tbuckley/cabot-search huggingface dataset:
Repairing the heart: State-of the art delivery strategies for biological therapeutics
Authors: Qiangbing Yang, Juntao Fang, Zhiyong Lei, Joost P.G. Sluijter, Raymond Schiffelers
Journal: Advanced Drug Delivery Reviews (2020)

Myocardial infarction (MI) is one of the leading causes of mortality worldwide. It is caused by an acute imbalance between oxygen supply and demand in the myocardium, usually caused by an obstruction in the coronary arteries. The conventional therapy is based on the application of (a combination of) anti-thrombotics, reperfusion strategies to open the occluded artery, stents and bypass surgery. However, numerous patients cannot fully recover after these interventions. In this context, new therapeutic methods are explored. Three decades ago, the first biologicals were tested to improve cardiac regeneration. Angiogenic proteins gained popularity as potential therapeutics. This is not straightforward as proteins are delicate molecules that in order to have a reasonably long time of activity need to be stabilized and released in a controlled fashion requiring advanced delivery systems. To ensure long-term expression, DNA vectors-encoding for therapeutic proteins have been developed. Here, the nuclear membrane proved to be a formidable barrier for efficient expression. Moreover, the development of delivery systems that can ensure entry in the target cell, and also correct intracellular trafficking towards the nucleus are essential. The recent introduction of mRNA as a therapeutic entity has provided an attractive intermediate: prolonged but transient expression from a cytoplasmic site of action. However, protection of the sensitive mRNA and correct delivery within the cell remains a challenge. This review focuses on the application of synthetic delivery systems that target the myocardium to stimulate cardiac repair using proteins, DNA or RNA.
Expression of leukotriene B4 receptor 1 defines functionally distinct DCs that control allergic skin inflammation
Authors: Tomoaki Koga, Fumiyuki Sasaki, Kazuko Saeki, Soken Tsuchiya, Toshiaki Okuno, Mai Ohba, Takako Ichiki, Satoshi Iwamoto, Hirotsugu Uzawa, Keiko Kitajima, Chikara Meno, Eri Nakamura, Norihiro Tada, Yoshinori Fukui, Junichi Kikuta, Masaru Ishii, Yukihiko Sugimoto, Mitsuyoshi Nakao, Takehiko Yokomizo
Journal: Cellular and Molecular Immunology (2020)

Abstract Leukotriene B 4 (LTB 4 ) receptor 1 (BLT1) is a chemotactic G protein-coupled receptor expressed by leukocytes, such as granulocytes, macrophages, and activated T cells. Although there is growing evidence that BLT1 plays crucial roles in immune responses, its role in dendritic cells remains largely unknown. Here, we identified novel DC subsets defined by the expression of BLT1, namely, BLT1 hi and BLT1 lo DCs. We also found that BLT1 hi and BLT1 lo DCs differentially migrated toward LTB 4 and CCL21, a lymph node-homing chemoattractant, respectively. By generating LTB 4 -producing enzyme LTA 4 H knockout mice and CD11c promoter-driven Cre recombinase-expressing BLT1 conditional knockout (BLT1 cKO) mice, we showed that the migration of BLT1 hi DCs exacerbated allergic contact dermatitis. Comprehensive transcriptome analysis revealed that BLT1 hi DCs preferentially induced Th1 differentiation by upregulating IL-12p35 expression, whereas BLT1 lo DCs accelerated T cell proliferation by producing IL-2. Collectively, the data reveal an unexpected role for BLT1 as a novel DC subset marker and provide novel insights into the role of the LTB 4 -BLT1 axis in the spatiotemporal regulation of distinct DC subsets.
Overdose Education and Naloxone Distribution Expanded
Authors: Bridget M. Kuehn
Journal: JAMA (2020)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Multiplex analysis of coronavirus and influenza antibodies using the ZIVA multiplex platform
Authors: Jon Schmuke, Ben Miller, Linda Meeh, Byran Witherbee
Journal: Clinical Cancer Research (2020)

