tbuckley/cabot-search huggingface dataset:
Abstract 1199: Adult Hispanic males experience a higher incidence of acute lymphoblastic leukemia compared to non-Hispanic Whites
Authors: Manuel R. Espinoza-Gutarra, Edgar Munoz, Dimpy P. Shah, Anand Karnad, Ruben A. Mesa, Amelie G. Ramirez
Journal: Cancer Research (2018)

Abstract Introduction: Acute leukemia is an important cause of morbidity and mortality with differences in incidence and outcomes between patients of different ethnic backgrounds. We conducted this study to examine the ethnic disparities in incidence of ALL as well as other types of acute leukemia in the Latino population in South Texas. Methods: Data were obtained from the U.S. Surveillance, Epidemiology and End Results 18 (SEER) Program and the Texas Cancer Registry (TCR) under Limited-Use Data Agreements between sources and authors. Adult patients (15 years or older) were identified in both SEER and TCR databases from 2000 to 2014 and ICD-O-3 codes were used to select specific malignancies: ALL (9727-9729, 9835-9837), acute promyelocytic leukemia (APL) (9866) and non-APL acute myeloid leukemia (AML) (9840, 9861, 9867, 9870-9874, 9891, 9895-9897, 9910, 9920, 9930, 9931). Ethnicity was classified as Hispanic (H) and non-Hispanic White (NHW) per the North American Association of Central Cancer Registry (NAACR) Hispanic Identification Algorithm. Cases were obtained from SEER 18 and TCR, including Texas and the 38 counties of South Texas. Comparisons used the SEER population of NHW as reference. We used SEER*Stat software v 8.3.4 (SEER*Stat, NIH), to generate 2000-2014 average annual age-specific and age-adjusted acute leukemia incidence rates (per 1000000), rate ratios (RR) and 95% confidence interval (CI) for Hispanic and NHW populations in SEER, Texas, and South Texas. Results: Table 1 shows Hispanic males in South Texas had significantly higher RR for development of ALL (p&amp;lt;0.05), and lower for non-APL AML; there was no statistical difference for APL RR compared to NHW. Males (15-39 and 70-79 years) had higher rates of ALL. Conclusion: Latinos in South Texas experience a higher incidence of ALL and a lower incidence of non-APL AML compared to NHW. Future studies are needed to identify specific risk factors associated with this higher burden in Hispanic population. Table 1SEERTCRTexasSouth TexasHNHWRR (95%CI)HNHWRR (95%CI)HNHWRR (95%CI)ALL213744421.50 (1.42-1.59)9789851.43 (1.33-1.53)3771071.63 (1.46-1.81)Non-APL AML3398047190.77 (0.75-0.80)216375930.41 (0.40-0.43)8488980.48 (0.45-0.51)APL77022241.22 (1.11-1.33)3094720.90 (0.80- 1.02)109510.94 (0.77- 1.14) Citation Format: Manuel R. Espinoza-Gutarra, Edgar Munoz, Dimpy P. Shah, Anand Karnad, Ruben A. Mesa, Amelie G. Ramirez. Adult Hispanic males experience a higher incidence of acute lymphoblastic leukemia compared to non-Hispanic Whites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1199.
Nanoengineering of nanorattles for tumor treatment by CT imaging-guided simultaneous enhanced microwave thermal therapy and managing inflammation
Authors: Qiong Wu, Jie Yu, Mei Li, Longfei Tan, Xiangling Ren, Changhui Fu, Zengzhen Chen, Feng Cao, Jun Ren, Laifeng Li, Ping Liang, Yu Zhang, Xianwei Meng
Journal: Biomaterials (2018)
Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care
Authors: Yana Vinogradova, Carol Coupland, Trevor Hill, Julia Hippisley-Cox
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To investigate the associations between direct oral anticoagulants (DOACs) and risks of bleeding, ischaemic stroke, venous thromboembolism, and all cause mortality compared with warfarin. <h3>Design</h3> Prospective open cohort study. <h3>Setting</h3> UK general practices contributing to QResearch or Clinical Practice Research Datalink. <h3>Participants</h3> 132 231 warfarin, 7744 dabigatran, 37 863 rivaroxaban, and 18 223 apixaban users without anticoagulant prescriptions for 12 months before study entry, subgrouped into 103 270 patients with atrial fibrillation and 92 791 without atrial fibrillation between 2011 and 2016. <h3>Main outcome measures</h3> Major bleeding leading to hospital admission or death. Specific sites of bleeding and all cause mortality were also studied. <h3>Results</h3> In patients with atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (adjusted hazard ratio 0.66, 95% confidence interval 0.54 to 0.79) and intracranial bleeding (0.40, 0.25 to 0.64); dabigatran was associated with a decreased risk of intracranial bleeding (0.45, 0.26 to 0.77). An increased risk of all cause mortality was observed in patients taking rivaroxaban (1.19, 1.09 to 1.29) or on lower doses of apixaban (1.27, 1.12 to 1.45). In patients without atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (0.60, 0.46 to 0.79), any gastrointestinal bleeding (0.55, 0.37 to 0.83), and upper gastrointestinal bleeding (0.55, 0.36 to 0.83); rivaroxaban was associated with a decreased risk of intracranial bleeding (0.54, 0.35 to 0.82). Increased risk of all cause mortality was observed in patients taking rivaroxaban (1.51, 1.38 to 1.66) and those on lower doses of apixaban (1.34, 1.13 to 1.58). <h3>Conclusions</h3> Overall, apixaban was found to be the safest drug, with reduced risks of major, intracranial, and gastrointestinal bleeding compared with warfarin. Rivaroxaban and low dose apixaban were, however, associated with increased risks of all cause mortality compared with warfarin.
Abstract 10846: Long-term Effects of Ezetimibe Plus Statin Combination vs Double-dose Statin Therapy on Low-density Lipoprotein Cholesterol Lowering in Coronary Artery Disease Patients Pre-treated with Statins; Focus on Proprotein Convertase Subtilisin/Kexin Type 9
Authors: Kozo Okada, Noriaki Iwahashi, Tsutomu Endo, Hideo Himeno, Kazuki Fukui, Shunichi Kobayashi, Makoto Shimizu, Yuji Iwasawa, Yukiko Morita, Atsushi Wada, Tomohiko Shigemasa, Yasuyuki Mochida, Tomoaki Shimizu, Reimin Sawada, Kazuaki Uchino, Satoshi Umemura, Kazuo Kimura
Journal: Circulation (2012)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to hepatic LDL receptor, causing its subsequent degradation. Although statin therapy is known to increase concentrations of P...
Efficacy of inverso isomer of CendR peptide on tumor tissue penetration
Authors: Ruifeng Wang, Qing Shen, Xue Li, Cao Xie, Weiyue Lu, Songli Wang, Jing Wang, Dongli Wang, Min Liu
Journal: Acta Pharmaceutica Sinica B (2018)

