tbuckley/cabot-search huggingface dataset:
Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development
Authors: Kevin Wiehe, Todd Bradley, R. Ryan Meyerhoff, Connor Hart, Wilton B. Williams, David Easterhoff, William J. Faison, Thomas B. Kepler, Kevin O. Saunders, S. Munir Alam, Mattia Bonsignori, Barton F. Haynes
Journal: Cell Host & Microbe (2018)

Highlights•HIV-1 broadly neutralizing antibodies are enriched with low-probability mutations•Improbable mutations can be functionally critical for bnAb neutralization breadth•Critical improbable mutations are high-value targets for selection with vaccinesSummaryHIV-1 broadly neutralizing antibodies (bnAbs) require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations for optimal neutralization potency. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. One bottleneck for induction of bnAbs is the evolution of viral envelopes (Envs) that can select bnAb B cell receptors (BCR) with improbable mutations. Here we define the probability of bnAb mutations and demonstrate the functional significance of key improbable mutations in three bnAb B cell lineages. We show that bnAbs are enriched for improbable mutations, which implies that their elicitation will be critical for successful vaccine induction of potent bnAb B cell lineages. We discuss a mutation-guided vaccine strategy for identification of Envs that can select B cells with BCRs that have key improbable mutations required for bnAb development.Graphical abstract
Current Concepts in Diagnosis and Treatment of Functional Neurological Disorders
Authors: Alberto J. Espay, Selma Aybek, Alan Carson, Mark J. Edwards, Laura H. Goldstein, Mark Hallett, Kathrin LaFaver, W. Curt LaFrance, Anthony E. Lang, Tim Nicholson, Glenn Nielsen, Markus Reuber, Valerie Voon, Jon Stone, Francesca Morgante
Journal: JAMA Neurology (2018)

Functional neurological disorders (FND) are common sources of disability in medicine. Patients have often been misdiagnosed, correctly diagnosed after lengthy delays, and/or subjected to poorly delivered diagnoses that prevent diagnostic understanding and lead to inappropriate treatments, iatrogenic harm, unnecessary and costly evaluations, and poor outcomes. Functional Neurological Symptom Disorder/Conversion Disorder was adopted by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, replacing the term psychogenic with functional and removing the criterion of psychological stress as a prerequisite for FND. A diagnosis can now be made in an inclusionary manner by identifying neurological signs that are specific to FNDs without reliance on presence or absence of psychological stressors or suggestive historical clues. The new model highlights a wider range of past sensitizing events, such as physical trauma, medical illness, or physiological/psychophysiological events. In this model, strong ideas and expectations about these events correlate with abnormal predictions of sensory data and body-focused attention. Neurobiological abnormalities include hypoactivation of the supplementary motor area and relative disconnection with areas that select or inhibit movements and are associated with a sense of agency. Promising evidence has accumulated for the benefit of specific physical rehabilitation and psychological interventions alone or in combination, but clinical trial evidence remains limited. Functional neurological disorders are a neglected but potentially reversible source of disability. Further research is needed to determine the dose and duration of various interventions, the value of combination treatments and multidisciplinary therapy, and the therapeutic modality best suited for each patient.
Focused ultrasound-enabled delivery of radiolabeled nanoclusters to the pons
Authors: Dezhuang Ye, Deborah Sultan, Xiaohui Zhang, Yimei Yue, Gyu Seong Heo, Satya V.V.N. Kothapalli, Hannah Luehmann, Yuan-chuan Tai, Joshua B. Rubin, Yongjian Liu, Hong Chen
Journal: Journal of Controlled Release (2018)
Statistical Tests Used to Validate the American Joint Committee on Cancer Eighth Edition Prognostic Stage Compared With the Anatomic Stage in Breast Cancer
Authors: Yilong Zhang, Xiaoxia Han
Journal: JAMA Oncology (2018)

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 Oncology 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 Oncology journal
Multidisciplinary conference to standardize survivorship care.
Authors: Beth Rudge, Megan Lanigan, Theresa M. Lee, Lisa Torp, Kit Yu Lu
Journal: Journal of Clinical Oncology (2018)

