tbuckley/cabot-search huggingface dataset:
Sphingosine Kinase 2 (SphK2) Deficiency Does Not Lower but Instead Surprisingly Increases the Level of Sphingosine-1-Phosphate (S1P) in Peripheral Blood, Providing a Novel Strategy for Stimulating Hematopoietic Stem Cell Mobilization By Inhibiting SphK2 Activity
Authors: Mateusz Adamiak, Lakshman Chelvarajan, Webster Santos, Kevin R Lynch, Ahmed Abdel-Latif, Mariusz Z Ratajczak
Journal: Blood (2017)
Generation of Vascular Smooth Muscle Cells From Induced Pluripotent Stem Cells
Authors: Mengcheng Shen, Thomas Quertermous, Michael P. Fischbein, Joseph C. Wu
Journal: Circulation Research (2021)

The developmental origin of vascular smooth muscle cells (VSMCs) has been increasingly recognized as a major determinant for regional susceptibility or resistance to vascular diseases. As a human material-based complement to animal models and human primary cultures, patient induced pluripotent stem cell iPSC-derived VSMCs have been leveraged to conduct basic research and develop therapeutic applications in vascular diseases. However, iPSC-VSMCs (induced pluripotent stem cell VSMCs) derived by most existing induction protocols are heterogeneous in developmental origins. In this review, we summarize signaling networks that govern in vivo cell fate decisions and in vitro derivation of distinct VSMC progenitors, as well as key regulators that terminally specify lineage-specific VSMCs. We then highlight the significance of leveraging patient-derived iPSC-VSMCs for vascular disease modeling, drug discovery, and vascular tissue engineering and discuss several obstacles that need to be circumvented to fully unleash the potential of induced pluripotent stem cells for precision vascular medicine.
Annexin A1 alleviates kidney injury by promoting the resolution of inflammation in diabetic nephropathy
Authors: Liang Wu, Changjie Liu, Dong-Yuan Chang, Rui Zhan, Jing Sun, Shi-He Cui, Sean Eddy, Viji Nair, Emily Tanner, Frank C. Brosius, Helen C. Looker, Robert G. Nelson, Matthias Kretzler, Jian-Cheng Wang, Ming Xu, Wenjun Ju, Ming-Hui Zhao, Min Chen, Lemin Zheng
Journal: Kidney International (2021)
Osteonecrosis of the jaw in metastatic renal cell carcinoma (mRCC) patients treated with zolendronic acid and denosumab: An observational retrospective multicenter trial.
Authors: Marco Stellato, Daniele Santini, Pierangela Sepe, Cecilia Anesi, Melanie Claps, Alessia Mennitto, Valentina Guadalupi, Ernesto Zecca, Paola Bracchi, Giuseppe Procopio, Elena Verzoni
Journal: Journal of Clinical Oncology (2021)

299 Background: Bone is one of the most common site of metastasis occurring in 30% of metastatic renal cell carcinoma (mRCC) patients (pts)3,4. Skeletal metastases from mRCC are usually osteolytic and associated to high rate of morbidity and complication through skeletal related events (SRE). Bone-targeted therapies (BTT) such as zolendronic acid (ZOL AC) and denosumab (Dmab), shown to decrease the time-to-first and subsequent SREs12. Osteonecrosis of the jaw (ONJ) is a rare but potentially serious adverse event associated with BTT. It occurs in 1-2% of pts treated with BTT and in 10-17% of mRCC pts treated with ZOL AC or Dmab. Vascular endothelial growth factor-Tyrosine kinase inhibitors (VEGF-TKI) represent the backbone treatment for mRCC. Nevertheless, it is unclear whether the association of DMAB and ZOL AC to VEGF-TKITTagents could be associated to higher incidence of ONJ. Methods: We retrospectively collected data, from 2 Italian referring centers for mRCC, about 74 pts with bone metastases from mRCC who received, concurrently or sequentially to VEGF-TKI or immune-oncology (IO), AC ZOL and DMAB from January 2013 to January 2020. All pts provided informed consent for inclusion in the study. Results: All pts received VEGF-TKI as first line treatment. 17 pts received AC ZOL whereas 57 received DMAB. All pts received odontological consultation and orthopantomography before start BTT. The median time of Dmab and AC ZOL exposure was 11.6 months. ONJ occurred in 10/74 pts (7.4%): 6/10 pts were on first line treatment and 4/10 on second line. Treatments administered at the time of ONJ diagnosis were nivolumab (1/10), cabozantinib (2/10), sorafenib (1/10), sorafenib (1/10), sunitinib (4/10) and one pts was off therapy. Conclusions: In this real-life Italian population, treatment with BTT in mRCC pts treated with VEGF-TKI inhibitors and IO is associated to higher incidence of ONJ compared to previous report of pts treated with BTT for bone metastasis and lower compared to previous reports in mRCC. Despite the retrospective collection, we provided one of the largest sample of pts treated concurrently with VEGF-TKI or IO and BTT. Physicians should be careful in the use of BTT combined with other treatments in mRCC pts.
B cell–activating factor modulates the factor VIII immune response in hemophilia A
Authors: Bhavya S. Doshi, Jyoti Rana, Giancarlo Castaman, Mostafa A. Shaheen, Radoslaw Kaczmarek, John S.S. Butterfield, Shannon L. Meeks, Cindy Leissinger, Moanaro Biswas, Valder R. Arruda
Journal: Journal of Clinical Investigation (2021)

