tbuckley/cabot-search huggingface dataset:
A meta-analysis of protein binding of flucloxacillin in healthy volunteers and hospitalized patients
Authors: Eveline Wallenburg, Roger J.M. Brüggemann, Jason A. Roberts, Nynke G.L. Jager, Marta Ulldemolins, Sarah Wilkes, Jeroen Schouten, Paul K.L. Chin, Rob ter Heine
Journal: Clinical Microbiology and Infection (2021)

The aim of this study was to develop a mechanistic protein-binding model to predict the unbound flucloxacillin concentrations in different patient populations.A mechanistic protein-binding model was fitted to the data using non-linear mixed-effects modelling. Data were obtained from four datasets, containing 710 paired total and unbound flucloxacillin concentrations from healthy volunteers, non-critically ill and critically ill patients. A fifth dataset with data from hospitalized patients was used for evaluation of our model. The predictive performance of the mechanistic model was evaluated and compared with the calculation of the unbound concentration with a fixed unbound fraction of 5%. Finally, we performed a fit-for-use evaluation, verifying whether the model-predicted unbound flucloxacillin concentrations would lead to clinically incorrect dose adjustments.The mechanistic protein-binding model predicted the unbound flucloxacillin concentrations more accurately than assuming an unbound fraction of 5%. The mean prediction error varied between -26.2% to 27.8% for the mechanistic model and between -30.8% to 83% for calculation with a fixed factor of 5%. The normalized root mean squared error varied between 36.8% and 69% respectively between 57.1% and 134%. Predicting the unbound concentration with the use of the mechanistic model resulted in 6.1% incorrect dose adjustments versus 19.4% if calculated with a fixed unbound fraction of 5%.Estimating the unbound concentration with a mechanistic protein-binding model outperforms the calculation with the use of a fixed protein binding factor of 5%, but neither demonstrates acceptable performance. When performing dose individualization of flucloxacillin, this should be done based on measured unbound concentrations rather than on estimated unbound concentrations from the measured total concentrations. In the absence of an assay for unbound concentrations, the mechanistic binding model should be preferred over assuming a fixed unbound fraction of 5%.
Abstract CT172: Phase 2 clinical trial of dianhydrogalactitol (VAL-083) in patients with newly diagnosed MGMT-unmethylated GBM
Authors: Zhong-ping Chen, Cheng-cheng Guo, Qun-ying Yang, Jia-wei Li, Shao-xiong Wu, John Langlands, Gregory Johnson, Claire Kwan, Sarath Kanekal, Richard Schwartz, Jeffrey Bacha, Anne Steino, Dennis Brown
Journal: Cancer Research (2021)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. The majority of glioblastoma multiforme (GBM) patients have an unmethylated MGMT promoter status, leading to limited response to TMZ and decreased survival. Current standard-of-care includes surgery followed by chemoradiation and TMZ. An unmethylated promoter for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is strongly correlated with poor outcomes. VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated drug-resistance and has demonstrated cytotoxicity in MGMT-unmethylated GBM cell lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. A Phase 2, open-label, biomarker-driven, study is being conducted to evaluate the tolerability and efficacy of VAL-083 in combination with radiation therapy (RT) in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 given IV at 20, 30, or 40 mg/m2/day x 3 days every 21 days and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study has 2 stages: Stage 1, dose-escalation, has identified a recommended dose of 30 mg/m2/day of VAL-083 in combination with RT as generally safe and well-tolerated. Stage 2, an expansion stage, has enrolled 20 additional patients at 30 mg/m2/day IV infusion on days 1, 2, and 3 of 21-day cycles. As of January 11, 2021, all 29 subjects in the study have been enrolled and completed the treatment stage of the study. Tumor response are assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. The trial is continuing as planned and an update on primary results on safety and efficacy, and pharmacokinetics will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736. Citation Format: Zhong-ping Chen, Cheng-cheng Guo, Qun-ying Yang, Jia-wei Li, Shao-xiong Wu, John Langlands, Gregory Johnson, Claire Kwan, Sarath Kanekal, Richard Schwartz, Jeffrey Bacha, Anne Steino, Dennis Brown. Phase 2 clinical trial of dianhydrogalactitol (VAL-083) in patients with newly diagnosed MGMT-unmethylated GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT172.
NeuroSAFE PROOF. Update on a multi-centre, pragmatic, RCT for men undergoing robot-assisted radical prostatectomy: Trial in progress
Authors: E. Dinneen, J. Grierson, A. Haider, C. Allen, D. Heffernan-Ho, R. Clow, A. Freeman, T. Briggs, S. Nathan, C. Brew-Graves, S. Mallett, N. Williams, R. Persad, J. Aning, J. Oxley, N. Oakley, S. Morgan, F. Tahir, I. Ahmad, L. Dutto, J. Salmond, R. Marzena, I. Ben-Salha, J. Kelly, G. Shaw
Journal: European Urology (2021)
A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice
Authors: Matthew W. Boudreau, Darjan Duraki, Lawrence Wang, Chengjian Mao, Ji Eun Kim, Madeline A. Henn, Bingtao Tang, Sean W. Fanning, Jeffrey Kiefer, Theodore M. Tarasow, Elizabeth M. Bruckheimer, Ramon Moreno, Spyro Mousses, Geoffrey L. Greene, Edward J. Roy, Ben Ho Park, Timothy M. Fan, Erik R. Nelson, Paul J. Hergenrother, David J. Shapiro
Journal: Science Translational Medicine (2021)

