tbuckley/cabot-search huggingface dataset:
Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial
Authors: Piero Ruggenenti, Paolo Cravedi, Eliana Gotti, Annarita Plati, Maddalena Marasà, Silvio Sandrini, Nicola Bossini, Franco Citterio, Enrico Minetti, Domenico Montanaro, Ettore Sabadini, Regina Tardanico, Davide Martinetti, Flavio Gaspari, Alessandro Villa, Annalisa Perna, Francesco Peraro, Giuseppe Remuzzi
Journal: PLoS Medicine (2021)

Background We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression. Methods and findings ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m 2 , p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design. Conclusions In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression. Trial registration ClinicalTrials.gov NCT00494741 ; EUDRACT 2006-005604-14 .
Relationship between desmoplastic pattern and lymphocytes infiltration in pancreatic cancer.
Authors: Takahiro Einama, Tadakazu Ao, Yoshiki Kajiwara, Takahiro Sueyama, Makoto Nishikawa, Takuji Noro, Mayumi Hoshikawa, Suefumi Aosasa, Yoshihisa Yaguchi, Shuichi Hiraki, Morikazu Miyamoto, Hitoshi Tsuda, Kazuo Hase, Hironori Tsujimoto, Hideki Ueno, Junji Yamamoto
Journal: Journal of Clinical Oncology (2018)

e16245 Background: The proposed histologic desmoplastic reaction (DR) categorization and lymphocyte infiltration (LI) directly reflects tumor behavior in a modulating stromal environment and could provide valuable prognostic information for colorectal cancer patients, but the prognostic role of DR and LI has not been investigated in pancreatic cancer patients. Methods: A total of 87 pancreatic cancer patients who underwent potentially curative surgery for their tumors in our hospital (2008 to 2013) were included. DR was classified as mature, intermediate, or immature on the basis of the existence of keloid-like collagen and myxoid stroma-distinctive histologic products of extracellular matrix remodeling. LI was classified as Pattern I; circumferential lymphocytes zone without disruptions around tumor, Pattern II; lymphocytes zone with partial disruptions and thinning around tumor, Pattern III; focal lymphocytes foci around tumor at most invasive border without lymphocyte zone, and Pattern IV; no lymphocyte foci around tumor. Results: With regard to DR, 0, 23, and 64 patients were classified as mature, intermediate, and immature, respectively. 5-year overall survival rates were higher in immature group (p = 0.0040) than those of intermediate group. Multivariate analysis revealed that DR was an independent prognostic factor along with residual tumor (p = 0.0300). With regard to LI, 0, 6, 70, and 11 patients were classified as Pattern I, Pattern II, Pattern III, and Pattern IV, respectively. There was no relationship between DR and LI. Conclusions: The DR categorization seemed to reflect tumor behavior and could provide valuable prognostic information for pancreatic cancer patients.
EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update
Authors: Annalisa Berzigotti, Emmanouil Tsochatzis, Jerome Boursier, Laurent Castera, Nora Cazzagon, Mireen Friedrich-Rust, Salvatore Petta, Maja Thiele
Journal: Journal of Hepatology (2021)
Abstract 596: Single circulating tumor cell enumeration and targeted sequencing in non-small cell lung cancer
Authors: Mouadh Barbirou, Yariswamy Manjunath, Amanda Miller, Arturo Ramirez, Nolan Ericson, Kevin F. Kevin F. Staveley-O'Carroll, Wes Warren, Guangfu Li, Peter J. Tonellato, Jussuf T. Kaifi
Journal: Cancer Research (2021)

