tbuckley/cabot-search huggingface dataset:
Abstract 10847: Circadian Variation of In-Hospital and Out-of-Hospital Sudden Cardiac Arrest
Authors: Yicheng Tang, Tarryn Tertulien, Samir Saba
Journal: Circulation (2021)

Introduction: Several studies have reported circadian periodicity of sudden cardiac arrest (SCA), most commonly a nadir in event frequency during overnight hours. It remains unclear to what extent this circadian pattern is influenced by variation in patients’ physical activities. One way to elucidate this is to compare patients with out-of-hospital (OHCA) versus in-hospital (IHCA) cardiac arrests, which has not been previously done. We hypothesize that the circadian pattern of SCA will be preserved in a mixed contemporary cohort of OHCA and IHCA survivors. Methods: A total of 1,433 consecutive survivors of SCA in the Pittsburgh area from 2002 to 2012 were included. Patient demographics including clinical histories and details of SCA were collected using records from emergency medical services and rapid response teams. Unwitnessed SCA and those with potential non-cardiac confounders were excluded. The distribution of SCA throughout the day and associated patient characteristics were tested for differences using chi-square test and student’s t-test. Results: Of the 1,224 patients analyzed, 706 had IHCA and 518 OHCA. We observed a nadir of SCA in the nighttime hours between 0000 - 0600 in both IHCA and OHCA groups (p&lt;0.001). Patients who arrested in this nighttime window had more co-morbidities (p=0.01) and lower percent of angiographically confirmed acute myocardial infarction (p=0.025). A similar circadian pattern was noted for patients with higher or lower comorbidity burden (p&lt;0.001), although more blunted in sicker patients, as well as for patients whose arrest was due to a shockable rhythm (p&lt;0.001). Correspondingly, the IHCA group had higher co-morbidity burden (p&lt;0.001) and a blunted nighttime nadir compared to the OHCA group (p&lt;0.001). We did not observe a temporal variation by day of week but did see a seasonal pattern with a peak in SCA in the Pittsburgh cold months (p&lt;0.001). Conclusion: The typical pattern of nighttime nadir in SCA is seen in both OHCA and IHCA but is more blunted in sicker patients and in the hospital. This suggests a common mechanism that transcends differences between the two settings but may be influenced by non-cardiac comorbidities or environmental factors such as activity level.
Milk-derived exosomes exhibit versatile effects for improved oral drug delivery
Authors: Lei Wu, Lingling Wang, Xi Liu, Yuli Bai, Ruinan Wu, Xiang Li, Yutong Mao, Ling Zhang, Yongxiang Zheng, Tao Gong, Zhirong Zhang, Yuan Huang
Journal: Acta Pharmaceutica Sinica B (2021)

As endogenous courier vesicles, exosomes play crucial roles in macromolecule transmission and intercellular communication. Therefore, exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years. However, few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration. Additionally, the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown. Herein, insulin-loaded milk-derived exosomes (EXO@INS) were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats. Surprisingly, EXO@INS (50 and 30 IU/kg) elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin. Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake, pH adaptation during gastrointestinal transit, nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration. This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration.
Myeloid Ikaros–SIRT1 signaling axis regulates hepatic inflammation and pyroptosis in ischemia-stressed mouse and human liver
Authors: Kentaro Kadono, Shoichi Kageyama, Kojiro Nakamura, Hirofumi Hirao, Takahiro Ito, Hidenobu Kojima, Kenneth J. Dery, Xiaoling Li, Jerzy W. Kupiec-Weglinski
Journal: Journal of Hepatology (2021)

