tbuckley/cabot-search huggingface dataset:
Angiotensin‐converting enzyme inhibitors prevent liver‐related events in nonalcoholic fatty liver disease
Authors: Xinrong Zhang, Grace Lai‐Hung Wong, Terry Cheuk‐Fung Yip, Yee‐Kit Tse, Lilian Yan Liang, Vicki Wing‐Ki Hui, Huapeng Lin, Guan‐Lin Li, Jimmy Che‐To Lai, Henry Lik‐Yuen Chan, Vincent Wai‐Sun Wong
Journal: Hepatology (2021)

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can inhibit liver fibrogenesis in animal models. We aimed to evaluate the impact of ACEI/ARB use on the risk of liver cancer and cirrhosis complications in patients with NAFLD.We conducted a retrospective, territory-wide cohort study of adult patients with NAFLD diagnosed between January 2000 and December 2014 to allow for at least 5 years of follow-up. ACEI or ARB users were defined as patients who had received ACEI or ARB treatment for at least 6 months. The primary endpoint was liver-related events (LREs), defined as a composite endpoint of liver cancer and cirrhosis complications. We analyzed data from 12,327 NAFLD patients (mean age, 54.2 ± 14.7 years; 6163 men [50.0%]); 6805 received ACEIs, and 2877 received ARBs. After propensity score weighting, ACEI treatment was associated with a lower risk of LREs (weighted subdistribution hazard ratio [SHR], 0.48; 95% CI, 0.35-0.66; p < 0.001), liver cancer (weighted SHR, 0.46; 95% CI, 0.28-0.75; p = 0.002), and cirrhosis complications (weighted SHR, 0.42; 95% CI, 0.27-0.66; p < 0.001), but ARB was not. In subgroup analysis, ACEI treatment was associated with greater reduction in LREs in patients with chronic kidney diseases (CKDs) than those without (CKD-weighted SHR, 0.74; 95% CI, 0.52-0.96; p = 0.036; non-CKD-weighted SHR, 0.15; 95% CI, 0.07-0.33; p < 0.001).ACEI, rather than ARB, treatment is associated with a lower risk of LREs in NAFLD patients, especially among those with CKD.
Abstract 11053: The Association Between the Systemic Immune-Inflammation Index with the Duration of Cardiopulmonary Bypass in Cardiac Surgery: A Retrospective, Single-Center Study
Authors: Yanan Hu, Yi Liu, Yongzhe Liu, Hui Chen, Wei Jiang, Longhe Xu
Journal: Circulation (2021)

Introduction: Systemic inflammatory response evoked by cardiac surgery involving a cardio-pulmonary bypass (CPB) in combination of surgical trauma, ischemia/reperfusion injury, hypothermia, and endotoxin release contributed to the postoperative morbidity and mortality. This study aimed to explore the potential of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) as novel markers to evaluate and predict the adverse clinical outcomes after longer CPB time in cardiac surgery. Methods: Patients who underwent cardiac surgery with or without CPB were allocated into two groups, CPB group (n=11) and N-CPB group (n=21). The time course of NLR, PLR, SII, and C-reactive protein (CPR) were analyzed at preoperative day 1 and postoperative day 1, 3, and 7. The baseline and postoperative parameters, the ICU and hospital stay were recorded. Results: There were no differences of baseline parameters between groups. The level of NLR, PLR, SII, and CPR at postoperative day 1 was higher than that in the preoperative day 1 in both groups (p &lt; 0.01). The level of NLR, SII and CPR at postoperative day 3 was higher than that in the preoperative day 1 in both groups (p &lt; 0.05). The NLR and SII at postoperative day 3 were higher in CPB group than that in N-CPB group (p &lt; 0.05). The ICU and hospital stay was longer in CPB group than N-CPB group (p &lt; 0.05). Conclusions: The longer duration of CPB time induced higher systemic inflammatory response characterized by higher level of NLR, PLR and SII. The SII predicted the poor outcome after longer CPB. The peak of systemic inflammatory response occurred on the third day after cardiac surgery.
Primary and metastatic peritoneal surface malignancies
Authors: Delia Cortés-Guiral, Martin Hübner, Mohammad Alyami, Aditi Bhatt, Wim Ceelen, Olivier Glehen, Florian Lordick, Robert Ramsay, Olivia Sgarbura, Kurt Van Der Speeten, Kiran K. Turaga, Manish Chand
Journal: Nature Reviews Disease Primers (2021)
Tumor-specific activatable biopolymer nanoparticles stabilized by hydroxyethyl starch prodrug for self-amplified cooperative cancer therapy
Authors: Yuxuan Xiong, Zibing Wang, Qiang Wang, Qingyuan Deng, Jitang Chen, Jianshuang Wei, Xiaoquan Yang, Xiangliang Yang, Zifu Li
Journal: Theranostics (2021)

