tbuckley/cabot-search huggingface dataset:
Abstract 17404: Intramolecular Inhibition of Ser473 Phosphorylation by Up-regulated Thr308 Phosphorylation in Akt Contributes to Enlargement of Infarct Size by Chronic Renal Failure
Authors: Toshiyuki Tobisawa, Toshiyuki Yano, Takayuki Miki, Masaya Tanno, Atushi Kuno, Hidemichi Kouzu, Makoto Ogasawara, Shingo Muratsubaki, Kohei Ohno, Keitaro Nishizawa, Masashi Mizuno, Wataru Ohwada, Satoko Ishikawa, Tetsuji Miura
Journal: Circulation (2015)

Objective: We previously showed that chronic renal failure (CRF) enlarges infarct size after ischemia/reperfusion (I/R) through impairment of reperfusion-induced Akt activation. Here we examined molecular mechanisms by which CRF impairs Akt activation, focusing on interplay between two phosphorylation sites in Akt, Thr308 and Ser473. Methods and results: Rats received 5/6 nephrectomy (SNx) or a sham operation (Sham). Development of CRF in SNx was confirmed by a 2.2-fold increase in serum creatinine level at 4 weeks after the operation. Infarct size after 20-min coronary occlusion/2-hr reperfusion was larger in SNx than in Sham (53.2±5.8 vs. 41.1±2.4% of risk area, p&lt;0.05), indicating impaired tolerance against I/R injury in CRF. Immunoblot analyses revealed that the level of phospho-Akt-Thr308 was higher by 375% in SNx than in Sham under baseline conditions, while the levels of phospho-Akt-Ser473 were similar in the two groups. Upon reperfusion, phosphorylation of Ser473 and that of Thr308 were similarly enhanced in Sham. However, reperfusion-induced phosphorylation of Ser473, but not that of Thr308, was blunted by 32.8% in SNx compared with that in Sham. Reduction in Akt activity after reperfusion in SNx was indicated by lower levels of phospho-p70S6K and phospho-GSK3β compared with those in Sham. The levels of PTEN, a negative regulator of Akt, and PDK1, a promoter of Thr308 phosphorylation, were similar in SNx and Sham. However, the level of PP2A regulatory subunit B55α, which specifically dephosphorylates Thr308, was lower by 23.6% in SNx than in Sham. To determine whether the constitutive phosphorylation of Thr308 mitigates reperfusion-induced phosphorylation of Ser473, HA-tagged wild-type Akt (HA-WT) and phospho-Thr308-mimetic mutant Akt (HA-T308D) were transiently transfected into HEK293 cells. IGF-1 (10 nmol/L)-induced phosphorylation of Ser473 in HA-T308D was lower by 30.5% than that in HA-WT, whereas that in endogenous Akt at Ser473 was comparable between cells overexpressing HA-T308D and HA-WT. Conclusion: Insufficient activation of Akt by its intramolecular interplay between Thr308 and Ser473 phosphorylation due to down-regulated B55α contributes to increased myocardial susceptibility to I/R injury in CRF.
Acute myeloid leukemia and myelodysplastic syndrome–associated Sweet syndrome: A comparative multicenter retrospective study of 39 patients
Authors: Marie Merlant, Clémence Lepelletier, Maxime Battistella, Marie-Dominique Vignon-Pennamen, Paul Duriez, Philippe Moguelet, Florence Brunet-Possenti, Martine Bagot, François Chasset, Jean David Bouaziz
Journal: Journal of the American Academy of Dermatology (2020)
Comparison of First-Line Treatments for Patients With Extensive-Stage Small Cell Lung Cancer
Authors: Ting Zhou, Zhonghan Zhang, Fan Luo, Yuanyuan Zhao, Xue Hou, Tingting Liu, Kai Wang, Hongyun Zhao, Yan Huang, Li Zhang
Journal: JAMA Network Open (2020)

