tbuckley/cabot-search huggingface dataset:
Linking the KIR phenotype with <i>STAT3</i> and <i>TET2</i> mutations to identify chronic lymphoproliferative disorders of NK cells
Authors: Cédric Pastoret, Fabienne Desmots, Gaëlle Drillet, Simon Le Gallou, Marie-Laure Boulland, Alexia Thannberger, Anne-Violaine Doncker, Véronique Salaun, Gandhi Laurent Damaj, Richard Veyrat-Masson, Olivier Tournilhac, Aline Moignet, Céline Pangault, Mikaël Roussel, Thierry Fest, Thierry Lamy
Journal: Blood (2021)
Ultra-small lipid nanoparticles encapsulating sorafenib and midkine-siRNA selectively-eradicate sorafenib-resistant hepatocellular carcinoma in vivo
Authors: Mahmoud A. Younis, Ikramy A. Khalil, Yaser H.A. Elewa, Yasuhiro Kon, Hideyoshi Harashima
Journal: Journal of Controlled Release (2021)
Subgroup analyses of patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) treated with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line (1L) therapy:Two-year clinical update.
Authors: Heinz-Josef Lenz, Sara Lonardi, Vittorina Zagonel, Eric Van Cutsem, M. Luisa Limon, Ka Yeung Mark Wong, Alain Hendlisz, Massimo Aglietta, Pilar Garcia-Alfonso, Bart Neyns, Gabriele Luppi, Dana Backlund Cardin, Tomislav Dragovich, Usman Shah, Jing Yang, Arteid Memaj, Michael J. Overman
Journal: Journal of Clinical Oncology (2021)

58 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI had robust, durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (median follow-up, 29.0 months [range, 24.2–33.7]) (Lenz et al. J Clin Oncol 2020;38:Abstract 4040; NCT02060188). Objective response rate (ORR) per investigator (INV) was achieved in 69% of pts (95% CI, 53–82); progressive disease rate was 13%. Median progression-free survival (PFS) and overall survival (OS) were not reached. Median duration of treatment was 19.1 months (95% CI, 11.1–29.0). Grade 3–4 treatment-related adverse events (TRAEs) occurred in 22% of pts. We present the post hoc subgroup analyses of efficacy and safety outcomes in pts from the same follow-up based on demographics and baseline disease characteristics. Methods: Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + low-dose IPI 1 mg/kg Q6W until disease progression or discontinuation. ORR (primary endpoint, RECIST v1.1) and PFS were assessed per INV. Post hoc subgroup analyses of efficacy (by ECOG performance status [PS], stage at initial diagnosis, primary tumor location, and BRAF/KRAS mutation status) and safety (by age and ECOG PS) are presented. Results: Among 45 treated pts, efficacy (Table) and safety were generally consistent across evaluated subgroups. ORR was similar in pt subgroups by BRAF/ KRAS mutation status, stage at initial diagnosis, primary tumor location, and ECOG PS (Table). Median PFS and OS were not reached (NR) in evaluated subgroups after a minimum follow-up of 24.2 months (Table). Incidence of grade 3–4 TRAEs for subgroups by age and ECOG PS were consistent with the overall population. Conclusions: NIVO + low-dose IPI demonstrated robust, durable clinical benefit; was well tolerated with 2-year follow-up; and was consistent in evaluated subgroups in 1L MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
Nanoliposomal irinotecan-based chemotherapy after regular irinotecan-based chemotherapy in patients with pancreas cancer.
Authors: Caleb J Smith, Tanios S. Bekaii-Saab, Kathryn Cook, Rachel Eiring, Thorvardur Ragnar Halfdanarson, Mina Samir Erian Hanna, Zhaohui Jin, Jacob A. Jochum, Wen Wee Ma, Jessica L Mitchell, Henry C. Pitot, Aminah Jatoi
Journal: Journal of Clinical Oncology (2021)

