tbuckley/cabot-search huggingface dataset:
The dawn of the future: 30 years from the first biopsy of a human embryo. The detailed history of an ongoing revolution
Authors: Danilo Cimadomo, Laura Rienzi, Antonio Capalbo, Carmen Rubio, Federica Innocenti, Carmen María García-Pascual, Filippo Maria Ubaldi, Alan Handyside
Journal: Human Reproduction Update (2020)

Following early studies showing no adverse effects, cleavage stage biopsy by zona drilling using acid Tyrode's solution, and removal of single blastomeres for preimplantation genetic testing (PGT) and identification of sex in couples at risk of X-linked disease, was performed by Handyside and colleagues in late 1989, and pregnancies reported in 1990. This method was later used for specific diagnosis of monogenic conditions, and a few years later also for chromosomal structural and/or numerical impairments, thereby establishing a valuable alternative option to prenatal diagnosis. This revolutionary approach in clinical embryology spread worldwide, and several other embryo biopsy strategies developed over three decades in a process that is still ongoing. The rationale of this narrative review is to outline the different biopsy approaches implemented across the years in the workflow of the IVF clinics that provided PGT: their establishment, the first clinical experiences, their downsides, evolution, improvement and standardization. The history ends with a glimpse of the future: minimally/non-invasive PGT and experimental embryo micromanipulation protocols. This grand theme review outlines a timeline of the evolution of embryo biopsy protocols, whose implementation is increasing worldwide together with the increasing application of PGT techniques in IVF. It represents a vade mecum especially for the past, present and upcoming operators and experts in this field to (re)live this history from its dawn to its most likely future.
Regulation of Cardiac Output
Authors: Arthur C. Guyton
Journal: New England Journal of Medicine (1967)

MOST physicians are surprised to learn that the heart has relatively little effect on the normal regulation of cardiac output, but all the physician has to do is to look at his patients, and he will see that this is true. He will see a patient with mitral valvular disease whose heart has a maximum pumping ability no greater than one third normal, but at rest cardiac output is normal or almost normal. He will see a patient who has had a severe heart attack a day earlier but with a cardiac output now almost normal even though the maximum . . .
Stem cell-derived exosomes prevent pyroptosis and repair ischemic muscle injury through a novel exosome/circHIPK3/ FOXO3a pathway
Authors: Bing Yan, Yu Zhang, Chun Liang, Bin Liu, Fengzhi Ding, Yanli Wang, Bao Zhu, Ranzun Zhao, Xi-Yong Yu, Yangxin Li
Journal: Theranostics (2020)

Rational: Ischemic injury of the skeletal muscle remains a serious clinical problem and currently there is no effective therapy. The aim of the present study is to determine whether human umbilical cord mesenchymal stem cells- derived exosomes (UMSC-Exo) could repair ischemic injury by releasing circular RNA. Methods and Results: To create hindlimb ischemia, we surgically ligated the left femoral artery in C57BL/6 mice. Using circRNA-seq analyses of total RNA from ischemic and control muscles, we found reduced expression of circHIPK3 in the ischemic muscle. To explore the role of circHIPK3 in ischemic injury, the mice were randomly assigned into three groups after surgery: 1) vehicle; 2) UMSC-Exo; 3) UMSC-Exo and siRNA targeting circHIPK3 (UMSC-Exo /si-circHIPK3). UMSC-Exo treatment significantly increased expression of circHIPK3 and improved blood perfusion, running distance and muscle force, which were reversed by injection of UMSC-Exo /si-circHIPK3, suggesting that UMSC-Exo improve muscle function by releasing circHIPK3. UMSC-Exo treatment also inhibited ischemia induced pyroptosis - cell death caused by inflammasome as evidenced by activation of NLRP3, cleaved caspase-1, and subsequent increase of IL-1β and IL-18, and the effects were reversed by injection UMSC-Exo /si-circHIPK3. Bioinformatic analysis identified miR-421/FOXO3a as a potential target for circHIPK3, which was confirmed by luciferase reporter assay. Knockdown of circHIPK3 in C2C12 cells resulted in increased expression of miR-421. We established an in vitro model of pyroptosis by stimulating C2C12 cells with LPS and ATP. LPS and ATP treatment resulted in reduced expression of circHIPK3 and increased expression of miR-421, which was prevented by UMSC-Exo. Western blot analysis showed reduced levels of NLRP3 and cleaved caspase-1 when cells were treated by UMSC-Exo. The expression of FOXO3a in C2C12 cells was increased in the presence of miR-421 inhibitor, and the expression was reduced when cells were treated by LPS and ATP. Importantly, the expression of FOXO3a was upregulated by UMSC-Exo but was reduced when si-circHIPK3 was present. Conclusions: Using loss/gain-of function method, we demonstrated that miR-421/FOXO3a is the direct target of circHIPK3, and UMSC-Exo prevent ischemic injury by releasing circHIPK3, which in turn down regulate miR-421, resulting in increased expression of FOXO3a, leading to inhibition of pyroptosis and release of IL-1β and IL-18.
Incidence, risk factors, and health service burden of sequelae of campylobacter and non-typhoidal salmonella infections in England, 2000–2015: A retrospective cohort study using linked electronic health records
Authors: Oluwaseun B. Esan, Rafael Perera, Noel McCarthy, Mara Violato, Thomas R. Fanshawe
Journal: Journal of Infection (2020)

