tbuckley/cabot-search huggingface dataset:
β2-adrenergic signals downregulate the innate immune response and reduce host resistance to viral infection
Authors: Elisabeth Wieduwild, Mathilde J. Girard-Madoux, Linda Quatrini, Caroline Laprie, Lionel Chasson, Rafaëlle Rossignol, Claire Bernat, Sophie Guia, Sophie Ugolini
Journal: The Journal of Experimental Medicine (2020)

In humans, psychological stress has been associated with a higher risk of infectious illness. However, the mechanisms by which the stress pathway interferes with host response to pathogens remain unclear. We demonstrate here a role for the β2-adrenergic receptor (β2-AR), which binds the stress mediators adrenaline and noradrenaline, in modulating host response to mouse cytomegalovirus (MCMV) infection. Mice treated with a β2-AR agonist were more susceptible to MCMV infection. By contrast, β2-AR deficiency resulted in a better clearance of the virus, less tissue damage, and greater resistance to MCMV. Mechanistically, we found a correlation between higher levels of IFN-γ production by liver natural killer (NK) cells and stronger resistance to MCMV. However, the control of NK cell IFN-γ production was not cell intrinsic, revealing a cell-extrinsic downregulation of the antiviral NK cell response by adrenergic neuroendocrine signals. This pathway reduces host immune defense, suggesting that the blockade of the β2-AR signaling could be used to increase resistance to infectious diseases.
Longitudinal 18F-FDG Images in Patients With Alzheimer Disease Over More Than 9 Years From a Preclinical Stage
Authors: Kenji Ishibashi, Airin Onishi, Kei Wagatsuma, Yoshinori Fujiwara, Kenji Ishii
Journal: Clinical Nuclear Medicine (2020)

Background Brain 18 F-FDG uptake reportedly starts to decline more than 10 years before the onset of cognitive decline in dominantly inherited Alzheimer disease (AD). We compared longitudinal 18 F-FDG images in sporadic AD to aging data from a large sample size to expand the current knowledge of 18 F-FDG reduction for AD progression. Methods Participants comprised 2 individuals (subjects A and B at ages 65 and 68 years, respectively) and 107 control subjects (67.9 [SD, 4.9] years). Subject A underwent 18 F-FDG PET a total of 8 times over 9 years from the preclinical to early dementia stages. Subject B underwent 18 F-FDG PET a total of 11 times over 12 years from the preclinical to mild cognitive impairment stages. Control subjects underwent 18 F-FDG PET twice over a mean follow-up period of 7.8 years. After placing the volume of interest on the AD-related hypometabolic regions, the longitudinal 18 F-FDG images were compared among the subjects and control subjects. Results For the control group, the rate of 18 F-FDG reduction was 2.2% per decade (ie, aging effects). The rates of 18 F-FDG reduction were 9.41% over 9 years and 9.07% over 12 years in subjects A and B, respectively. We estimated that 18 F-FDG uptake started to decrease 4 and 2 years before indications of memory loss in subjects A and B, respectively. Conclusions The present study suggests that the time between the beginning of 18 F-FDG reduction and the onset of cognitive decline may be shorter in elderly individuals with AD compared with the recently estimated period in dominantly inherited AD.
Dynamics of ACTH and Cortisol Secretion and Implications for Disease
Authors: Stafford L Lightman, Matthew T Birnie, Becky L Conway-Campbell
Journal: Endocrine Reviews (2020)

Abstract The past decade has seen several critical advances in our understanding of hypothalamic–pituitary–adrenal (HPA) axis regulation. Homeostatic physiological circuits need to integrate multiple internal and external stimuli and provide a dynamic output appropriate for the response parameters of their target tissues. The HPA axis is an example of such a homeostatic system. Recent studies have shown that circadian rhythmicity of the major output of this system—the adrenal glucocorticoid hormones corticosterone in rodent and predominately cortisol in man—comprises varying amplitude pulses that exist due to a subhypothalamic pulse generator. Oscillating endogenous glucocorticoid signals interact with regulatory systems within individual parts of the axis including the adrenal gland itself, where a regulatory network can further modify the pulsatile release of hormone. The HPA axis output is in the form of a dynamic oscillating glucocorticoid signal that needs to be decoded at the cellular level. If the pulsatile signal is abolished by the administration of a long-acting synthetic glucocorticoid, the resulting disruption in physiological regulation has the potential to negatively impact many glucocorticoid-dependent bodily systems. Even subtle alterations to the dynamics of the system, during chronic stress or certain disease states, can potentially result in changes in functional output of multiple cells and tissues throughout the body, altering metabolic processes, behavior, affective state, and cognitive function in susceptible individuals. The recent development of a novel chronotherapy, which can deliver both circadian and ultradian patterns, provides great promise for patients on glucocorticoid treatment.
Novel calreticulin-nanoparticle in combination with focused ultrasound induces immunogenic cell death in melanoma to enhance antitumor immunity
Authors: Sri Nandhini Sethuraman, Mohit Pratap Singh, Girish Patil, Shitao Li, Steven Fiering, P. Jack Hoopes, Chandan Guha, Jerry Malayer, Ashish Ranjan
Journal: Theranostics (2020)