Although Ikaros (IKZF1) is a well-established transcriptional regulator in leukocyte lymphopoiesis and differentiation, its role in myeloid innate immune responses remains unclear. Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. Whether SIRT1 signaling is essential in myeloid cell activation remains uncertain, while the molecular communication between Ikaros and SIRT1, two major transcriptional regulators, has not been studied.We undertook molecular and functional studies to interrogate the significance of the myeloid Ikaros-SIRT1 axis in innate immune activation and whether it may serve as a homeostatic sentinel in human liver transplant recipients (hepatic biopsies) and murine models of sterile hepatic inflammation (liver warm ischemia-reperfusion injury in wild-type, myeloid-specific Sirt1-knockout, and CD11b-DTR mice) as well as primary bone marrow-derived macrophage (BMM) cultures (Ikaros silencing vs. overexpression).In our clinical study, we identified increased post-reperfusion hepatic Ikaros levels, accompanied by augmented inflammasome signaling yet depressed SIRT1, as a mechanism of hepatocellular damage in liver transplant recipients. In our experimental studies, we identified infiltrating macrophages as the major source of Ikaros in IR-stressed mouse livers. Then, we demonstrated that Ikaros-regulated pyroptosis - induced by canonical inflammasome signaling in BMM cultures - was SIRT1 dependent. Consistent with the latter, myeloid-specific Ikaros signaling augmented hepatic pyroptosis to aggravate pro-inflammatory responses in vivo by negatively regulating SIRT1 in an AMPK-dependent manner. Finally, myeloid-specific SIRT1 was required to suppress pyroptosis, pro-inflammatory phenotype, and ultimately mitigate hepatocellular injury in ischemia-stressed murine livers.These findings identify the Ikaros-SIRT1 axis as a novel mechanistic biomarker of pyroptosis and a putative checkpoint regulator of homeostasis in response to acute hepatic stress/injury in mouse and human livers.This report describes how crosstalk between Ikaros and SIRT1, two major transcriptional regulators, influence acute hepatic inflammation in murine models of liver ischemia-reperfusion injury and liver transplant recipients. We show that the myeloid Ikaros-SIRT1 axis regulates inflammasome-pyroptotic cell death and hepatocellular damage in stressed livers. Thus, the Ikaros-SIRT1 axis may serve as a novel checkpoint regulator that is required for homeostasis in response to acute liver injury in mice and humans.
Chronic pancreatitis: about some complications and features of their pathogenesis and course
Authors: T.N. Hristich, D.O. Hontsariuk
Journal: GASTROENTEROLOGY (2021)

The review article provides up-to-date information on the complications of pancreatitis that are important for the tactics and strategy of patient management both at the inpatient and outpatient stages of observation. The purpose of the review was to emphasize the importance of complications for the course and life of patients with chronic pancreatitis. The authors draw the attention of internists to the course of such complications as pseudocysts, cysts, fistulas, thrombohemorrhagic, cholestatic syndromes, compression syndrome of adjacent organs, pancreatic encephalopathy (acute and chronic). The symptomatology of complications of chronic pancreatitis is discussed in detail, which is very important for differential diagnosis with the corresponding diseases. Such complications include the formation of erosive and ulcerative lesions, varicose veins of the esophagus and bleeding from varicose veins of the esophagus and stomach, portal hypertension syndrome with pancreatic ascites and chronic pancreatic encephalopathy, idiopathic non-cirrhotic portal hypertension, pancreatic cancer. The authors emphasize the need to analyze the corresponding symptoms, indicating the possibility of complications, negative consequences with each recurrence or exacerbation of chronic pancreatitis, since it concerns the prognosis and life of the patient.
Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis
Authors: Steven M. Kawut, Michael J. Krowka, Kimberly A. Forde, Nadine Al-Naamani, Karen L. Krok, Mamta Patel, Carlo R. Bartoli, Margaret Doyle, Jude Moutchia, Grace Lin, Jae K. Oh, Carl D. Mottram, Paul D. Scanlon, Michael B. Fallon
Journal: European Respiratory Journal (2021)

Background Hepatopulmonary syndrome affects 10–30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation. Methods The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar–arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age &gt;64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease. Results We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12–19) versus 14 (10–17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03–3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02–3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome. Conclusion Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.
Atezolizumab Treatment of Tumors with High Tumor Mutational Burden from MyPathway, a Multicenter, Open-Label, Phase IIa Multiple Basket Study
Authors: Claire F. Friedman, John D. Hainsworth, Razelle Kurzrock, David R. Spigel, Howard A. Burris, Christopher J. Sweeney, Funda Meric-Bernstam, Yong Wang, Jonathan Levy, Jessica Grindheim, David S. Shames, Katja Schulze, Arisha Patel, Charles Swanton
Journal: Cancer Discovery (2021)

Abstract High tumor mutational burden (TMB-H) correlates with improved immunotherapy response. We assessed atezolizumab 1,200 mg every 3 weeks for TMB-H tumors from MyPathway (NCT02091141), a phase IIa multibasket study. One hundred twenty-one patients had advanced solid tumors with TMB ≥10 mut/Mb by any Clinical Laboratory Improvement Amendments (CLIA)–certified assay. The preplanned primary endpoint was objective response rate (ORR) in patients with TMB ≥16 mut/Mb tumors by FoundationOne TMB testing [F1(CDx)]. Patients with F1(CDx) TMB ≥10 and &amp;lt;16 mut/Mb were also evaluated. Ninety patients with 19 tumor types and F1(CDx) TMB ≥10 mut/Mb were efficacy evaluable. In 42 patients with F1(CDx) TMB ≥16 mut/Mb, confirmed ORR was 38.1% [16/42; 95% confidence interval (CI), 23.6–54.4], and disease control rate was 61.9% (26/42; 95% CI, 45.6–76.4) versus 2.1% (1/48; 95% CI, 0.1–11.1) and 22.9% (11/48; 95% CI, 12.0–37.3) for 48 patients with TMB ≥10 and &amp;lt;16 mut/Mb. Responses were observed in nine different tumor types (47%; 9/19). Significance: Atezolizumab monotherapy had promising, durable clinical activity across a variety of advanced solid tumor types in patients with TMB ≥16 mut/Mb tumors lacking other suitable treatment options and who were immunotherapy-naïve at enrollment, regardless of microsatellite instability status. Limited activity was observed in tumors with TMB ≥10 and &amp;lt;16 mut/Mb. See related commentary by Maron and Klempner, p. 602. This article is highlighted in the In This Issue feature, p. 587
Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma
Authors: Ann-Lii Cheng, Shukui Qin, Masafumi Ikeda, Peter R. Galle, Michel Ducreux, Tae-You Kim, Ho Yeong Lim, Masatoshi Kudo, Valeriy Breder, Philippe Merle, Ahmed O. Kaseb, Daneng Li, Wendy Verret, Ning Ma, Alan Nicholas, Yifan Wang, Lindong Li, Andrew X. Zhu, Richard S. Finn
Journal: Journal of Hepatology (2021)

