Kobayashi, Takumi Kimura, Ingela Schnittger, Ian S Rogers, David P Lee, William F Fearon, Alan C Yeung, Marcia L Stefanick, Jennifer A Tremmel
Journal: Circulation (2017)

Introduction:  A comprehensive invasive evaluation of patients with angina in the absence of obstructive coronary artery disease (CAD) may identify occult coronary abnormalities contributing to symptoms, and may also help guide therapy. However, whether this has an impact on symptoms and quality of life (QOL) is unclear. Our objective was to study the long-term follow-up of anginal symptoms in patients with endothelial dysfunction, microvascular dysfunction (MVD), and/or a myocardial bridge (MB).   Methods:  Before and after invasive testing, we administered a Seattle angina questionnaire (SAQ) to 157 women and 48 men found to have no obstructive CAD on angiography. Endothelial dysfunction was defined as a decrease in luminal diameter of >20% after intracoronary (IC) acetylcholine, MVD was defined as an index of microvascular resistance ≥ 25, and an MB was defined as an echolucent half-moon sign and/or ≥10% systolic compression on intravascular ultrasound.   Results:  Median follow up was 1.9 (1.7 - 2.2) years. Endothelial dysfunction was present in 113 (55%) patients, MVD in 47 (23%), and MB in 93 (45%). Medical treatment and lifestyle changes were suggested according to the diagnosis of the testing. Eleven had surgical unroofing of an MB. There were no MACE, including MI, revascularization, or stroke. There were 2 deaths (both cancer). There was significant improvement in physical limitations due to angina, anginal stability, anginal frequency, treatment satisfaction, and QOL (p    Conclusion:  A comprehensive invasive evaluation can identify occult coronary abnormalities in patients with angina in the absence of obstructive CAD and help guide therapy, which ultimately results in an improvement in patients’ symptoms and QOL.
Abstract 14342: The Underappreciated Occurrence of Discrete Subaortic Membranes Producing LV Outflow Obstruction in Patients With Hypertrophic Cardiomyopathy
Authors: Muhil Kannappan, Barry J Maron, Hassan Rastegar, Natesa G Pandian, Martin S Maron, Ethan J Rowin
Journal: Circulation (2016)

Background: Subaortic obstruction due to systolic anterior motion (SAM) of the mitral valve with ventricular septal contact is a major cause of progressive heart failure (HF) symptoms in hypertroph...
The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids
Authors: Cholsoon Jang, Sheng Hui, Wenyun Lu, Alexis J. Cowan, Raphael J. Morscher, Gina Lee, Wei Liu, Gregory J. Tesz, Morris J. Birnbaum, Joshua D. Rabinowitz
Journal: Cell Metabolism (2018)
Doctor who failed to curb his abusive behaviour is struck off
Authors: Clare Dyer
Journal: BMJ (2018)

A doctor who was suspended by a medical practitioners’ tribunal for writing derogatory emails about a colleague and a patient who complained about him has been struck off the UK medical register after writing “a stream of abusive emails” about the General Medical Council regulators handling his case.

Kamal Hameed Ubaid Al-Any, a former middle grade doctor who worked in the emergency department at the Whittington Hospital in London, was initially suspended for four months by a medical practitioners’ tribunal in 2016.

That case stemmed from a 2013 incident in which he had seen a young patient referred to the hospital for suspected pyelonephritis, who came …
ADA2 deficiency: Clonal lymphoproliferation in a subset of patients
Authors: Luca Trotta, Timi Martelius, Timo Siitonen, Timo Hautala, Sari Hämäläinen, Hanna Juntti, Mervi Taskinen, Mette Ilander, Emma Irene Andersson, Andrey Zavialov, Meri Kaustio, Riikka Keski-Filppula, Michael Hershfield, Satu Mustjoki, Terhi Tapiainen, Mikko Seppänen, Janna Saarela
Journal: Journal of Allergy and Clinical Immunology (2018)
Intensified Dosing of Mycophenolate Mofetil Is Associated with Slower Progression of Chronic Renal Allograft Injury – Results from a Randomized Controlled Trial
Authors: Mladen Knotek, Miha Arnol, Jadranka Buturovic-Ponikvar, Danica Galešic Ljubanović, Nika Kojc
Journal: Journal of the American Society of Nephrology (2016)
Noninvasive Immunometabolic Cardiac Inflammation Imaging Using Hyperpolarized Magnetic Resonance
Authors: Andrew J.M. Lewis, Jack J. Miller, Angus Z. Lau, Mary K. Curtis, Oliver J. Rider, Robin P. Choudhury, Stefan Neubauer, Charles H. Cunningham, Carolyn A. Carr, Damian J. Tyler
Journal: Circulation Research (2018)