Reactive arthritis, irritable bowel syndrome (IBS), Guillain-Barré syndrome, ulcerative colitis, and Crohn's disease may be sequelae of Campylobacter or non-typhoidal Salmonella (NTS) infections. Proton pump inhibitors (PPI) and antibiotics may increase the risk of gastrointestinal infections (GII); however, their impact on sequelae onset is unclear. We investigated the incidence of sequelae, their association with antibiotics and PPI prescription, and assessed the economic impact on the NHS.Data from the Clinical Practice Research Datalink for patients consulting their GP for Campylobacter or NTS infection, during 2000-2015, were linked to hospital, mortality, and Index of Multiple Deprivation data. We estimated the incidence of sequelae and deaths in the 12 months following GII. We conducted logistic regression modelling for the adjusted association with prescriptions. We compared differences in resource use and costs pre- and post-infection amongst patients with and without sequelae.Of 20,471 patients with GII (Campylobacter 17,838), less than 2% (347) developed sequelae, with IBS (268) most common. Amongst Campylobacter patients, those with prescriptions for PPI within 12 months before and cephalosporins within 7-days before/after infection had elevated risk of IBS (adjusted odds ratio [aOR] 2.1, 1.5-2.9) and (aOR 3.6, 1.1-11.7) respectively. Campylobacter sequelae led to ∼ £1.3 million, (£750,000, £1.7 million) in additional annual NHS expenditure.Sequelae of Campylobacter and NTS infections are rare but associated with increased NHS costs. Prior prescription of PPI may be a modifiable risk factor. Incidence of sequelae, healthcare resource use and costs are essential parameters for future burden of disease studies.
Effects of downhill walking in pulmonary rehabilitation for patients with COPD: a randomised controlled trial
Authors: Carlos Augusto Camillo, Christian Robert Osadnik, Chris Burtin, Stephanie Everaerts, Miek Hornikx, Heleen Demeyer, Matthias Loeckx, Fernanda Machado Rodrigues, Karen Maes, Ghislaine Gayan-Ramirez, Wim Janssens, Thierry Troosters
Journal: European Respiratory Journal (2020)

