tbuckley/cabot-search huggingface dataset:
SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of resveratrol against neurodevelopment damage by fluoride
Authors: Qian Zhao, Zhiyuan Tian, Guoyu Zhou, Qiang Niu, Jingwen Chen, Pei Li, Lixin Dong, Tao Xia, Shun Zhang, Aiguo Wang
Journal: Theranostics (2020)

Rationale: Potential adverse effects of fluoride on neurodevelopment has been extensively explored and mitochondria have been recognized as critical targets. Mitochondrial biogenesis serves a crucial role in maintaining mitochondrial homeostasis and salubrious properties of resveratrol (RSV) has been well-defined. However, the molecular mechanisms governing mitochondrial biogenesis in developmental fluoride neurotoxicity remain unclear and the related therapeutic dietary agent is lacking. Methods: In vitro neuroblastoma SH-SY5Y cells and in vivo Sprague-Dawley rat model of developmental fluoride exposure were adopted. A total population of 60 children under long-term stable fluoride exposure were also recruited. This work used a combination of biochemical and behavioral techniques. Biochemical methods included analysis of mitochondrial function and mitochondrial biogenesis, as well as mRNA and protein expression of mitochondrial biogenesis signaling molecules, including silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Behavioral studies investigated spatial learning and memory ability of rats. Results: Both in vivo and in vitro experiments showed that sodium fluoride (NaF) caused mitochondrial dysfunction and impaired mitochondrial biogenesis. Also, NaF elevated SIRT1 levels and suppressed SIRT1 deacetylase activity along with decreased levels of PGC-1α, NRF1 and TFAM, suggestive of dysregulation of mitochondrial biogenesis signaling molecules. Moreover, enhancement of mitochondrial biogenesis by TFAM overexpression alleviated NaF-induced neuronal death through improving mitochondrial function in vitro. Further in vivo and in vitro studies identified RSV, the strongest specific SIRT1 activator, improved mitochondrial biogenesis and subsequent mitochondrial function to protect against developmental fluoride neurotoxicity via activating SIRT1-dependent PGC-1α/NRF1/TFAM signaling pathway. Noteworthy, epidemiological data indicated intimate correlations between disturbed circulating levels of mitochondrial biogenesis signaling molecules and fluoride-caused intellectual loss in children. Conclusions: Our data suggest the pivotal role of impaired mitochondrial biogenesis in developmental fluoride neurotoxicity and the underlying SIRT1 signaling dysfunction in such neurotoxic process, which emphasizes RSV as a potential therapeutic dietary agent for relieving developmental fluoride neurotoxicity.
Abstract 15131: Seasonal Effect of Acute Atmospheric Pressure Changes on the Occurrence of ST-Segment Elevation Myocardial Infarction: A Provincial Case-Crossover Study
Authors: Yongzhe Hong, Michelle Graham, Rhonda Rosychuk, Danielle Southern, Michael S McMurtry
Journal: Circulation (2018)

Introduction: Previous studies have shown that atmospheric pressure may play an important role in the development of ST-segment elevation myocardial infarction (STEMI). However, little is known whe...
Potential Emerging Risks Among Children Following Parental Opioid-Related Overdose Death
Authors: Eric G. Hulsey, Yuan Li, Karen Hacker, Karl Williams, Kathryn Collins, Erin Dalton
Journal: JAMA Pediatrics (2020)

Research letter.
The opioid epidemic is also affecting families and, most importantly, children. People who died of an overdose were most frequently between age 25 to 54 years and in their child-rearing years. The goal of this study was to determine the number of children who experienced unexpected parental loss because of opioid-related overdoses in Allegheny County. It also sought to understand their human service encounters and mental health services use subsequent to parental loss.
Immune Thrombocytopenic Purpura in a Patient with Covid-19
Authors: Abrar-Ahmad Zulfiqar, Noël Lorenzo-Villalba, Patrick Hassler, Emmanuel Andrès
Journal: New England Journal of Medicine (2020)