IMbrave150 demonstrated that atezolizumab plus bevacizumab led to significantly improved overall survival (OS) and progression-free survival (PFS) compared with sorafenib in patients with unresectable hepatocellular carcinoma at the primary analysis (after a median 8.6 months of follow-up). We present updated data after 12 months of additional follow-up.Patients with systemic treatment-naive, unresectable hepatocellular carcinoma were randomized 2:1 to receive 1,200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks or 400 mg sorafenib orally twice daily in this open-label, phase III study. Co-primary endpoints were OS and PFS by independently assessed RECIST 1.1 in the intention-to-treat population. Secondary efficacy endpoints included objective response rates and exploratory subgroup efficacy analyses. This is a post hoc updated analysis of efficacy and safety.From March 15, 2018, to January 30, 2019, 501 patients (intention-to-treat population) were randomly allocated to receive atezolizumab plus bevacizumab (n = 336) or sorafenib (n = 165). On August 31, 2020, after a median 15.6 (range, 0-28.6) months of follow-up, the median OS was 19.2 months (95% CI 17.0-23.7) with atezolizumab plus bevacizumab and 13.4 months (95% CI 11.4-16.9) with sorafenib (hazard ratio [HR] 0.66; 95% CI 0.52-0.85; descriptive p <0.001). The median PFS was 6.9 (95% CI 5.7-8.6) and 4.3 (95% CI 4.0-5.6) months in the respective treatment groups (HR 0.65; 95% CI 0.53-0.81; descriptive p < 0.001). Treatment-related grade 3/4 adverse events occurred in 143 (43%) of 329 and 72 (46%) of 156 safety-evaluable patients in the respective groups, and treatment-related grade 5 events occurred in 6 (2%) and 1 (<1%) patients.After longer follow-up, atezolizumab plus bevacizumab maintained clinically meaningful survival benefits over sorafenib and had a safety profile consistent with the primary analysis.NCT03434379.The primary analysis of IMbrave150 showed that atezolizumab plus bevacizumab had significantly greater benefits than sorafenib in patients with advanced hepatocellular carcinoma, but survival data were not yet mature. At this updated analysis done 12 months later, median overall survival was 5.8 months longer with atezolizumab plus bevacizumab than sorafenib, and the severity profile of treatment-related side effects remained similar. These updated results confirm atezolizumab plus bevacizumab as the first-line standard of care for advanced hepatocellular carcinoma.
169TiP Tocilizumab, ipilimumab, and nivolumab for the treatment of advanced melanoma, non-small cell lung cancer, or urothelial carcinoma
Authors: A. Diab, N. Abdel-Wahab, S.E. Bentebibel, E.J. Montazari, C.A. Spillson, S. Ekmekcioglu, J. Gao, M. Altan
Journal: Annals of Oncology (2021)
COCu: A Robust Self‐Regenerative Hydrogel with Applicability as Both Hydrated Gel Dressing and Dry Suture for Seamless Tissue Fixation and Repair
Authors: Tian Hu, Chuncheung Chan, Min‐Zhao Lin, Huaitian Bu, Bin Liu, Gang‐Biao Jiang
Journal: Advanced Healthcare Materials (2021)