The dense extracellular matrix and high interstitial fluid pressure of tumor tissues prevent the ability of anti-tumor agents to penetrate deep into the tumor parenchyma for treatment effects. C-end rule (CendR) peptides can enhance the permeability of tumor blood vessels and tumor tissues via binding to neuropilin-1 (NRP-1), thus aiding in drug delivery. In this study, we selected one of the CendR peptides (sequence RGERPPR) as the parent l-peptide and substituted d-amino acids for the l-amino acids to synthesize its inverso peptide D(RGERPPR). We investigated the NRP-1 binding activity and tumor-penetrating ability of D(RGERPPR). We found that the binding affinity of D(RGERPPR) with NRP-1 and the cellular uptake was significantly higher than that of RGERPPR. Evans Blue tests revealed that D(RGERPPR) exhibited improved tumor-penetrating ability in C6, U87 and A549 tumor-bearing nude mice. Using nude mice bearing A549 xenograft tumors as a model, we found that the rate of tumor growth in the group co-administered with D(RGERPPR) and gemcitabine (Gem) was significantly lower than the gemcitabine-treated group with a tumor suppression rate (TSR%) of 55.4%. Together, our results demonstrate that D(RGERPPR) is a potential tumor-penetrating peptide.
Safety investigation practices can be adapted from aviation for use in healthcare
Authors: Kevin Stewart, Carl Macrae, Nick Toff
Journal: BMJ (2018)

Oliver is right about healthcare being different from aviation1; it is also different from firefighting, deep sea fishing, oil exploration, and every other high risk industry. Attempts to implement safety practices from other industries are often naive, failing to appreciate the need to adapt to the very different context of healthcare. Moreover, one safety model will not fit all of healthcare …
Match injury incidence during the Super Rugby tournament is high: a prospective cohort study over five seasons involving 93 641 player-hours
Authors: Martin P Schwellnus, Esme Jordaan, Charl Janse van Rensburg, Helen Bayne, Wayne Derman, Clint Readhead, Rob Collins, Alan Kourie, Jason Suter, Org Strauss
Journal: British Journal of Sports Medicine (2018)