402 Background: Pancreas cancer is an aggressive malignancy with limited therapeutic options. Nanoliposomal irinotecan (Nal-IRI) is a preferred second-line treatment, and current guidelines recommend its use in the absence of prior irinotecan. This study aimed to assess whether patients who had received regular irinotecan derive benefit from Nal-IRI. Methods: Medical records of metastatic pancreas cancer patients who had received regular irinotecan and then Nal-IRI were reviewed. The following information was extracted from each medical record: patient demographics, confirmation of a diagnosis of exocrine pancreas cancer, initial cancer stage, dates of administration of the drugs of interest, adverse events that occurred with Nal-IRI treatment, reasons for stopping regular irinotecan, and reasons for starting and stopping Nal-IRI. The primary endpoint was overall survival after the initiation of Nal-IRI (an a priori threshold of &gt; 4 months defined success). Survival data were censored based on date of last follow up. Direct quotes from the medical record were documented to provide insight on prescribing Nal-IRI when guidelines advised the contrary. Results: Sixty four patients met eligibility criteria with a median age of 65 years (range: 36, 80 years). Prior to Nal-IRI, 61 patients had received FOLFIRINOX, and 3 FOLFIRI. Of these, 32 patients manifested progressive disease on regular irinotecan-based therapy. Nal-IRI was prescribed with a fluoropyrimidine; only one patient received monotherapy. At time of analysis, 54 patients had died. Median overall survival from initiation of Nal-IRI was 5.1 months (95% confidence interval (CI): 5.6, 4.3, months). An exploratory comparison, based on no cancer progression with regular irinotecan versus progression, showed improved survival with Nal-IRI in the former group: 6.1 months (95% CI: 9.3, 5.1 months) versus 4.3 months (95% CI: 4.8, 2.3 months); p=0.0006. Nal-IRI adverse events occurred as expected. Qualitative data illustrated several themes, including “limited treatment options,” which appeared to drive the decision to prescribe Nal-IRI. Conclusions: Nal-IRI might be considered in pancreas cancer patients who had received regular irinotecan, particularly in the absence of disease progression with the latter.
Lung function and cardiovascular disease: a two-sample Mendelian randomisation study
Authors: Daniel H. Higbee, Raquel Granell, Eleanor Sanderson, George Davey Smith, James W. Dodd
Journal: European Respiratory Journal (2021)

Background Observational studies suggest an association between reduced lung function and risk of coronary artery disease and ischaemic stroke, independent of shared cardiovascular risk factors such as cigarette smoking. We use the latest genetic epidemiological methods to determine whether impaired lung function is causally associated with an increased risk of cardiovascular disease. Methods and findings Mendelian randomisation uses genetic variants as instrumental variables to investigate causation. Preliminary analysis used two-sample Mendelian randomisation with lung function single nucleotide polymorphisms. To avoid collider bias, the main analysis used single nucleotide polymorphisms for lung function identified from UKBiobank in a multivariable Mendelian randomisation model conditioning for height, body mass index and smoking. Multivariable Mendelian randomisation shows strong evidence that reduced forced vital capacity (FVC) causes increased risk of coronary artery disease (OR 1.32, 95% CI 1.19–1.46 per standard deviation). Reduced forced expiratory volume in 1 s (FEV 1 ) is unlikely to cause increased risk of coronary artery disease, as evidence of its effect becomes weak after conditioning for height (OR 1.08, 95% CI 0.89–1.30). There is weak evidence that reduced lung function increases risk of ischaemic stroke. Conclusion There is strong evidence that reduced FVC is independently and causally associated with coronary artery disease. Although the mechanism remains unclear, FVC could be taken into consideration when assessing cardiovascular risk and considered a potential target for reducing cardiovascular events. FEV 1 and airflow obstruction do not appear to cause increased cardiovascular events; confounding and collider bias may explain previous findings of a causal association.
Second primary cancers in patients with sporadic deficient mismatch repair (dMMR) colorectal cancer (CRC).
Authors: Ayman Alidina, Lara Rachel Lipton, Lucy Gately, Iain Skinner, Shehara Ramyalini Mendis, Wei Hong, Catherine Dunn, Jin Cho, Yat Hang To, Malcolm Steel, Ian Jones, Margaret Lee, Jeanne Tie, Suzanne Kosmider, Rachel Wong, Justin Yeung, Peter Gibbs
Journal: Journal of Clinical Oncology (2021)

