tbuckley/cabot-search huggingface dataset:
Sex Differences in the Epilepsies and Associated Comorbidities: Implications for Use and Development of Pharmacotherapies
Authors: Catherine A. Christian, Doodipala Samba Reddy, Jamie Maguire, Patrick A. Forcelli
Journal: Pharmacological Reviews (2020)

The epilepsies are common neurologic disorders characterized by spontaneous recurrent seizures. Boys, girls, men, and women of all ages are affected by epilepsy and, in many cases, by associated comorbidities as well. The primary courses of treatment are pharmacological, dietary, and/or surgical, depending on several factors, including the areas of the brain affected and the severity of the epilepsy. There is a growing appreciation that sex differences in underlying brain function and in the neurobiology of epilepsy are important factors that should be accounted for in the design and development of new therapies. In this review, we discuss the current knowledge on sex differences in epilepsy and associated comorbidities, with emphasis on those aspects most informative for the development of new pharmacotherapies. Particular focus is placed on sex differences in the prevalence and presentation of various focal and generalized epilepsies; psychiatric, cognitive, and physiologic comorbidities; catamenial epilepsy in women; sex differences in brain development; the neural actions of sex and stress hormones and their metabolites; and cellular mechanisms, including brain-derived neurotrophic factor signaling and neuronal-glial interactions. Further attention placed on potential sex differences in epilepsies, comorbidities, and drug effects will enhance therapeutic options and efficacy for all patients with epilepsy. <h3>Significance Statement</h3> Epilepsy is a common neurological disorder that often presents together with various comorbidities. The features of epilepsy and seizure activity as well as comorbid afflictions can vary between men and women. In this review, we discuss sex differences in types of epilepsies, associated comorbidities, pathophysiological mechanisms, and antiepileptic drug efficacy in both clinical patient populations and preclinical animal models.
In patients with ASCVD and elevated LDL-C with maximal statin therapy, inclisiran reduced LDL-C levels at 18 months
Authors: Jennifer Clark, Victor Montori
Journal: Annals of Internal Medicine (2020)

Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382:1507-19. 32187462.
Critically Ill Patients with CKD Deserve Better Mortality Prediction Scores
Authors: Sarah F. Sanghavi
Journal: Journal of the American Society of Nephrology (2020)

To the Editor, I sincerely appreciate the article by Silberzweig et al. ,[1][1] which addresses the potential effect of health care resource rationing on patients with CKD. The authors discuss the ethical principles underpinning the scarce resource allocation systems considered in the throes of the
Functional outcomes in symptomatic versus asymptomatic patients undergoing incisional hernia repair: Replacing one problem with another? A prospective cohort study in 1312 patients
Authors: Gijs H.J. de Smet, Dimitri Sneiders, Yagmur Yurtkap, Anand G. Menon, Johannes Jeekel, Gert-Jan Kleinrensink, Johan F. Lange, Jean-François Gillion, E. Abet, J.-F. Ain, L. Arnalsteen, O. Baraket, M. Beck, A. Bellouard, E. Benizri, C. Berney, D. Bilem, D. Binot, B. Blanc, D. Blazquez, A. Bonan, T. Boukortt, O. Brehant, O. Cas, A. Champault-Fezais, A. Chau, J.-M. Chollet, M. Constantin, J.-P. Cossa, A. Dabrowski, A. David, S. Demaret, V. Dubuisson, T. Dugue, I. El Nakadi, J.-P. Faure, P. Frileux, G. Fromont, N. Gadiri, J.-F. Gillion, O. Glehen, S. Hennequin, M. Isambert, F. Jurczak, H. Khalil, A. Lamblin, C. Largenton, M. Lavy, M. Lepère, N. Le Toux, E. Magne, S. Manfredelli, C. Mariette, Y. Marion, H.-A. Mercoli, N. Mesli Smain, D. Moszkowicz, M. Najim, O. Oberlin, E. Odet, P. Ortega Deballon, X. Pavis d’Escurac, V. Pichot Delahaye, J.B. Putinier, J.M. Regimbeau, Y. Renard, B. Romain, D. Rouquie, M. Soler, J. Soufron, S. Roos, J.-M. Thillois, P. Tiry, A. Vauchaussade De Chaumont, E. Vinatier, P. Vu, R. Verhaeghe, C. Zaranis, M. Zeineb