Detection of antibodies to upper respiratory pathogens is critical to surveillance, assessment of the immune status ofindividuals, vaccine development, and basic biology  The urgent need for antibody detection tools has provenparticularly acute in the COVID-19 era  We have used Arrayed Imaging Reflectometry (AIR™), a label-free proteinmicroarray technology that relies on the target binding-induced perturbation of an antireflective coating on thesurface of a silicon chip, to create a multiplex antibody detection array  ZIVA is a new multiplex protein detectionplatform that leverages AIR™ technology  We have used ZIVA technology to develop an acute respiratory viruspanel capable of detecting the presence of antibodies specific for coronavirus and influenza including, but not limitedto, detection of antibodies to SARS-CoV-2, SARS-CoV-1, MERS, three circulating coronavirus strains (HKU1, 229E, OC43), and multiple strains of influenza  We find that the array is readily able to distinguish uninfected fromconvalescent COVID-19 subjects and provides quantitative information about total IgG, as well as IgG- and IgM-specific responses  Samples may also be evaluated with ZIVA cytokine assays to monitor the cytokine storm inconjunction with viral antibody response
A Model Based on Noninvasive Markers Predicts Very Low Hepatocellular Carcinoma Risk After Viral Response in Hepatitis C Virus–Advanced Fibrosis
Authors: Sonia Alonso López, María Luisa Manzano, Francisco Gea, María Luisa Gutiérrez, Adriana Maria Ahumada, María José Devesa, Antonio Olveira, Benjamin Arturo Polo, Laura Márquez, Inmaculada Fernández, Juan Carlos Ruiz Cobo, Laura Rayón, Daniel Riado, Sonia Izquierdo, Clara Usón, Yolanda Real, Diego Rincón, Conrado M. Fernández‐Rodríguez, Rafael Bañares
Journal: Hepatology (2020)

Background and Aims Patients with hepatitis C virus (HCV) and advanced fibrosis remain at risk of hepatocellular carcinoma (HCC) after sustained viral response (SVR) and need lifelong surveillance. Because HCC risk is not homogenous and may decrease with fibrosis regression, we aimed to identify patients with low HCC risk based on the prediction of noninvasive markers and its changes after SVR. Approach and Results This is a multicenter cohort study, including patients with HCV and compensated advanced fibrosis that achieved SVR after direct antivirals. Clinical and transient elastography (TE) data were registered at baseline, 1 year, and 3 years after the end of treatment (EOT). All patients underwent liver ultrasound scan every 6 months. Patients with clinical evaluation 1 year after EOT were eligible. Univariate and multivariate Cox regression analysis were performed, and predictive models were constructed. HCC occurrence rates were evaluated by Kaplan‐Meier. Nine hundred and ninety‐three patients were eligible (56% male; 44% female; median age 62 years), 35 developed HCC (3.9%), and the median follow‐up was 45 months (range 13‐53). Baseline liver stiffness measurement (LSM) (HR 1.040; 95% CI 1.017‐1.064), serum albumin (HR 0.400; 95% CI 0.174‐0.923), 1‐year DeltaLSM (HR 0.993; 95% CI 0.987‐0.998), and 1‐year FIB‐4 score (HR 1.095; 95% CI 1.046‐1.146) were independent factors associated with HCC. The TE‐based HCC risk model predicted 0% of HCC occurrence at 3 years in patients with score 0 (baseline LSM ≤ 17.3 kPa, albumin &gt;4.2 g/dL, and 1‐year DeltaLSM &gt; 25.5%) versus 5.2% in patients with score 1‐3 (Harrell’s C 0.779; log‐rank 0.002). An alternative model with FIB‐4 similarly predicted HCC risk. Conclusions A combination of baseline and dynamic changes in noninvasive markers may help to identify patients with a very low risk of HCC development after SVR.
The effects of COVID-19 on new oral oncolytic treatments.
Authors: Rachel L. Mitchell, Edward Arrowsmith, Jack L. Taylor, Stephen Matthew Schleicher, Natalie R. Dickson, Stacey McCullough
Journal: Journal of Clinical Oncology (2020)