Rationale: Some studies have shown that the local activation of immunogenic cell death (ICD) by upregulating calreticulin (CRT) expression in solid tumors can improve antitumor effects.Although a promising approach, a key current challenge in ICD tumor therapy is the absence of a clinically translatable method for reproducibly inducing the CRT expression.Herein, we report a novel calreticulin-nanoparticle (CRT-NP) that enhances ICD and synergizes with focused ultrasound (FUS) to achieve local and systemic antitumor effects.Methods: Full-length clone DNA of calreticulin was encapsulated in NPs made from DOTAP and cholesterol.Three CRT-NP intratumoral injections of 20 µg each were given 2 days apart, and FUS heating (42-45°C, ~15min) was applied sequentially 24h after each injection to induce ICD.To investigate ICD specific immune effect, the splenocytes of mice vaccinated with CRT-NP (± FUS) treated B16F10 cells were evaluated ex-vivo for TRP-2 antigen specific immunity.Additionally, the long-term protection was evaluated by re-challenging with the melanoma cells in the flank regions of tumor bearing mice.Results: CRT-NP plus FUS (CFUS) upregulated CRT expression, expanded the population of melanoma TRP-2 specific functional CD4+ and CD8+ T cells and tumor-suppressing M1 phenotype, and increased PD-1 and PD-L1 marker expression in the T cells.Therapeutically, CFUS suppressed B16 melanoma growth by >85% vs. that seen in untreated controls, and >~50% vs. CRT-NP or FUS alone, and prevented tumor growth in distal untreated sites.Conclusions: CRT-NP amplifies the FUS and ICD therapeutic outcomes against melanoma, suggesting that the proposed combinatorial methodology may be clinically translatable.
Extracorporeal membrane oxygenation for refractory cardiac arrest: a retrospective multicenter study
Authors: Dirk Lunz, Lorenzo Calabrò, Mirko Belliato, Enrico Contri, Lars Mikael Broman, Anna Maria Scandroglio, Daniel Patricio, Maximilian Malfertheiner, Jacques Creteur, Alois Philipp, Fabio Silvio Taccone, Federico Pappalardo
Journal: Intensive Care Medicine (2020)
The impact of patient sex on the response to intramyocardial mesenchymal stem cell administration in patients with non-ischaemic dilated cardiomyopathy
Authors: Victoria Florea, Angela C Rieger, Makoto Natsumeda, Bryon A Tompkins, Monisha N Banerjee, Ivonne H Schulman, Courtney Premer, Aisha Khan, Krystalenia Valasaki, Bettina Heidecker, Alejandro Mantero, Wayne Balkan, Raul D Mitrani, Joshua M Hare
Journal: Cardiovascular Research (2020)

Abstract Aims Sex differences impact the occurrence, presentation, prognosis, and response to therapy in heart disease. Particularly, the phenotypic presentation of patients with non-ischaemic dilated cardiomyopathy (NIDCM) differs between men and women. However, whether the response to mesenchymal stem cell (MSC) therapy is influenced by sex remains unknown. We hypothesize that males and females with NIDCM respond similarly to MSC therapy. Methods and results Male (n = 24) and female (n = 10) patients from the POSEIDON-DCM trial who received MSCs via transendocardial injections were evaluated over 12 months. Endothelial function was measured at baseline and 3 months post-transendocardial stem cell injection (TESI). At baseline, ejection fraction (EF) was lower (P = 0.004) and end-diastolic volume (EDV; P = 0.0002) and end-systolic volume (ESV; P = 0.0002) were higher in males vs. females. In contrast, baseline demographic characteristics, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-min walk test (6MWT) were similar between groups. EF improved in males by 6.2 units (P = 0.04) and in females by 8.6 units (P = 0.04; males vs. females, P = 0.57). EDV and ESV were unchanged over time. The MLHFQ score, New York Heart Association (NYHA) class, endothelial progenitor cell-colony forming units, and serum tumour necrosis factor alpha improved similarly in both groups. Conclusion Despite major differences in phenotypic presentation of NIDCM in males and females, this study is the first of its kind to demonstrate that MSC therapy improves a variety of parameters in NIDCM irrespective of patient sex. These findings have important clinical and pathophysiologic implications regarding the impact of sex on responses to cell-based therapy for NIDCM.
What diagnostic strategies can help differentiate cellulitis from other causes of red legs in primary care?
Authors: George Edwards, Karoline Freeman, Martin J Llewelyn, Gail Hayward
Journal: BMJ (2020)