17 Background: Survivors of breast cancer can face a multitude of long term and late effects after completing active treatment. Recommendations for side effect management can vary widely based on professional society guidelines, a provider’s clinical experience, and patient preference. When providing survivorship care in a multidisciplinary institution, maintaining consistent recommendations between providers and disciplines can be a daunting challenge. A cohesive approach is extremely important for a satisfying patient-clinician relationship and for patient safety. Our objective is to create standardized management of breast cancer survivorship issues. Methods: A quarterly Survivorship Multidisciplinary Conference (SMC) was initiated for case review and education on side effect management. The multidisciplinary group included medical and radiation oncologists, surgeons, nurse practitioners, nurse navigators, dieticians, physical therapists, social workers, spiritual care, and a genetic counselor. We used an evidence-based approach, including ASCO and NCCN guidelines as well as published peer-reviewed recommendations to create a treatment consensus for side effect management. Clinicians attending SMC were surveyed regarding their approach to late and long term effects of breast cancer pre- and post-SMC and their overall satisfaction with the conference. Results: Prior to involvement in SMC, most providers based their treatment of side effects on their own professional society’s guidelines and their personal clinical experience. After implementing SMC, 60% of providers reported a change in their practice and there was a 37.5% reported increase in the use of ASCO and NCCN survivorship guidelines across disciplines. 94% of providers reported the SMC is effective in providing evidence based guidelines. Providers also reported a high level of satisfaction and that SMC provided opportunity for a more collaborative multidisciplinary approach. Conclusions: Survivorship Multidisciplinary Conference brings multiple specialties together for review of evidence-based approaches to survivorship care, increasing consistency in management of survivors' late and long term effects after completing breast cancer treatment.
Abstract #1413: Allele-specific copy number analysis of human osteosarcoma by single nucleotide polymorphism (SNP) array identifies several monoallelic amplicons independent of MYC in chromosome 8 q-arm (8q)
Authors: Dhong Hyun Lee, Stephen Moore, Marc Hansen, Jennifer Akunowicz, Carl Miller, Masashi Sanada, Motohiro Kato, Tadayuki Akagi, Norihiko Kawamata, Seishi Ogawa, Rhona Schreck, Phillip Koeffler
Journal: Cancer Research (2009)

In an attempt to fully characterize the complex chromosomal changes of osteosarcoma (OS), 58 human OS samples including 40 primary OS tumors, 11 OS explants, and 7 OS cell lines were subjected to Affymetrix 50K and 250K single nucleotide polymorphism (SNP) array analysis. Allele-specific copy number (CN) analysis using anonymous references (AsCNAR) algorithm revealed many allele-specific events previously undetectable by conventional analysis. Common regions of high CN amplifications were identified in 1q21.1-q24.1 (14% of the samples), 6p21.1-p12.1 (14%), 8q23.3-qter (16%), 14q11.2-q12 (17%), and 17p12-p11.2 (16%). Interestingly, many amplicons showed allele-specific amplification frequently accompanying deletion of the other allele. The most prominent allele-specific amplifications were found in 8q23.3-qter. 59 % of the samples showed various levels of CN gains in this region. All human OS cell lines (U2OS, G292, MG63, HT161, HOS, and SAOS2) except SJSA (86 % of the cell lines) showed high CN amplification in the region. Although amplification of chromosome 8 q-arm (8q) targeting MYC oncogene is frequently found in many cancers, Many amplicons identified in the region were MYC-independent. Fluoresence In-Situ Hybridization (FISH) using BAC clones verified the presence of MYC-independent amplicons as well as frequent fusion and translocation of the amplicons into other chromosomes. To check the possibility of new cancer-related genes other than MYC gene in 8q, we checked the mRNA expression levels of all known genes in the amplicons of 7 human OS cell lines by quantitative reverse transcription PCR (qRT-PCR). Gene expression levels were normalized to the expression level in normal human osteoblast cell line hFOB1.19. Many genes in the region showed increased mRNA expression level: TRPS1 (median value of 34-fold increased expression), RAD21 (5-fold), THRAP6 (6-fold), CCN3 (24-fold), ENPP2 (10-fold), DEPDC6 (7-fold), SNTB1 (8-fold), FBXO32 (5-fold), ADCY8 (5-fold), CCN4 (12-fold), and PTK2 (4-fold) showed more than 10-fold increase in two or more cell lines. Common regions of homozygous deletions were also identified: 3q13.31 (16% of the samples), 7q35-q36.3 (9%), 9p21.3 (7%), and Xp21 (7%) were frequently deleted. Interestingly, many deletions targeted membrane associated guanylate kinase (MAGUK) family genes such as MAGI2, DLG2, and DLGAP2. In conclusion, our results suggest that there are several possible cancer-related genes in 8q regions as well as in homozygously deleted regions in OS. These findings will help developing new diagnostic markers and therapeutic targets.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1413.
Abstract 12116: Long-term Effects of Cumulative Fine Particulate Matter Exposures on Hemorrhagic Stroke Event: Nationwide Cohort Study
Authors: Juhwan Noh, Jungwoo Sohn, Jaelim Cho, Changsoo Kim, Dong Chun Shin
Journal: Circulation (2016)