Journal: International Journal of Surgery (2020)

Incisional hernias can be associated with pain or discomfort. Surgical repair especially mesh reinforcement, may likewise induce pain. The primary objective was to assess the incidence of pain after hernia repair in patients with and without pre-operative pain or discomfort. The secondary objectives were to determine the preferred mesh type, mesh location and surgical technique in minimizing postoperative pain or discomfort. A registry-based prospective cohort study was performed, including patients undergoing incisional hernia repair between September 2011 and May 2019. Patients with a minimum follow-up of 3–6 months were included. The incidence of hernia related pain and discomfort was recorded perioperatively. A total of 1312 patients were included. Pre-operatively, 1091 (83%) patients reported pain or discomfort. After hernia repair, 961 (73%) patients did not report pain or discomfort (mean follow-up = 11.1 months). Of the pre-operative asymptomatic patients (n = 221), 44 (20%, moderate or severe pain: n = 14, 32%) reported pain or discomfort after mean follow-up of 10.5 months. Of those patients initially reporting pain or discomfort (n = 1091), 307 (28%, moderate or severe pain: n = 80, 26%) still reported pain or discomfort after a mean follow-up of 11.3 months postoperatively. In symptomatic incisional hernia patients, hernia related complaints may be resolved in the majority of cases undergoing surgical repair. In asymptomatic incisional hernia patients, pain or discomfort may be induced in a considerable number of patients due to surgical repair and one should be aware if this postoperative complication.
Progress against childhood and adolescent acute lymphoblastic leukaemia in the Netherlands, 1990–2015
Authors: Ardine M. J. Reedijk, Jan Willem W. Coebergh, Hester A. de Groot-Kruseman, Inge M. van der Sluis, Leontien C. Kremer, Henrike E. Karim-Kos, Rob Pieters
Journal: Leukemia (2020)

Abstract We assessed the epidemiologic progress against childhood and adolescent acute lymphoblastic leukaemia (ALL) in the Netherlands over a 26 year period. ALL patients &lt;18 years were selected from the Netherlands Cancer Registry and the Dutch Childhood Oncology Group. Trend analyses were performed over time and by age group and ALL subtype. Between 1990 and 2015, 2997 ALL patients were diagnosed, i.e. 115 patients (range 87–147) per year. Overall incidence remained stable at 37 per million children, despite increases for B-cell precursor ALL (BCP-ALL) at age 10–14 years (AAPC + 1.4%, p = 0.04) and T-cell ALL at 15–17 years (AAPC + 3.7%, p = 0.01). Five-year survival increased from 80% in 1990–94 to 91% in 2010–15 ( p &lt; 0.01). Mortality decreased by 4% annually ( p &lt; 0.01). Patients 15–17 years were increasingly treated in a paediatric oncology centre, from 35% in 1990–94 to 87% in 2010–15 and experienced a 70% reduction of risk of death compared to those treated outside such a centre ( p &lt; 0.01). Significant progress against childhood ALL has been made in the Netherlands, visible by improved survival rates coinciding with declining mortality rates. These outcomes were accompanied by stable incidence rates, despite increases for BCP-ALL at age 10–14 years and T-cell ALL at age 15–17 years.
