tbuckley/cabot-search huggingface dataset:
Neurodevelopmental Outcomes at Age 5 Years After Prophylactic Early High-Dose Recombinant Human Erythropoietin for Neuroprotection in Very Preterm Infants
Authors: Giancarlo Natalucci, Bea Latal, Brigitte Koller, Christoph Rüegger, Beate Sick, Leonhard Held, Jean-Claude Fauchère
Journal: JAMA (2020)

This study reports 5-year neurodevelopmental outcomes for Swiss children born before 32 weeks' gestation and randomized at birth to receive early high-dose recombinant human erythropoietin (rhEpo) vs placebo.
Identification of a novel long-acting 4’-modified nucleoside reverse transcriptase inhibitor against HBV
Authors: Nobuyo Higashi-Kuwata, Sanae Hayashi, Hiroki Kumamoto, Hiromi Ogata-Aoki, Debananda Das, David Venzon, Shin-ichiro Hattori, Haydar Bulut, Mai Hashimoto, Masaki Otagiri, Nobutoki Takamune, Naoki Kishimoto, David A. Davis, Shogo Misumi, Masakazu Kakuni, Yasuhito Tanaka, Hiroaki Mitsuya
Journal: Journal of Hepatology (2020)

While certain nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are efficacious in treating HBV infection, their effects are yet to be optimized and the emergence of NRTI-resistant HBV variants is an issue because of the requirement for lifelong treatment. The development of agents that more profoundly suppress wild-type and drug-resistant HBVs, and that have a long-acting effect, are crucial to improve patient outcomes.Herein, we synthesized a novel long-acting 4'-modified NRTI termed E-CFCP. We tested its anti-HBV activity in vitro, before evaluating its anti-HBV activity in HBV-infected human-liver-chimeric mice (PXB-mice). E-CFCP's long-acting features and E-CFCP-triphosphate's interactions with the HBV reverse transcriptase (HBV-RT) were examined.E-CFCP potently blocked HBVWTD1 production (IC50qPCR_cell=1.8 nM) in HepG2.2.15 cells and HBVWTC2 (IC50SB_cell=0.7 nM), entecavir (ETV)-resistant HBVETV-RL180M/S202G/M204V (IC50SB_cell=77.5 nM), and adefovir-resistant HBVADV-RA181T/N236T production (IC50SB_cell=14.1 nM) in Huh7 cells. E-CFCP profoundly inhibited intracellular HBV DNA production to below the detection limit, but ETV and tenofovir alafenamide (TAF) failed to do so. E-CFCP also showed less toxicity than ETV and TAF. E-CFCP better penetrated hepatocytes and was better tri-phosphorylated; E-CFCP-triphosphate persisted intracellularly for longer than ETV-triphosphate. Once-daily peroral E-CFCP administration over 2 weeks (0.02~0.2 mg/kg/day) reduced HBVWTC2-viremia by 2-3 logs in PXB-mice without significant toxicities and the reduction persisted over 1-3 weeks following treatment cessation, suggesting once-weekly dosing capabilities. E-CFCP also reduced HBVETV-RL180M/S202G/M204V-viremia by 2 logs over 2 weeks, while ETV completely failed to reduce HBVETV-RL180M/S202G/M204V-viremia. E-CFCP's 4'-cyano and fluorine interact with both HBVWT-RT and HBVETV-RL180M/S202G-M204 -RT via Van der Waals and polar forces, being important for E-CFCP-triphosphate's interactions and anti-HBV potency.E-CFCP represents the first reported potential long-acting NRTI with potent activity against wild-type and treatment-resistant HBV.Although there are currently effective treatment options for HBV, treatment-resistant variants and the need for lifelong therapy pose a significant challenge. Therefore, the development of new treatment options is crucial to improve outcomes and quality of life. Herein, we report preclinical evidence showing that the anti-HBV agent, E-CFCP, has potent activity against wild-type and treatment-resistant variants. In addition, once-weekly oral dosing may be possible, which is preferrable to the current daily dosing regimens.