Abstract Purpose: Circulating tumor cells (CTCs) may be novel biomarkers to predict cancer prognosis and monitor therapeutic efficacy. In the current study, we investigated the use of the time-dependent enumeration and targeted DNA sequensing of single CTCs as liquid biopsy based biomarkers of non-small cell lung cancer (NSCLC) patients for diagnosis, prognosis, therapeutic choice and outcome monitoring. Experimental Design: In a prospective study, we tested the AccuCyte® system (RareCyte®, Inc. Seattle, WA) for CTC enumeration in NSCLC using FDA criteria (CK/EpCAM+/CD45- with a nucleus). Whole blood (7.5 ml) from healthy donors was spiked with human lung adenocarcinoma (A549 cell line) cells at specific numbers (N=0, 100, 200, 1000). CTC detection and single-CTC picking was performed. NSCLC subjects' (N=20) and chronic smokers without cancer on screening low-dose CT subjects' (N=10) blood were collected (amount, method, biotechnology). For all blood samples, CTC detection and single CTC picking was performed. DNA was isolated from CTCs (N=3) and white blood cells (N=2) per sample. DNA libraries were prepared for targeted oncogene characterization using the CleanPlex® OncoZoom® panel. Somatic variant analysis and comparisons were performed. Results: AccuCyte enumeration of A549 cells spiked at four levels in healthy subjects' whole blood showed (Spiked #, Detected #): (0, 0); (100, 76); (200, 208); (1000, 1223). NSCLC subjects' (N=20; age: 64.85±6.64; BMI: 28.00±8.15sex ratio: 0.42) blood had a mean CTC count of 13.4 (SD=52, median=0, range [0, 237]). Ten screening controls without cancer (64.2±5.81, 1, 28.50±6.13, 0.66) had a mean CTC count of 0.20 (0.42, 0, [0, 1]). Significant association was noted regarding a higher number of CTCs found in NSCLC compared to screening subjects without cancer according to the (p= 0.020, Wilcoxon signed rank). CTC numbers increased with NSCLC AJCC stage. Somatic variant analysis on patient-matched single CTCs and WBCs is ongoing. Conclusions: The molecular investigation of patient matched single CTCs and white blood cells will fundamentally advance understanding on the NSCCL carcinogenic signature of these blood born cells and their potential value as cancer detection and therapy management liquid biopsy-based biomarkers. Citation Format: Mouadh Barbirou, Yariswamy Manjunath, Amanda Miller, Arturo Ramirez, Nolan Ericson, Kevin F. Kevin F. Staveley-O'Carroll, Wes Warren, Guangfu Li, Peter J. Tonellato, Jussuf T. Kaifi. Single circulating tumor cell enumeration and targeted sequencing in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 596.
Reply to Ishaq et al.
Authors: Omid Sanaei, Mouen A. Khashab
Journal: Endoscopy (2021)

See also:Zenker's peroral endoscopic myotomy (Z-POEM) for recurrent Zenker diverticulum: not so fast!Endoscopy 2021; 53(07): 767-767DOI: 10.1055/a-1337-2660See also:Impact of prior treatment on feasibility and outcomes of Zenker’s peroral endoscopic myotomy (Z-POEM) Endoscopy 2021; 53(07): 722-726DOI: 10.1055/a-1276-0219
Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRASG12C
Authors: Cuicui Li, Ni Zhao, Luyan An, Zhen Dai, Xiaoyi Chen, Fan Yang, Qidong You, Bin Di, Chi Hu, Lili Xu
Journal: Acta Pharmaceutica Sinica B (2021)

Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health. Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying 80% of all lung cancer subtypes. Except for other mutations (e.g., KRASG12V/D) that are also vital for the occurrence, KRASG12C gene mutation is a significant driving force of NSCLC, with a prevalence of approximately 14% of all NSCLC patients. However, there are only a few therapeutic drugs targeting KRASG12C mutations currently. Here, we synthesized hydrocarbon-stapled peptide 3 that was much shorter and more stable with modest KRASG12C binding affinity and the same anti-tumor effect based on the α-helical peptide mimic SAH-SOS1A. The stapled peptide 3 effectively induced G2/M arrest and apoptosis, inhibiting cell growth in KRAS-mutated lung cancer cells via disrupting the KRAS-mediated RAF/MEK/ERK signaling, which was verified from the perspective of genomics and proteomics. Peptide 3 also exhibited strong anti-trypsin and anti-chymotrypsin abilities, as well as good plasma stability and human liver microsomal metabolic stability. Overall, peptide 3 retains the equivalent anti-tumor activity of SAH-SOS1A but with improved stability and affinity, superior to SAH-SOS1A. Our work offers a structural optimization approach of KRASG12C peptide inhibitors for cancer therapy.
PP45. GEOGRAPHICAL INEQUALITIES OF ACCESS TO 5-AMINOLEVULINIC ACID IN THE UK – BARRIERS TO IMPLEMENTING RESEARCH FINDINGS INTO CLINICAL PRACTICE
Authors: Mr Stephen Price
Journal: Neuro-Oncology (2017)