TGF-β1 modulates temozolomide resistance in glioblastoma via altered microRNA processing and elevated MGMT
Authors: Er Nie, Xin Jin, Faan Miao, Tianfu Yu, Tongle Zhi, Zhumei Shi, Yingyi Wang, Junxia Zhang, Manyi Xie, Yongping You
Journal: Neuro-Oncology (2020)

Abstract Background Our previous studies have indicated that miR-198 reduces cellular methylguanine DNA methyltransferase (MGMT) levels to enhance temozolomide sensitivity. Transforming growth factor beta 1 (TGF-β1) switches off miR-198 expression by repressing K-homology splicing regulatory protein (KSRP) expression in epidermal keratinocytes. However, the underlying role of TGF-β1 in temozolomide resistance has remained unknown. Methods The distribution of KSRP was detected by western blotting and immunofluorescence. Microarray analysis was used to compare the levels of long noncoding RNAs (lncRNAs) between TGF-β1–treated and untreated cells. RNA immunoprecipitation was performed to verify the relationship between RNAs and KSRP. Flow cytometry and orthotopic and subcutaneous xenograft tumor models were used to determine the function of TGF-β1 in temozolomide resistance. Results Overexpression of TGF-β1 contributed to temozolomide resistance in MGMT promoter hypomethylated glioblastoma cells in vitro and in vivo. TGF-β1 treatment reduced cellular MGMT levels through suppressing the expression of miR-198. However, TGF-β1 upregulation did not affect KSRP expression in glioma cells. We identified and characterized 2 lncRNAs (H19 and HOXD-AS2) that were upregulated by TGF-β1 through Smad signaling. H19 and HOXD-AS2 exhibited competitive binding to KSRP and prevented KSRP from binding to primary miR-198, thus decreasing miR-198 expression. HOXD-AS2 or H19 upregulation strongly promoted temozolomide resistance and MGMT expression. Moreover, KSRP depletion abrogated the effects of TGF-β1 and lncRNAs on miR-198 and MGMT. Finally, we found that patients with low levels of TGF-β1 or lncRNA expression benefited from temozolomide therapy. Conclusions Our results reveal an underlying mechanism by which TGF-β1 confers temozolomide resistance. Furthermore, our findings suggest that a novel combination of temozolomide with a TGF-β inhibitor may serve as an effective therapy for glioblastomas.
Coexpression of CD71 and CD117 Identifies an Early Unipotent Neutrophil Progenitor Population in Human Bone Marrow
Authors: Huy Q. Dinh, Tobias Eggert, Melissa A. Meyer, Yanfang Peipei Zhu, Claire E. Olingy, Ryan Llewellyn, Runpei Wu, Catherine C. Hedrick
Journal: Immunity (2020)
Effect of cotreatment with statins and farnesyltranferase inhibitors on acute myeloid leukemia cells
Authors: Karen van der Weide, Susan de Jonge Peeters, Folkert Kuipers, Elisabeth de Vries, Edo Vellenga
Journal: Cancer Research (2008)

4359  The cholesterol metabolism is dysregulated in many malignancies, including acute myeloid leukemia (AML). Previously, we demonstrated an active cholesterol metabolism in primitive normal haematopoietic cells and in a subgroup of AML cells at RNA level. We also found an inhibitory effect of cholesterol synthesis inhibitors (statins) on cell survival in AML patient samples. Consequently, a role for statins to improve standard anti-leukemic treatment has been suggested. The antitumor effects of statins have been assumed to be primarily due to their blockade of isoprenylation. However, statin concentrations necessary to inhibit specific protein isoprenylation are 100-500 fold higher than those required to inhibit cholesterol synthesis. Therefore a combination between a cholesterol synthesis inhibitor and a isoprenylation inhibitor like tipifarnib appears promising.  