The 9p21.3 Genetic Region and Coronary Heart Disease: Where Do We Go From Here?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Joseph B. Muhlestein, Jeffrey L. Anderson
Journal: Journal of the American College of Cardiology (2011)
84TiP Neo-CheckRay: Radiation therapy and adenosine pathway blockade to increase benefit of immuno-chemotherapy in early stage luminal B breast cancer: A randomized phase II trial
Authors: A. De Caluwe, L. Buisseret, P. Poortmans, C. Sotiriou, D. Larsimont, D. Van Gestel, A. Laragione, A. Desmet, R. Van Den Begin, C. Philippson, D. Eiger, M. Piccart, E. Romano, M. Ignatiadis
Journal: Annals of Oncology (2020)
PATH-19. MOLECULAR CLASSIFICATION BASED ON THE DNA METHYLATION PROFILE OF CENTRAL NERVOUS SYSTEM (CNS) TUMORS IN CHILDREN: TWO-YEARS EXPERIENCE AT THE BAMBINO GESÙ HOSPITAL
Authors: Evelina Miele, Sabrina Rossi, Lucia Pedace, Francesca Diomedi Camassei, Manila Antonelli, Antonella Cacchione, Giovanna Stefania Colafati, Andrea Carai, Francesca Gianno, Hiba Alzoubi, Marco Gessi, Marco Tartaglia, Felice Giangaspero, Franco Locatelli, Angela Mastronuzzi
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Pediatric brain tumors (PBT) represent the second most common pediatric cancer, with the highest mortality rate among childhood malignancies. Improvement of PBT diagnostic accuracy is fundamental to optimize treatment strategy. OBJECTIVES: We aimed to explore the impact of DNA methylation arrays implementation in PBT clinical practice. METHODS 214 PBT were analyzed by Illumina 850KEPICmethylation array. Low score and discordant cases were collegially reviewed. RESULTS Calibrated score was 0.8 or higher in 159 cases (74.3%), with pathological diagnosis confirmation in 132 cases and molecular subgroup definition in 47 of them, including cases of medulloblastoma, CNS neuroblastoma FOXR2, HGNET MN1; methylation profiling amended diagnosis in 10 cases, e.g. HGNET BCOR and anaplastic PXA, was non-contributory in 4 and misleading in 12 cases, including glioneural tumors and tumors arising in syndromic contexts. Calibrated score ranged between 0.8 and 0.3 in 37 cases (17.3%) and was below 0,3 (no match) in 18 cases (8.4%). Calibrated score below 0,8 was more frequently assigned to low grade gliomas and low grade glioneural tumors (p &amp;lt;0.0006). Challenging/very rare cases, e.g. intracranial AFH with EWSR1:CREM fusion and nonRELA supratentorial ependymomas, were assigned to “no match subgroup”; in syndromic patients the score tended to be lower (p=0.07); no correlation between score and age &amp;lt; 3-years was found (p=0.1). CONCLUSION Methylation profiling refine on diagnostic accuracy in PBT classification. Improvements are needed in classifying low grade glioma/glioneuronal tumors and challenging/very rare PBT. In syndromic cases, there is a high rate of misleading profiles and/or low scores.