45 Background: Patients with hereditary non polyposis colorectal cancer (HNPCC) diagnosed with CRC have an elevated risk of a second primary CRC (SPCRC) and of rapid primary cancer development. This informs both initial surgical approach and endoscopic surveillance intervals. A feature of HNPCC is dMMR, also found in 15% of sporadic CRC, where the risk of SPCRC has yet to be defined. Methods: We examined a multi-site comprehensive CRC database (Melbourne, Australia), where prospectively collected data includes family history (including HNPCC), histology, surgery performed and incidence of second primary cancer. Sporadic dMMR included any case with a BRAF V600E mutation, confirmed hypermethylation, negative germline testing, or age over 60 years. We explored the incidence and timing of SPCRC in patients with early stage sporadic dMMR (or MSI-H) versus pMMR cancers. Results: From February 2004 to December 2019, 7442 patients diagnosed with stage I-III CRC were recorded. MMR status was known in 4079 (54.8%), including 714 with dMMR colorectal cancer (17.4%) of which 575 (14.6%) were deemed sporadic dMMR. Sporadic dMMR patients were older (mean 76.2 years vs 65.9 years, p = &lt; 0.001), more likely to be female (65.2% vs 42%, p = &lt; 0.001) and have a right sided primary (80.9% vs 32.8%, p = &lt; 0.001), compared to patients with pMMR CRC. A SPCRC was diagnosed in 11/575 patients (1.91%) with sporadic dMMR CRC versus 27/3365 (0.83%) patients with pMMR CRC (HR = 2.57, 95% CI 1.28 - 5.17, p = 0.008). Median time to SPCRC was 1.13 years vs 2.38 years (p = 0.49). The SPCRC diagnosed in sporadic dMMR CRC vs pMMR CRC were more likely to be dMMR ((72.7%) vs (25.9%), p = 0.03), but a similar number were stage I or II ((81.8%) vs (81.5%)) and a similar number were surveillance detected ((72.7%) vs (77.8%). Conclusions: Patients with sporadic dMMR appear to have a significantly elevated risk of SPCRC compared to the pMMR population and were diagnosed at a shorter interval. The SPCRC is also more likely to also be dMMR. Increased colonoscopic surveillance of patients presenting with an initial sporadic dMMR cancer should be considered where clinically appropriate.
Response by Vandecasteele et al to Letter Regarding Article, “Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure”
Authors: Grégoire Vandecasteele, Delphine Mika, Jean Piero Margaria, Alessandra Ghigo, Emilio Hirsch, Jérôme Leroy, Rodolphe Fischmeister
Journal: Circulation (2021)

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Abstract 146: Association Between Quantitative Waveform Measures of the Ventricular Fibrillation Electrocardiogram and Defibrillation Success in the ROC ALPS Trial
Authors: David D Salcido, Robert H Schmicker, Allison C Koller, Matthew L Sundermann, Katharyn L Flickinger, James J Menegazzi
Journal: Circulation (2018)

Introduction: During out-of-hospital cardiac arrest (OHCA), features of the ventricular fibrillation electrocardiogram (ECG) have been correlated with outcomes. Understanding factors affecting the variability of these features may elucidate their utility. We examined the association between quantitative waveform measures (QWM) of the VF ECG and defibrillation success in the context of the Resuscitation Outcomes Consortium (ROC) amiodarone, lidocaine and placebo (ALPS) trial. Methods: We retrospectively obtained case data for patients enrolled in the ALPS trial from the ROC data coordinating center (DCC). The primary trial enrolled emergency medical services (EMS) – treated OHCA patients with at least one failed defibrillation from 2012 to 2015 at 10 sites across the ROC network for randomization to amiodarone, lidocaine or placebo. We included all enrolled cases with an ECG file available through the DCC. ECG signals were analyzed with custom, semi-automatic software to identify shocks, parse pre-shock ECG segments, and identify pre- and post- defibrillation rhythms, including post-shock return of organized rhythm (ROOR). Three QWM – AMSA, centroid frequency (CF), and median slope (MS) – were calculated for pre-shock ECG segments. Multivariable logistic regression models accounting for repeated shocks were constructed with outcome ROOR, adjusting for ALPS treatment arm, shock number and relevant case characteristics. Results: A total of 1242 cases were available for analysis, comprising a total of 5,408 defibrillation events with identifiable pre-shock VF. Mean (SD) QWM values for all shocks were: AMSA{6.74 (10.80)}, CF{3.98 (1.68)} , MS{0.02 (0.02)}. CF, but not AMSA or MS, differed significantly between ALPS treatment arms when controlling for shock number (p amio &lt; 0.001; p lido = 0.016). All QWM were significantly directly associated with defibrillation success in multivariable models (OR AMSA =1.03 [95%CI: 1.02 – 1.04]; OR CF =1.35 [95%CI: 1.26 – 1.45]); OR MS =1.05 [95%CI: 1.04 – 1.06]). Conclusions: In the ROC ALPS trial, QWM were associated with defibrillation success independent of shock number or treatment arm.
Evaluating the intratumor microbiome of pancreatic ductal adenocarcinoma (PDAC) by analyzing the fresh frozen tissues obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA).
Authors: Shintaro Nakano, Yasuyuki Kawamoto, Kazuaki Harada, Satoshi Yuki, Ken Ito, Rika Saitoh, Takahiro Yamamura, Hajime Hirata, Yunosuke Takishin, Ryutaro Furukawa, Kousuke Nagai, Masaki Kuwatani, Yoshito Komatsu, Naoya Sakamoto
Journal: Journal of Clinical Oncology (2021)