Our objective was to evaluate whether treatment of AML cells with simvastatin in combination with the farnesyltransferase inhibitor (FTI) tipifarnib has beneficial effects over treatment with simvastatin alone, and whether this especially concerns primitive CD34+ cells. Normal and AML mononuclear cells were sorted into CD34+ and CD34- fractions. These fractions and AML cell lines TF-1 and KG1A, were incubated with different concentrations of simvastatin (5, 25 and 50 μM) and tipifarnib (0.2, 1 and 5 μM) for 24 (primary samples) or 48 hours (cell lines). The percentage of surviving cells was determined using a chemoluminescence cell viability assay. In cell lines westernblots on p-ERK and p-PKB were performed, cell numbers were determined and cell death and cell cycle progression were determined by Annexin V/PI staining and PI staining respectively.  Both simvastatin and tipifarnib decreased cell numbers and viability of TF-1 and KG1A cells. This inhibitory effect of simvastatin as well as tipifarnib was shown to consist of both cell cycle inhibition and cell death induction, which appeared to be additive or synergistic when using the combination. Treatment with both tipifarnib and simvastatin resulted in an increased downregulation of p-ERK and p-PKB compared to either compound alone. A heterogenous response pattern was observed in AML patient samples after treatment with simvastatin and tipifarnib. A group of normal and abnormal responders were identified based on (dis)similarity in cell viability compared to normal CD34+ cells after treatment. A similar response pattern was found in CD34- cells. Whereas a minority of AML samples appeared sensitive to either simvastatin or tipifarnib treatment, over 50% of the AML samples were significantly affected by the combination treatment. Abnormal responders had significantly higher CD34+ percentages compared to normal responders.  These data strongly suggest a benefit for combination treatment with statins and FTIs in a subgroup of AML patients.
Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity
Authors: Natasha D Sheybani, Alexandra R Witter, Eric A Thim, Hideo Yagita, Timothy N J Bullock, Richard J Price
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Triple-negative breast cancer (TNBC) remains recalcitrant to most targeted therapy approaches. However, recent clinical studies suggest that inducing tumor damage can render TNBC responsive to immunotherapy. We therefore tested a strategy for immune sensitization of murine TNBC (4T1 tumors) through combination of focused ultrasound (FUS) thermal ablation and a chemotherapy, gemcitabine (GEM), known to attenuate myeloid-derived suppressor cells (MDSCs). Methods We applied a sparse-scan thermally ablative FUS regimen at the tumor site in combination with systemically administered GEM. We used flow cytometry analysis to investigate the roles of monotherapy and combinatorial therapy in mediating local and systemic immunity. We also tested this combination in Rag1 −/− mice or T cell-depleted wild-type mice to determine the essentiality of adaptive immunity. Further, we layered Programmed cell death protein 1 (PD-1) blockade onto this combination to evaluate its impact on tumor outgrowth and survival. Results The immune-modulatory effect of FUS monotherapy was insufficient to promote a robust T cell response against 4T1, consistent with the dominant MDSC-driven immunosuppression evident in this model. The combination of FUS+GEM significantly constrained primary TNBC tumor outgrowth and extended overall survival of mice. Tumor control correlated with increased circulating antigen-experienced T cells and was entirely dependent on T cell-mediated immunity. The ability of FUS+GEM to control primary tumor outgrowth was moderately enhanced by either neoadjuvant or adjuvant treatment with anti-PD-1. Conclusion Thermally ablative FUS in combination with GEM restricts primary tumor outgrowth, improves survival and enhances immunogenicity in a murine metastatic TNBC model. This treatment strategy promises a novel option for potentiating the role of FUS in immunotherapy of metastatic TNBC and is worthy of future clinical evaluation. Trial registration numbers NCT03237572 and NCT04116320 .