Self-regenerative hydrogels have recently been developed, and represent a special type of self-healing hydrogels with the ability to restore a dehydrated hydrogel with physical damage. In this study, a self-regenerative hydrogel (COCu) based on two chitosan polymers assembled by slow-released Cu2+ is developed. The COCu hydrogel displays an excellent regeneration ability after being dehydrated and fractured. By simple hydration at room temperature, the fragments of the dehydrated gel fuse into one seamless whole, thereby preserving the mechanical properties and functionalities of the original hydrogel. The regeneration process can be conducted repeatedly after different methods of dehydration (natural volatilization, heat drying, lyophilization) and various modes of deconstruction (flakes, powder, lumpy sponge, etc.). Furthermore, the COCu hydrogel provides ultra-stretchability, and it can be stretched into thin (0.01-0.1 mm) filaments, which, when dried (dtCOCu), can be used as suture lines. Moreover, when used as a dry suture, it regenerates into the hydrogel in the presence of the tissue fluid, forming an excellent sealant to immobilize tissues and seamlessly seal wounds. The fast self-regeneration allows for its facile application as both a hydrated gel dressing and dry suture, and offers customized strategies for fixing and repair of different wounds in soft tissues.
Estimation of radiation-induced health hazards from a “dirty bomb” attack with radiocesium under different assault and rescue conditions
Authors: Alexis Rump, Stefan Eder, Cornelius Hermann, Andreas Lamkowski, Patrick Ostheim, Michael Abend, Matthias Port
Journal: Military Medical Research (2021)

In the case of a terrorist attack by a "dirty bomb", blast injuries, external irradiation and the incorporation of radioactivity are to be expected. Departing from information about the radiological attack scenario with cesium-137 in the U.S. National Scenario Planning Guide, we estimated the radiological doses absorbed. Similar calculations were performed for a smaller plume size and a detonation in a subway. For conditions as described in the U.S. scenario, the committed effective dose amounted to a maximum of 848 mSv, even for very unfavorable conditions. Red bone marrow equivalent doses are insufficient to induce acute radiation sickness (ARS). In the case of a smaller plume size, the ARS threshold may be exceeded in some cases. In a subway bombing, doses are much higher and the occurrence of ARS should be expected. The health hazards from a dirty bomb attack will depend on the location and the explosive device. The derived Haddon matrix indicates that preparing for such an event includes education of all the medical staff about radiation effects, the time lines of radiation damages and the treatment priorities. Further determinants of the outcome include rapid evacuation even from difficult locations, the availability of a specific triage tool to rapidly identify victims at risk for ARS, the availability of an antidote stockpile and dedicated hospital beds to treat seriously irradiated victims.
Stimuli-responsive nano vehicle enhances cancer immunotherapy by coordinating mitochondria-targeted immunogenic cell death and PD-L1 blockade
Authors: Qiuyi Li, Cheng Chen, Jinxia Kong, Lian Li, Junlin Li, Yuan Huang
Journal: Acta Pharmaceutica Sinica B (2021)

Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin (DOX) massively amplified ICD via substantial generation of reactive oxygen species (ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways: (1) ROS elevated endoplasmic reticulum (ER) stress, leading to surface exposure of calreticulin; (2) ROS promoted release of various mitochondria-associated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback, we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.
Sedation and Ventilator Liberation Protocol vs Usual Care and Duration of Invasive Ventilation in Pediatric Intensive Care Units—Reply
Authors: Bronagh Blackwood, Daniel F. McAuley, Mark J. Peters
Journal: JAMA (2021)

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Neuronal exposure induces neurotransmitter signaling and synaptic mediators in tumors early in brain metastasis
Authors: Krutika Deshpande, Vahan Martirosian, Brooke Naomi Nakamura, Mukund Iyer, Alex Julian, Rachel Eisenbarth, Ling Shao, Frank Attenello, Josh Neman
Journal: Neuro-Oncology (2021)

Brain metastases (BM) are responsible for neurological decline and poor overall survival. Although the pro-metastatic roles of glial cells, and the acquisition of neuronal attributes in established BM tumors have been described, there are no studies that investigate the initial interplay between neurons and brain-seeking tumor cells. The aim of this study was to characterize early tumor-neuron interactions and the induced CNS-adaptive changes in tumor cells prior to macro-colonization.Utilizing pure neuronal cultures and brain-naïve and patient-derived BM tumor cells, we surveyed the early induction of mediators of neurotransmitter (NT) and synaptic signaling in breast and lung tumor cells. Reliance on microenvironmental GABA in breast-to-brain metastatic cells (BBMs) was assessed in vitro and in vivo.Coculture with neurons induces early expression of classical NT receptor genes (HTR4, GRIA2, GRIN2B, GRM4, GRM8, DRD1) and neuronal synaptic mediators (CNR1, EGR2, ARC, NGFR, NRXN1) in breast and lung cancer cells. NT-dependent classification of tumor cells within the neuronal niche shows breast cancer cells become GABAergic responsive brain metastases (GRBMs) and transition from relying on autocrine GABA, to paracrine GABA from adjacent neurons; while autocrine Dopaminergic breast and lung tumor cells persist. In vivo studies confirm reliance on paracrine GABA is an early CNS-acclimation strategy in breast cancer. Moreover, neuronal contact induces early resurgence in Reelin expression in tumor cells through epigenetic activation, facilitating CNS adaptation.Tumor-neuron interactions allow for CNS adaptation early in the course of brain metastasis.