Introduction: Epidemiological studies have revealed adverse associations between ambient fine particulate matter (PM 2.5 ; aerodynamic diameter &lt; 2.5 μm) and cardiovascular diseases. Recently, there has been increased interest in investigating the association between long-term PM 2.5 exposure and hemorrhagic stroke (HS) and identifying the most susceptible subpopulations to the PM 2.5 exposure, if any. Hypothesis: We assessed the hypothesis that long-term cumulative averages of PM 2.5 exposure affect HS and its effect might be modified by risk factors. Methods: This study was based on a nationwide representative cohort of 1,025,340 participants, or 2% of the National Health Insurance Service enrollees in Korea (2002-2013). We analyzed the effects of PM 2.5 on time to first hospital diagnosis for HS for participants living in Seoul. A time-dependent Cox proportional hazards model was used with adjustments for age, sex, household income, insurance type, body mass index, smoking status, exercise, medical history, and family history. Annual cumulative mean PM 2.5 concentrations for 25 districts were used as the time-dependent variables. Subgroup analyses were performed to evaluate potential effect modification. Results: Cumulative PM 2.5 exposure was associated with HS events with a hazard ratio of 1.04 (95% confidence interval [CI]: 1.01-1.07) per 1 μg/m 3 elevation in PM 2.5 . Its adverse effects were modified by risk factors with greater effects observed among women (1.05 [1.01-1.09]) and subgroups with hypertension (1.06 [1.03-1.10]), without diabetes (1.05 [1.02-1.09]), or without family history of stroke (1.04 [1.01-1.07]). Conclusions: To our best knowledge, this is the first study to investigate the effect of cumulative averages of PM 2.5 exposure on time to first hospital diagnosis for HS. Cumulative PM 2.5 exposure might increase the risk of HS. Participants with hypertension, without diabetes or family history of stroke, or women were more susceptible to PM 2.5 exposure. Our findings show the first time that long-term cumulative PM 2.5 exposure could be crucial to cerebrovascular event and have public health implications.
Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration
Authors: Manjit S. Mehat, Venki Sundaram, Caterina Ripamonti, Anthony G. Robson, Alexander J. Smith, Shyamanga Borooah, Martha Robinson, Adam N. Rosenthal, William Innes, Richard G. Weleber, Richard W.J. Lee, Michael Crossland, Gary S. Rubin, Baljean Dhillon, David H.W. Steel, Eddy Anglade, Robert P. Lanza, Robin R. Ali, Michel Michaelides, James W.B. Bainbridge
Journal: Ophthalmology (2018)

PurposeTransplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area.DesignPhase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832).ParticipantsTwelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults.MethodsSubretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks.Main Outcome MeasuresThe primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT.ResultsFocal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change.ConclusionsSubretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation.
Serum complement factor C5a in IgG<sub>4</sub>-related disease
Authors: Shoichi Fukui, Yuya Fujita, Tomoki Origuchi, Takahiro Maeda, Atsushi Kawakami
Journal: Annals of the Rheumatic Diseases (2018)

We read with great interest the correspondence by Umehara et al 1 which discussed the difficulties in the diagnosis of IgG4-related disease (IgG4-RD). They mention that increased IgG4 concentration is not a specific marker for IgG4-RD. Therefore, the markers for the diagnosis and the disease activity of IgG4-RD are demanded.

Approximately a quarter of patients with active IgG4-RD have hypocomplementaemia defined by the lower normal limit of C3 or C4 levels.2 Complement pathways consist of three pathways: classical, alternative and lectin pathways.3 Here, we focus on complement factors as makers of IgG4-RD and attempt to evaluate the entire complement system in IgG4-RD.

We enrolled 28 patients with active and untreated IgG4-RD, diagnosed based on the 2011 comprehensive diagnostic criteria4 and 28 sex-matched and age-matched healthy donors. We evaluated the characteristics of patients with IgG4-RD, the number of affected organs and the IgG4-RD Responder Index (IgG4-RD RI).5 None of the healthy donors had a history of inflammatory disease.

In the sera of the patients with …
Antibacterial Activity of Silver Nanoparticles: Structural Effects
Authors: Shaoheng Tang, Jie Zheng
Journal: Advanced Healthcare Materials (2018)

Abstract The increase of antibiotic resistance in bacteria has become a major concern for successful diagnosis and treatment of infectious diseases. Over the past few decades, significant progress has been achieved on the development of nanotechnology‐based medicines for combating multidrug resistance in microorganisms. Among this, silver nanoparticles (AgNPs) hold great promise in addressing this challenge due to their broad‐spectrum and robust antimicrobial properties. This review illustrates the antibacterial mechanisms of silver nanoparticles and further elucidates how different structural factors including surface chemistry, size, and shape, impact their antibacterial activities, which are expected to promote the future development of more potent silver nanoparticle‐based antibacterial agents.
Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study
Authors: Philippe Moreau, Maria-Victoria Mateos, James R Berenson, Katja Weisel, Antonio Lazzaro, Kevin Song, Meletios A Dimopoulos, Mei Huang, Anita Zahlten-Kumeli, A Keith Stewart
Journal: The Lancet Oncology (2018)
Overall survival following locoregional surgery of the primary tumor in de novo stage IV breast cancer patients.
Authors: Herui Yao, Yunfang Yu, Ying Wang, Tuping Fu, Junrong Jiang, Jianli Zhao, Yongjian Chen, Jun Tang, Guolin Ye, Erwei Song
Journal: Journal of Clinical Oncology (2018)