Rationale: Chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the anticancer activity of CDT is impeded by the insufficient Fenton catalytic efficiency and the high concentration of glutathione (GSH) in the tumor cells. Also, it is challenging to eliminate tumors with CDT alone. Thus, simple strategies aimed at constructing well-designed nanomedicines that can improve therapeutic efficiency of CDT and simultaneously incorporate extra therapeutic modes as helper are meaningful and highly required. Method: Tailored to specific features of tumor microenvironment (TME), in this study, we developed a biosafe, stable and TME-activated theranostic nanoplatform (P(HSD-Cu-DA)) for photoacoustic imaging (PAI) and self-amplified cooperative therapy. This intelligent nanoplatform was fabricated following a simple one-pot coordination and polymerization strategy by using dopamine and Cu2+ as precursors and redox-responsive hydroxyethyl starch prodrugs (HES-SS-DOX) as stabilizer. Results: Interestingly, the pre-doped Cu2+ in polydopamine (PDA) framework can endow P(HSD-Cu-DA) NPs with tumor-specific CDT ability and remarkably enhance NIR absorption of PDA. PAI and biodistribution tests proved such nanoplatform can effectively accumulate in tumor tissues. Following enrichment, massive amounts of toxic hydroxyl radicals (·OH, for CDT) and free DOX (for chemotherapy) were generated by the stimulation of TME, which was further boosted by local hyperthermia. Concomitantly, in the process of activating these therapeutic functions, GSH depletion triggered by disulfide bond (-SS-) breakage and Cu2+ reduction within tumor cells occurred, further amplifying intratumoral oxidative stress. Importantly, the framework structure dominated by bioinspired polydopamine and clinical-used HES guaranteed the long-term biosafety of in vivo treatment. As a result, the mutual promotion among different components yields a potent tumor suppression outcome and minimized systemic toxicity, with one dosage of drug administration and laser irradiation, respectively. Conclusion: This work provides novel insights into designing efficient and tumor-specific activatable nanotherapeutics with significant clinical translational potential for cancer therapy.
Crystalloid Composition and Rate of Fluid Administration When Resuscitating Patients in the Intensive Care Unit
Authors: Simon Finfer, Fernando G. Zampieri, Paul J. Young
Journal: JAMA (2021)

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Abstract 17234: Cisplatin Induced Coronary Artery Atherosclerosis Leading To St-elevation Myocardial Infarction: A Case Report
Authors: Sheikh Bilal B Khalid, Javaria Mahmood
Journal: Circulation (2021)