Immune Thrombocytopenic Purpura and Covid-19 Immune thrombocytopenia with lower-extremity purpura, mucosal bleeding, and cerebral microhemorrhage developed during the clinical course in a 65-year-o...
The miR-185/PAK6 axis predicts therapy response and regulates survival of drug-resistant leukemic stem cells in CML
Authors: Hanyang Lin, Katharina Rothe, Min Chen, Andrew Wu, Artem Babaian, Ryan Yen, Jonathan Zeng, Jens Ruschmann, Oleh I. Petriv, Kieran O'Neill, Tobias Maetzig, David J. H. F. Knapp, Naoto Nakamichi, Ryan Brinkman, Inanc Birol, Donna L. Forrest, Carl Hansen, R. Keith Humphries, Connie J. Eaves, Xiaoyan Jiang
Journal: Blood (2020)
Improvements in Dysphagia and Pain With Swallowing in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension
Authors: Evan S. Dellon, Margaret H. Collins, David A. Katzka, Stacie Hudgens, Lan Lan, James Williams, Montserrat Vera-Llonch, Ikuo Hirano
Journal: Clinical Gastroenterology and Hepatology (2020)

Quantification of eosinophilic esophagitis (EoE) symptoms is crucial for assessing treatment outcomes. We aimed to explore the effect of budesonide oral suspension (BOS) on dysphagia and pain with swallowing.We performed a secondary analysis of data from a phase 2 multicenter, double-blind, trial (conducted from July 2012 through October 2014) of patients with EoE, 11-40 y old, who were randomly assigned to groups given placebo or BOS (2.0 mg twice daily) for 12 weeks. Symptoms were quantified using the Dysphagia Symptom Questionnaire (DSQ) from baseline to week 12 of therapy.Overall, 93 patients were randomly assigned to groups; the prespecified modified intention-to-treat analysis set comprised 87 patients (38 from the placebo group and 49 from the BOS group). Improvements from baseline in least-squares mean (standard error) DSQ (Q2+Q3) scores were observed. The difference between groups was statistically significant only at week 12 (placebo vs BOS: week 4, -4.9 [1.7] vs -7.4 [1.5]; P = .265; week 8, -7.4 [2.1] vs -10.3 [1.8]; P = .288; week 12, -7.5 [1.9] vs -14.3 [1.7]; P = .01). Similar findings were observed for pain (Q4) scores (placebo vs BOS: week 4, -2.5 [0.8] vs -3.3 [0.7]; P = .484; week 8, -3.0 [0.8] vs -4.9 [0.7]; P = .066; week 12, -3.1 [0.8] vs -4.9 [0.7]; P = .109). More severe DSQ and DSQ+pain scores were associated with presence of other symptoms (such as regurgitation) and physician-rated severity. Improvements in DSQ and DSQ+pain scores were greater in patients with either a histologic or endoscopic response than in patients without a response.In a secondary analysis of data from a phase 2 trial of patients with EoE, we found evidence for improvements in dysphagia and pain scores in patients who received BOS (2.0 mg twice daily) vs placebo. Pain with swallowing should be considered in the clinical assessment of patients with EoE. ClinicalTrials.gov no: NCT01642212.
Sonographic B-Lines, Fluid Resuscitation, and Hypoxemia in Malawian Patients with Suspected Sepsis
Authors: Richard J. Wang, Grace Katha, Miriam Phiri, Philip Delbridge, Stephen B. Gordon, Carolyn S. Calfee, Laurence Huang, Jamie Rylance
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Author(s): Wang, Richard J; Katha, Grace; Phiri, Miriam; Delbridge, Philip; Gordon, Stephen B; Calfee, Carolyn S; Huang, Laurence; Rylance, Jamie
An alternative workflow for molecular detection of SARS-CoV-2 – escape from the NA extraction kit-shortage, Copenhagen, Denmark, March 2020
Authors: Anna S. Fomsgaard, Maiken Worsøe Rosenstierne
Journal: Eurosurveillance (2020)