Azimilide: Another Effort to Prevent Implantable Cardioverter-Defibrillator Shocks and Their Sequelae: Why it Is Important and How it Works⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: David S. Cannom, Brett Gidney
Journal: Journal of the American College of Cardiology (2008)
Accelerometer measured physical activity and the incidence of cardiovascular disease: Evidence from the UK Biobank cohort study
Authors: Rema Ramakrishnan, Aiden Doherty, Karl Smith-Byrne, Kazem Rahimi, Derrick Bennett, Mark Woodward, Rosemary Walmsley, Terence Dwyer
Journal: PLoS Medicine (2021)

Background Higher levels of physical activity (PA) are associated with a lower risk of cardiovascular disease (CVD). However, uncertainty exists on whether the inverse relationship between PA and incidence of CVD is greater at the highest levels of PA. Past studies have mostly relied on self-reported evidence from questionnaire-based PA, which is crude and cannot capture all PA undertaken. We investigated the association between accelerometer-measured moderate, vigorous, and total PA and incident CVD. Methods and findings We obtained accelerometer-measured moderate-intensity and vigorous-intensity physical activities and total volume of PA, over a 7-day period in 2013–2015, for 90,211 participants without prior or concurrent CVD in the UK Biobank cohort. Participants in the lowest category of total PA smoked more, had higher body mass index and C-reactive protein, and were diagnosed with hypertension. PA was associated with 3,617 incident CVD cases during 440,004 person-years of follow-up (median (interquartile range [IQR]): 5.2 (1.2) years) using Cox regression models. We found a linear dose–response relationship for PA, whether measured as moderate-intensity, vigorous-intensity, or as total volume, with risk of incident of CVD. Hazard ratios (HRs) and 95% confidence intervals for increasing quarters of the PA distribution relative to the lowest fourth were for moderate-intensity PA: 0.71 (0.65, 0.77), 0.59 (0.54, 0.65), and 0.46 (0.41, 0.51); for vigorous-intensity PA: 0.70 (0.64, 0.77), 0.54 (0.49,0.59), and 0.41 (0.37,0.46); and for total volume of PA: 0.73 (0.67, 0.79), 0.63 (0.57, 0.69), and 0.47 (0.43, 0.52). We took account of potential confounders but unmeasured confounding remains a possibility, and while removal of early deaths did not affect the estimated HRs, we cannot completely dismiss the likelihood that reverse causality has contributed to the findings. Another possible limitation of this work is the quantification of PA intensity-levels based on methods validated in relatively small studies. Conclusions In this study, we found no evidence of a threshold for the inverse association between objectively measured moderate, vigorous, and total PA with CVD. Our findings suggest that PA is not only associated with lower risk for of CVD, but the greatest benefit is seen for those who are active at the highest level.
NCOG-42. INITIAL PRESENTATION AND OUTPATIENT VISIT COMPLIANCE OF INMATES WITH BRAIN TUMORS
Authors: Iyad Alnahhas, Appaji Rayi, Yasmeen Rauf, Shirley Ong, Pierre Giglio, Vinay Puduvalli
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION While advocacy for inmates with cancer has recently gained momentum, little is known about management of brain tumors in inmates. Delays in acknowledging or recognizing nonspecific initial symptoms can lead to delayed diagnosis and treatment. Inmates with cancer are reported to either be ignored or receive substandard care due in part to cost or logistics (American Civil Liberties Union; ASCO Post 2018). METHODS In this retrospective study, we identified inmates with gliomas seen in the Ohio State University Neuro-oncology Center between 1/1/2010-4/20/2019. RESULTS Twelve patients were identified. Median age at presentation was 39.5 years (range 28-62). Eleven patients were Caucasian and one was African American. Diagnoses included glioblastoma (GBM) (n=6), anaplastic astrocytoma (n=1), anaplastic oligodendroglioma (n=1), low-grade astrocytoma (n=3) and anaplastic pleomorphic xanthroastrocytoma (n=1). Patients were more likely to present early after seizures or focal neurologic deficits (9/12) than after headaches alone. Patients with GBM started RT 12-71 days after surgery (median 34.5). One patient’s post-RT MRI was delayed by a month and another with GBM had treatment held after 4 cycles of adjuvant temozolomide (TMZ) due to “incarceration issues”. For one patient who received adjuvant TMZ, the facility failed to communicate with the primary team throughout treatment. Two patients suffered significant nausea while on chemotherapy due to inability to obtain ondansetron in prison, or due to wrong timing. 7/12 (58%) patients were lost to follow-up for periods of 3-15 months during treatment. Three patients refused adjuvant treatment. CONCLUSIONS Although this is a small series, our results highlight the inequities and challenges faced by inmates with gliomas who are more likely to forego treatments or whose incarceration prevents them from keeping appropriate treatment and follow-up schedules. Additional studies are needed to define and address these deficiencies in the care of inmates with brain tumors and other cancers.