P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice
Authors: Zhi Ruan, Jean-Christophe Delpech, Srinidhi Venkatesan Kalavai, Alicia A. Van Enoo, Jianqiao Hu, Seiko Ikezu, Tsuneya Ikezu
Journal: Molecular Neurodegeneration (2020)

Abstract Background Neuronal accumulation of misfolded microtubule-associated protein tau is a hallmark of neuropathology in Alzheimer’s disease, frontotemporal dementia, and other tauopathies, and has been a therapeutic target. Microglia can spread tau pathology by secreting tau-containing exosomes, although the specific molecular target is yet to be identified for the therapeutic intervention. P2X purinoceptor 7 (P2RX7) is an ATP-gated cation channel, enriched in microglia and triggers exosome secretion. The purpose of the study is to examine the therapeutic effect of an orally applicable, CNS-penetrant P2RX7 specific inhibitor on the early disease stage of a tauopathy mouse model. Methods Three-months-old P301S tau mice were treated with P2RX7-specific inhibitor GSK1482160 or vehicle for 30 days, followed by behavioral, biochemical and immunohistochemical assessment. GSK1482160 was also tested for exosome secretion from primary cultured murine astrocytes, neurons and microglia in vitro. Results Oral administration of GSK1482160 significantly reduced accumulation of MC1 + and Alz50 + misfolded tau in hippocampal regions, which was accompanied with reduced accumulation of Tsg101, an exosome marker, in hippocampal neurons. Proximity ligation assay demonstrated complex formation of Alz50 + tau and Tsg101 in hippocampal neurons, which was reduced by GSK1482160. On the other hand, GSK1482160 had no effect on microglial ramification or CD68 expression, which was significantly enhanced in P301S mice, or pro/anti-inflammatory cytokine gene expression. Strikingly, GSK1482160-treated P301S mice show significantly improved working and contextual memory as determined by Y-maze and fear conditioning tests. GSK1482160 also significantly increased accumulation of Tsg101 and CD81 in microglia in vivo , suggesting its suppression of P2RX7-induced exosome secretion from microglia . This effect was confirmed in vitro, as ATP-induced secretion of tau-containing exosome was significantly suppressed by GSK1482160 treatment from primary murine microglia, but not from neurons or astrocytes. Discussion The oral administration of P2RX7 inhibition mitigates disease phenotypes in P301S mice, likely by suppressing release of microglial exosomes. P2RX7 could be a novel therapeutic target for the early stage tauopathy development.
Impact of a bundle on surgical site infections after hip arthroplasty: A cohort study in Italy (2012–2019)
Authors: Costanza Vicentini, Alessio Corradi, Alessandro Scacchi, Heba Safwat Mhmoued Abdo Elhadidy, Maria Francesca Furmenti, Francesca Quattrocolo, Carla Maria Zotti
Journal: International Journal of Surgery (2020)
<i>Notes from the Field:</i> COVID-19 Prevention Practices in State Prisons — Puerto Rico, 2020
Authors: Elizabeth Davlantes, Mayra Toro, Raúl Villalobos, Liliana Sanchez-Gonzalez
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

As of August 17, 2020, the Puerto Rico Department of Health had reported 11,723 confirmed cases of coronavirus disease 2019 , 15,037 probable cases, and 335 deaths.Among persons incarcerated in state prisons, a high-risk congregate setting, only two COVID-19 cases and no associated deaths had been reported* (1).These results followed implementation in mid-March of a protocol (2) for the diagnosis, management, and prevention of COVID-19 in all Puerto Rico Department of Correction and Rehabilitation prisons based on CDC's interim guidance on management of COVID-19 in correctional and detention facilities (3).The protocol featured wide-ranging measures, from visitor restrictions to enhanced cleaning; this report focuses specifically on COVID-19 mitigation measures directed toward incarcerated persons.To minimize SARS-CoV-2 transmission from newly incarcerated persons, all state prison intakes in Puerto Rico now occur at a single location, in the municipality of Bayamon.All new intake procedures include SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) testing regardless of symptoms.Asymptomatic persons awaiting test results are cohorted in groups of no more than 20 in the intake area.If everyone in the group tests negative for SARS-CoV-2, and all remain asymptomatic during 14 days of quarantine, they are released into the general prison population.Those who test positive and those with any medical concerns are immediately isolated and referred to the onsite medical facility.If any cohort member tests positive for SARS-CoV-2, either from the intake assessment or after becoming symptomatic in quarantine, the entire cohort must restart the intake process.Incarcerated persons who leave the prison grounds for any reason (e.g., medical appointments or court appearances) must restart the intake process upon their return.During March 16-July 31, 2020, 1,340 persons entered Puerto Rico Department of Correction and Rehabilitation prisons, and two (0.1%) had positive SARS-CoV-2 RT-PCR test results.Both patients were asymptomatic, and no persons in their cohorts developed COVID-19.* Four additional COVID-19 cases were identified in persons awaiting trial.