The World Health Organization has declared COVID-19 caused by the newly discovered SARS-CoV-2 a pandemic. Due to growing demand for reagents and/or kits to extract SARS-CoV-2 RNA for subsequent RT-qPCR diagnostics, there is a worldwide risk of shortages. With a detection sensitivity of 97.4% (95% CI: 86.2–99.9%), we describe a simple, fast, alternative workflow for molecular detection of SARS-CoV-2, where samples are simply heat-processed for 5 min at 98 °C before a commonly-used RT-qPCR procedure.
Phase I/II Trial of Glasdegib in Heavily Pre-Treated Patients with Primary or Secondary Myelofibrosis
Authors: Aaron T. Gerds, Tetsuzo Tauchi, Ellen K. Ritchie, Michael W. Deininger, Catriona Hm Jamieson, Ruben Mesa, Mark Lawrence Heaney, Norio Komatsu, Hironobu Minami, M. Naveed Shaik, Xiaoxi Zhang, Christine DiRienzo, Mirjana Zeremski, Geoffrey Chan, Moshe Talpaz
Journal: Blood (2017)
Bio-orthogonal click-targeting nanocomposites for chemo-photothermal synergistic therapy in breast cancer
Authors: Jianan Qiao, Fengchun Tian, Yudi Deng, Yunkai Shang, Shijie Chen, Enhao Chang, Jing Yao
Journal: Theranostics (2020)

Chemo-photothermal synergistic treatment has a high potential to complement traditional cancer therapy and amplify its outcome.Precision in the delivery of these therapeutic agents to tumor cells has been indicated as being key to maximizing their therapeutic effects.Method: We developed a bio-orthogonal copper-free click-targeting nanocomposite system (DLQ/DZ) that markedly improved specific co-delivery of the chemotherapeutic agent doxorubicin and the photosensitizer zinc phthalocyanine to breast cancer cells via a two-step mechanism.In the first step, an azide-modified sugar (tetraacetylated N-azidoacetyl-D-mannosamine, Ac4ManNAz) was injected intratumorally for glycoengineering of the tumor cell surface.Subsequently, DLQ/DZ was administered to achieve tumor enrichment via bio-orthogonal copper-free click-targeting.Results: During the first step in our experiments, high density azide groups (3.23×10 7 /cell) were successfully glycoengineered on the surface of tumor cells following Ac4ManNAz administration in vitro.Subsequently, the highly efficient bio-orthogonal click chemical reaction between receptor-like azide groups on tumor cells and DBCO on nanocomposites significantly enhanced the cellular uptake and tumor-specific distribution (4.6x increase) of the nanocomposites in vivo.Importantly, Ac4ManNAz+DLQ/DZ treatment augmented the anti-cancer effect of combined chemotherapy and PTT (96.1% inhibition rate), nearly ablating the tumor.Conclusions: This bio-orthogonal click-targeting combination strategy may provide a promising treatment approach for surficial breast cancers.
Expert‐level automated malaria diagnosis on routine blood films with deep neural networks
Authors: Petru Manescu, Michael J. Shaw, Muna Elmi, Lydia Neary‐Zajiczek, Remy Claveau, Vijay Pawar, Iasonas Kokkinos, Gbeminiyi Oyinloye, Christopher Bendkowski, Olajide A. Oladejo, Bolanle F. Oladejo, Tristan Clark, Denis Timm, John Shawe‐Taylor, Mandayam A. Srinivasan, Ikeoluwa Lagunju, Olugbemiro Sodeinde, Biobele J. Brown, Delmiro Fernandez‐Reyes
Journal: American Journal of Hematology (2020)