Activation of the unfolded protein response induces regression of estrogen receptor α–positive breast cancer xenografts in mice.
Mitochondria-targeted and ultrasound-responsive nanoparticles for oxygen and nitric oxide codelivery to reverse immunosuppression and enhance sonodynamic therapy for immune activation
Authors: Changwei Ji, Jingxing Si, Yan Xu, Wenjing Zhang, Yaqian Yang, Xin He, Hao Xu, Xiaozhou Mou, Hao Ren, Hongqian Guo
Journal: Theranostics (2021)

Background: Sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate antitumor immune responses for immunotherapy. However, the hypoxic and immunosuppressive tumor microenvironment limits its therapeutic efficacy and suppresses immune response. Methods: In this study, mitochondria-targeted and ultrasound-responsive nanoparticles were developed to co-deliver oxygen (O2) and nitric oxide (NO) to enhance SDT and immune response. This system (PIH-NO) was constructed with a human serum albumin-based NO donor (HSA-NO) to encapsulate perfluorodecalin (FDC) and the sonosensitizer (IR780). In vitro, the burst release of O2 and NO with US treatment to generate reactive oxygen species (ROS), the mitochondria targeting properties and mitochondrial dysfunction were evaluated in tumor cells. Moreover, in vivo, tumor accumulation, therapeutic efficacy, the immunosuppressive tumor microenvironment, immunogenic cell death, and immune activation after PIH-NO treatment were also studied in 4T1 tumor bearing mice. Results: PIH-NO could accumulate in the mitochondria and relive hypoxia. After US irradiation, O2 and NO displayed burst release to enhance SDT, generated strongly oxidizing peroxynitrite anions, and led to mitochondrial dysfunction. The release of NO increased blood perfusion and enhanced the accumulation of the formed nanoparticles. Owing to O2 and NO release with US, PIH-NO enhanced SDT to inhibit tumor growth and amplify immunogenic cell death in vitro and in vivo. Additionally, PIH-NO promoted the maturation of dendritic cells and increased the number of infiltrating immune cells. More importantly, PIH-NO polarized M2 macrophages into M1 phenotype and depleted myeloid-derived suppressor cells to reverse immunosuppression and enhance immune response. Conclusion: Our findings provide a simple strategy to co-deliver O2 and NO to enhance SDT and reverse immunosuppression, leading to an increase in the immune response for cancer immunotherapy.
Pax5 regulates B cell immunity by promoting PI3K signaling via PTEN down-regulation
Authors: Lesly Calderón, Karina Schindler, Stephen G. Malin, Alexandra Schebesta, Qiong Sun, Tanja Schwickert, Chiara Alberti, Maria Fischer, Markus Jaritz, Hiromi Tagoh, Anja Ebert, Martina Minnich, Adrian Liston, Luisa Cochella, Meinrad Busslinger
Journal: Science Immunology (2021)

Pax5 controls the generation, proliferation, and survival of all mature B cells by promoting PI3K signaling via PTEN down-regulation.
Therapeutic regulation of autophagy in hepatic metabolism
Authors: Katherine Byrnes, Sophia Blessinger, Niani Tiaye Bailey, Russell Scaife, Gang Liu, Bilon Khambu
Journal: Acta Pharmaceutica Sinica B (2021)

Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. Though classically known for selective or bulk degradation of cellular components or energy-dense macromolecules, emerging evidence indicates autophagy selectively regulates various signaling proteins to directly impact the expression levels of metabolic enzymes or their upstream regulators. Hence, we review three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. The plasticity of the autophagic function is unraveling a new therapeutic approach. Thus, we will also discuss the potential translation of promising preclinical data on autophagy modulation into therapeutic strategies that can be used in the clinic to treat common metabolic disorders.
MO5-5 Lesion-level response to immune checkpoint inhibitor in patients with advanced gastric cancer and esophageal cancer
Authors: Iori Motoo, Takayuki Ando, Aiko Murayama, Shinya Kajiura, Kohei Ogawa, Kenichiro Tsukada, Akira Ueda, Nobuhiro Suzuki, Naokatsu Nakada, Shunsuke Takatori, Koji Nakashima, Ayumu Hosokawa, Mayo Fuchino, Sohachi Nanjo, Haruka Fujinami, Ichiro Yasuda
Journal: Annals of Oncology (2021)
Peripheral B cells repress B-cell regeneration in aging through a TNF-α/IGFBP-1/IGF-1 immune-endocrine axis
Authors: Reem Dowery, David Benhamou, Eli Benchetrit, Ofer Harel, Alex Nevelsky, Simona Zisman-Rozen, Yolanda Braun-Moscovici, Alexandra Balbir-Gurman, Irit Avivi, Arik Shechter, Daniela Berdnik, Tony Wyss-Coray, Doron Melamed
Journal: Blood (2021)
Blinatumomab vs Chemotherapy Among Children With Relapsed Acute Lymphoblastic Leukemia
Authors: Motoharu Shibusawa, Keisuke Kidoguchi, Tetsuya Tanimoto
Journal: JAMA (2021)

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
Abstract 13222: Cardiopulmonary Best Abstract Award: Long Noncoding RNA H19 in the Pathogenesis of Right Ventricular Failure Associated With Pulmonary Arterial Hypertension -A Putative Novel Biomarker and Therapeutic Target
Authors: Junichi Omura, Karima Habbout, Sandra Martineau, Sandra Breuils-Bonnet, François Potus, Stephen L Archer, Roxane Paulin, Steeve Provencher, Olivier Boucherat, Sebastien Bonnet
Journal: Circulation (2018)

Background: Right ventricular failure (RVF) is the major prognostic factor for both morbidity and mortality in pulmonary hypertension. A better understanding of the molecular mechanisms accounting ...
US bill ends some restrictions on global funding of abortion and reproductive health
Authors: Janice Hopkins Tanne
Journal: BMJ (2021)

The US House of Representatives passed a spending bill without the usual restrictions on abortion on 29 July, the same day that Republican governors and legislators asked the Supreme Court to overturn Roe v Wade , its 1973 ruling that permitted abortions until fetal viability.

If the spending bill is passed by the Senate, where Democrats hold a one vote majority, funding for international family planning will increase. In particular, US contributions to the United Nations Population Fund, which promotes reproductive health in about 150 countries, would almost double and would reverse cuts enacted by the previous president, Donald Trump.

The spending bill is part of a group of appropriations bills in the house that would end all federal funding restrictions on abortions. It did …
Characterization of the human <scp><i>ABO</i></scp> genotypes and their association to common inflammatory and cardiovascular diseases in the <scp>UK Biobank</scp>
Authors: Julia Höglund, Torgny Karlsson, Therese Johansson, Weronica E. Ek, Åsa Johansson
Journal: American Journal of Hematology (2021)