Inhibitors of factor VIII (FVIII) remain the most challenging complication of FVIII protein replacement therapy in hemophilia A (HA). Understanding the mechanisms that guide FVIII-specific B cell development could help identify therapeutic targets. The B cell–activating factor (BAFF) cytokine family is a key regulator of B cell differentiation in normal homeostasis and immune disorders. Thus, we used patient samples and mouse models to investigate the potential role of BAFF in modulating FVIII inhibitors. BAFF levels were elevated in pediatric and adult HA inhibitor patients and decreased to levels similar to those of noninhibitor controls after successful immune tolerance induction (ITI). Moreover, elevations in BAFF levels were seen in patients who failed to achieve FVIII tolerance with anti-CD20 antibody–mediated B cell depletion. In naive HA mice, prophylactic anti-BAFF antibody therapy prior to FVIII immunization prevented inhibitor formation and this tolerance was maintained despite FVIII exposure after immune reconstitution. In preimmunized HA mice, combination therapy with anti-CD20 and anti-BAFF antibodies dramatically reduced FVIII inhibitors via inhibition of FVIII-specific plasma cells. Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors and/or anti-FVIII B cells. Finally, anti-CD20/anti-BAFF combination therapy may be clinically useful for ITI.
Long Noncoding RNA Tykril Plays a Role in Pulmonary Hypertension by Controlling the p53 Mediated Regulation of PDGFRβ
Authors: Zehendner Christoph M, Valasarajan Chanil, Thal Serge, Werner Astrid, Boeckel Jes-Niels, Bischoff Florian C, John David, Weirick Tyler, Glaser Simone-Franziska, Rossbach Oliver, Jaé Nicolas, Demolli Shemsi, Hummel Regina, Kreitner Karl-Friedrich, Möllmann Christian, Michalik Katharina M, Chen Wei, Seeger Werner, Uchida Shizuka, Zeiher Andreas M, Dimmeler Stefanie, Pullamsetti Soni
Journal: Circulation (2019)
Local Cerebral Recombinant Tissue Plasminogen Activator Concentrations During Acute Stroke
Authors: Fabian Essig, Alexander M. Kollikowski, Wolfgang Müllges, Guido Stoll, Karl Georg Haeusler, Michael K. Schuhmann, Mirko Pham
Journal: JAMA Neurology (2021)

Tissue plasminogen activator (t-PA) converts plasminogen to plasmin, which degrades fibrin. 1 Efficacy of intravenous recombinant t-PA (rt-PA) in acute ischemic stroke (IS) is attributed to timely recanalization by clot fibrinolysis.In largevessel occlusion (LVO) stroke, guidelines advocate rt-PA before mechanical thrombectomy (MT) because rt-PA may recanalize LVO earlier.However, recanalization by rt-PA before MT occurs in only about 10% of cases. 2 Another potential mode of action has been suggested by experimental observation 3 : rt-PA acts beneficially on the ischemic microvasculature even before recanalization despite occlusion.Local cerebral concentrations of exogenous rt-PA and endogenous t-PA (in patients not receiving rt-PA) are unknown.We applied a sampling and sample preparation protocol of local microcatheter aspiration from within the occluded vascular field (before recanalization) that is novel and efficient for measuring local concentrations.
Drug-Resistant Yeast Infections Spread in COVID-19 Unit: The Journal of the American Medical Association
Authors: Bridget M. M. S. J. Kuehn
Journal: JAMA (2021)