RARE-34. UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG): GUIDELINES FOR THE MANAGEMENT OF MENINGIOMA IN CHILDREN, TEENAGERS AND YOUNG ADULTS
Authors: Elwira Szychot, John Goodden, Whitfield Gillian, Sarah Curry
Journal: Neuro-Oncology (2020)

Abstract Primary tumours of the meninges are rare accounting for only 0.4–4.6% of all paediatric tumours of the central nervous system. Due to the rarity of these tumours in children, and the consequent absence of collaborative prospective trials, there is no clear consensus on how the unique characteristics of paediatric meningiomas impact clinical status, management approach, and survival. Much of the evidence and treatment recommendations for paediatric meningiomas are extrapolated from adult data. Translating and adapting adult treatment recommendations into paediatric practice can be challenging and might inadvertently lead to inappropriate management. In 2009 Traunecker et al. published guidelines for the management of intracranial meningioma in children and young people on behalf of UK Children’s Cancer and Leukaemia Group (CCLG). Ten years later we have developed the updated guidelines following a comprehensive appraisal of the literature. Complete surgical resection is the treatment of choice for symptomatic meningiomas, while radiotherapy remains the only available adjuvant therapy and may be necessary for those tumours that cannot be completely removed. However, significant advances have been made in the identification of the genetic and molecular alterations of meningioma, which has not only a potential value in development of therapeutic agents but in surveillance of childhood meningioma survivors. This guideline builds upon the CCLG 2009 guideline. We summarise recommendations for the diagnosis, treatment, surveillance and long-term follow up of children and adolescents with meningioma.
Identification of novel CD44v6-binding peptides that block CD44v6 and deliver a pro-apoptotic peptide to tumors to inhibit tumor growth and metastasis in mice
Authors: Fatima Khan, Smriti Gurung, Gowri Rangaswamy Gunassekaran, Sri Murugan Poongkavithai Vadevoo, Lianhua Chi, Uttapol Permpoon, Md. Enamul Haque, Yun-Ki Lee, Soo-Woong Lee, Soyoun Kim, Byungheon Lee
Journal: Theranostics (2020)

CD44v6, a splice variant of the cell surface glycoprotein CD44, acts as a co-receptor for c-Met and is upregulated in tumors with high metastatic potential. Methods: We screened a phage-displayed peptide library for peptides that selectively bind to CD44v6-overexpressing cells and exploited them to block CD44v6 and deliver a pro-apoptotic peptide to tumors for cancer therapy. Results: CNLNTIDTC (NLN) and CNEWQLKSC (NEW) peptides bound preferentially to CD44v6-high cells than to CD44v6-low cells. The binding affinities of NLN and NEW to CD44v6 protein were 253 ± 79 and 85 ± 18 nM, respectively. Peptide binding to CD44v6-high cells was inhibited by the knockdown of CD44v6 gene expression and competition with an anti-CD44v6 antibody. A pull-down assay with biotin-labeled peptides enriched CD44v6 from cell lysates. NLN and NEW induced CD44v6 internalization and inhibited hepatocyte growth factor-induced c-Met internalization, c-Met and Erk phosphorylation, and cell migration and invasion. In mice harboring tumors, intravenously administered NLN and NEW homed to the tumors and inhibited metastasis to the lungs. When combined with crizotinib, a c-Met inhibitor, treatment with each peptide inhibited metastatic growth more efficiently than each peptide or crizotinib alone. In addition, KLAKLAKKLAKLAK pro-apoptotic peptide guided by NLN (NLN-KLA) or NEW (NEW-KLA) killed tumor cells and inhibited tumor growth and metastasis. No significant systemic side effects were observed after treatments. Conclusions: These results suggest that NLN and NEW are promising metastasis-inhibiting peptide therapeutics and targeting moieties for CD44v6-expressing metastases.
Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
Authors: Feng He, Yanrui Huang, Zhi Song, Huanjiao Jenny Zhou, Haifeng Zhang, Rachel J. Perry, Gerald I. Shulman, Wang Min
Journal: The Journal of Experimental Medicine (2020)

White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB-dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.