### What you need to know

Cellulitis is the most common bacterial infection causing red legs. It is treated with antibiotics, and patients with severe disease may need to be hospitalised.1234 In 2017-18, 317 522 patients were given a diagnosis of cellulitis in UK hospitals.5 The true incidence, including patients managed through primary care, is likely to be higher.

Redness is often accompanied by other classic signs of inflammation: tenderness, warmth, and swelling. Other causes of red legs can present with some, or all, of these common symptoms6 (table 1). These conditions may be misdiagnosed as cellulitis. Studies in US emergency departments have reported that between 28% and 30.7%789 of cellulitis diagnoses are incorrect. Misdiagnosis can result in unnecessary antibiotic treatment10 and hospitalisation. Conversely, untreated cellulitis can have complications such as extensive tissue damage and necrosis, disseminated infection, septic shock, and potentially death.11Figures 1 and 2 show alternative diagnoses for red legs.

View this table:

Table 1 
Distinguishing cellulitis from other causes of red legs. Major alternatives to consider and diagnostic considerations, adapted from clinical guidelines124





Fig 1 
Alternative diagnoses of red legs: (a) cellulitis, (b) varicose eczema, (c) deep vein thrombosis, (d) gout





Fig 2 
Concurrent cellulitis and deep vein thrombosis. The manifestation of skin diseases can vary between ethnic groups and skin colours



Differentiating red legs …
Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein
Authors: Shuai Xia, Yun Zhu, Meiqin Liu, Qiaoshuai Lan, Wei Xu, Yanling Wu, Tianlei Ying, Shuwen Liu, Zhengli Shi, Shibo Jiang, Lu Lu
Journal: Cellular and Molecular Immunology (2020)
Detection of Lymph Node Metastases by Ultra-pH-Sensitive Polymeric Nanoparticles
Authors: Zachary T. Bennett, Qiang Feng, Justin A. Bishop, Gang Huang, Baran D. Sumer, Jinming Gao
Journal: Theranostics (2020)

Lymph node (LN) dissection followed by histological analysis is the current standard for diagnosis of LN metastasis but the method suffers from patient morbidity and low sensitivity of detection.Ultra-pH sensitive (UPS) nanoparticles show remarkable accuracy in the delineation of primary tumor margins for precision cancer surgery.Herein we investigate the effectiveness of UPS nanoparticles to detect cancer-involved LNs.Methods: We synthesized a series of indocyanine green (ICG) conjugated UPS nanoparticles with distinct pK a (UPS 5.3 , UPS 6.1 , and UPS 6.9 ).Systemically administered UPS-ICG nanoparticles in the 4T1.2-BALB/cj mouse model were imaged with real-time, near-infrared fluorescence (NIRF) to guide removal of LNs.Ex vivo imaging of gross tissue enabled quantification of fluorescence intensity.Histological analysis was used as the gold standard diagnostic test.Results: Macrophage uptake of UPS nanoparticles elevates the background signal in benign LNs.However, cancer foci within LNs show distinctive clustering of UPS-ICG fluorescence.UPS 5.3 achieves accurate detection of metastatic LNs as shown by a receiver operating characteristic (ROC) area under the curve (AUC) of 0.96 ± 0.03.UPS 6.1 and UPS 6.9 offer decreased discriminatory power at ROC AUC of 0.73 ± 0.1 and 0.88 ± 0.07, respectively.Conclusions: All UPS compositions show cancer-specific discrimination of metastatic LNs over benign LNs with the best outcomes from UPS 5.3 .Detection of micro-metastatic LNs (cancer foci < 2 mm) remains a challenge.This study provides information on the detection of LN status for image-guided resection of metastatic LNs.
Characterization of duvelisib in patients with refractory marginal zone lymphoma : data from the phase 2 DYNAMO trial
Authors: Eric Jacobsen, Juraj Ura, Kirit Ardeshna, Mohamad Cherry, Fritz Offner, Jiri Mayer, Fontanet Bijou, Monica Tani, Gerardo Musuraca, Michele Merli, Roberto Marasca, David T Weaver, Stephanie Lustgarten, Hagop Youssoufian, Pier Luigi Zinzani
Journal: American Journal of Hematology (2019)
An EPR Strategy for Bio-responsive Fluorescence Guided Surgery with Simulation of the Benefit for Imaging
Authors: Harrison C. Daly, Emer Conroy, Mihai Todor, Dan Wu, William M. Gallagher, Donal F. O'Shea
Journal: Theranostics (2020)