The development of contractile muscle fatigue (CMF) affects training responses in patients with chronic obstructive pulmonary disease (COPD). Downhill walking induces CMF with lower dyspnoea and fatigue than level walking. This study compared the effect of pulmonary rehabilitation (PR) comprising downhill walking training (DT) to PR comprising level walking (conventional training (CT)) in patients with COPD. In this randomised controlled trial, 35 patients (62±8 years; forced expiratory volume in 1 s (FEV 1 ) 50±17% predicted) were randomised to DT or CT. Exercise tolerance (6-minute walk test distance (6MWD); primary outcome), muscle function, symptoms, quality-of-life and physical activity levels were assessed before and after PR. Absolute training changes and the proportion of patients exceeding the 30 m 6MWD minimally important difference (MID) were compared between groups. Quadriceps muscle biopsies were collected after PR in a subset of patients to examine physiological responses to long-term eccentric training. No between-group differences were observed in absolute 6MWD improvement (mean 6MWD change 77±46 m DT versus 56±47 m CT; p=0.45), however 94% of patients in DT exceeded the 6MWD MID compared to 65% in CT (p=0.03). Patients in DT tended to have larger improvements than CT in other outcomes. Muscle biopsy analyses did not differ between groups. PR incorporating downhill walking confers similar magnitudes of effects to PR with conventional walking across clinical outcomes in patients with COPD, however, offers a more reliable stimulus to maximise the achievement of clinically relevant gains in functional exercise tolerance in people with COPD.
Comorbidities and rheumatological diseases at the time of COVID-19. Response to: ‘Rheumatic diseases in intensive care unit patients with COVID-19’ by Moiseev <i>et al</i>
Authors: Sara Monti, Carlomaurizio Montecucco
Journal: Annals of the Rheumatic Diseases (2020)

Comorbidities and rheumatological diseases at the time of COVID-19.Response to: 'Rheumatic diseases in intensive care unit patients with COVID-19' by Moiseev et alWe thank Dr Moiseev et al 1 for their comment on our previous paper on the clinical course of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) disease 2019 (COVID-19) in patients treated with biologic and targeted synthetic diseasemodifying anti-rheumatic drugs. 2 The authors assessed the outcome of patients with inflammatory rheumatic diseases among patients admitted to the intensive care unit (ICU) and reported findings in line with our cohort of outpatients. 2Admission to the ICU due to COVID-19 in patients with rheumatic diseases did not exceed those expected in the general population.Nevertheless, the mortality of these patients was 50%.Interestingly, Moiseev et al 1 reported that the majority of rheumatologic patients admitted to the ICU had concurrent conditions including hypertension, previous cardiovascular events or diabetes mellitus.These same comorbidities had been previously identified as risk factors associated with worse outcome also in the general population affected by This comment confirms the cautious impression that patients with rheumatologic diseases might not have a worse prognosis during COVID-19 and that underlying concomitant cardiovascular comorbidities might influence the severity of the infection. Nvertheless, the mortality rate of patients admitted to the ICU is still relevant, and patients with a significant comorbidity burden might be particularly at risk.Comorbidities are frequent in patients with rheumatologic diseases, even at a younger age compared with control populations, 4 5 and these might expose our patients to an excessive risk in case of severe SARS-CoV-2 infection.
Pulmonary interstitial glycogenosis cells express mesenchymal stem cell markers
Authors: Csaba Galambos, Eric Wartchow, Jason P. Weinman, Steven H. Abman
Journal: European Respiratory Journal (2020)

<b>Pulmonary interstitial glycogenesis (PIG) is characterised by a unique but poorly characterised cell population in developmental lung disease. This study reports that PIG cells express cellular markers, suggesting a mesenchymal stem cell lineage.</b>https://bit.ly/2YNdDIY
Zwitterionic-to-cationic charge conversion polyprodrug nanomedicine for enhanced drug delivery
Authors: Sheng Wang, Fuwu Zhang, Guocan Yu, Zhantong Wang, Orit Jacobson, Ying Ma, Rui Tian, Hongzhang Deng, Weijing Yang, Zhi-Yi Chen, Xiaoyuan Chen
Journal: Theranostics (2020)