To determine the incidence and nature of injuries in the Super Rugby tournament over a 5-year period.482 male professional rugby union players from six South African teams participating in the Super Rugby tournament were studied (1020 player-seasons). Medical staff of participating teams (2012-2016 tournaments) recorded all time loss injuries (total injuries and match injuries) and exposure hours (93 641 total playing hours; 8032 match hours). Injury incidence, injured player proportion, severity (time lost), anatomical location, tissue type and activity/phase during which injury occurred are reported.The overall incidence of match injuries (per 1000 player-hours; 95% CI) for each year was as follows: 2012 (83.3; 69.4-99.2); 2013 (115.1; 98.7-133.5); 2014 (95.9; 80.8-113.1), 2015 (112.3; 96.6-129.9) and 2016 (93.2; 79.9-107.9). The injured player proportion for each year was as follows: 2012 (54.6%); 2013 (49.4%); 2014 (52.0%); 2015 (50.0%); and 2016 (39.8%). The thigh, knee, head/face and shoulder/clavicle are the most frequently injured locations, and muscle/tendon and joint/ligament injuries account for the majority of injuries. Most injuries (79%) occur in contact situations, in particular during a tackle (54%).The incidence of match injuries and the injured player proportion in South African teams competing in the Super Rugby tournament is high. Match injury incidence is consistently higher than previously reported for senior male rugby players at elite/professional level. Targeted risk management strategies are therefore needed in the Super Rugby tournament to manage risk of injury.
Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced <i>ERBB2/HER2</i>-Positive Metastatic Breast Cancer
Authors: Virginia F. Borges, Cristiano Ferrario, Nathalie Aucoin, Carla Falkson, Qamar Khan, Ian Krop, Stephen Welch, Alison Conlin, Jorge Chaves, Philippe L. Bedard, Marc Chamberlain, Todd Gray, Alex Vo, Erika Hamilton
Journal: JAMA Oncology (2018)

<h3>Importance</h3> Treatment options for patients with disease progression after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) are limited. Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for<i>ERBB2/HER2</i>-positive breast cancer. <h3>Objective</h3> To determine the maximum tolerated dosage of tucatinib in combination with T-DM1 in the treatment of patients with<i>ERBB2/HER2</i>-positive metastatic breast cancer with and without brain metastases. <h3>Design, Setting, and Participants</h3> In this phase 1b open-label, multicenter, clinical trial, 57 participants enrolled between January 22, 2014, and June 22, 2015, were 18 years of age or older with<i>ERBB2/HER2</i>-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Data were analyzed between January and March 2018. <h3>Interventions</h3> Tucatinib 300 mg or 350 mg administered orally twice per day for 21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days. <h3>Main Outcomes and Measures</h3> Safety assessments, pharmacokinetics, and response were assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3 cycles. <h3>Results</h3> Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were treated. The tucatinib maximum tolerated dosage was determined to be 300 mg administered twice per day with dose-limiting toxic reactions seen at 350 mg twice per day. Pharmacokinetic analysis showed that there was no drug-drug interaction with T-DM1. Adverse events seen among the 50 patients treated at the maximum tolerated dosage regardless of causality included nausea (36 patients; 72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22 patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%), constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%). <h3>Conclusions and Relevance</h3> In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated patients with<i>ERBB2/HER2</i>-positive metastatic breast cancer with and without brain metastases. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01983501
NHS must make urgent plans for no-deal Brexit, MPs hear
Authors: Jacqui Wise
Journal: BMJ (2018)

Expert witnesses have told MPs that the recently announced 3.4% a year funding boost for the NHS, though welcome, was still not enough. They also remained sceptical about whether it could be funded from a “Brexit dividend” and called on the NHS to make urgent plans in case of a no-deal Brexit.