Tumor Microenvironment and Clonal Monocytes of Chronic Myelomonocytic Leukemia Induce a Procoagulant Climate within the Tumor Niche
Authors: Natacha Mauz, Mathieu Meunier, Landry Seyve, Julie Brault, Jean-Yves Cahn, Fabrice Cognasse, Benoit Polack, Sophie Park
Journal: Blood (2017)
pH-sensitive multi-drug liposomes targeting folate receptor β for efficient treatment of non-small cell lung cancer
Authors: Yong Il Park, Seung-Hae Kwon, Gibok Lee, Keiichi Motoyama, Min Woo Kim, Min Lin, Takuro Niidome, Jung Hoon Choi, Ruda Lee
Journal: Journal of Controlled Release (2020)

Non-small cell lung cancer (NSCLC) is the leading cause of lung cancer-related deaths worldwide. Tumor-associated macrophages (TAMs), which can be polarized into tumor-promoting M2 phenotype, overexpress folate receptor beta (FRβ) and are associated with poor prognosis in NSCLC. In addition, calpain-2 (CAPN2) is overexpressed in NSCLC and is involved in tumor growth. To improve the anticancer efficacy of drugs and reduce their side effects in the treatment of NSCLC, it is important to develop smart drug delivery systems with specific targeting ability and controlled release mechanisms. In this study, FRβ-targeted pH-sensitive liposomes were designed as carriers to ensure efficient drug delivery and acid-responsive release in NSCLC cells. Folate-mediated targeting of FRβ in M2 TAMs and NSCLC cells effectively inhibited tumor growth and the stimulus-responsive drug release reduced the toxic side effects of the drug. The combination of doxycycline (anti-CAPN2) and docetaxel (anticancer drug) showed a synergistic inhibitory effect on tumor growth by suppressing CAPN2 expression.
Covid-19: Many poor countries will see almost no vaccine next year, aid groups warn
Authors: Owen Dyer
Journal: BMJ (2020)

Covid-19: Many poor countries will see almost no vaccine next year, aid groups warn Owen DyerAt least 90% of people in 67 low income countries stand little chance of getting vaccinated against covid-19 in 2021 because wealthy nations have reserved more than they need and developers will not share their intellectual property, says the People's Vaccine Alliance, which includes Amnesty International, Frontline AIDS, Global Justice Now, and Oxfam. 1 "Unless something changes dramatically, billions of people around the world will not receive a safe and effective vaccine for covid-19 for years to come," said Anna Marriott, Oxfam's health policy manager.
HGG-12. A CASE OF PEDIATRIC SPINAL HIGH-GRADE GLIOMA WITH NTRK1 GENE FUSION
Authors: Tamaki Morisako, Daisuke Umebayashi, Kazuaki Kamata, Hiroyuki Yamamoto, Takumi Yamanaka, Hayato Takeuchi, Yoshinobu Takahashi, Kazunori Tatsuzawa, Mitsuru Miyachi, Shigeki Yagyu, Tomoko Iehara, Hajime Hosoi, Naoya Hashimoto
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Tumors arising from the spinal cord are uncommon, especially high-grade tumors in pediatric patients. We report a case of high-grade glioma in the spinal cord harboring NTRK1 gene fusion, who received effective entrectinib therapy. CASE REPORT: A 5-year-old boy presented right hemiparesis and MR imaging revealed an intramedullary enhancing mass at the vertebral body level between C3 and Th1. He underwent microsurgical partial resection and the histological diagnosis was low-grade astrocytoma. After the first-line chemotherapy with vincristine and carboplatin, his right hemiparesis deteriorated and recurrent MR imaging showed growth of the tumor. He underwent microsurgical partial resection again and the histological examination was high-grade glioma with endothelial proliferation and necrosis. The chemoradiotherapy with temozolomide and focal irradiation of 50.4 Gy were given, and his neurological symptom slightly improved. One month later, he presented respiratory disturbance and required assisted ventilation with tracheostomy. MR imaging showed tumor progression invading upward to medulla oblongata. NTRK1 gene fusion was detected in the previous surgical specimen by a gene panel testing, and he received entrectinib, a potent inhibitor of tropomyosin receptor kinase (TRK). Since then, no tumor progression has been demonstrated for several months by MRI and he has been stable neurologically. CONCLUSION High-grade spinal cord tumors are rare and effective treatment strategies have not been addressed. Although the frequency of the gene fusion is very low in pediatric gliomas, identification of the driver gene aberration like in this case by a gene panel can provide potential targeted therapies for selected patients.