A successful matching of a PEG group size with the EPR effect for an off-to-on responsive NIR-fluorophore conjugate has been accomplished which allows two distinct in vivo tumor imaging periods, the first being the switch on during the initial tumor uptake via enhanced permeability into the ROI (as background is suppressed) and a second, later, due to enhanced retention within the tumor.Methods: Software simulation (https://mihaitodor.github.io/particle_simulation/index.html),synthetic chemistry, with in vitro and in vivo imaging have been synergistically employed to identify an optimal PEG conjugate of a bio-responsive NIR-AZA fluorophore for in vivo tumor imaging.Results: A bio-responsive NIR-AZA fluorophore conjugated to a 10 kDa PEG group has shown excellent in vivo imaging performance with sustained high tumor to background ratios and peak tumor emission within 24 h.Analysis of fluorescence profiles over 7 days has provided evidence for the EPR effect playing a positive role.Conclusion: Preclinical results show that exploiting the EPR effect by utilizing an optimized PEG substituent on a bio-responsive fluorophore may offer a means for intraoperative tumor margin delineation.The off-to-on responsive nature of the fluorophore makes tumor imaging achievable without waiting for clearance from normal tissue.
Journey of a Thai Taxi Driver and Novel Coronavirus
Authors: Wannarat A. Pongpirul, Krit Pongpirul, Anuttra C. Ratnarathon, Wisit Prasithsirikul
Journal: New England Journal of Medicine (2020)

A Thai Taxi Driver with Covid-19 The authors describe a taxi driver in Thailand who was infected with the novel coronavirus, potentially from passengers who were tourists from China, in January 202...
Posttherapeutic Critical Organ Dosimetry of Extensive 177Lu-PSMA Inhibitor Therapy With Metastatic Castration-Resistant Prostate Cancer
Authors: Ahu Özkan, Burcu Uçar, Hülya Seymen, Yasemin Yildiz Yarar, Fikri Okan Falay, Mehmet Onur Demirkol
Journal: Clinical Nuclear Medicine (2020)

Purpose 177 Lu-PSMA inhibitor peptide receptor radioligand therapy (RLT) is playing an increasing role in metastatic castration-resistant prostate cancer. We aimed to estimate the absorbed radiation doses for critical organs (eg, kidneys, parotid glands, submandibular glands, and lacrimal glands) of patients treated with 4 to 6 cycles by 177 Lu-PSMA inhibitor RLT, retrospectively, and to evaluate the findings extensively in order to determine the critical organ radiation-absorbed limitations and the number of prospective RLT. Materials and Methods A total of 51 cycles 177 Lu-PSMA inhibitor RLT in 10 patients was analyzed. Therapies have been applied in 4 to 6 cycles with 8 to 10 weeks' intervals. Dosimetric estimates of kidneys, parotid glands, submandibular glands, and lacrimal glands have been calculated based on MIRD scheme pamphlet no. 16. Regions of interest were drawn with GE Xeleris Functional Imaging Workstation. OLINDA/EXM 1.1 simulation software was used to calculate radiation-absorbed doses. Results Mean radiation-absorbed doses were 0.70 ± 0.24 Gy/GBq for kidneys, 1.34 ± 0.78 Gy/GBq for parotid glands, 0.94 ± 0.45 Gy/GBq for submandibular glands, and 2.28 ± 1.29 Gy/GBq for lacrimal glands. Conclusions Due to the critical target organ risks and the optimal therapy doses, patient-specific dosimetry is a deterministic factor in radionuclide therapy. Even when the absorbed kidney doses were above the ICRP critical dose limits in patients who had 4 to 6 cycles of therapy, mortality due to nephrotoxicity has not been observed. Mild increased tolerated radiation dose is acceptable for the patient groups with very low survival rate.
Abstract ES1-3: Assessment of PD-L1 in Breast Cancer to Predict Response to Immunotherapy
Authors: DL Rimm
Journal: Cancer Research (2020)