418 Background: Recent studies implied that intratumor microbiome was associated with carciniogenesis, development, prognosis and chemoresistance of pancreatic cancer (PC). There was more abundant bacteria in tumor tissue of pancreatic cancer than that of healthy controls. In clinical setting, diversity of intratumor bacteria was associated with good outcome of patients with resected pancreatic cancer. Specific intratumor bacteria could inactivate gemcitabine, which is crucial drug for PDAC, and may contribute to the resistance of gemcitabine.While most previous studies analyzed intratumor bacteria in PC by using resected tumor tissues, it was often impossible to obtain tumor sample from unresectable advanced PC. In addition, it is unclear whether tiny tissue obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is useful for analyzing intratumor microbiome.Therefore, we planned to evaluate the intratumor microbiome by analyzing the sample from EUS-FNA. Methods: This study was carried out as a single center, prospective observational study. The patients with PC were eligible for this study. PC tissues were collected from patients who undergo EUS-FNA. Biopsy tissues from the duodenal and gastric mucosa were also collected from the same patients. All samples were immediately stored at -80°C until use. Bacterial DNA was extracted from these specimens and 16S rRNA sequencing was performed. The endpoints of this study were success rate of detecting intratumor bacteria and association between intratumor bacteria and bacteria on the duodenal or gastric mucosa. Results: A total of 90 tissue samples from 30 patients were collected. The median age was 70 years (range 54-86 years), 19/5/6 patients had pancreatic head/body/tail tumor, 16s rRNA sequencing analyses showed that 24 samples (80%) of FNA from pancreatic tumor, 30 samples (100%) of gastric mucosa and 29 samples (97%) of duodenum mucosa could be analyzed. In diversity analyses, PC showed a lower alpha diversity compared to gastric or duodenum tissue. There was a significant difference in microbial structure between PC and duodenum tissue. In PC, dominant phylum was Proteobacteria and dominant genus was Acinetobacter. Conclusions: PC tissues obtained by EUS-FNA were useful for analyzing intratumor microbiome.
FRI0079 Enbrel® (etanercept) in addition to methotrexate (mtx) in rheumatoid arthritis (ra): long-term observations
Authors: RM Fleischmann, ME Weinblatt, JM Kremer, AD Bankhurst, KJ Bulpitt, DJ Burge
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Results have been previously presented from a long-term trial of ENBREL as additional therapy in 79 patients with persistent RA despite treatment with MTX. Patients have now received therapy for a median of 32 months (max. 37). <h3>Objectives</h3> Continue to observe the safety and clinical benefit of ENBREL plus MTX. <h3>Methods</h3> Disease activity was evaluated using ACR criteria. Adverse events were compared with data from a previous controlled study. <h3>Results</h3> Of the 79 patients who entered the long-term trial, 9 have withdrawn: 3 for lack of efficacy, 2 for adverse events, 1 prior to a total knee replacement, 2 who planned to conceive, and 1 who started taking commercial ENBREL. Seventy of the 79 patients who entered the long-term study remain on therapy. No differences have been seen in the type and rate of adverse events observed over time, compared to the earlier controlled study. In the initial 6-month blinded study of ENBREL plus MTX, 2/59 patients were hospitalised for infections; in the extension study, 2/79 patients had a similar event. One patient developed NHL of the parotid gland in the initial study. In the extension study, two patients developed malignancies (squamous cell carcinoma of the larynx and breast carcinoma). Both of these patients in the extension study recovered and have resumed treatment with ENBREL. At baseline, all 79 patients were taking MTX and the mean dose was 18 mg. As allowed by the protocol, 54 (68%) patients have reduced their MTX dose by a mean of 63%, and 22/79 (28%) patients have discontinued taking MTX. In the 45 patients taking corticosteroids, the mean dose of prednisone was 6.3 mg. As allowed by the protocol, 30 (67%) patients have reduced their steroid dose by a mean of 78%, and 19 (42%) patients have discontinued steroids. Improvement of disease activity has been sustained even though MTX and steroids were reduced or discontinued. At the most recent visit, 69% of patients had achieved the ACR 20, 51% the ACR 50, and 27% the ACR 70. Also at the most recent visit, 19 patients had no tender joints, 10 had no swollen joints, and a zero HAQ score was achieved by 12 patients. <h3>Conclusion</h3> ENBREL plus MTX remains safe and well tolerated. Improvement of disease activity is sustained even with reduced or discontinued doses of MTX and/or steroids. <h3>References</h3> Kremer JM, <i>et al</i>. Arthritis Rheum. 2000;43:S270 Weinblatt ME, <i>et al</i>. NEJM 1999;340:253–9
Two-hit mechanism of cardiac arrhythmias in diabetic hyperglycaemia: reduced repolarization reserve, neurohormonal stimulation, and heart failure exacerbate susceptibility
Authors: Bence Hegyi, Christopher Y Ko, Julie Bossuyt, Donald M Bers
Journal: Cardiovascular Research (2021)