The ABO gene contains three major alleles that encodes different antigens; A, B, and O, which determine an individual's blood group. Previous studies have primarily focused on identifying associations between ABO blood groups and diseases risk. Here, we sought to test for association between ABO genotypes (OO, OA, AA; OB, BB, and AB) and a large set of common inflammatory and cardiovascular diseases in UK Biobank as well as disease-related protein biomarkers in NSPHS. We first tested for association by conducting a likelihood ratio test, testing whether ABO contributed significantly to the risk for 24 diseases, and 438 plasma proteins. For phenotypes with FDR < 0.05, we tested for pair-wise differences between genetically determined ABO genotypes using logistic or linear regression. Our study confirmed previous findings of a strong association between ABO and cardiovascular disease, identified associations for both type 1 and type 2 diabetes, and provide additional evidence of significant differences between heterozygous and homozygous allele carriers for pulmonary embolism, deep vein thrombosis, but also for von Willebrand factor levels. Furthermore, the results indicated an additive effect between genotypes, even between the two most common A subgroups, A1 and A2. Additionally, we found that ABO contributed significantly to 39 plasma proteins, of which 23 have never been linked to the ABO locus before. These results show the need of incorporating ABO genotype information in the consultation and management of patients at risk, rather than classifying patients into blood groups.
Generation of functional human thymic cells from induced pluripotent stem cells
Authors: Stephan A Ramos, John J Morton, Prabha Yadav, Brendan Reed, Sheila I Alizadeh, Ali H Shilleh, Loni Perrenoud, James Jaggers, John Kappler, Antonio Jimeno, Holger A Russ
Journal: Journal of Allergy and Clinical Immunology (2021)
Incidence of Axillary Adenopathy in Breast Imaging After COVID-19 Vaccination
Authors: Kristin A. Robinson, Santo Maimone, Denise A. Gococo-Benore, Zhuo Li, Pooja P. Advani, Saranya Chumsri
Journal: JAMA Oncology (2021)

pansion states.These findings are consistent with age-adjusted state cancer mortality data reported by the US Centers for Disease Control and Prevention, which do not clearly demonstrate a difference that favors either expansion or nonexpansion states (Figure 1). 4 Baseline cancer mortality between expansion and nonexpansion states being the same after adjusting for predictors of cancer outcomes known to differ from state to state suggests similar care is being offered in different states.Clinically meaningful baseline differences in cancer survival between expansion and nonexpansion states before the US Affordable Care Act, combined with unmeasured social, community-level, and state Medicaid program differences, could obscure any association of Medicaid expansion with cancer survival (unpublished data; Ermer 2021).Moreover, similar baseline trends are a key assumption of difference-in-difference analysis, which is one of the most common statistical approaches currently used to study expansion.One of the limitations of this study is that despite capturing 70% of new cancer diagnoses, the National Cancer Database only captures data from 30% of US hospitals. 5Therefore, potential differences in mortality across states secondary to noncaptured hospitals are not represented.However, the study indicates that, overall, similar cancer care is being offered in states that did and did not expand Medicaid.
Healthcare Costs Associated with Venous Thromboembolism in Cancer Patients Treated with Anticoagulants
Authors: Michael B. Streiff, Keith McCrae, Dejan Milentijevic, Nora McCormick, François Laliberté, Concetta Crivera, Patrick Lefebvre, Dominique Lejeune, Heather Rozjabek, Jeff Schein, Alok A. Khorana
Journal: Blood (2017)
O11-5 Durvalumab(D) ± tremelimumab(T) + platinum-etoposide(EP) in 1L ES-SCLC: Characterization of long-term benefit in CASPIAN
Authors: Haruhiro Saito, Jonathan W. Goldman, Marina Chiara Garassino, Yuanbin Chen, Niels Reinmuth, Katsuyuki Hotta, Artem Poltoratskiy, Dmytro Trukhin, Maximilian J. Hochmair, Mustafa Özgüroğlu, Jun Ho Ji, Galina Statsenko, Oleksandr Voitko, Nikolay V. Conev, Igor Bondarenko, Stuart Spencer, Mingchao Xie, Stephanie Jones, April Franks, Yashaswi Shrestha, Luis Paz-Ares
Journal: Annals of Oncology (2021)
Rare Brain Metastasis in Parotid Adenoid Cystic Carcinoma Detected on 68Ga-PSMA PET/CT
Authors: Shreya Datta Gupta, Geetanjali Arora, Deepak Kumar, Ashu Seith Bhalla, Kapil Sikka, Shamim A. Shamim
Journal: Clinical Nuclear Medicine (2021)