Abstract Many tumors showed promise in phase one trials of immunotherapy, but breast cancer was not high on the list. Since then, focus in breast cancer has shifted to Triple Negative Breast Cancer (TNBC) which has shown promise in both the metastatic and neo-adjuvant setting. This presentation will provide a history of the PD-L1 assay to select response to therapy in lung cancer where it was most successful and then discuss its transition to breast cancer. In TNBC, there are successful trials and even FDA approval, but there is also deep concerns related to the IHC-based patient selection assay. This presentation will discuss the breast cancer PD-L1 assay(s) and the controversy surrounding its implementation. Citation Format: DL Rimm. Assessment of PD-L1 in Breast Cancer to Predict Response to Immunotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES1-3.
Rheumatic disorders associated with immune checkpoint inhibitors: what about myositis? An analysis of the WHO’s adverse drug reactions database
Authors: Thủy Nguyễn, Alexandre Thibault Jacques Maria, Chayma Ladhari, Pascale Palassin, Xavier Quantin, Candice Lesage, Guillaume Taïeb, Xavier Ayrignac, Patricia Rullier, Dominique Hillaire-Buys, Olivier Lambotte, Philippe Guilpain, Jean-Luc Faillie
Journal: Annals of the Rheumatic Diseases (2020)

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A prognostic model to personalize monitoring regimes for patients with incidental asymptomatic meningiomas
Authors: Abdurrahman I Islim, Ruwanthi Kolamunnage-Dona, Midhun Mohan, Richard D C Moon, Anna Crofton, Brian J Haylock, Nitika Rathi, Andrew R Brodbelt, Samantha J Mills, Michael D Jenkinson
Journal: Neuro-Oncology (2019)

Abstract Background Asymptomatic meningioma is a common incidental finding with no consensus on the optimal management strategy. We aimed to develop a prognostic model to guide personalized monitoring of incidental meningioma patients. Methods A prognostic model of disease progression was developed in a retrospective cohort (2007–2015), defined as: symptom development, meningioma-specific mortality, meningioma growth or loss of window of curability. Secondary endpoints included non-meningioma-specific mortality and intervention. Results Included were 441 patients (459 meningiomas). Over a median of 55 months (interquartile range, 37–80), 44 patients had meningioma progression and 57 died (non-meningioma-specific). Forty-four had intervention (at presentation, n = 6; progression, n = 20; nonprogression, n = 18). Model parameters were based on statistical and clinical considerations and included: increasing meningioma volume (hazard ratio [HR] 2.17; 95% CI: 1.53–3.09), meningioma hyperintensity (HR 10.6; 95% CI: 5.39–21.0), peritumoral signal change (HR 1.58; 95% CI: 0.65–3.85), and proximity to critical neurovascular structures (HR 1.38; 95% CI: 0.74–2.56). Patients were stratified based on these imaging parameters into low-, medium- and high-risk groups and 5-year disease progression rates were 3%, 28%, and 75%, respectively. After 5 years of follow-up, the risk of disease progression plateaued in all groups. Patients with an age-adjusted Charlson comorbidity index ≥6 (eg, an 80-year-old with chronic kidney disease) were 15 times more likely to die of other causes than to receive intervention at 5 years following diagnosis, regardless of risk group. Conclusions The model shows that there is little benefit to rigorous monitoring in low-risk and older patients with comorbidities. Risk-stratified follow-up has the potential to reduce patient anxiety and associated health care costs.
International consensus guideline for reporting transmission electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria)
Authors: Amelia Shoemark, Mieke Boon, Christoph Brochhausen, Zuzanna Bukowy-Bieryllo, Maria M. De Santi, Patricia Goggin, Paul Griffin, Richard G. Hegele, Robert A. Hirst, Margaret W. Leigh, Alison Lupton, Karen MacKenney, Heymut Omran, Jean-Claude Pache, Andreia Pinto, Finn P. Reinholt, Josep Schroeder, Panayotis Yiallouros, Estelle Escudier
Journal: European Respiratory Journal (2020)

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic condition. European and North American diagnostic guidelines recommend transmission electron microscopy (TEM) as one of a combination of tests to confirm a diagnosis. However, there is no definition of what constitutes a defect or consensus on reporting terminology. The aim of this project was to provide an internationally agreed ultrastructural classification for PCD diagnosis by TEM. A consensus guideline was developed by PCD electron microscopy experts representing 18 centres in 14 countries. An initial meeting and discussion were followed by a Delphi consensus process. The agreed guideline was then tested, modified and retested through exchange of samples and electron micrographs between the 18 diagnostic centres. The final guideline a) provides agreed terminology and a definition of Class 1 defects which are diagnostic for PCD; b) identifies Class 2 defects which can indicate a diagnosis of PCD in combination with other supporting evidence; c) describes features which should be included in a ciliary ultrastructure report to assist multidisciplinary diagnosis of PCD; and d) defines adequacy of a diagnostic sample. This tested and externally validated statement provides a clear guideline for the diagnosis of PCD by TEM which can be used to standardise diagnosis internationally.