102 Background: Dependable and timely dispensing and delivery of oral oncolytics to patients with a new indication for therapy is a central part of modern cancer care. The COVID-19 pandemic has presented numerous impediments and challenges to patients receiving oral therapy from many specialty pharmacies in a timely due to remote pharmacy staffing and drug shipment. Tennessee Oncology has an integrated URAC and ACHC accredited Specialty Pharmacy to ensure the seamless care for our patients prescribed oral oncolytics. We investigated the effect of COVID-19 on the number of patients initiating care with an oral oncolytic and the time to fill during the pandemic. Methods: We analyzed the number of overall new patients to the practice and new patients receiving oral oncolytics in two year-to-year comparisons: (1) January-March 2019 vs. January-March 2020 and (2) April-May 2019 vs. April-May 2020. We then compared the average pharmacy turnaround time (defined as the time of entry of a regimen in the electronic medical record that contained an oral oncolytic until the time that prescription was ready for shipment) and the average time from regimen entry until the patient received that medication. Prescriptions received and filled on the day of order entry were recorded as a one-day turnaround time. Results: A year to year increase of 7% in practice new-patient volume was associated with a 13% increase in new oral oncolytic patients from January-March 2020. Year to year April and May comparisons, noted a 33% decrease in new-patient volume to our practice with an associated 10% decrease in new oral oncolytic patients. Time to fill remained consistent in March and April 2020 at 1.84 days vs. 1.78 for 2019. The time from regimen entry to patient shipment receipt was also stable year to year (3.10 vs. 3.06 days). Conclusions: Our in-house Specialty Pharmacy was able to continue delivery of new prescriptions for oral oncolytics during the COVID-19 pandemic. There was a fall in the number of new patient dispensing in April-May 2020 that we attribute to a decrease in cancer diagnoses related to COVID-19 as reflected by a fall in total practice new patients. New patient on-boarding activities including prior authorizations, co-pay assistance, patient education were maintained and the measured time to fill from regimen entry to patient receipt were unchanged.
Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial
Authors: James Welsh, Hari Menon, Dawei Chen, Vivek Verma, Chad Tang, Mehmet Altan, Kenneth Hess, Patricia de Groot, Quynh-Nhu Nguyen, Rejani Varghese, Nathan I Comeaux, George Simon, Ferdinandos Skoulidis, Joe Y Chang, Vasiliki Papdimitrakopoulou, Steven H Lin, John V Heymach
Journal: Journal for ImmunoTherapy of Cancer (2020)

In this phase I/II trial, we evaluated the safety and effectiveness of pembrolizumab, with or without concurrent radiotherapy (RT), for lung and liver lesions from metastatic non-small cell lung cancer (mNSCLC).Patients with lung or liver lesions amenable to RT plus at least one additional non-contiguous lesion were included regardless of programmed death-ligand 1 (PD-L1) status. Pembrolizumab was given at 200 mg every 3 weeks for up to 32 cycles with or without concurrent RT. Metastatic lesions were treated with stereotactic body RT (SBRT; 50 Gy in 4 fractions) if clinically feasible or with traditionally fractionated RT (45 Gy in 15 fractions) if not. The primary end point was the best out-of-field lesion response, and a key secondary end point was progression-free survival (PFS).The median follow-up time was 20.4 months. One hundred patients (20 phase I, 80 phase II) were evaluable for toxicity, and 72 phase II patients were evaluable for treatment response. No patients in the phase I group experienced grade 4-5 events; in the phase II group, two had grade 4 events and nine had grade 3 events. The ORR in the combined-modality cohort (irrespective of RT schema) was 22%, vs 25% in the pembrolizumab group (irrespective of receipt of salvage RT) (p=0.99). In the concurrent pembrolizumab+RT groups, the out-of-field ORRs were 38% in the pembrolizumab+SBRT group and 10% in the pembrolizumab+traditional RT group. When examining the pembrolizumab-alone patients, the out-of-field ORRs were 33% in those designated to receive salvage SBRT (if required) and 17% for salvage traditional RT. In all patients, the median PFS for pembrolizumab alone was 5.1 months (95% CI 3.4 to 12.7 months), and pembrolizumab/RT (regardless of schema) was 9.1 months (95% CI 3.6 to 18.4 months) (p=0.52). An exploratory analysis revealed that for patients with low PD-L1 expression, the median PFS was 4.6 vs 20.8 months for pembrolizumab with and without RT, respectively (p=0.004).Concurrent immunoradiotherapy for mNSCLC is safe, although larger trials are required to address which patients benefit most from RT.NCT02444741.
Mechanosensitive Control of Articular Cartilage and Subchondral Bone Homeostasis in Mice Requires Osteocytic Transforming Growth Factor β Signaling
Authors: Karsyn N. Bailey, Jeffrey Nguyen, Cristal S. Yee, Neha S. Dole, Alexis Dang, Tamara Alliston
Journal: Arthritis & Rheumatology (2020)