The House of Commons Health and Social Care Committee questioned witnesses on the implications of the five year funding plan, which would mean the NHS receiving an additional £20.5bn a year.12

Chris Ham, chief executive of the health think tank the King’s Fund, gave a qualified welcomed to the announcement. But he said that it fell short of the 4% extra a year that the King’s Fund and fellow think …
David Oliver: England’s social care models harm the poorest areas
Authors: David Oliver
Journal: BMJ (2018)

Current models of local government funding systematically disadvantage people in deprived areas, compounding already entrenched health inequalities.1 The Joseph Rowntree Foundation found in 2015 that the most deprived English local authorities had experienced cuts of £182 more per head than the most affluent, “breaking the historic link between the amount a local authority spends per head and local deprivation levels.”23

A 2018 analysis showed that 25% of services in England’s most deprived local authority areas were rated inadequate by the Care Quality Commission, compared with only 15% in the 10 most affluent areas.4 It was published by the Labour Party’s research team, but the conclusions are compelling.

Local government relies on three main sources of income5: direct support grants from national government, business …
Abstract 4440: Differential regulation of p63 isoforms by alternative polyadenylation
Authors: Shakur Mohibi, Jin Zhang, Xinbin Chen
Journal: Cancer Research (2018)

Abstract p63, a transcription factor belonging to the p53 family, plays vital roles in epidermal development and tumorigenesis. p63 expresses from two different promoters generating two classes of proteins, TAp63 and ΔNp63 that differ in their N-terminus. Moreover, alternative splicing of the TA and ΔN isoforms in the C-terminus creates additional isoforms (α-ϵ); thus generating five TA and five ΔN p63 isoforms. The factors that give rise to this repertoire of p63 isoforms are not very well understood. Alternative polyadenylation (APA) can generate multiple isoforms of a gene with alternative 3' ends based on the polyadenylation site selection during cleavage and polyadenylation of mRNA. APA can give rise to isoforms that differ in the coding region (CDS APA) or that have varying lengths of 3' UTR (3' UTR APA). Recently, PABPN1 protein that binds the 3' poly(A) tail of mRNAs has emerged as a key regulator of APA. Here, we show that PABPN1 differentially regulates p63α and p63γ isoforms by alternative polyadenylation. Specifically, knockdown of PABPN1 increases the levels of p63γ mRNA as well as protein by regulating CDS APA of p63 gene. Moreover, knockdown of PABPN1 also generates p63α mRNAs with varying 3' UTR lengths. Although the mRNA levels of p63α remain unchanged upon PABPN1 KD, p63α protein is significantly decreased, suggesting that PABPN1 also regulates p63α protein translation. Interestingly, we also show that PABPN1 is a p63α target and that p63 transcriptionally regulates PABPN1 by binding to its promoter forming a negative feedback loop. Taken together, our study identifies PABPN1 as a novel regulator of various p63 isoforms by APA and that p63 in turn regulates PABPN1 transcriptionally. Citation Format: Shakur Mohibi, Jin Zhang, Xinbin Chen. Differential regulation of p63 isoforms by alternative polyadenylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4440.
Author Correction: T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation
Authors: Brandon Kwong, Rejane Rua, Yuanyuan Gao, John Flickinger, Yan Wang, Michael J Kruhlak, Jinfang Zhu, Eric Vivier, Dorian B McGavern, Vanja Lazarevic
Journal: Nature Immunology (2018)
Association Between Preoperative Proteinuria and Postoperative Acute Kidney Injury and Readmission
Authors: Tyler S. Wahl, Laura A. Graham, Melanie S. Morris, Joshua S. Richman, Robert H. Hollis, Caroline E. Jones, Kamal M. Itani, Todd H. Wagner, Hillary J. Mull, Jeffrey C. Whittle, Gordon L. Telford, Amy K. Rosen, Laurel A. Copeland, Edith A. Burns, Mary T. Hawn
Journal: JAMA Surgery (2018)