Combinations of chemotherapy with immunotherapy or bevacizumab in first-line treatments of extensive-stage small cell lung cancer (ES-SCLC) have been evaluated in various clinical trials. However, it remains unclear what the optimal combination regimen is.To clarify which first-line combination regimen is associated with the best tumor response among patients with ES-SCLC.Electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were systematically searched to extract eligible literature from database inception to December 2019.Head-to-head randomized clinical trials on first-line treatments for patients with ES-SCLC were included with outcomes and toxic effects reported, including objective response rate (ORR, involving complete response and partial response), disease control rate (DCR, involving complete response, partial response, and stable disease), progression-free survival (PFS), overall survival (OS), and treatment related adverse events (TRAEs) of grades 3 to 5. Of 199 eligible articles, 14 were included.Data were independently extracted and collected by 2 reviewers based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Data were pooled using a random-effects model.Main outcomes were OS, PFS, DCR, ORR, and TRAEs of grades 3 to 5.A total of 3 phase 2 and 11 phase 3 randomized clinical trials involving 4838 patients were included. Programmed cell death ligand 1 (PD-L1) inhibitor (durvalumab and atezolizumab) plus etoposide-based chemotherapy, compared with etoposide-based chemotherapy alone, showed the most favorable OS (hazard ratio, 1.40; 95% CI, 1.09-1.80) and the best DCR (odds ratio [OR], 0.42; 95% CI, 0.21-0.81). Bevacizumab plus etoposide-based chemotherapy provided the best PFS compared with etoposide-based chemotherapy alone (hazard ratio, 1.54; 95% CI, 1.09-2.27), although this was not translated into OS benefit. The addition of PD-L1 inhibitors to etoposide-platinum chemotherapy caused no more toxic effects in general (compared with etoposide-based chemotherapy alone: OR, 1.14; 95% CI, 0.36-2.31), while bevacizumab plus etoposide-platinum regimen induced the most TRAEs grades 3 to 5 among all first-line treatments (eg, compared with irinotecan-platinum regimen: OR, 4.24; 95% CI, 1.26-14.57). Based on the surface under the cumulative ranking curve value, PD-L1 inhibitor plus etoposide-platinum had the highest probability of being ranked first for OS (0.87) and DCR (0.97).The findings of this systematic review and network meta-analysis suggest that the combination of a PD-L1 inhibitor (durvalumab and atezolizumab) and etoposide-based chemotherapy may be an optimal first-line treatment option for patients with ES-SCLC patients.
Efficacy and safety profile of deep responders to carfilzomib-based therapy: a subgroup analysis from ASPIRE and ENDEAVOR
Authors: Katja Weisel, Maria-Victoria Mateos, Francesca Gay, Michel Delforge, Gordon Cook, Zsolt Szabo, Renaud Desgraz, Lucy DeCosta, Philippe Moreau
Journal: Leukemia (2020)

Abstract To understand the profile of best responders (complete response or better [≥CR]) to carfilzomib, we described the characteristics, progression-free survival (PFS), overall survival (OS) data, and the safety of patients who achieved ≥CR to carfilzomib-based treatment in ASPIRE and ENDEAVOR. In post hoc analyses from ASPIRE and ENDEAVOR, median PFS and OS were longer for ≥CR patients versus those who achieved a very good partial response or partial response (VGPR/PR). In the carfilzomib arm of ASPIRE, median PFS was 50.4 months for ≥CR versus 22.1 months for VGPR/PR; median OS was 67.0 versus 44.2 months, respectively. In the carfilzomib arm of ENDEAVOR, median PFS was 34.0 for ≥CR versus 20.4 months for VGPR/PR; median OS was non-estimable. Despite the longer treatment duration, fewer patients with ≥CR versus VGPR/PR experienced treatment-emergent adverse events that led to discontinuation of carfilzomib-based treatment in ASPIRE or ENDEAVOR. Low serum lactate dehydrogenase was the only factor associated with achieving ≥CR vs patients not achieving CR in ASPIRE in multivariate regression analyses. No association was found between cytogenetic risk status and reaching ≥CR. Carfilzomib treatment may lead to rapid and deep responses, irrespective of most patient characteristics.
Immigration in science
Authors: Jean-Laurent Casanova, David M. Holtzman, Susan M. Kaech, Lewis L. Lanier, Carl F. Nathan, Alexander Y. Rudensky, David Tuveson, Jedd D. Wolchok
Journal: The Journal of Experimental Medicine (2020)

The advance of science is dependent upon collaboration, which does not have a visa attached to it. Indeed, over 40% of all American-based Nobel Prize winners are immigrants, and data from the National Science Foundation show that 49% of postdocs and 29% of science and engineering faculty in the US are foreign-born. However, restrictive new immigration policies in the US have left many scientists deeply concerned about their future and many American-based laboratories worried about attracting the best talent. At JEM, we’re celebrating immigration by sharing the experiences of immigrant and nonimmigrant scientists on our editorial board. Alexander Rudensky and Jean-Laurent Casanova give their firsthand perspective on immigrating to the US, while Jedd Wolchok, Carl Nathan, David Holtzman, Susan Kaech, Lewis Lanier, and David Tuveson reflect on how immigration has affected their laboratories.
Abstract 17987: Structural and Senescence Changes in the Atria of Lone Atrial Fibrillation Patients
Authors: Montserrat Batlle, Naiara Calvo, Manel Castellà, Elena Sandoval, Pablo Ramos, Félix Pérez-Villa, José Ramírez, Eduard Guasch, Josep Brugada, Lluís Mont
Journal: Circulation (2015)