Objective Transforming growth factor β (TGFβ) signaling plays a complex tissue‐specific and nonlinear role in osteoarthritis (OA). This study was conducted to determine the osteocytic contributions of TGFβ signaling to OA. Methods To identify the role of osteocytic TGFβ signaling in joint homeostasis, we used 16‐week‐old male mice (n = 9–11 per group) and female mice (n = 7–11 per group) with an osteocyte‐intrinsic ablation of TGFβ receptor type II (TβRII ocy−/− mice) and assessed defects in cartilage degeneration, subchondral bone plate (SBP) thickness, and SBP sclerostin expression. To further investigate these mechanisms in 16‐week‐old male mice, we perturbed joint homeostasis by subjecting 8‐week‐old mice to medial meniscal/ligamentous injury (MLI), which preferentially disrupts the mechanical environment of the medial joint to induce OA. Results In all contexts, independent of sex, genotype, or medial or lateral joint compartment, increased SBP thickness and SBP sclerostin expression were spatially associated with cartilage degeneration. Male TβRII ocy−/− mice, but not female TβRII ocy−/− mice, had increased cartilage degeneration, increased SBP thickness, and higher levels of SBP sclerostin compared with control mice (all P &lt; 0.05), demonstrating that the role of osteocytic TGFβ signaling on joint homeostasis is sexually dimorphic. With changes in joint mechanics following injury, control mice had increased SBP thickness, subchondral bone volume, and SBP sclerostin expression (all P &lt; 0.05). TβRII ocy−/− mice, however, were insensitive to subchondral bone changes with injury, suggesting that mechanosensation at the SBP requires osteocytic TGFβ signaling. Conclusion Our results provide new evidence that osteocytic TGFβ signaling is required for a mechanosensitive response to injury, and that osteocytes control SBP homeostasis to maintain cartilage health, identifying osteocytic TGFβ signaling as a novel therapeutic target for OA.
Correction to: Prognostic impact of sustained new-onset atrial fibrillation in critically ill patients
Authors: Takuo Yoshida, Shigehiko Uchino, Yusuke Sasabuchi, Yasuhiro Hagiwara, Tomonao Yoshida, Hiroshi Nashiki, Hajime Suzuki, Hiroshi Takahashi, Yuki Kishihara, Shinya Nagasaki, Tomoya Okazaki, Shinshu Katayama, Masaaki Sakuraya, Takayuki Ogura, Satoki Inoue, Masatoshi Uchida, Yuka Osaki, Akira Kuriyama, Hiromasa Irie, Michihito Kyo, Nozomu Shima, Junichi Saito, Izumi Nakayama, Naruhiro Jingushi, Kei Nishiyama, Takahiro Masuda, Yasuyuki Tsujita, Masatoshi Okumura, Haruka Inoue, Yoshitaka Aoki, Takashiro Kondo, Isao Nagata, Takashi Igarashi, Nobuyuki Saito, Masato Nakasone
Journal: Intensive Care Medicine (2020)
Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib: Development and Validation of a Four-Factor Prognostic Model
Authors: Inhye E. Ahn, Xin Tian, David Ipe, Mei Cheng, Maher Albitar, L. Claire Tsao, Lei Zhang, Wanlong Ma, Sarah E. M. Herman, Erika M. Gaglione, Susan Soto, James P. Dean, Adrian Wiestner
Journal: Journal of Clinical Oncology (2020)

PURPOSE Randomized trials established the superiority of ibrutinib-based therapy over chemoimmunotherapy in chronic lymphocytic leukemia. Durability of progression-free survival (PFS) with ibrutinib can vary by patient subgroup. Clinical tools for prognostication and risk-stratification are needed. PATIENTS AND METHODS Patients treated with ibrutinib in phase II and III trials provided the discovery data set and were subdivided into discovery and internal validation cohorts. An external validation cohort included 84 patients enrolled in our investigator-initiated phase II trial. Univariable analysis of 18 pretreatment parameters was performed using PFS and overall survival (OS) end-points. Multivariable analysis and machine-learning algorithms identified four factors for a prognostic model that was validated in internal and external cohorts. RESULTS Factors independently associated with inferior PFS and OS were as follows: TP53 aberration, prior treatment, β-2 microglobulin ≥ 5 mg/L, and lactate dehydrogenase &gt; 250 U/L. Each of these four factors contributed one point to a prognostic model that stratified patients into three risk groups: three to four points, high risk; two points, intermediate risk; zero to one point, low risk. The 3-year PFS rates for all 804 patients combined were 47%, 74%, and 87% for the high-, the intermediate-, and the low-risk group, respectively ( P &lt; .0001). The 3-year OS rates were 63%, 83%, and 93%, respectively ( P &lt; .0001). The model remained significant when applied to treatment-naïve and relapsed/refractory cohorts individually. For 84 patients in the external cohort, BTK and PLCG2 mutations were tested cross-sectionally and at progression. The cumulative incidences of mutations were strongly correlated with the model. In the external cohort, Richter’s transformation occurred in 17% of the high-risk group, and in no patient in the low-risk group. CONCLUSION Patients at increased risk of ibrutinib failure can be identified at treatment initiation and considered for clinical trials.
Comparison of 99mTc-Tilmanocept and Hybrid Indocyanine Green–99mTc-Albumin Nanocolloid Drainage in a Patient With Melanoma in the Scalp
Authors: Raquel Valhondo-Rama, Nuria Sánchez Izquierdo, Andrés Tapias Mesa, Andrés Perissinotti, Sergi Vidal-Sicart
Journal: Clinical Nuclear Medicine (2020)

