tbuckley/cabot-search huggingface dataset:
Persistent Nontumoral High-Amino-Acid Uptake on Brain [11C]Methionine PET/CT in a Patient After Combined Glioma Treatment
Authors: Tatiana Yu. Skvortsova, Zhanna I. Savintceva, Anastasia S. Zhavoronkova, Alexander F. Gurchin, Polina L. Andropova
Journal: Clinical Nuclear Medicine (2021)

A 44-year-old man after combined left temporal low-grade glioma treatment presented with daily multiple series of seizures. MRI demonstrated diffuse cortical swelling in the left frontal lobe with intensive gyral enhancement. PET with [11C]methionine (PET-MET) revealed increased radiotracer uptake strictly confined to the cortical ribbon of the left cerebral hemisphere, which persisted for 3 months. Tumor recurrence was suggested, and biopsy was performed. No evidence of recurrent tumor was found. During a 2-year follow-up, a diffuse gyral enhancement in the left hemisphere has persisted on MRI; PET has shown high [11C]methionine uptake in the left frontal and parietal cortex with gradual positive dynamics.
Defining and Intervening on Cumulative Environmental Neurodevelopmental Risks: Introducing a Complex Systems Approach
Authors: Devon C. Payne-Sturges, Deborah A. Cory-Slechta, Robin C. Puett, Stephen B. Thomas, Ross Hammond, Peter S. Hovmand
Journal: Environmental Health Perspectives (2021)

Background: The combined effects of multiple environmental toxicants and social stressor exposures are widely recognized as important public health problems contributing to health inequities. However cumulative environmental health risks and impacts have received little attention from U.S. policy makers at state and federal levels to develop comprehensive strategies to reduce these exposures, mitigate cumulative risks, and prevent harm. An area for which the inherent limitations of current approaches to cumulative environmental health risks are well illustrated is children’s neurodevelopment, which exhibits dynamic complexity of multiple interdependent and causally linked factors and intergenerational effects. Objectives: We delineate how a complex systems approach, specifically system dynamics, can address shortcomings in environmental health risk assessment regarding exposures to multiple chemical and nonchemical stressors and reshape associated public policies. Discussion: Systems modeling assists in the goal of solving problems by improving the “mental models” we use to make decisions, including regulatory and policy decisions. In the context of disparities in children’s cumulative exposure to neurodevelopmental stressors, we describe potential policy insights about the structure and behavior of the system and the types of system dynamics modeling that would be appropriate, from visual depiction (i.e., informal maps) to formal quantitative simulation models. A systems dynamics framework provides not only a language but also a set of methodological tools that can more easily operationalize existing multidisciplinary scientific evidence and conceptual frameworks on cumulative risks. Thus, we can arrive at more accurate diagnostic tools for children’s’ environmental health inequities that take into consideration the broader social and economic environment in which children live, grow, play, and learn. https://doi.org/10.1289/EHP7333
Consequences of Selling a Kidney in India—Reply
Authors: Madhav Goyal, Ravindra L. Mehta, Lawrence J. Schneiderman, Ashwini R. Sehgal
Journal: JAMA (2003)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
NPM1-ALK Overexpression-Driven Toxicity in ALCL Is Partner Dependent and Mediated By STAT1 Antagonism of STAT3 Survival Signaling, Revealing a Novel Therapeutic Strategy
Authors: Soumya Sundara Rajan, Amit Dipak Amin, Lingxiao Li, Delphine C. M. Rolland, Haiquan Li, Soham Puvvada, Yves Lussier, Megan S. Lim, Jonathan H. Schatz
Journal: Blood (2017)
AIM2 controls microglial inflammation to prevent experimental autoimmune encephalomyelitis
Authors: Chunmei Ma, Sheng Li, Yingchao Hu, Yan Ma, Yuqing Wu, Chunyan Wu, Xue Liu, Bingwei Wang, Gang Hu, Jiawei Zhou, Shuo Yang
Journal: The Journal of Experimental Medicine (2021)