AIMS: Evidence based medicine aims to improve patient care by applying evidence from research studies. This implies that new research findings can be implemented into routine clinical practice. All too often, particularly in the current cash-strapped NHS, it is not possible to implement these research findings. When it is implemented it is often patchy, leaving patients with a ‘post-code lottery’ of whether they will be able to benefit from these findings. To explore this, I have used uptake of 5-aminolevulinc acid (5-ALA) fluorescence guided surgery for glioblastomas as an example of implementing research findings. A multicentre Phase III study was published in 2006 showing improved rate of complete resection of enhancing tumour, improved progression free survival and reduced re-operation rate without impact on neurological function. These findings were confirmed on another prospective cohort study. Subsequent studies have shown improved survival where complete resection of enhancing tumour is achieved. Despite this evidence the uptake in the UK has been patchy. This study aims to identify the geographical distribution of 5-ALA usage in the UK 10 years after publication of this trial. METHODS: A survey of the UK was undertaken by contacting neuro-oncology surgeons at each unit. For each unit the approximate geographical catchment area was estimated from the hospitals that referred tumour patients to these units. Usage of 5-ALA was classified as full use, limited access (including where it is paid for with charity funds) or no access. Where there was no access, the reasons for this were explored. In addition, the training log kept by Medac GmBH was reviewed to identify units without trained surgeons. A map of the uptake of 5-ALA was created from this data. RESULTS: Data was available from 24 of the 30 adult neuroscience units. Full access was available in 8/24 (33%) of the units where data was available, limited access in 7/24 (29%) and no access in 9/24 units (38%). The geographical distribution shows good access in Scotland and the south east of England but limited access in the north of England. There was no access in the south west of England and southern Wales as well as across areas of the midlands and Northern Island. In the units with no access the primary reason is the cost of 5-ALA. Data from the Medac training logs show there are trained surgeons in every neurosurgical unit in the UK. CONCLUSIONS: 10 years after publication of this study there still is limited uptake of 5-ALA in the UK with clear geographical variation. The main reason for this is lack of funding despite favourable published cost-effectiveness data. Further work is needed to explore the decision making process around implementing research findings into clinical practice.
Abstract 467: Glucose Promotes M2-related Transcriptional Reprogramming of Resident Cardiac Macrophages in Response to Hypothermic Ischemic Arrest and Reperfusion
Authors: Ahmed Bux, Hernan Vasquez, Heinrich Taegtmeyer, Romain Harmancey
Journal: Circulation Research (2016)

Stress hyperglycemia and inflammation frequently develop in open heart surgery patients. Although both factors independently contribute to increased peri-operative morbidity and mortality, the impact of high glucose levels on cardiac inflammatory response remains unknown. We investigated the isolated working rat heart as a model to study cardiac early stress response to surgery. Hearts of male Sprague Dawley rats were cold-arrested and subjected to 60 minutes normothermic reperfusion in the working mode with Krebs-Henseleit buffer supplemented with ketone bodies and propionate plus glucose (25 mM) or mannitol (25 mM; osmotic control). Alterations of gene expression in the left ventricle were determined by microarray and real-time PCR analyses. Compared to non-perfused hearts, perfused hearts displayed a more than twofold increased expression for 71 genes (mannitol group) and 103 genes (glucose group) connected to inflammation, cell proliferation, and apoptosis. The transcriptional changes were highly similar to gene alterations previously reported in the right atrium ( P &lt; 2.34E-16) and left ventricle ( P &lt; 4.83E-46) of patients who underwent cardiac surgery with cardiopulmonary bypass. Pathway analysis with Reactome revealed an up-regulation of metabolic processes associated with the proliferation and activation of immune cells, including glycolysis, glutaminolysis, fatty acid synthesis, polyamine synthesis, and hexosamine synthesis. Although the transcriptional remodeling occurred independently from the presence of glucose, glucose significantly increased further the expression of several transcription factors and markers associated with M2 polarization of macrophages, including Myc (1.6-fold), Nr4a1 (1.3-fold), Nr4a2 (1.8-fold), Zc3h12a (1.3-fold), Fosl2 (1.4-fold), Cebpb (1.2-fold), and Arg1 (1.7-fold). Interestingly, glucose failed to enhance the expression of M2-related genes in the heart of rats rendered insulin resistant by high-sucrose feeding. Besides demonstrating that the isolated working rat heart accurately reproduces the stress response associated with open heart surgery, the results also suggest that glucose promotes the alternative activation of resident cardiac macrophages in the stressed heart.
Abstract 72: The Tumor Suppressor Gene Tip30 Supports Cardiac Compensation During Overload and Inhibits Myocardial Protein Synthesis
Authors: Andrea Grund, Malgorzata Szaroszyk, Mortimer Korf-Klingebiel, Christopher Tiedje, Matthias Gaestel, Sandor Batkai, Thomas Thum, Andreas Jungmann, Ralf Bauer, Xiaoke Yin, Manuel Mayr, Kai C Wollert, Andreas Pich, Hua Xiao, Hugo A Katus, Johann Bauersachs, Oliver J Müller, Joerg Heineke
Journal: Circulation Research (2016)