Zwitterionic surface modification is a promising strategy for nanomedicines to achieve prolonged circulation time and thus effective tumor accumulation.However, zwitterion modified nanoparticles suffer from reduced cellular internalization efficiency.Methods: A polyprodrug-based nanomedicine with zwitterionic-to-cationic charge conversion ability (denoted as ZTC-NMs) was developed for enhanced chemotherapeutic drug delivery.The polyprodrug consists of pH-responsive poly(carboxybetaine)-like zwitterionic segment and glutathione-responsive camptothecin prodrug segment. Results:The ZTC-NMs combine the advantages of zwitterionic surface and polyprodrug.Compared with conventional zwitterionic surface, the ZTC-NMs can respond to tumor microenvironment and realize ZTC surface charge conversion, thus improve cellular internalization efficiency of the nanomedicines.Conclusions: This ZTC method offers a strategy to promote the drug delivery efficiency and therapeutic efficacy, which is promising for the development of cancer nanomedicines.
Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1
Authors: Eric Olinger, Patrick Hofmann, Kendrah Kidd, Inès Dufour, Hendrica Belge, Céline Schaeffer, Anne Kipp, Olivier Bonny, Constantinos Deltas, Nathalie Demoulin, Thomas Fehr, Daniel G. Fuster, Daniel P. Gale, Eric Goffin, Kateřina Hodaňová, Uyen Huynh-Do, Andreas Kistler, Johann Morelle, Gregory Papagregoriou, Yves Pirson, Richard Sandford, John A. Sayer, Roser Torra, Christina Venzin, Reto Venzin, Bruno Vogt, Martina Živná, Anna Greka, Karin Dahan, Luca Rampoldi, Stanislav Kmoch, Anthony J. Bleyer, Olivier Devuyst
Journal: Kidney International (2020)

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.
Development of a long acting FGF21 analogue-albumin fusion protein and its anti-diabetic effects
Authors: Hiroshi Watanabe, Masako Miyahisa, Mayuko Chikamatsu, Kento Nishida, Yuki Minayoshi, Mei Takano, Shota Ichimizu, Yoshihiro Kobashigawa, Hiroshi Morioka, Hitoshi Maeda, Toru Maruyama
Journal: Journal of Controlled Release (2020)
SOX2, frequently down-regulated in gastric cancers, inhibits cell growth and its DNA hypermethylation is associated with poor prognosis in gastric cancer patients
Authors: Takeshi Otsubo, Yoshimitsu Akiyama, Yasuhito Yuasa
Journal: Cancer Research (2008)

4276  SOX transcription factors are essential for embryonic development and play critical roles in cell fate determination, differentiation and proliferation. We previously reported that the SOX2 protein is expressed in normal gastric mucosae but down-regulated in some human gastric carcinomas. However, the mechanisms underlying loss of SOX2 expression in gastric cancers and how SOX2 is involved in gastric carcinogenesis remain unclear. In this study, we analyzed whether SOX2 is epigenetically silenced by aberrant promoter methylation in human cultured and primary gastric cancer cells. To further clarify the roles of SOX2 in gastric carcinogenesis, we also carried out functional characterization of SOX2 in gastric epithelial cell lines. We initially examined SOX2 expression levels in human gastric cancer cell lines and primary gastric carcinoma tissues by RT-PCR. SOX2 mRNA was significantly reduced in 7 of 10 cell lines and 6 of 13 cases, compared with the levels of the normal stomach mucosae. By using methylation-specific PCR and bisulfite sequencing, we observed promoter CpG island hypermethylation in two of 10 gastric cancer cell lines, both of which exhibited undetectable SOX2 expression. These two cell lines up-regulated SOX2 expression after treatment with a demethylating agent but not with a histone deacetyltransferase inhibitor. In primary gastric carcinoma tissues, 12 of 74 (16.2%) cases exhibited the hypermethylation signals of SOX2, whereas none of the 24 corresponding non-cancerous tissues did (P=0.027). Importantly, among the 52 patients with advanced gastric cancers, those with cancers showing SOX2 methylation had a significantly shorter survival time than those without this methylation (P=0.0062). Exogenous expression of SOX2 induced inhibition of cell proliferation through cell cycle arrest and apoptosis. We also found that SOX2-mediated cell cycle arrest was strongly associated with decreased levels of cyclin D1 and phosphorylated Rb, and an increased p27Kip1 level. These cells exhibited further characteristics of apoptosis, such as DNA laddering and caspase-3 activation. Our data indicate that SOX2 plays important roles in growth inhibition through cell cycle arrest and apoptosis in gastric epithelial cells, and loss of SOX2 expression due to aberrant DNA methylation may contribute to gastric carcinogenesis. Furthermore, SOX2 methylation can be a clinically useful prognostic marker for advanced gastric cancer patients.
Instant labeling of therapeutic cells for multimodality imaging
Authors: Hossein Nejadnik, Kyung Oh Jung, Ashok J. Theruvath, Louise Kiru, Anna Liu, Wei Wu, Todd Sulchek, Guillem Pratx, Heike E. Daldrup-Link
Journal: Theranostics (2020)