Introduction: Cisplatin-based chemotherapeutic regimen (CBCR) is known for increasing risk of venous thromboembolic (TE) disease. We report a unique case of STEMI associated with CBCR which we believe was caused by coronary artery thrombosis. Case description: A 31-yo man with a past history of germ cell tumor presented with chest pain radiating to back and left arm. It started this morning and intensity did not worsen with exertion. He denied any dyspnea, diaphoresis or palpitations. He was non-smoker and non-obese. He denied any family history of premature coronary artery disease. He had undergone unilateral orchiectomy a year ago, and was currently receiving chemotherapy with bleomycin, etoposide and cisplatin; the last dose of his 3 rd cycle was given the day before. EKG showed ST elevation in leads I, aVL, V4 and V5. Troponin I was high to 6.9 ng/ml (ULN 0.045 ng/ml). He received intravenous infusion of thrombolytic. An angiogram done the next day showed moderate mid-LAD disease with residual clot. A CT scan and an echocardiogram later showed left ventricular thrombus (LVT). He was kept on therapeutic enoxaparin along with aspirin. Follow up echocardiogram showed resolution of the thrombus. His chemotherapy was stopped, and he has been kept on active surveillance since then. Discussion: Most cases of CBCR-associated myocardial infarction that have been reported have been seen in the older population with other risk factors for coronary artery disease. Cases where angiographic data was available, coronary artery vasospasm appeared to be the culprit rather than a true plaque rupture. While the presence of LVT raises possibility of thromboembolism to coronaries causing MI, the angiographic findings support accelerated plaque formation to be the cause of infarction. In earlier reports, elevated pre-treatment level of von Willebrand factor has been postulated to have some role in the disease pathogenesis. Other possible mechanisms for pathogenesis include endothelial cell damage, platelet activation, and imbalance between thromboxane-prostacyclin levels. This case emphasizes the need to keep cardiac etiologies of chest pain in the differential when evaluating patients on CBCR as timely intervention is life saving and prevent morbidity.
Cancer-Causative Mutations Occurring in Early Embryogenesis
Authors: Fresia Pareja, Ryan N. Ptashkin, David N. Brown, Fatemeh Derakhshan, Pier Selenica, Edaise M. da Silva, Andrea M. Gazzo, Arnaud Da Cruz Paula, Kelsey Breen, Ronglai Shen, Antonio Marra, Ahmet Zehir, Ryma Benayed, Michael F. Berger, Ozge Ceyhan-Birsoy, Sowmya Jairam, Margaret Sheehan, Utsav Patel, Yelena Kemel, Jacklyn Casanova-Murphy, Christopher J. Schwartz, Mahsa Vahdatinia, Elizabeth Comen, Laetitia Borsu, Xin Pei, Nadeem Riaz, David H. Abramson, Britta Weigelt, Michael F. Walsh, Anna-Katerina Hadjantonakis, Marc Ladanyi, Kenneth Offit, Zsofia K. Stadler, Mark E. Robson, Jorge S. Reis-Filho, Diana Mandelker
Journal: Cancer Discovery (2021)

Abstract Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSG). Their contribution to apparently sporadic cancers is currently unknown. Analysis of paired tumor/blood sequencing data of 35,310 patients with cancer revealed 36 pathogenic mosaic variants affecting CSGs, most of which were not detected by prior clinical genetic testing. These CSG mosaic variants were consistently detected at varying variant allelic fractions in microdissected normal tissues (n = 48) from distinct embryonic lineages in all individuals tested, indicating their early embryonic origin, likely prior to gastrulation, and likely asymmetrical propagation. Tumor-specific biallelic inactivation of the CSG affected by a mosaic variant was observed in 91.7% (33/36) of cases, and tumors displayed the hallmark pathologic and/or genomic features of inactivation of the respective CSGs, establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers. Significance: Here, we demonstrate that mosaic variants in CSGs arising in early embryogenesis contribute to the oncogenesis of seemingly sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may affect therapeutic decisions as well as prophylactic measures for patients and their offspring. See related commentary by Liggett and Sankaran, p. 889. This article is highlighted in the In This Issue feature, p. 873
Erratum for the Research Article: “Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses” by E. A. Bordt, L. L. Shook, C. Atyeo, K. M. Pullen, R. M. De Guzman, M.-C. Meinsohn, M. Chauvin, S. Fischinger, L. J. Yockey, K. James, R. Lima, L. M. Yonker, A. Fasano, S. Brigida, L. M. Bebell, D. J. Roberts, D. Pepin, J. R. Huh, S. D. Bilbo, J. Z. Li, A. Kaima, D. J. Schust, K. J. Gray, D. Lauffenburger, G. Alter, A. G. Edlow
Journal: Science Translational Medicine (2021)