Pandemic-related lapses in infection control practices may have caused an outbreak of multidrug-resistant Candida auris yeast infections in a Florida hospital's coronavirus disease 2019 (COVID-19) unit, investigators from the US CDC and the Florida Department of Health reported  A growing public health threat in the US, C auris can cause life-threatening and difficult-to-treat infections in hospitalized patients  Florida has tracked C auris cases since 2017 to limit their spread  After the state's health department received reports last July about 3 cases in a hospital's dedicated COVID-19 unit, additional screening found that 52% of 67 COVID-19 patients in the unit were colonized with the yeast
Associations of the natural and built environment with mental health and wellbeing during COVID-19: Irish perspectives from the GreenCOVID study
Authors: Viveka Guzman, Marco Garrido-Cumbrera, Olta Braçe, Denise Hewlett, Ronan Foley
Journal: The Lancet Global Health (2021)

BackgroundIn several countries public health efforts to contain the COVID-19 pandemic have included movement restrictions that confine residents to their home or to reduced catchment areas. Household characteristics and assets of nearby spaces may be particularly relevant to support wellbeing and mental health in this context. The aim of this study was to explore wellbeing and mental health associations with factors of the immediate natural and built environment among adults in Ireland during the first wave of the COVID-19 pandemic.MethodsWe did cross-sectional analyses using Irish data from the GreenCOVID study. Participants were recruited online between June and July, 2020, with a convenience sampling approach. All respondents who provided informed consent and data on variables of interest were included in analysis. Wellbeing was assessed with the WHO-5 Wellbeing Index, and mental health with the Kessler Psychological Distress Scale. Means and SD were used to describe the perceived importance of views to green and blue spaces and physical access to outdoor spaces (range 0–10). We used χ2 tests and multiple linear regression models to explore associations of wellbeing and mental health with household type, household problems, number of bedrooms, number of co-habitants, spaces enabling physical access to the outdoors, quality of views and views to green spaces from home. Regression models were controlled by age, gender, city versus non-city household location, marital status, and self-perceived health.FindingsWe included data from 243 participants; mean age was 43 years (SD 16) and most participants were women (n=174 [72%]). Participants perceived that the outdoors helped them cope with restriction measures to a high extent (mean score 8·54 [SD 1·79]; 43% of respondents reported the maximum score), and highly valued views to blue (7·82 [2·45]) and green spaces (8·84 [1·76]). Household problems were significantly associated with lower wellbeing scores (beta=–9·78 [95% CI −15·675 to −3·885]) and increased likelihood of mental disorders (0·583 [0·284 to 0·889]).InterpretationOur findings show high perceived benefits of views to green and blue spaces and access to the outdoors from home during the first wave of COVID-19. Moreover, those living in a household with problems had higher likelihood of poor mental health outcomes. This study highlights the importance of natural and built environment in helping people cope with the negative effects of the restrictions imposed during the COVID-19 pandemic.FundingHealth Research Board (HRB), grant no. SPHeRE-2019-1.
INNOVATE (NRG-GU008): A randomized phase III trial of salvage radiotherapy and androgen deprivation therapy (ADT) with/without abiraterone and apalutamide for patients with node-positive prostate cancer after radical prostatectomy.
Authors: Ronald C. Chen, Theodore Karrison, Colleen Anne Lawton, William Adrian Hall, Hala Borno, Mihaela Rosu, Ashesh B. Jani, David M. Schuster, Michael J. Seider, Jason A. Efstathiou, Edwin Melencio Posadas, Paul L. Nguyen, Felix Y Feng
Journal: Journal of Clinical Oncology (2021)