Introduction: Hypertension and structural heart disease (SHD) are the most frequent causes of Atrial Fibrillation (AF). Hemodynamic overload and inflammation are key mediators of the arrhythmogenic substrate, at least partly by triggering accelerated senescence. Remarkably, up to one third of AF patients have no associated SHD (lone AF), and their arrhythmogenic substrate is largely unknown. We sought to compare structural and senescence changes in AF patients with or without SHD. Methods: Atrial appendage samples from four groups of patients were analyzed; patients with no SHD (AF_lone, n=10), AF patients with SHD (AF_Card, n=14), controls with no AF but with other cardiovascular diseases (CVD) (C_CVD, n=18) and controls with no CVD (C_Healthy, n=5). The percentage of intramyocardial collagen deposition was quantified by sirius red staining and morphometric analysis, and connexin-43 was analyzed by immunohistochemistry. Tissue senescence was evaluated with telomere length quantification and mRNA levels of a family of proteins involved in cellular senescence (Sirtuin-1, -2, -3 and -6). Results: There were no differences in age (overall mean 60 ± 2 years) and the percentage of male gender (overall 67%) between groups of patients. AF patients had a marked increase in atrial fibrosis, with no differences between AF_lone and AF_Card (Figure A). Connexin-43 quantification and distribution was similar in AF patients with or without SHD. Nevertheless, telomeres were longer in AF_lone than in AF_Card patients (Figure B). Also, AF_lone samples had higher mRNA levels of sirtuin-2 and -3 compared to AF_Card samples with no changes in sirtuin-1 and -6. Conclusions: Even though a similar degree of structural remodelling was found, AF_Card patients presented an accelerated atrial senescence when compared to AF_lone patients. These results could have important implications in the prognosis and therapeutic options of AF_lone patients.
Abstract 16989: Use of Screening Echocardiography to Improve Healthcare in Underserved Areas of Brazil: Data From the PROVAR+ Study
Authors: Adriana C Diamantino, Maria Carmo P Nunes, Craig Sable, Bruno R Nascimento, Emily M Lima, Larissa N Martins, Enrico A Colossimo, Tatiana C Diamantino, Breno D Rezende, João Pedro P Rios, Andrea Z Beaton, Antonio Luiz P Ribeiro
Journal: Circulation (2018)

Introduction: Access to public health care is limited in Brazil, especially in remote areas and many patients remain on long waiting lists for echocardiography (echo). Advances in handheld echo and telemedicine provide an opportunity for integration of screening for cardiovascular disease into the existing primary care system. This may improve early detection of heart disease (HD) and guide prioritization of referrals. We aimed to test the accuracy of screening echo to identify significant HD in this setting. Methods: Patients on waiting lists for the echos were eligible and answered a standardized clinical questionnaire. All subjects underwent focused 7-view screening echo (GE VSCAN), acquired by non-physicians in primary care centers and interpreted remotely by experts through cloud-storage and telemedicine. All patients underwent standard echo (GE Vivid Q), performed by an expert, blinded for the screening echo images and diagnoses. Significant HD was defined as any ventricular dysfunction, moderate to severe valve disease, moderate to severe left ventricle hypertrophy, aortic root dilatation or congenital heart disease. Statistical analysis was performed using classification and regression tree analysis based on 70% of the sample for training and 30% for test. Results: Over 9 months we evaluated 569 patients. Median age was 58.7 years, 61.4% were females, 71.6% had hypertension, 22.9% diabetes, 16.3% Chagas disease, 9.3% coronary disease, 4.8% valve disease. The most frequent symptoms were chest pain, dyspnea and palpitations, isolated or in combination, and 29.5% were asymptomatic. The presence of symptoms was not a good predictor for abnormal echo findings. Significant HD was observed in 147 (25.8%) patients on the standard echo. The model utilizing clinical features alone didn′t show a good accuracy on detecting significant HD. The screening echo alone had a negative predictive value of 0.94, with an overall accuracy of 78%. The integration of the screening echo variables with clinical features on the decision tree generated an accuracy of 82.4%, using the variables with statistical significance (Chagas disease, valve disease, coronary disease, body mass index, gender and age). Conclusions: Integration of screening echo into primary care is feasible in Brazil and should ensure that patients with higher needs have priority access to standard echocardiography and referrals. The burden of HD observed and the accuracy of screening echo performed by non-physicians suggests this tool may help deliver health care to underserved areas.
Two vs One Forward View Examination of Right Colon on Adenoma Detection: An International Multicenter Randomized Trial
Authors: Raymond S.Y. Tang, Jonathan W.J. Lee, Li-Chun Chang, David E.H. Ong, Han-Mo Chiu, Takahisa Matsuda, Hyun-Soo Kim, Masau Sekiguchi, Rupert W. Leong, Andrew M.Y. Ho, Thomas Y.T. Lam, Yee Kit Tse, Lucy Lin, Khay-Guan Yeoh, James Y.W. Lau, Joseph J.Y. Sung
Journal: Clinical Gastroenterology and Hepatology (2020)
Detection and discrimination of influenza B Victoria lineage deletion variant viruses by real-time RT-PCR
Authors: Bo Shu, Marie K Kirby, Christine Warnes, Wendy M Sessions, William G Davis, Ji Liu, Malania M Wilson, Stephen Lindstrom, David E Wentworth, John R Barnes
Journal: Eurosurveillance (2020)