Abstract Aims Diabetic hyperglycaemia is associated with increased arrhythmia risk. We aimed to investigate whether hyperglycaemia alone can be accountable for arrhythmias or whether it requires the presence of additional pathological factors. Methods and results Action potentials (APs) and arrhythmogenic spontaneous diastolic activities were measured in isolated murine ventricular, rabbit atrial, and ventricular myocytes acutely exposed to high glucose. Acute hyperglycaemia increased the short-term variability (STV) of action potential duration (APD), enhanced delayed afterdepolarizations, and the inducibility of APD alternans during tachypacing in both murine and rabbit atrial and ventricular myocytes. Hyperglycaemia also prolonged APD in mice and rabbit atrial cells but not in rabbit ventricular myocytes. However, rabbit ventricular APD was more strongly depressed by block of late Na+ current (INaL) during hyperglycaemia, consistent with elevated INaL in hyperglycaemia. All the above proarrhythmic glucose effects were Ca2+-dependent and abolished by CaMKII inhibition. Importantly, when the repolarization reserve was reduced by pharmacological inhibition of K+ channels (either Ito, IKr, IKs, or IK1) or hypokalaemia, acute hyperglycaemia further prolonged APD and further increased STV and alternans in rabbit ventricular myocytes. Likewise, when rabbit ventricular myocytes were pretreated with isoproterenol or angiotensin II, hyperglycaemia significantly prolonged APD, increased STV and promoted alternans. Moreover, acute hyperglycaemia markedly prolonged APD and further enhanced STV in failing rabbit ventricular myocytes. Conclusion We conclude that even though hyperglycaemia alone can enhance cellular proarrhythmic mechanisms, a second hit which reduces the repolarization reserve or stimulates G protein-coupled receptor signalling greatly exacerbates cardiac arrhythmogenesis in diabetic hyperglycaemia.
Early Childhood Adversity, Toxic Stress, and the Impacts of Racism on the Foundations of Health
Authors: Jack P. Shonkoff, Natalie Slopen, David R. Williams
Journal: Annual Review of Public Health (2021)

Inequalities in health outcomes impose substantial human and economic costs on all societies-and the relation between early adversity and lifelong well-being presents a rich scientific framework for fresh thinking about health promotion and disease prevention broadly, augmented by a deeper focus on how racism influences disparities more specifically. This review begins with an overview of advances in the biology of adversity and resilience through an early childhood lens, followed by an overview of the unique effects of racism on health and a selective review of findings from related intervention research. This article presents a framework for addressing multiple dimensions of the public health challenge-including institutional/structural racism, cultural racism, and interpersonal discrimination-and concludes with the compelling need to protect the developing brain and other biological systems from the physiological disruptions of toxic stress that can undermine the building blocks of optimal health and development in the early childhood period.
OBF1 and Oct factors control the germinal center transcriptional program
Authors: Shuang Song, Chun Cao, Mohamed-Amin Choukrallah, Fengyuan Tang, Gerhard Christofori, Hubertus Kohler, Fabian Wu, Barna D. Fodor, Mathias Frederiksen, Simon N. Willis, Jacob T. Jackson, Stephen L. Nutt, Stefan Dirnhofer, Michael B. Stadler, Patrick Matthias
Journal: Blood (2021)
Reply to Satoshi Funada, Takashi Yoshioka, and Luo Yan's Letter to the Editor re: Guohua Zeng, Chao Cai, Xianzhong Duan, et al. Mini Percutaneous Nephrolithotomy Is a Noninferior Modality to Standard Percutaneous Nephrolithotomy for the Management of 20–40 mm Renal Calculi: A Multicenter Randomized Controlled Trial. Eur Urol 2021;79:114–21
Authors: Chao Cai, Guohua Zeng
Journal: European Urology (2020)