Abstract We present the planar lymphoscintigraphies and SPECT/CT images of a 60-year-old man diagnosed as having melanoma (Breslow 1.8 mm) in left parietal scalp, close to head midline. Sentinel lymph node biopsy using 99m Tc-tilmanocept was performed, but the surgery was canceled. Two weeks later, sentinel lymph node biopsy was repeated, but using the hybrid radiotracer indocyanine green– 99m Tc-albumin nanocolloid. The lymphatic drainage in left laterocervical region was similar with these 2 radiotracers, but on the right side, more sentinel lymph nodes were detected with nanocolloid compared with tilmanocept.
Impact of age on the toxicity of immune checkpoint inhibition
Authors: Amit Samani, Shuai Zhang, Laura Spiers, Ali Abdulnabi Suwaidan, Sophie Merrick, Zayd Tippu, Miranda Payne, Guy Faust, Sophie Papa, Paul Fields, Mieke Van Hemelrijck, Debra H Josephs
Journal: Journal for ImmunoTherapy of Cancer (2020)

Indications for immune checkpoint inhibitor therapy are increasing. As the population ages, many patients receiving such drugs will be older adults. Such patients are under-represented in clinical trials, and therefore the safety of immune checkpoint inhibitors in this population has not been adequately assessed. A retrospective multicenter analysis of toxicities was performed in patients with advanced or metastatic solid cancers receiving anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies across three age cohorts (<65 years, 65-74 years and ≥75 years) using univariable and multivariable analyzes. Eligible patients (n=448) were divided into age cohorts: <65 years (n=185), 65-74 years (n=154) and ≥75 years (n=109). Fewer patients in the oldest cohort (7.3%) received an anti-CTLA4 antibody containing regimen compared with the younger cohorts (21.1% and 17.5%). There was no significant difference overall in all grade or ≥G3 toxicities between age cohorts. Significantly fewer patients in the older (65-74 years and ≥75 years) age cohorts discontinued treatment because of toxicity (10.1% and 7.4%) compared with in the <65 years cohort (20.5%; p=0.006). Using logistic regression, only treatment type (ipilimumab containing) was significantly associated with all grade toxicity. However, there was a significantly lower incidence of all-grade endocrine toxicity in the oldest cohort (11.0%) compared with the youngest cohort (22.7%, p=0.02; OR 0.43, 95% CI 0.21 to 0.87), while all-grade dermatological toxicity showed the reverse trend (28.4% vs 18.9%; OR 1.85, 95% CI 1.04 to 3.30). Results were corroborated in the sensitivity analysis using only data from patients who received PD-1 inhibitor monotherapy. This multicenter, real-world cohort demonstrates that immune checkpoint inhibitor therapy is safe and well tolerated regardless of age, with no appreciable increase in adverse events in older adult patients.
Lymphatic immunomodulation using engineered drug delivery systems for cancer immunotherapy
Authors: Margaret P. Manspeaker, Susan N. Thomas
Journal: Advanced Drug Delivery Reviews (2020)

Though immunotherapy has revolutionized the treatment of cancer to improve disease outcomes, an array of challenges remain that limit wider clinical success, including low rate of response and immune-related adverse events. Targeting immunomodulatory drugs to therapeutically relevant tissues offers a way to overcome these challenges by potentially enabling enhanced therapeutic efficacy and decreased incidence of side effects. Research highlighting the importance of lymphatic tissues in the response to immunotherapy has increased interest in the application of engineered drug delivery systems (DDSs) to enable specific targeting of immunomodulators to lymphatic tissues and cells that they house. To this end, a variety of DDS platforms have been developed that enable more efficient uptake into lymphatic vessels and lymph nodes to provide targeted modulation of the immune response to cancer. This can occur either by delivery of immunotherapeutics to lymphatics tissues or by direct modulation of the lymphatic vasculature itself due to their direct involvement in tumor immune processes. This review will highlight DDS platforms that, by enabling the activities of cancer vaccines, chemotherapeutics, immune checkpoint blockade (ICB) antibodies, and anti- or pro-lymphangiogenic factors to lymphatic tissues through directed delivery and controlled release, augment cancer immunotherapy.