1082 Background: Current guidelines lack definitive evidences about the relative benefits of locoregional surgery for the primary tumor in de novo stage IV breast cancer. The aim of this study was to comprehensively investigate the role of locoregional surgery for primary tumor in de novo stage IV breast cancer. Methods: We conducted a Chinese multicenter real-world study of patient-level data to investigate the effect of locoregional surgery versus no surgery of the primary tumor in de novo stage IV breast cancer. We used propensity score matching to compare similar patients who underwent locoregional surgery and no surgery. Overall survival (OS) was estimated using the Kaplan-Meier method and the log-rank test. A meta-analysis also was performed of prospective and retrospective studies, respectively. Results: Among 353 patients, 189 (53.6%) received locoregional surgery and 164 (46.4%) underwent no surgery. We matched 202 patients treated with locoregional surgery with similar patients who received no surgery. The median follow-up time was 22.1 (95%CI, 18.8 to 25.9) months, 5-year overall survival was 62.4% in the locoregional surgery group versus 60.3% in the no surgery group, and there was no significant difference in OS (Hazard ratio [HR] 0.88, 95%CI 0.49 to 1.57, P = 0.66). In stratified analysis, the association between locoregional surgery and improved survival was particularly marked in patients with Ki67 ≥ 20% (HR 0.47, 95%CI 0.22 to 0.97). In addition, pooled results from 42 retrospective studies with 130,153 individuals indicated that locoregional surgery resulted into a significantly prolonged OS (HR 0.65, 95% CI 0.61 to 0.69) compared with no surgery. In contrast, we analyzed the meta-analysis from five prospective trials with 857 participants, finding that there was no significant difference in OS (HR 0.84, 95% CI 0.61 to 1.15) between two groups. Conclusions: Based on the evidences of our real-world study, prospective and retrospective meta-analysis, we concluded that locoregional surgery of the primary tumor have no significant survival benefit in de novo stage IV breast cancer. Patients with Ki67 ≥ 20% improved survival while receiving locoregional surgery.
A phase I study of a PD-L1 antibody (Durvalumab) in combination with trastuzumab in HER-2 positive metastatic breast cancer (MBC) progressing on prior anti HER-2 therapies (CCTG IND.229)[NCT02649686].
Authors: Stephen K. L. Chia, Philippe L. Bedard, John Hilton, Eitan Amir, Karen A. Gelmon, Rachel Anne Goodwin, Diego Villa, Michael Cabanero, Heather Ritter, Dongsheng Tu, Ming Sound Tsao, Lesley Seymour
Journal: Journal of Clinical Oncology (2018)

1029 Background: Immune checkpoint inhibitors are active in a broad range of advanced cancers. Antibody dependent cell mediated cytotoxicity is a mechanism of action of trastuzumab. The combination of the two may enhance activity and/or overcome acquired resistance. We performed a phase I study of durvalumab and trastuzumab in HER-2 positive MBC previously treated with chemotherapy and anti HER-2 antibodies to assess safety, efficacy and correlative end-points. Methods: Patients with HER-2 positive MBC, PS 0-2, and previously treated with taxanes and trastuzumab were enrolled on a standard 3+3 dose escalation schedule. Dose level 1 was standard doses of durvalumab (1125 mg i.v. day 1) and trastuzumab (8 mg/kg i.v. loading then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed baseline and post cycle 1 tumor biopsies. The primary endpoint of the study was to establish the RP2D. Results: 15 patients were accrued across 3 Canadian centres from April – December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40-86), the majority had visceral disease (87%); ≥3 prior lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%) and TDM1 (93%) for MBC. No dose limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed ≥ grade 3 irAE (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4/14 (29%) demonstrating stable disease as best response at week 6 (median duration 2.7 months). All patients had < 1% PD-L1 expression on archival tissue (7/15) or pre-study biopsy (8/15). In the dose expansion cohort, evaluable pre-treatment and on-treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration. Work on the serial ctDNA collected is ongoing. Conclusions: The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in heavily pre-treated HER-2 positive MBC patients with evidence of cytotoxic T-cell exhaustion. Clinical trial information: NCT02649686.