Abstract Over 200 million malaria cases globally lead to half a million deaths annually. Accurate malaria diagnosis remains a challenge. Automated imaging processing approaches to analyze Thick Blood Films (TBF) could provide scalable solutions, for urban healthcare providers in the holoendemic malaria sub‐Saharan region. Although several approaches have been attempted to identify malaria parasites in TBF, none have achieved negative and positive predictive performance suitable for clinical use in the west sub‐Saharan region. While malaria parasite object detection remains an intermediary step in achieving automatic patient diagnosis, training state‐of‐the‐art deep‐learning object detectors requires the human‐expert labor‐intensive process of labeling a large dataset of digitized TBF. To overcome these challenges and to achieve a clinically usable system, we show a novel approach. It leverages routine clinical‐microscopy labels from our quality‐controlled malaria clinics, to train a Deep Malaria Convolutional Neural Network classifier (DeepMCNN) for automated malaria diagnosis. Our system also provides total Malaria Parasite (MP) and White Blood Cell (WBC) counts allowing parasitemia estimation in MP/μL, as recommended by the WHO. Prospective validation of the DeepMCNN achieves sensitivity/specificity of 0.92/0.90 against expert‐level malaria diagnosis. Our approach PPV/NPV performance is of 0.92/0.90, which is clinically usable in our holoendemic settings in the densely populated metropolis of Ibadan. It is located within the most populous African country (Nigeria) and with one of the largest burdens of Plasmodium falciparum malaria. Our openly available method is of importance for strategies aimed to scale malaria diagnosis in urban regions where daily assessment of thousands of specimens is required.
The scandals of covid-19
Authors: Kamran Abbasi
Journal: BMJ (2020)

Last seen in public clapping on the doorstep of Number 10 Downing Street for the NHS while self isolating, the prime minister was in intensive care four days later (doi:10.1136/bmj.m1433). Covid19, the virus that is turning the world upside down, does not respect borders or political leanings (doi:10.1136/bmj.m1336). It isn’t a virus in some other place, sparing health systems in richer countries. Covid-19 is here and everywhere. And, through hubris, much of the world was scandalously unprepared.

In time, a chance will come to reshape our world, prioritise health and wellbeing, work as equal partners with Africa and Asia, and build international solidarity. The agendas …
Tumor reoxygenation for enhanced combination of radiation therapy and microwave thermal therapy using oxygen generation in situ by CuO nanosuperparticles under microwave irradiation
Authors: Zengzhen Chen, Wenna Guo, Qiong Wu, Longfei Tan, Tengchuang Ma, Changhui Fu, Jie Yu, Xiangling Ren, Jianming Wang, Ping Liang, Xianwei Meng
Journal: Theranostics (2020)

As known, radiation therapy (RT) can exacerbate the degree of hypoxia of tumor cells, which induces serious resistance to RT and in turn, is the greatest obstacle to RT. Reoxygenation can restore the hypoxic state of tumor cells, which plays an important role in reshaping tumor microenviroment for achieving optimal therapeutic efficacy.Herein, we report for the first time that microwave (MW)-triggered IL-Quercetin-CuO-SiO2@ZrO2-PEG nanosuperparticles (IQuCS@Zr-PEG NSPs) have been used to achieve an optimal RT therapeutic outcomes by the strategy of upregulating tumor reoxygenation, i.e. hypoxic cells acquire oxygen and return to normal state.Methods: We prepared a promising multifunctional nanosuperparticle to upregulate tumor reoxygenation by utilizing CuO nanoparticle to generate oxygen under MW irradiation in the tumor microenvironment.The IQuCS@Zr-PEG NSPs were obtained by introducing CuO nanoparticles, MW sensitizer of 1-butyl-3-methylimidazolium hexafluorophosphate (IL), radiosensitizer of Quercetin (Qu) and surface modifier of monomethoxy polyethylene glycol sulfhyl (mPEG-SH, 5k Da) into mesoporous sandwich SiO2@ZrO2 nanosuperparticles (SiO2@ZrO2 NSPs).The release oxygen by IQuCS@Zr-PEG NSPs under MW irradiation was investigated by a microcomputer dissolved oxygen-biochemical oxygen demand detector (DO-BOD) test.Finally, we used the 99m Tc-HL91 labeled reoxygenation imaging, Cellular immunofluorescence, immunohistochemistry, and TUNEL experiments to verify that this unique MW-responsive reoxygenation enhancer can be used to stimulate reshaping of the tumor microenvironment.Results: Through experiments we found that the IQuCS@Zr-PEG NSPs can persistently release oxygen under the MW irradiation, which upregulates tumor reoxygenation and improve the combined tumor treatment effect of RT and microwave thermal therapy (MWTT).Cellular immunofluorescence and immunohistochemistry experiments demonstrated that the IQuCS@Zr-PEG NSPs can downregulate the expression of hypoxia-inducible factor 1α (HIF-1α) under MW irradiation.The 99m Tc-HL91 labeled reoxygenation imaging experiment also showed that the oxygen generated by IQuCS@Zr-PEG NSPs under MW irradiation can significantly increase the reoxygenation capacity of tumor cells, thus reshaping the tumor microenvironment.The high inhibition rate of 98.62% was achieved in the antitumor experiments in vivo.In addition, the IQuCS@Zr-PEG NSPs also had good computed tomography (CT) imaging effects, which can be used to monitor the treatment of tumors in real-time. Ivyspring
The role of adjuvant therapy after R0 resection for patients with intrahepatic and perihilar cholangiocarcinoma.
Authors: Young Saing Kim, Inkeun Park, Sung Yong Oh, Se-Il Go, Jung Hun Kang, Haa-na Song, Joon Oh Park, Jun Ho Ji, In Gyu Hwang, JoungSoon Jang
Journal: Journal of Clinical Oncology (2016)