Background During the 2016/17 influenza season, influenza B/VIC lineage variant viruses emerged with two (K 162 N 163 ) or three (K 162 N 163 D 164 ) amino acid (aa) deletions in the haemagglutinin (HA) protein. There are currently five antigenically distinct HA proteins expressed by co-circulating influenza B viruses: B/YAM, B/VIC V1A (no deletion), B/VIC V1A-2DEL (2 aa deletion) and two antigenically distinguishable groups of B/VIC V1A-3DEL (3 aa deletion). The prevalence of these viruses differs across geographical regions, making it critical to have a sensitive, rapid diagnostic assay that detects and distinguishes these influenza B variant viruses during surveillance. Aim Our objective was to develop a real-time RT-PCR (rRT-PCR) assay for detection and discrimination of influenza B/VIC lineage variant viruses. Methods We designed a diagnostic assay with one pair of conserved primers and three probes specific to each genetic group. We used propagated influenza B/VIC variant viruses and clinical specimens to assess assay performance. Results This rRT-PCR assay detects and distinguishes the influenza B/VIC V1A, B/VIC V1A-2DEL, and B/VIC V1A-3DEL variant viruses, with no cross-reactivity. This assay can be run as a multiplex reaction, allowing for increased testing efficiency and reduced cost. Conclusion Coupling this assay with the Centers for Disease Control and Prevention’s Human Influenza Virus Real-Time RT-PCR Diagnostic Panel Influenza B Lineage Genotyping Kit results in rapid detection and characterisation of circulating influenza B viruses. Detailed surveillance information on these distinct influenza B variant viruses will provide insight into their prevalence and geographical distribution and could aid in vaccine recommendations.
Telemonitoring in patients with chronic heart failure and moderate depressed symptoms: results of the <scp>Telemedical Interventional Monitoring in Heart Failure</scp> ( <scp>TIM‐HF</scp> ) study
Authors: Johanna Koehler, Andreas Stengel, Tobias Hofmann, Karl Wegscheider, Kerstin Koehler, Susanne Sehner, Matthias Rose, Oliver Deckwart, Stefan D. Anker, Friedrich Koehler, Ulrich Laufs
Journal: European Journal of Heart Failure (2020)

Depression is a frequent comorbidity in patients with chronic heart failure (CHF). Telemonitoring has emerged as a novel option in CHF care. However, patients with depression have been excluded in most telemedicine studies. This pre-specified subgroup analysis of the Telemedical Interventional Monitoring in Heart Failure (TIM-HF) trial investigates the effect of telemonitoring on depressive symptoms over a period of 12 months.The TIM-HF study randomly assigned 710 patients with CHF to either usual care (UC) or a telemedical intervention (TM) using non-invasive devices for daily monitoring electrocardiogram, blood pressure and body weight. Depression was evaluated by the 9-item Patient Health Questionnaire (PHQ-9) with scores ≥10 defining clinically relevant depressive symptoms. Mixed model repeated measures were performed to calculate changes in PHQ-9 score. Quality of life was measured by the Short Form-36. At baseline, 156 patients had a PHQ-9 score ≥10 points (TM: 79, UC: 77) with a mean of 13.2 points indicating moderate depressiveness. Patients randomized to telemedicine showed an improvement of their PHQ-9 scores, whereas UC patients remained constant (P = 0.004). Quality of life parameters were improved in the TM group compared to UC. Adjustment was performed for follow-up, New York Heart Association class, medication, age, current living status, number of hospitalizations within the last 12 months and serum creatinine. In the study population without depression, the PHQ-9 score was similar at baseline and follow-up.Telemedical care improved depressive symptoms and had a positive influence on quality of life in patients with CHF and moderate depression.
Comparison of Prostate-Specific Membrane Antigen PET/CT and Contrast-Enhanced Magnetic Resonance Imaging in Follow-up Assessment of Juvenile Nasal Angiofibroma—A Novel Pilot Study
Authors: Alok Thakar, Pirabu Sakthivel, Sreedharan Thankarajan Arunraj, Ashu Seith Bhalla, Aanchal Kakkar, Rakesh Kumar, Rakesh Kumar
Journal: Clinical Nuclear Medicine (2020)