Abstract We present the case of a 45-year-old woman with known adenoid cystic carcinoma of the right parotid gland, postexcision and postoperative radiation therapy. She was followed up on 18 F-FDG PET/CT, which revealed minimal local residual disease and bilateral lung nodules, for which chemotherapy was initiated. Postchemotherapy, 18 F-FDG PET/CT showed residual lung metastases. As a part of ongoing project, 68 Ga-PSMA PET/CT done revealed additional focal uptake in the right cerebellum, missed on FDG PET/CT. The brain lesion was confirmed upon MRI.
MO30-5 Updated efficacy and safety of patritumab deruxtecan (HER3-DXd; U3-1402), a HER3 directed antibody drug conjugate, in EGFRm NSCLC
Authors: Hidetoshi Hayashi, Helena A. Yu, Christina Baik, Kathryn Gold, Melissa L. Johnson, Marianna Koczywas, Haruyasu Murakami, Makoto Nishio, Conor Steuer, Wu-Chou Su, James C.H. Yang, Samer Karam, Zhenhao Qui, Yang Qiu, Shuquan Chen, Channing Yu, Pasi A. Janne
Journal: Annals of Oncology (2021)
P34-1 Pilot study learning needs of palliative care team who care for cancer patients undergoing therapeutic for new cancer agents
Authors: Masako Nakamura, Masayuki Ejiri, Yu Kobayashi, Aki Jyo, Yasue Endo, Mari Ito, Satiyo Ikeda, Miho Sakurai, Chiharu Yasunaga, Beniko Itokawa
Journal: Annals of Oncology (2021)
P-131 External validation of prognostic ALAN score in patients with inoperable bile duct cancer treated with second-line chemotherapy
Authors: R. Giampieri, C. Liguori, S. Crocetti, F. Pecci, A. Bittoni, E. Lenci, L. Cantini, M. Giulia, A. Lanese, G. Pinterpe, E. Giglio, C. Copparoni, A. Lupi, T. Meletani, E. De Simoni, R. Berardi
Journal: Annals of Oncology (2021)
Evaluation of the effects of an artificial intelligence system on endoscopy quality and preliminary testing of its performance in detecting early gastric cancer: a randomized controlled trial
Authors: Lianlian Wu, Xinqi He, Mei Liu, Huaping Xie, Ping An, Jun Zhang, Heng Zhang, Yaowei Ai, Qiaoyun Tong, Mingwen Guo, Manling Huang, Cunjin Ge, Zhi Yang, Jingping Yuan, Jun Liu, Wei Zhou, Xiaoda Jiang, Xu Huang, Ganggang Mu, Xinyue Wan, Yanxia Li, Hongguang Wang, Yonggui Wang, Hongfeng Zhang, Di Chen, Dexin Gong, Jing Wang, Li Huang, Jia Li, Liwen Yao, Yijie Zhu, Honggang Yu
Journal: Endoscopy (2021)

Abstract Background Esophagogastroduodenoscopy (EGD) is a prerequisite for detecting upper gastrointestinal lesions especially early gastric cancer (EGC). An artificial intelligence system has been shown to monitor blind spots during EGD. In this study, we updated the system (ENDOANGEL), verified its effectiveness in improving endoscopy quality, and pretested its performance in detecting EGC in a multicenter randomized controlled trial. Methods ENDOANGEL was developed using deep convolutional neural networks and deep reinforcement learning. Patients undergoing EGD in five hospitals were randomly assigned to the ENDOANGEL-assisted group or to a control group without use of ENDOANGEL. The primary outcome was the number of blind spots. Secondary outcomes included performance of ENDOANGEL in predicting EGC in a clinical setting. Results 1050 patients were randomized, and 498 and 504 patients in the ENDOANGEL and control groups, respectively, were analyzed. Compared with the control group, the ENDOANGEL group had fewer blind spots (mean 5.38 [standard deviation (SD) 4.32] vs. 9.82 [SD 4.98]; P &lt; 0.001) and longer inspection time (5.40 [SD 3.82] vs. 4.38 [SD 3.91] minutes; P &lt; 0.001). In the ENDOANGEL group, 196 gastric lesions with pathological results were identified. ENDOANGEL correctly predicted all three EGCs (one mucosal carcinoma and two high grade neoplasias) and two advanced gastric cancers, with a per-lesion accuracy of 84.7 %, sensitivity of 100 %, and specificity of 84.3 % for detecting gastric cancer. Conclusions In this multicenter study, ENDOANGEL was an effective and robust system to improve the quality of EGD and has the potential to detect EGC in real time.
Association between traditional systemic anti-psoriatic drugs and tuberculosis risk in patients with psoriasis with or without psoriatic arthritis: Results from a nationwide cohort study
Authors: 陳怡如(Yi-Ju Chen), 吳俊穎(Chun-Ying Wu), 沈瑞隆(Jui-Lung Shen), 陳姿婷(Tzu-Ting Chen), 張雲亭(Yun-Ting Chang)
Journal: Journal of the American Academy of Dermatology (2013)