302 Background: There is still debated regarding the optimal treatment strategy in cholangiocarcinoma (CC) after curative resection. The aim of this study was to analyze the role of adjuvant therapy in R0-resected intrahepatic and perihilar CC. Methods: We retrospectively reviewed the medical records of patients who underwent R0 resection for intrahepatic and perihilar CC between January 2001 and December 2013 at six cancer centers. Adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of our study were recurrence-free survival (RFS) and overall survival (OS). Multivariable Cox proportional hazards model was used to identify prognostic factors for survival. Results: A total of 137 patients were included in the analysis; 58.4% of patients had intrahepatic CC and 25.5% had lymph node involvement. Seventy-three patients (53.3%) received adjuvant therapy (CT/CRT/RT: 48/13/12, respectively). A greater percentage of patients receiving adjuvant therapy had stage III-IVA (P = 0.010), high histologic grade (P = 0.035), and positive lymph nodes (P = 0.088). Multivariable analysis identified positive nodes (hazard ratio (HR), 3.60; P &lt; 0.001), poor tumor differentiation (HR, 2.35, P = 0.048), and high baseline CA 19-9 level (HR, 1.97; P = 0.013) as predictors of decreased OS. The effect of adjuvant therapy varied according to the treatment modality. Adjuvant CRT was significantly associated with longer RFS (HR, 0.44; P = 0.036) but OS benefit was non-significant HR, 0.56; P = 0.245). In node-positive patients, CRT had a trend for longer OS (HR, 0.24; P = 0.097). In contrast, CT did not improve RFS (HR, 1.13; P = 0.617) or OS (HR, 1.70; P = 0.114). RT alone was associated shorter RFS (HR 3.08; P = 0.009) and OS (HR, 6.86, P &lt; 0.001). Conclusions: Adjuvant CT and RT were not associated with a survival advantage in R0-resected intrahepatic and perihilar CC. CRT appears to be appropriate treatment after complete resection especially in lymph node-positive patients.
ILROG emergency guidelines for radiation therapy of hematological malignancies during the COVID-19 pandemic
Authors: Joachim Yahalom, Bouthaina Shbib Dabaja, Umberto Ricardi, Andrea Ng, N. George Mikhaeel, Ivan R. Vogelius, Tim Illidge, Shunan Qi, Andrew Wirth, Lena Specht
Journal: Blood (2020)
Erythrocyte Metabolic Reprogramming by Sphingosine 1-Phosphate in Chronic Kidney Disease and Therapies
Authors: Tingting Xie, Changhan Chen, Zhangzhe Peng, Benjamin C. Brown, Julie A. Reisz, Ping Xu, Zhen Zhou, Anren Song, Yujin Zhang, Mikhail V. Bogdanov, Rodney E. Kellems, Angelo D’Alessandro, Weiru Zhang, Yang Xia
Journal: Circulation Research (2020)