The specific identification of residual/recurrent juvenile nasal angiofibroma (JNA) following surgical treatment remains difficult. Contrast MRI and CT may not enable the differentiation of tumor from postsurgical reparative tissue. Functional imaging with prostate-specific membrane antigen (PSMA) PET/CT targeting tumor-associated neovasculature has recently demonstrated universal positive uptake in primary JNA and offers promise of greater accuracy in the detection or exclusion of recurrent/residual JNA.In this prospective study, 18 postsurgical JNA patients with high suspicion for residual disease evinced by follow-up MR scan, or nasal endoscopy, or recent epistaxis during September 2018-November 2019 were included. All patients underwent head and neck spot PSMA PET/CT imaging. Postcontrast enhancement of a definite lesion was considered as a criterion for residual/recurrent tumor in contrast-enhanced MRI (CEMRI). In PSMA PET/CT, any abnormal uptake apart from physiological sites in the head and neck was considered as residual lesions. Radiological results were categorized as negative, suspicious, and residual/recurrent tumors. Any discrepancy between CEMRI and PSMA was resolved by surgical biopsies. The sensitivity, specificity, and positive and negative predictive values were separately calculated for CEMRI and PSMA PET/CT for diagnosing residual lesions. The interrater agreement κ value was also calculated.On CEMRI evaluation, 14 of 18 patients had residual tumors, 2 had suspicious residual lesions, and 2 had normal postoperative scans. On PSMA PET/CT, 12 of 18 patients had residual tumors, and 6 had normal negative scans. Surgical biopsy in all 4 discordant cases was negative for tumors and revealed only fibrosis. In 1 patient with residual tumor on both scans, discrepancy was noted with regard to tumor extent demonstrated by the 2 scans, and further surgical excision confirmed the imaging findings of PSMA PET/CT as accurate. The sensitivity, specificity, and positive and negative predictive values of CEMRI were 100%, 33.33%, and 75% and 100%, respectively. The sensitivity, specificity, and positive and negative predictive values of PSMA PET/CT were 100% for all parameters. The interrater agreement between the 2 tests (κ) is 0.5 (95% confidence interval, 0.19-0.81).The Ga-PSMA PET/CT is noted as more specific than the current standard of CEMRI in the identification of residual/recurrent JNA. It is the first radionuclide imaging scan that has found application in postoperative assessment of JNA.Clinical Trials Registry of India (CTRI/2018/08/015479).
Polymeric Nanoparticles Controlled by On‐Chip Self‐Assembly Enhance Cancer Treatment Effectiveness
Authors: Sungjin Jung, Junseok Lee, Junha Lim, Jeeyeon Suh, Taeyoung Kim, Jungho Ahn, Won Jong Kim, YongTae Kim
Journal: Advanced Healthcare Materials (2020)

Nanoparticle (NP)-based drug delivery systems or nanomedicines have broadened the horizon of translational research for decades. Conventional bulk mixing synthesis methods have impeded successful clinical translations of nanomedicines due to the limited ability of the controlled, scalable production with high uniformity. Herein, an on-chip preparation of self-assembled, drug-encapsulated polymeric NPs is presented for their improved uniformity and homogeneity that results in enhanced anti-cancer effect in vitro and in vivo. The NPs are formulated through rapid convective mixing of two aqueous solutions of a hydrophilic polymer and an anti-cancer drug, doxorubicin (DOX), in the swirling microvortex reactor (SMR). Compared to conventional bulk-mixed NPs (BMPs), the microvortex-synthesized NPs (MVPs) exhibit narrower size distributions and better size tunability. It is found that the improved uniformity and homogeneity of the MVPs not only enhance cellular uptake and anti-cancer effect with pH-responsive drug release in vitro, but also result in an improved tumor regression and decreased side effects at off-targeted organs in vivo. The findings demonstrate that uniformly designed NPs with more homogeneous properties can induce a significant enhancement of an anti-cancer effect in vivo. The results show the potential of a high-speed on-chip synthesis as a scalable manufacturing platform for reliable clinical translations of nanomedicines.