TPS179 Background: Node-positive prostate cancer comprises for approximately 13% of newly-diagnosed patients and represents an aggressive form of the disease, but has been historically understudied in therapeutic clinical trials. Cure rates remain suboptimal for these patients with early stage IV disease, so clinical trials to intensify systemic treatment are warranted. Abiraterone and apalutamide have each demonstrated efficacy in improving metastasis-free survival and/or overall survival in the advanced stage setting, including both castrate-resistant and metastatic castration-sensitive prostate cancer. The mechanisms of action of abiraterone and apalutamide are complementary, and combination therapy has been shown in a prior Phase Ib trial to be safe and well-tolerated. Methods: Patients with pathologic node-positive disease by radical prostatectomy and who subsequently have a detectable PSA are eligible for this randomized controlled trial. All patients are required to receive molecular imaging (FACBC, PSMA, or choline PET scan) at trial entry and must have no radiographic evidence of distant metastasis in order to remain eligible. Eligible patients are randomized 1:1 to (control arm) salvage radiation therapy with 2 years of ADT vs (experimental arm) addition of 2 years of abiraterone/prednisone and apalutamide. The primary endpoint is metastasis-free survival. With a sample size of 586 and with a potential for 10% loss to follow-up, the trial has 90% power with one-sided alpha=0.025 to detect a HR of 0.53 for the experimental arm vs control arm for the primary endpoint. Secondary endpoints include quality of life (EPIC-26, EQ5D-5L, Brief Pain Inventory, PROMIS-Fatigue), overall survival, time to castrate resistance, and other disease-related outcomes. In addition, data will be collected to validate the Decipher score and PAM50-based classification as predictive biomarkers in this node-positive patient population. Trial was activated on March 5, 2020, and is currently enrolling patients. This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA196067 (NRG Oncology Specimen Bank) from the National Cancer Institute (NCI) and Janssen and GenomeDX. Clinical trial information: NCT04134260.
<i>Akkermansia muciniphila</i> and environmental enrichment reverse cognitive impairment associated with high-fat high-cholesterol consumption in rats
Authors: Sara G. Higarza, Silvia Arboleya, Jorge L. Arias, Miguel Gueimonde, Natalia Arias
Journal: Gut Microbes (2021)

Nonalcoholic steatohepatitis (NASH) is one of the most prevalent diseases globally. A high-fat, high-cholesterol (HFHC) diet leads to an early NASH model. It has been suggested that gut microbiota mediates the effects of diet through the microbiota-gut-brain axis, modifying the host's brain metabolism and disrupting cognition. Here, we target NASH-induced cognitive damage by testing the impact of environmental enrichment (EE) and the administration of either Lacticaseibacillus rhamnosus GG (LGG) or Akkermansia muciniphila CIP107961 (AKK). EE and AKK, but not LGG, reverse the HFHC-induced cognitive dysfunction, including impaired spatial working memory and novel object recognition; however, whereas AKK restores brain metabolism, EE results in an overall decrease. Moreover, AKK and LGG did not induce major rearrangements in the intestinal microbiota, with only slight changes in bacterial composition and diversity, whereas EE led to an increase in Firmicutes and Verrucomicrobia members. Our findings illustrate the interplay between gut microbiota, the host's brain energy metabolism, and cognition. In addition, the findings suggest intervention strategies, such as the administration of AKK, for the management of the cognitive dysfunction related to NASH.
10-Year Follow-Up of Patients With Everolimus-Eluting Versus Bare-Metal Stents After ST-Segment Elevation Myocardial Infarction
Authors: Salvatore Brugaletta, Josep Gomez-Lara, Luis Ortega-Paz, Victor Jimenez-Diaz, Marcelo Jimenez, Pilar Jiménez-Quevedo, Roberto Diletti, Vicente Mainar, Gianluca Campo, Antonio Silvestro, Jaume Maristany, Xacobe Flores, Loreto Oyarzabal, Antonio De Miguel-Castro, Andrés Iñiguez, Antonio Serra, Luis Nombela-Franco, Alfonso Ielasi, Maurizio Tespili, Mattie Lenzen, Nieves Gonzalo, Pascual Bordes, Matteo Tebaldi, Simone Biscaglia, Juan Jose Rodriguez-Arias, Soheil Al-Shaibani, Victor Arevalos, Rafael Romaguera, Joan Antoni Gomez-Hospital, Patrick W. Serruys, Manel Sabaté
Journal: Journal of the American College of Cardiology (2021)
Neoadjuvant immunotherapy for non–small cell lung cancer: State of the art
Authors: Jin Kang, Chao Zhang, Wen‐Zhao Zhong
Journal: Cancer Communications (2021)