Background: Here, we examined the currently unknown cardiac expression and function of Tip30, which has previously emerged as a tumor suppressor gene. Results: Myocardial TIP30 mRNA and protein were significantly upregulated in response to experimental transverse aortic constriction (TAC). TIP30 contributed to cardiac compensation, since a reduction of cardiac TIP30 in heterozygous Tip30 knock-out mice (HET) led to exaggerated hypertrophy and cardiac dysfunction compared to wild-type mice (WT) after TAC. In turn, TIP30 overexpression by an adenovirus in isolated neonatal cardiomyocytes or by an adeno-associated-virus (AAV9) in mouse hearts led to reduced hypertrophy after pro-hypertrophic stimulation in cells and reduced hypertrophy and improved cardiac function after TAC in mice. Interestingly, cardiac TIP30 levels were strongly diminished in mouse models of genetic cardiomyopathy (mdx mice) and in endstage human cardiomyopathy. Reduced cardiac TIP30 contributed to disease progression, since reconstitution of myocardial TIP30 via AAV9 in mdx mice prevented hypertrophy and improved cardiac function. A protein interaction screen and subsequent characterization showed that TIP30 interacts with the middle domain of the eukaryotic translation factor 1A1 (eEF1A1). As revealed by immunoprecipitation and in situ proximity ligation assay, the cellular interaction of eEF1A1 and its essential cofactor eEF1B was diminished by TIP30 overexpression, but enhanced in cardiomyocytes isolated from HET mice after pro-hypertrophic stimulation. Because eEF1A1 is a crucial mediator of translational elongation, we hypothesized that TIP30 regulates cardiac hypertrophy by interfering with protein synthesis. Indeed, overexpression of TIP30 inhibited cardiac protein synthesis during pro-hypertrophic stimulation, while reduced TIP30 levels in HET (vs. WT) mice triggered enhanced protein synthesis after TAC. Interestingly, administration of the eEF1A1 inhibitor narciclasine ablated the increased hypertrophy in HET mice after TAC. Conclusion: TIP30 inhibits protein synthesis by binding to eEF1A1 and inhibiting its interaction with eEF1B. It thereby reduces pathological hypertrophy and supports cardiac compensation during overload.
Preservation of biomaterials and cells by freeze-drying: Change of paradigm
Authors: Arto Merivaara, Jacopo Zini, Elle Koivunotko, Sami Valkonen, Ossi Korhonen, Francisco M. Fernandes, Marjo Yliperttula
Journal: Journal of Controlled Release (2021)

Freeze-drying is the most widespread method to preserve protein drugs and vaccines in a dry form facilitating their storage and transportation without the laborious and expensive cold chain. Extending this method for the preservation of natural biomaterials and cells in a dry form would provide similar benefits, but most results in the domain are still below expectations. In this review, rather than consider freeze-drying as a traditional black box we "break it" through a detailed process thinking approach. We discuss freeze-drying from process thinking aspects, introduce the chemical, physical, and mechanical environments important in this process, and present advanced biophotonic process analytical technology. In the end, we review the state of the art in the freeze-drying of the biomaterials, extracellular vesicles, and cells. We suggest that the rational design of the experiment and implementation of advanced biophotonic tools are required to successfully preserve the natural biomaterials and cells by freeze-drying. We discuss this change of paradigm with existing literature and elaborate on our perspective based on our new unpublished results.
HIV/HBV coinfection: temporal trends and patient characteristics, Spain, 2002 to 2018
Authors: Leire Pérez-Latorre, Juan Berenguer, Rafael Micán, Marta Montero, Carmen Cifuentes, Teresa Puig, José Sanz, Oscar L Ferrero, Belén De La Fuente, Carmen Rodríguez, Sergio Reus, José Hernández-Quero, Gabriel Gaspar, Laura Pérez-Martínez, Coral García, Luis Force, Sergio Veloso, Marta De Miguel, Inmaculada Jarrín, Juan González-García
Journal: Eurosurveillance (2021)

Background Recent and reliable estimates on the prevalence of coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) in Europe are lacking. Aim Leveraged on a study designed to assess HIV/HCV coinfection prevalence, we assessed the prevalence of HIV/HBV coinfection in Spain in 2018 and compared the results with five similar studies performed since 2002. Methods This cross-sectional prevalence study was carried out in 43 centres, and patients were selected using simple random sampling. The reference population comprised 40,322 patients and the sample size were 1,690 patients. Results The prevalence of HIV/HBV coinfection in Spain at the end of 2018 was 3.2%. The prevalence in 2002, 2009, 2015, 2016 and 2017 was 4.9%, 3.4%, 3%, 3.9% and 3%, respectively. Among the HIV/HBV-coinfected patients identified in 2018, 16.7% had cirrhosis according to transient elastography and 26.3% tested positive for antibodies against hepatitis D virus. All HIV/HBV-coinfected patients were receiving drugs with activity against HBV, and 97% of those tested for HBV DNA had an HBV DNA load &lt; 80 IU/mL. Conclusions The prevalence of HIV/HBV coinfection in Spain remained stable at around 3% for a decade. Our data could facilitate the design of national programmes to control HBV infection and help identify areas of patient management that need improvement.