The role of the PYHIN family member absent in melanoma 2 (AIM2), another important inflammasome sensor, in EAE remains unclear. In this study, we found that AIM2 negatively regulates the pathogenesis of EAE independent of inflammasome activation. AIM2 deficiency enhanced microglia activation and infiltration of peripheral immune cells into the CNS, thereby promoting neuroinflammation and demyelination during EAE. Mechanistically, AIM2 negatively regulates the DNA-PK–AKT3 in microglia to control neuroinflammation synergistically induced by cGAS and DNA-PK. Administration of a DNA-PK inhibitor reduced the severity of the EAE. Collectively, these findings identify a new role for AIM2 in controlling the onset of EAE. Furthermore, delineation of the underlying inflammasome-independent mechanism highlights cGAS and DNA-PK signaling as potential targets for the treatment of heterogeneous MS.
Pharmacodynamic Study of Copanlisib in Patients with Non-Hodgkin's Lymphoma and Advanced Solid Tumors: Confirmation of on-Target PI3K Inhibitory Activity
Authors: Franck Morschhauser, Ahmad Awada, Jean-Pascal Machiels, Gilles Andre Salles, Sylvie Rottey, Simon Rule, David Cunningham, Frederic Peyrade, Christophe Fruchart, Hendrik-Tobias Arkenau, Isabelle Genvresse, Li Liu, Christoph Kneip, Carol Pena, Joachim Grevel, Jun Zhang, Galia Cisternas, Susanne Reschke, Camille Granvil
Journal: Blood (2017)
Lysosome-associated membrane protein 3 misexpression in salivary glands induces a Sjögren’s syndrome-like phenotype in mice
Authors: Hiroyuki Nakamura, Tsutomu Tanaka, Thomas Pranzatelli, Youngmi Ji, Hongen Yin, Paola Perez, Sandra A Afione, Shyh-Ing Jang, Corrine Goldsmith, Chang Yu Zheng, William D Swaim, Blake M Warner, Noriyuki Hirata, Masayuki Noguchi, Tatsuya Atsumi, John A Chiorini
Journal: Annals of the Rheumatic Diseases (2021)

Sjögren's syndrome (SS) is an autoimmune sialadenitis with unknown aetiology. Although extensive research implicated an abnormal immune response associated with lymphocytes, an initiating event mediated by salivary gland epithelial cell (SGEC) abnormalities causing activation is poorly characterised. Transcriptome studies have suggested alternations in lysosomal function are associated with SS, but a cause and effect linkage has not been established. In this study, we demonstrated that altered lysosome activity in SGECs by expression of lysosome-associated membrane protein 3 (LAMP3) can initiate an autoimmune response with autoantibody production and salivary dysfunction similar to SS.Retroductal cannulation of the submandibular salivary glands with an adeno-associated virus serotype 2 vector encoding LAMP3 was used to establish a model system. Pilocarpine-stimulated salivary flow and the presence of autoantibodies were assessed at several time points post-cannulation. Salivary glands from the mice were evaluated using RNAseq and histologically.Following LAMP3 expression, saliva flow was significantly decreased and serum anti-Ro/SSA and La/SSB antibodies could be detected in the treated mice. Mechanistically, LAMP3 expression increased apoptosis in SGECs and decreased protein expression related to saliva secretion. Analysis of RNAseq data suggested altered lysosomal function in the transduced SGECs, and that the cellular changes can chemoattract immune cells into the salivary glands. Immune cells were activated via toll-like receptors by damage-associated molecular patterns released from LAMP3-expressing SGECs.These results show a critical role for lysosomal trafficking in the development of SS and establish a causal relationship between LAMP3 misexpression and the development of SS.
KEYNOTE-365 cohort B: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)–pretreated patients with metastatic castration-resistant prostate cancer (mCRPC)—New data after an additional 1 year of follow-up.
Authors: Leonard Joseph Appleman, Michael Paul Kolinsky, William R. Berry, Margitta Retz, Loic Mourey, Josep M. Piulats, Emanuela Romano, Gwenaelle Gravis, Howard Gurney, Johann S. De Bono, Martin Boegemann, Urban Emmenegger, Anthony M. Joshua, Christophe Massard, Srikala S. Sridhar, Henry Jacob Conter, Xin Tong Li, Charles Schloss, Christian Heinrich Poehlein, Evan Y. Yu
Journal: Journal of Clinical Oncology (2021)