International electronic health record-derived COVID-19 clinical course profiles: the 4CE consortium
Authors: Gabriel A. Brat, Griffin M. Weber, Nils Gehlenborg, Paul Avillach, Nathan P. Palmer, Luca Chiovato, James Cimino, Lemuel R. Waitman, Gilbert S. Omenn, Alberto Malovini, Jason H. Moore, Brett K. Beaulieu-Jones, Valentina Tibollo, Shawn N. Murphy, Sehi L’ Yi, Mark S. Keller, Riccardo Bellazzi, David A. Hanauer, Arnaud Serret-Larmande, Alba Gutierrez-Sacristan, John J. Holmes, Douglas S. Bell, Kenneth D. Mandl, Robert W. Follett, Jeffrey G. Klann, Douglas A. Murad, Luigia Scudeller, Mauro Bucalo, Katie Kirchoff, Jean Craig, Jihad Obeid, Vianney Jouhet, Romain Griffier, Sebastien Cossin, Bertrand Moal, Lav P. Patel, Antonio Bellasi, Hans U. Prokosch, Detlef Kraska, Piotr Sliz, Amelia L. M. Tan, Kee Yuan Ngiam, Alberto Zambelli, Danielle L. Mowery, Emily Schiver, Batsal Devkota, Robert L. Bradford, Mohamad Daniar, Christel Daniel, Vincent Benoit, Romain Bey, Nicolas Paris, Patricia Serre, Nina Orlova, Julien Dubiel, Martin Hilka, Anne Sophie Jannot, Stephane Breant, Judith Leblanc, Nicolas Griffon, Anita Burgun, Melodie Bernaux, Arnaud Sandrin, Elisa Salamanca, Sylvie Cormont, Thomas Ganslandt, Tobias Gradinger, Julien Champ, Martin Boeker, Patricia Martel, Loic Esteve, Alexandre Gramfort, Olivier Grisel, Damien Leprovost, Thomas Moreau, Gael Varoquaux, Jill-Jênn Vie, Demian Wassermann, Arthur Mensch, Charlotte Caucheteux, Christian Haverkamp, Guillaume Lemaitre, Silvano Bosari, Ian D. Krantz, Andrew South, Tianxi Cai, Isaac S. Kohane
Journal: npj Digital Medicine (2020)

We leveraged the largely untapped resource of electronic health record data to address critical clinical and epidemiological questions about Coronavirus Disease 2019 (COVID-19). To do this, we formed an international consortium (4CE) of 96 hospitals across five countries (www.covidclinical.net). Contributors utilized the Informatics for Integrating Biology and the Bedside (i2b2) or Observational Medical Outcomes Partnership (OMOP) platforms to map to a common data model. The group focused on temporal changes in key laboratory test values. Harmonized data were analyzed locally and converted to a shared aggregate form for rapid analysis and visualization of regional differences and global commonalities. Data covered 27,584 COVID-19 cases with 187,802 laboratory tests. Case counts and laboratory trajectories were concordant with existing literature. Laboratory tests at the time of diagnosis showed hospital-level differences equivalent to country-level variation across the consortium partners. Despite the limitations of decentralized data generation, we established a framework to capture the trajectory of COVID-19 disease in patients and their response to interventions.
Microrna-21 (Mir-21) Expression and Clinical Outcome in Pancreatic Ductal Adenocarcinoma
Authors: E. Vasile, E. Giovannetti, N. Funel, M. Del Chiaro, L. Leon, L. Pollina, S. Caponi, L. Ginocchi, L. Erozenci, Alfredo Falcone, Daniela Campani, Romano Danesi, G. Peters, Ugo Boggi, H. Verheul
Journal: Annals of Oncology (2010)