Abstract Lung cancer mortality has decreased over the past decade and can be partly attributed to advances in targeted therapy and immunotherapy. Immune checkpoint inhibitors (ICIs) have rapidly evolved from investigational drugs to standard of care for the treatment of metastatic non‐small cell lung cancer (NSCLC). In particular, antibodies that block inhibitory immune checkpoints, such as programmed cell death protein 1 (PD‐1) and programmed cell death 1 ligand 1 (PD‐L1), have revolutionized the treatment of advanced NSCLC, when administered alone or in combination with chemotherapy. Immunotherapy is associated with higher response rates, improved overall survival (OS), and increased tolerability compared with conventional cytotoxic chemotherapy. These benefits may increase the utility of immunotherapy and its combinational use with chemotherapy in the neoadjuvant treatment of patients with NSCLC. Early findings from various ongoing clinical trials suggest that neoadjuvant ICIs alone or combined with chemotherapy may significantly reduce systemic recurrence and improve long‐term OS or cure rates in resectable NSCLC. Here we further summarize the safety and efficacy of various neoadjuvant treatment regimens including immunotherapy from ongoing clinical trials and elaborate the role of neoadjuvant immunotherapy in patients with resectable NSCLC. In addition, we discuss several unresolved challenges, including the evaluations to assess neoadjuvant immunotherapy response, the role of adjuvant treatment after neoadjuvant immunotherapy, the efficacy of treatment for oncogenic‐addicted tumors, and predictive biomarkers. We also provide our perspective on ways to overcome current obstacles and establish neoadjuvant immunotherapy as a standard of care.
A framework for living evidence synthesis in cancer: Living, interactive network meta-analysis for first-line treatment of metastatic renal cell carcinoma (mRCC).
Authors: Irbaz Bin Riaz, Huan He, Alexander J. Ryu, Rabbia Siddiqi, Syed Arsalan Ahmed Naqvi, Yuan Yao, Muhammad Husnain, Deepa Maheswari, Qurat Ul Ain Riaz Sipra, Victor Montori, Richard Wayne Joseph, Hongfang Liu, Zhen Wang, Vitaly Herasevich, Parminder Singh, Thai Huu Ho, Alan Haruo Bryce, Lance C. Pagliaro, M. Hassan Murad, Brian Addis Costello
Journal: Journal of Clinical Oncology (2021)

335 Background: Systematic reviews are outdated quickly when the evidence is rapidly evolving as the process is laborious and there is little incentive for primary author team of an index SRMA to update the evidence. Consequently, there is an epidemic of redundant SRMAs performed by different teams—sometimes with conflicted results—for treatment of first line mRCC. Methods: We have created a living, interactive systematic review (LISR)and network meta-analysis(LINMA) for the treatment of first line mRCC using an Artificial intelligence (AI) assisted framework for evidence synthesis (Living, Interactive evidence synthesis framework) (LIvE) . The framework is implemented in five-layered architecture (application layer, shared module layer, core service layer, middleware layer, and storage layer) which work together to automate the identification of new studies and analysis and semi-automate the screening and data extraction. Dynamic features such as interactive tables, figures and evidence maps are enabled using Python and JavaScript programming languages. Results: We have maintained a living, interactive evidence profile for the first line treatment mRCC since September 2019 ( LIVING WEBSITE) . Living search strategy identifies new studies as they become available. As of October 13, 2020 LISR, includes data 14 clinical trials ( PRISMA ). Baseline characteristics are summarized in an interactive table ( TABLE) . Cabozantinib&amp; Nivolumab (Cabo-Nivo) is the highest ranked drug for improving Overall Response (OR), Progression Free Survival (PFS) and Overall Survival (OS) whereas Ipilimumab in combination with Nivolumab (Ipi-Nivo) is highest ranked drug for achieving complete response (CR). Ipi-Nivo and Atezolizumab &amp; Bevacizumab (Ate-Bev) ranked highest and Cabo-Nivo ranked lowest for treatment related Adverse events (TRAEs). Results of network meta-analysis are summarized as interactive tables and plots ( NMA ), summary of findings tables ( MULTIPLE COMAPRISONS ) and evidence maps ( MAP ). Conclusions: LISRs can potentially reduce redundancy, increase transparency, reproducibility, enable shared-decision making (at a guideline level, or in a patient-clinician dyad) and support living guidelines.
An Evidence-Based Beneficial Shortcut for Distal Pancreatic Resection
Authors: Pauli Puolakkainen, Paulina Salminen
Journal: JAMA Surgery (2021)

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