10 Background: For men with mCRPC, systemic therapies such as docetaxel and cabazitaxel improve survival, but more effective treatments are needed. KEYNOTE-365 (NCT02861573) is a phase 1b/2 study to examine the safety and efficacy of pembro in combination with 4 different study medications (cohorts A, B, C, D) in mCRPC. Previous data from cohort B with a median of 20 months of follow-up showed that pembro + docetaxel and prednisone was well tolerated and had antitumor activity in patients (pts) with mCRPC previously treated with abi or enza. New efficacy and safety data after an additional year of follow-up are presented. Methods: Cohort B enrolled pts who did not respond to or were intolerant to ≥4 weeks of abi or enza in the prechemotherapy mCRPC state and whose disease progressed within 6 months of screening (determined by PSA progression or radiologic bone/soft tissue progression). Pts received pembro 200 mg IV every 3 weeks (Q3W), docetaxel 75 mg/m 2 IV Q3W, and oral prednisone 5 mg twice daily. Primary end points were safety, PSA response rate (PSA decrease &gt;50% from baseline), and ORR per RECIST v1.1 by blinded independent central review. Efficacy and safety were assessed in all pts as treated. Results: Of the 104 treated pts, median age was 68.0 years (range, 50-86), 23.1% had PD-L1–positive tumors (combined positive score ≥1), 25.0% had visceral disease, and 50.0% had measurable disease. Median time from enrollment to data cutoff was 32.4 months (range 13.9-40.3); 101 pts discontinued, primarily because of disease progression (77.9%). Efficacy outcomes are reported in the table below. Treatment-related adverse events (TRAEs) occurred in 100 pts (96.2%); the most frequent (≥30%) were diarrhea (41.3%), fatigue (41.3%), and alopecia (40.4%). Grade 3-5 TRAEs occurred in 46 pts (44.2%). Five pts (4.8%) died of AEs; 2 were treatment-related pneumonitis. Conclusions: After another year of follow-up, pembro + docetaxel and prednisone showed improved ORR and PSA response rates compared to the prior dataset in pts with mCRPC previously treated with abi or enza. Safety was consistent with known profiles of each agent and will be further evaluated in a phase 3 study (KEYNOTE-921). Clinical trial information: NCT02861573. [Table: see text]
Climate change and child health: a scoping review and an expanded conceptual framework
Authors: Daniel Helldén, Camilla Andersson, Maria Nilsson, Kristie L Ebi, Peter Friberg, Tobias Alfvén
Journal: The Lancet Planetary Health (2021)

Climate change can have detrimental effects on child health and wellbeing. Despite the imperative for a fuller understanding of how climate change affects child health and wellbeing, a systematic approach and focus solely on children (aged <18 years) has been lacking. In this Scoping Review, we did a literature search on the impacts of climate change on child health from January, 2000, to June, 2019. The included studies explicitly linked an alteration of an exposure to a risk factor for child health to climate change or climate variability. In total, 2970 original articles, reviews, and other documents were identified, of which 371 were analysed. Employing an expanded framework, our analysis showed that the effects of climate change on child health act through direct and indirect pathways, with implications for determinants of child health as well as morbidity and mortality from a range of diseases. This understanding can be further enhanced by using a broader range of research methods, studying overlooked populations and geographical regions, investigating the costs and benefits of mitigation and adaptation for child health, and considering the position of climate change and child health within the UN Sustainable Development Goals. Present and future generations of children bear and will continue to bear an unacceptably high disease burden from climate change.
Evaluation of treatment patterns and outcomes in patients diagnosed with genitourinary (GU) cancers with linked claims plus prior authorization data.
Authors: Lincy S. Lal, Caitlin Elliott, Stephanie Korrer, Stacey DaCosta Byfield, Benjamin Chastek, Tejas Patel
Journal: Journal of Clinical Oncology (2021)