Rationale: Current cardiovascular clinical imaging techniques offer only limited assessment of innate immune cell-driven inflammation, which is a potential therapeutic target in myocardial infarction (MI) and other diseases. Hyperpolarized magnetic resonance (MR) is an emerging imaging technology that generates contrast agents with 10- to 20 000-fold improvements in MR signal, enabling cardiac metabolite mapping. Objective: To determine whether hyperpolarized MR using [1- 13 C]pyruvate can assess the local cardiac inflammatory response after MI. Methods and Results: We performed hyperpolarized [1- 13 C]pyruvate MR studies in small and large animal models of MI and in macrophage-like cell lines and measured the resulting [1- 13 C]lactate signals. MI caused intense [1- 13 C]lactate signal in healing myocardial segments at both day 3 and 7 after rodent MI, which was normalized at both time points after monocyte/macrophage depletion. A near-identical [1- 13 C]lactate signature was also seen at day 7 after experimental MI in pigs. Hyperpolarized [1- 13 C]pyruvate MR spectroscopy in macrophage-like cell suspensions demonstrated that macrophage activation and polarization with lipopolysaccharide almost doubled hyperpolarized lactate label flux rates in vitro; blockade of glycolysis with 2-deoxyglucose in activated cells normalized lactate label flux rates and markedly inhibited the production of key proinflammatory cytokines. Systemic administration of 2-deoxyglucose after rodent MI normalized the hyperpolarized [1- 13 C]lactate signal in healing myocardial segments at day 3 and also caused dose-dependent improvement in IL (interleukin)-1β expression in infarct tissue without impairing the production of key reparative cytokines. Cine MRI demonstrated improvements in systolic function in 2-DG (2-deoxyglucose)–treated rats at 3 months. Conclusions: Hyperpolarized MR using [1- 13 C]pyruvate provides a novel method for the assessment of innate immune cell-driven inflammation in the heart after MI, with broad potential applicability across other cardiovascular disease states and suitability for early clinical translation.
Medical Specialties of Clinicians Providing Mechanical Thrombectomy to Patients With Acute Ischemic Stroke in the United States
Authors: Hooman Kamel, Caroline D. Chung, Gbambele J. Kone, Ajay Gupta, Nicholas A. Morris, Matthew E. Fink, Babak B. Navi
Journal: JAMA Neurology (2018)

Optimal stroke management requires sufficient availability of physicians qualified to perform mechanical thrombectomy.Little is known about the US workforce for this recently established, evidence-based procedure. 1thods | We performed a cross-sectional study using a data set from the US Centers for Medicare and Medicaid Services containing claims for care provided between January 1, 2009, and September 30, 2015, to a nationally representative 5% sample of Medicare beneficiaries.The institutional review board at Weill Cornell Medical College approved this study.The institutional review board waived the requirement for informed consent for this minimal-risk research.We included beneficiaries 65 years or older who had been enrolled in fee-for-service Medicare for 1 year or longer within the 6-year timeframe of the data set, or until death, without concurrent Medicare Advantage enrollment.We analyzed the claims submitted during hospitalizations for acute ischemic stroke, defined by validated International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes. 2,3We defined mechanical thrombectomy as a claim with Current Procedural Terminology code 37184 combined with an ICD-9-CM code for cerebrovascular disease (430-438).We classified specialties using codes that reflect the selfdesignated specialty of clinicians at the time of enrollment in Medicare.Python software was used to look up the physician name and specialty associated with the National Provider Identifier (NPI) numbers that appeared on claims.Investigators blinded to the specialty designations used these names and NPI numbers to search public online records (via Google) regarding the residency and fellowship training of each clinician.In sensitivity analyses, we redefined thrombectomy as a physician claim with an isolated Current Procedural Terminol-ogy code of 37184 plus an ischemic stroke ICD-9-CM diagnosis code as the sole indication.We also limited the sample to ICD-9-CM code 434.11 for embolic stroke.We used descriptive statistics with 95% CIs, κ statistics, and χ 2 tests with 2-tailed α = .05.Analyses were performed using Python version 3.6.
American Society of Clinical Oncology Statement: Biosimilars in Oncology
Authors: Gary H. Lyman, Edward Balaban, Michael Diaz, Andrea Ferris, Anne Tsao, Emile Voest, Robin Zon, Michael Francisco, Sybil Green, Shimere Sherwood, R. Donald Harvey, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2018)

As many biosimilars come to market in the next several years, their use in oncology will play an important role in the future care of patients with cancer. ASCO is committed to providing education and guidance to the oncology community on the use of biosimilars in the cancer setting; therefore, ASCO has developed this statement to offer guidance in the following areas: (1) naming, labeling, and other regulatory considerations, (2) safety and efficacy of biosimilars, (3) interchangeability, switching, and substitution, (4) value of biosimilars, and (5) prescriber and patient education.
Tuberous sclerosis complex–associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt
Authors: Paola Zordan, Manuela Cominelli, Federica Cascino, Elisa Tratta, Pietro L. Poliani, Rossella Galli
Journal: Journal of Clinical Investigation (2018)

Tuberous sclerosis complex (TSC) is a dominantly inherited disease caused by hyperactivation of the mTORC1 pathway and characterized by the development of hamartomas and benign tumors, including in the brain. Among the neurological manifestations associated with TSC, the tumor progression of static subependymal nodules (SENs) into subependymal giant cell astrocytomas (SEGAs) is one of the major causes of morbidity and shortened life expectancy. To date, mouse modeling has failed in reproducing these 2 lesions. Here we report that simultaneous hyperactivation of mTORC1 and Akt pathways by codeletion of Tsc1 and Pten, selectively in postnatal neural stem cells (pNSCs), is required for the formation of bona fide SENs and SEGAs. Notably, both lesions closely recapitulate the pathognomonic morphological and molecular features of the corresponding human abnormalities. The establishment of long-term expanding pNSC lines from mouse SENs and SEGAs made possible the identification of mTORC2 as one of the mediators conferring tumorigenic potential to SEGA pNSCs. Notably, in spite of concurrent Akt hyperactivation in mouse brain lesions, single mTOR inhibition by rapamycin was sufficient to strongly impair mouse SEGA growth. This study provides evidence that, concomitant with mTORC1 hyperactivation, sustained activation of Akt and mTORC2 in pNSCs is a mandatory step for the induction of SENs and SEGAs, and, at the same time, makes available an unprecedented NSC-based in vivo/in vitro model to be exploited for identifying actionable targets in TSC.