Autologous therapeutic cells are typically harvested and transplanted in one single surgery. This makes it impossible to label them with imaging biomarkers through classical transfection techniques in a laboratory. To solve this problem, we developed a novel microfluidic device, which provides highly efficient labeling of therapeutic cells with imaging biomarkers through mechanoporation. Methods: Studies were performed with a new, custom-designed microfluidic device, which contains ridges, which compress adipose tissue-derived stem cells (ADSCs) during their device passage. Cell relaxation after compression leads to cell volume exchange for convective transfer of nanoparticles and nanoparticle uptake into the cell. ADSCs were passed through the microfluidic device doped with iron oxide nanoparticles and 18F-fluorodeoxyglucose (FDG). The cellular nanoparticle and radiotracer uptake was evaluated with DAB-Prussian blue, fluorescent microscopy, and inductively coupled plasma spectrometry (ICP). Labeled and unlabeled ADSCs were imaged in vitro as well as ex vivo in pig knee specimen with magnetic resonance imaging (MRI) and positron emission tomography (PET). T2 relaxation times and radiotracer signal were compared between labeled and unlabeled cell transplants using Student T-test with p<0.05. Results: We report significant labeling of ADSCs with iron oxide nanoparticles and 18F-FDG within 12+/-3 minutes. Mechanoporation of ADSCs with our microfluidic device led to significant nanoparticle (> 1 pg iron per cell) and 18F-FDG uptake (61 mBq/cell), with a labeling efficiency of 95%. The labeled ADSCs could be detected with MRI and PET imaging technologies: Nanoparticle labeled ADSC demonstrated significantly shorter T2 relaxation times (24.2±2.1 ms) compared to unlabeled cells (79.6±0.8 ms) on MRI (p<0.05) and 18F-FDG labeled ADSC showed significantly higher radiotracer uptake (614.3 ± 9.5 Bq / 1×104 cells) compared to controls (0.0 ± 0.0 Bq/ 1×104 cells) on gamma counting (p<0.05). After implantation of dual-labeled ADSCs into pig knee specimen, the labeled ADSCs revealed significantly shorter T2 relaxation times (41±0.6 ms) compared to unlabeled controls (90±1.8 ms) (p<0.05). Conclusion: The labeling of therapeutic cells with our new microfluidic device does not require any chemical intervention, therefore it is broadly and immediately clinically applicable. Cellular labeling using mechanoporation can improve our understanding of in vivo biodistributions of therapeutic cells and ultimately improve long-term outcomes of therapeutic cell transplants.
Conservative Surgery and Radiation for Intraductal Breast Carcinoma
Authors: A J Fishleder
Journal: JAMA (1992)

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129P Phase II study of pembrolizumab and nab-paclitaxel in HER2-negative metastatic breast cancer: Hormone receptor-positive cohort
Authors: Y. Novik, N. Klar, S. Zamora, M. Kwa, J. Speyer, R. Oratz, F. Muggia, M. Meyers, T. Hochman, J. Goldberg, S. Adams
Journal: Annals of Oncology (2020)
The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges
Authors: G.R. Tundo, D. Sbardella, A.M. Santoro, A. Coletta, F. Oddone, G. Grasso, D. Milardi, P.M. Lacal, S. Marini, R. Purrello, G. Graziani, M. Coletta
Journal: Pharmacology & Therapeutics (2020)