284 Background: Integration of clinical and claims data allows for the examination of outcomes and characteristics which is essential for real world evidence generation and clinical decision making. We describe utilization of clinical data collected from an oncology Prior Authorization (PA) program integrated with claims data to evaluate treatment patterns, resource utilization, and total costs of care during therapy for patients with newly diagnosed metastatic and non-metastatic renal (R), bladder (B), and testicular (T) cancers. Methods: Commercially insured patients with a GU cancer diagnosis, from 2/2016 to 12/2019 with both clinical information from a PA tool (based on NCCN guidelines) and claims from the Optum Research Database were identified. Demographics, clinical information (metastatic status and line of therapy), treatment duration, resource utilization, and all-cause costs were collected, and uploaded to a dynamic web-based Tableau dashboard. Analysis was conducted for non-metastatic and metastatic settings based on the first observed treatment episode. Drug additions or switches incremented line of therapy; single drug discontinuations did not. All cost data were adjusted to 2019 values. Results: A total of 3,736 patients were included; 13% were censored (i.e. on treatment at the end of the study period). 916 patients (25%) were metastatic and 2,820 (75%) were in their adjuvant/neoadjuvant (A/N) line. 60% of the population was ≥55 years old and 85% were male. The top regimen in A/N line for each cancer type were: nivolumab (R), BCG(B), bleomycin + carboplatin/cisplatin+ etoposide (T). The top regimen in metastatic cancer were: nivolumab (R), carboplatin/cisplatin + gemcitabine (B), bleomycin + carboplatin/cisplatin + etoposide (T). The median duration of A/N line ranged from 50(B) to 119(R) days while the median duration for metastatic line range from 71(T) to 82(R) days. The highest rate of inpatient admissions was observed in patients with R (31%). Of the three cancers, R was the most expensive in the A/N and metastatic settings with mean (standard deviation) costs of $192,308 ($269,358) and $136,293 ($146,632), respectively. Conclusions: Combination of clinical and claims data provide valuable information on real world outcomes in routine clinical care and may support treatment selection decisions at the point of care.
Predictive biomarkers with isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma
Authors: Paul G. Richardson, Thierry Facon, William I. Bensinger, Xavier Leleu, Frank Campana, Sandrine Macé, Marielle Chiron, Helgi van de Velde, Joseph Mikhael
Journal: Blood Cancer Journal (2021)
Therapeutic Targeting of Checkpoint Receptors within the DNAM1 Axis
Authors: Zoya Alteber, Maya F. Kotturi, Sarah Whelan, Sudipto Ganguly, Emmanuel Weyl, Drew M. Pardoll, John Hunter, Eran Ophir
Journal: Cancer Discovery (2021)

Therapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. However, relapse following early response, attributable to primary and adaptive resistance, is frequently observed. Additional immunomodulatory pathways are being studied in patients with primary or acquired resistance to CTLA4 or PD-1 blockade. The DNAM1 axis is a potent coregulator of innate and adaptive immunity whose other components include the immunoglobulin receptors TIGIT, PVRIG, and CD96, and their nectin and nectin-like ligands. We review the basic biology and therapeutic relevance of this family, which has begun to show promise in cancer clinical trials. SIGNIFICANCE: Recent studies have outlined the immuno-oncologic ascendancy of coinhibitory receptors in the DNAM1 axis such as TIGIT and PVRIG and, to a lesser extent, CD96. Biological elucidation backed by ongoing clinical trials of single-agent therapy directed against TIGIT or PVRIG is beginning to provide the rationale for testing combination regimens of DNAM1 axis blockers in conjunction with anti-PD-1/PD-L1 agents.
Doctors unhappy at proposed 1% pay rise for consultants and salaried GPs in England
Authors: Abi Rimmer
Journal: BMJ (2021)

The BMA has described a proposed 1% pay rise for consultants and salaried GPs working in England as a dereliction of the government’s moral duty to the NHS workforce.

On 4 March the Department of Health and Social Care (DHSC) published the evidence it submitted to the Review Body on Doctors’ and Dentists' Remuneration (DDRB) for the 2021 to 2022 pay round.1

The review body gathers evidence from the government, the BMA, and other interested parties before making recommendations on doctors’ pay rises each year. This year it will make recommendations for consultants and salaried GPs. A multiyear agreement has been agreed in principle for specialty and associate specialist (SAS) doctors, so only those SAS doctors who choose not …
Genomic alterations in KMT2 family predict outcome of immune checkpoint therapy in multiple cancers
Authors: Peng Zhang, Yixuan Huang
Journal: Journal of Hematology & Oncology (2021)