[Figure: see text].
High-dose <i>versus</i> low-dose prednisolone in symptomatic patients with post-COVID-19 diffuse parenchymal lung abnormalities: an open-label, randomised trial (the COLDSTER trial)
Authors: Sahajal Dhooria, Shivani Chaudhary, Inderpaul Singh Sehgal, Ritesh Agarwal, Siddhant Arora, Mandeep Garg, Nidhi Prabhakar, Goverdhan Dutt Puri, Ashish Bhalla, Vikas Suri, Lakshmi Narayana Yaddanapudi, Valliappan Muthu, Kuruswamy Thurai Prasad, Ashutosh Nath Aggarwal
Journal: European Respiratory Journal (2021)

In some patients, respiratory symptoms and imaging abnormalities persist after acute coronavirus disease 2019 (COVID-19) pneumonia [1–3]. Chest computed tomography (CT) scans generally show diffuse parenchymal lung abnormalities consistent with organising pneumonia [4]. It has been proposed that the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could act as a trigger to exalt the presence of pre-existing interstitial lung abnormalities encountered in the general population, especially in smokers. Previous observational studies reported improvement with glucocorticoids in symptomatic patients with post-COVID-19 diffuse parenchymal lung abnormalities (PC-DPLAS) [4–6]. A recent guideline recommended glucocorticoids for treating PC-DPLAS [3]. However, there are no randomised controlled trials on therapies for this condition. High-dose prednisolone may not be superior to a low-dose 6-week regimen in improving clinical, physiological and radiological outcomes, or health-related quality of life, in patients with symptomatic post-COVID-19 diffuse parenchymal lung abnormalities <https://bit.ly/32zqnXt>
Bridging mRNA and Polycation Using RNA Oligonucleotide Derivatives Improves the Robustness of Polyplex Micelles for Efficient mRNA Delivery
Authors: Naoto Yoshinaga, Satoshi Uchida, Anjaneyulu Dirisala, Mitsuru Naito, Kyoko Koji, Kensuke Osada, Horacio Cabral, Kazunori Kataoka
Journal: Advanced Healthcare Materials (2021)

Polyplex for messenger RNA (mRNA) delivery requires strong yet reversible association between mRNA and polycation for extracellular robustness and selective intracellular disintegration. Herein, RNA oligonucleotide (OligoRNA) derivatives that bridge mRNA and polycation are developed to stabilize polyplex micelles (PMs). A set of the OligoRNAs introduced with a polyol moiety in their 5' end is designed to hybridize to fixed positions along mRNA strand. After PM preparation from the hybridized mRNA and poly(ethylene glycol)-polycation block copolymer derived with phenylboronic acid (PBA) moieties in its cationic segment, PBA moieties form reversible phenylboronate ester linkages with a polyol moiety at 5' end of OligoRNAs and a diol moiety at their 3' end ribose, in the PM core. The OligoRNAs work as a node to bridge ionically complexed mRNA and polycation, thereby improving PM stability against polyion exchange reaction and ribonuclease attack in extracellular environment. After cellular uptake, intracellular high concentration of adenosine triphosphate triggers the cleavage of phenylboronate ester linkages, resulting in mRNA release from PM. Ultimately, the PM provides efficient mRNA introduction in cultured cells and mouse lungs after intratracheal administration, demonstrating the potential of the bridging strategy in polyplex-based mRNA delivery.
Targeting AMPK and the Nrf2/HO-1 axis: a promising therapeutic strategy in acute lung injury
Authors: Stefan W. Ryter
Journal: European Respiratory Journal (2021)