Proteinuria indicates renal dysfunction and is a risk factor for morbidity among medical patients, but less is understood among surgical populations. There is a paucity of studies investigating how preoperative proteinuria is associated with surgical outcomes, including postoperative acute kidney injury (AKI) and readmission.To assess preoperative urine protein levels as a biomarker for adverse surgical outcomes.A retrospective, population-based study was conducted in a cohort of patients with and without known preoperative renal dysfunction undergoing elective inpatient surgery performed at 119 Veterans Affairs facilities from October 1, 2007, to September 30, 2014. Data analysis was conducted from April 4 to December 1, 2016. Preoperative dialysis, septic, cardiac, ophthalmology, transplantation, and urologic cases were excluded.Preoperative proteinuria as assessed by urinalysis using the closest value within 6 months of surgery: negative (0 mg/dL), trace (15-29 mg/dL), 1+ (30-100 mg/dL), 2+ (101-300 mg/dL), 3+ (301-1000 mg/dL), and 4+ (>1000 mg/dL).Primary outcome was postoperative predischarge AKI and 30-day postdischarge unplanned readmission. Secondary outcomes included any 30-day postoperative outcome.Of 346 676 surgeries, 153 767 met inclusion criteria, with the majority including orthopedic (37%), general (29%), and vascular procedures (14%). Evidence of proteinuria was shown in 43.8% of the population (trace: 20.6%, 1+: 16.0%, 2+: 5.5%, 3+: 1.6%) with 20.4%, 14.9%, 4.3%, and 0.9%, respectively, of the patients having a normal preoperative estimated glomerular filtration rate (eGFR). In unadjusted analysis, preoperative proteinuria was significantly associated with postoperative AKI (negative: 8.6%, trace: 12%, 1+: 14.5%, 2+: 21.2%, 3+: 27.6%; P < .001) and readmission (9.3%, 11.3%, 13.3%, 15.8%, 17.5%, respectively, P < .001). After adjustment, preoperative proteinuria was associated with postoperative AKI in a dose-dependent relationship (trace: odds ratio [OR], 1.2; 95% CI, 1.1-1.3, to 3+: OR, 2.0; 95% CI, 1.8-2.2) and 30-day unplanned readmission (trace: OR, 1.0; 95% CI, 1.0-1.1, to 3+: OR, 1.3; 95% CI, 1.1-1.4). Preoperative proteinuria was associated with AKI independent of eGFR.Proteinuria was associated with postoperative AKI and 30-day unplanned readmission independent of preoperative eGFR. Simple urine assessment for proteinuria may identify patients at higher risk of AKI and readmission to guide perioperative management.
Microenvironmental Cues Determine Tumor Cell Susceptibility to Neutrophil Cytotoxicity
Authors: Maya Gershkovitz, Tanya Fainsod-Levi, Saleh Khawaled, Merav E. Shaul, Ronit V. Sionov, Leonor Cohen-Daniel, Rami I. Aqeilan, Yoav D. Shaul, Zvi G. Fridlender, Zvi Granot
Journal: Cancer Research (2018)

We have recently shown that neutrophil antitumor cytotoxicity is Ca2+ dependent and is mediated by TRPM2, an H2O2-dependent Ca2+ channel. However, neutrophil antitumor activity is dependent on context and is manifested in the premetastatic niche, but not at the primary site. We therefore hypothesized that expression of TRPM2 and the consequent susceptibility to neutrophil cytotoxicity may be associated with the epithelial/mesenchymal cellular state. We found that TRPM2 expression was upregulated during epithelial-to-mesenchymal transition (EMT), and mesenchymal cells were more susceptible to neutrophil cytotoxicity. Conversely, cells undergoing mesenchymal-to-epithelial transition (MET) expressed reduced levels of TRPM2, rendering them resistant to neutrophil cytotoxicity. Cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung. These data identify TRPM2 as the link between environmental cues at the primary tumor site, tumor cell susceptibility to neutrophil cytotoxicity, and disease progression. Furthermore, these data identify EMT as a process enhancing tumor-cell immune susceptibility and, by contrast, MET as a novel mode of immune evasion.Significance: EMT is required for metastatic spread and concomitantly enhances tumor cell susceptibility to neutrophil cytotoxicity. Cancer Res; 78(17); 5050-9. ©2018 AACR.
“How Foraging Works”: Let's not forget the physiological mechanisms of energy balance
Authors: Tom V. Smulders, Timothy Boswell, Lindsay J. Henderson
Journal: Behavioral and Brain Sciences (2019)

Abstract Anselme &amp; Güntürkün propose a novel mechanism to explain the increase in foraging motivation when experiencing an unpredictable food supply. However, the physiological mechanisms that maintain energy homeostasis already control foraging intensity in response to changes in energy balance. Therefore, unpredictability may just be one of many factors that feeds into the same dopaminergic “wanting” system to control foraging intensity.
Different Population and End Point Definitions in Reproduction Analysis Based on Shared Data—Reply
Authors: Hawkins C. Gay, Abigail S. Baldridge, Mark D. Huffman
Journal: JAMA Cardiology (2018)

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