Hypoxia promotes renal damage and progression of chronic kidney disease (CKD). The erythrocyte is the only cell type for oxygen (O2) delivery. Sphingosine 1-phosphate (S1P)-a highly enriched biolipid in erythrocytes-is recently reported to be induced under high altitude in normal humans to enhance O2 delivery. However, nothing is known about erythrocyte S1P in CKD.To investigate the function and metabolic basis of erythrocyte S1P in CKD with a goal to explore potential therapeutics.Using erythrocyte-specific SphK1 (sphingosine kinase 1; the only enzyme to produce S1P in erythrocytes) knockout mice (eSphK1-/-) in an experimental model of hypertensive CKD with Ang II (angiotensin II) infusion, we found severe renal hypoxia, hypertension, proteinuria, and fibrosis in Ang II-infused eSphk1-/- mice compared with controls. Untargeted metabolomics profiling and in vivo U-13C6 isotopically labeled glucose flux analysis revealed that SphK1 is required for channeling glucose metabolism toward glycolysis versus pentose phosphate pathway, resulting in enhanced erythroid-specific Rapoport-Luebering shunt in Ang II-infused mice. Mechanistically, increased erythrocyte S1P functioning intracellularly activates AMPK (AMP-activated protein kinase) 1α and BPGM (bisphosphoglycerate mutase) by reducing ceramide/S1P ratio and inhibiting PP2A (protein phosphatase 2A), leading to increased 2,3-bisphosphoglycerate (an erythrocyte-specific metabolite negatively regulating Hb [hemoglobin]-O2-binding affinity) production and thus more O2 delivery to counteract kidney hypoxia and progression to CKD. Preclinical studies revealed that an AMPK agonist or a PP2A inhibitor rescued the severe CKD phenotype in Ang II-infused eSphK1-/- mice and prevented development of CKD in the control mice by inducing 2,3-bisphosphoglycerate production and thus enhancing renal oxygenation. Translational research validated mouse findings in erythrocytes of hypertensive CKD patients and cultured human erythrocytes.Our study elucidates the beneficial role of eSphk1-S1P in hypertensive CKD by channeling glucose metabolism toward Rapoport-Luebering shunt and inducing 2,3-bisphosphoglycerate production and O2 delivery via a PP2A-AMPK1α signaling pathway. These findings reveal the metabolic and molecular basis of erythrocyte S1P in CKD and new therapeutic avenues.
Diagnosis and Management of Obstructive Sleep Apnea
Authors: Daniel J. Gottlieb, Naresh M. Punjabi
Journal: JAMA (2020)

<h3>Importance</h3> Obstructive sleep apnea (OSA) affects 17% of women and 34% of men in the US and has a similar prevalence in other countries. This review provides an update on the diagnosis and treatment of OSA. <h3>Observations</h3> The most common presenting symptom of OSA is excessive sleepiness, although this symptom is reported by as few as 15% to 50% of people with OSA in the general population. OSA is associated with a 2- to 3-fold increased risk of cardiovascular and metabolic disease. In many patients, OSA can be diagnosed with home sleep apnea testing, which has a sensitivity of approximately 80%. Effective treatments include weight loss and exercise, positive airway pressure, oral appliances that hold the jaw forward during sleep, and surgical modification of the pharyngeal soft tissues or facial skeleton to enlarge the upper airway. Hypoglossal nerve stimulation is effective in select patients with a body mass index less than 32. There are currently no effective pharmacological therapies. Treatment with positive airway pressure lowers blood pressure, especially in patients with resistant hypertension; however, randomized clinical trials of OSA treatment have not demonstrated significant benefit on rates of cardiovascular or cerebrovascular events. <h3>Conclusions and Relevance</h3> OSA is common and the prevalence is increasing with the increased prevalence of obesity. Daytime sleepiness is among the most common symptoms, but many patients with OSA are asymptomatic. Patients with OSA who are asymptomatic, or whose symptoms are minimally bothersome and pose no apparent risk to driving safety, can be treated with behavioral measures, such as weight loss and exercise. Interventions such as positive airway pressure are recommended for those with excessive sleepiness and resistant hypertension. Managing asymptomatic OSA to reduce cardiovascular and cerebrovascular events is not currently supported by high-quality evidence.