Acute lung injury (ALI) is defined as pulmonary conditions leading to severe hypoxaemia, with human acute respiratory distress syndrome (ARDS) representing its most severe manifestation [1]. The primary causes of ARDS are trauma, bacterial and viral pneumonia, sepsis and adverse drug reactions [2]. The development of effective therapeutics for ALI/ARDS remains an urgent unmet need [3]. The overall crude incidence of ALI from all sources has been estimated at 76.9 per 100 000 person-years (86.2 after age adjustment) [4]; or ∼200 000 cases per year in the USA [1]. ALI is generally associated with endothelial and epithelial cell injury, loss of alveolar–capillary membrane integrity, neutrophil influx into the lung, and release of pro-inflammatory mediators [1]. Exposure to halogen gases, such as bromine (Br2) and chlorine (Cl2), as well as to halogenated organic compounds, can cause severe ALI. Although many experimental animal models of ALI have been developed [5], halogen gas-induced ALI has been less widely studied. Halogen gas-induced ALI/ARDS remains a public health concern as it can arise from industrial occupational and accidental exposures. Despite individual case reports, there is a lack of more precise epidemiological data on the incidence of halogen-gas specific ALI [6]. Therapeutic targeting of AMPK can improve acute lung injury via upregulation of the cytoprotective enzyme heme oxygenase-1 <https://bit.ly/3DLf1xT>
Program Access, Depressive Symptoms, and Medical Errors Among Resident Physicians With Disability
Authors: Lisa M. Meeks, Karina Pereira-Lima, Elena Frank, Erene Stergiopoulos, Katherine E.T. Ross, Srijan Sen
Journal: JAMA Network Open (2021)

This cohort study uses data from a survey of US medical interns to assess the prevalence of self-reported disability and program accommodations and the association between accommodations, depressive symptoms, and self-reported medical errors among resident physicians.
GWAS in Mice Maps Susceptibility to HIV-Associated Nephropathy to the Ssbp2 Locus
Authors: Nicholas J. Steers, Yask Gupta, Vivette D. D’Agati, Tze Y. Lim, Natalia DeMaria, Anna Mo, Judy Liang, Kelsey O. Stevens, Dina F. Ahram, Wan Yee Lam, Mihai Gagea, Lalitha Nagarajan, Simone Sanna-Cherchi, Ali G. Gharavi
Journal: Journal of the American Society of Nephrology (2021)

To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS that often arises in the setting of viral infections, we performed a genome-wide association study (GWAS) among inbred mouse strains using a murine model of HIV-1 associated nephropathy (HIVAN).
Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial
Authors: Jason Gotlib, Andreas Reiter, Deepti H. Radia, Michael W. Deininger, Tracy I. George, Jens Panse, Alessandro M. Vannucchi, Uwe Platzbecker, Iván Alvarez-Twose, Andrzej Mital, Olivier Hermine, Ingunn Dybedal, Elizabeth O. Hexner, Lisa K. Hicks, Lambert Span, Ruben Mesa, Prithviraj Bose, Kristen M. Pettit, Mark L. Heaney, Stephen T. Oh, Jayita Sen, Hui-Min Lin, Brenton G. Mar, Daniel J. DeAngelo
Journal: Nature Medicine (2021)

Abstract Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655 ) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM ( n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met ( P = 1.6 × 10 -9 ), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.
A clickable photoaffinity probe of betulinic acid identifies tropomyosin as a target
Authors: Pedro Martín-Acosta, Qianli Meng, John Klimek, Ashok P. Reddy, Larry David, Stefanie Kaech Petrie, Bingbing X. Li, Xiangshu Xiao
Journal: Acta Pharmaceutica Sinica B (2021)

Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge, unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid.
Updated Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents
Authors: Guillermo Montalban-Bravo, Elias J. Jabbour, Zeev E. Estrov, Tapan M. Kadia, Farhad Ravandi, Kelly S. Chien, Graciela M. Nogueras González, Xiao Qin Dong, Stefan Faderl, Heather Schneider, Rosmy B. John, Meghan Anne Meyer, Hagop Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2021)
Perimyocardial Injury Specific for SARS-CoV-2-Induced Myocarditis in Comparison With Non-COVID-19 Myocarditis
Authors: Maciej Haberka, Justyna Rajewska-Tabor, Dagmara Wojtowicz, Anna Jankowska, Karol Miszalski-Jamka, Magdalena Janus, Karolina Dorniak, Dorota Kulawiak-Gałąska, Bartłomiej Stasiow, Szymon Rozmiarek, Edyta Szurowska, Waldemar Elikowski, Marzena Ławrynowicz, Mateusz Śpiewak, Marek Koziński, Małgorzata Pyda
Journal: JACC. Cardiovascular imaging (2021)