Abstract Immune checkpoint therapy (ICT) can produce durable antitumor responses in various cancer types; however, the responses are not universal, and the predictive biomarkers are urgently needed. Growing evidence points to a link between epigenetic regulation and anti-tumor immunity, while clinical data on the association of genomic alterations in transcriptional dysregulation-related genes and ICT clinical benefit are lacking. Histone–lysine N -methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility, which is associated with tumorigenesis, mutagenesis, and immune tolerance in various cancers, indicating its possible correlation with the output of immune checkpoint therapy. We hypothesized that genomic mutations in the KMT2 family have the potential to be a novel predictor of immunotherapeutic efficacy. Through integrative cancer genomic analyses of baseline tumor tissues from multiple cohorts involving immunotherapeutic patients, we uncovered a remarkable correlation between KMT2 family mutation and better immune checkpoint therapy responses in multiple patient cohorts. Then, we gathered all the independent ICT-treated datasets as a combination cohort consisted of 418 patients. Significant enrichment of KMT2 family genomic alterations in responding tumors was observed (odds ratio = 2.60, P value = 1.67e−04). This work distinguished the mutations in the KMT2 family as a potential predictor of favorable ICT response in multiple cancers, highlighting the importance of genomic profiling in immunotherapy.
Hyperthermia, bladder pressure, and intravesical drug delivery.
Authors: Dominic C. Grimberg, Scott P. Campbell, Wiguins Etienne, Ping Fan, Paolo F. Maccarini, Ivan Spasojevic, Rohith Arcot, Ankeet Shah, Brant Allen Inman
Journal: Journal of Clinical Oncology (2021)

469 Background: Little is known about the pharmacokinetics of intravesical chemotherapies. Various parameters can be altered including temperature, dwell time, drug concentration, and bladder pressure. Here, we hypothesize that increasing bladder pressure during instillation will improve drug delivery. Methods: An ex-vivo porcine model was developed to evaluate determinants of drug penetration into the bladder wall. Porcine bladders were suspended in isotonic saline at 37°C with a three-way Foley catheter in the bladder. Temperature probes were positioned in the extravesical bathing solution, bladder lumen, and sutured to the detrusor to ensure maintenance of desired temperatures. 2g gemcitabine in 100mL normal saline was heated to 43°C and circulated through the bladder using the Combat Bladder Recirculation System. Bladder pressures were monitored throughout each trial. After 60 minutes of dwell time, rapid dissection was performed to obtain full-thickness bladder samples from the bladder dome, posterior wall, trigone, and left and right lateral walls. Tissue was homogenized and liquid chromatography with tandem mass spectrometry (LC/MS/MS) was performed to measure gemcitabine concentration within the bladder wall. Linear regression and Pearson correlation were performed to determine the association between mean bladder pressure during instillation and drug concentration within the bladder wall. Multiple linear regression was conducted to control for bladder location and thickness. Results: Gemcitabine concentration within the bladder wall was measured 25 times across five trials. Mean gemcitabine concentration within bladder wall was 3.68 mg/g (sd 1.35). Pressure ranged from 149.8 mmHg to 277.7 mmHg (mean 194.8, sd 22.0). On univariate analysis, higher pressure was associated with increased gemcitabine concentration within the bladder wall (correlation = 0.49, p = 0.013). This result persisted after adjusting for bladder location (ß = 0.49, p = 0.006) and thickness (ß = 0.70, p = 0.03). Unstandardized regression coefficient in each of the models was 0.099 (mmHg x g)/mg, demonstrating that for each pressure increase of 10mmHg there was an associated increase in gemcitabine concentration of approximately 1 mg/g (Table). Conclusions: Data suggest that bladder pressure dramatically improves the extent of gemcitabine penetration into the bladder wall. Future research is needed to evaluate the therapeutic effect of increased gemcitabine delivery to target tissue in patients with bladder cancer. [Table: see text]
Outcomes and Mortality Among Adults Hospitalized With COVID-19 at US Medical Centers
Authors: Ninh T. Nguyen, Justine Chinn, Jeffry Nahmias, Sarah Yuen, Katharine A. Kirby, Sam Hohmann, Alpesh Amin
Journal: JAMA Network Open (2021)

This cohort study assesses characteristics and outcomes among adults hospitalized with coronavirus disease 2019 (COVID-19) at US medical centers as well as COVID-19–related mortality over the initial 6 months of the pandemic.