tbuckley/cabot-search huggingface dataset:
Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer
Authors: Kimberly McClinch, Rita A. Avelar, David Callejas, Sudeh Izadmehr, Danica Wiredja, Abbey Perl, Jaya Sangodkar, David B. Kastrinsky, Daniela Schlatzer, Maxwell Cooper, Janna Kiselar, Agnes Stachnik, Shen Yao, Divya Hoon, Daniel McQuaid, Nilesh Zaware, Yixuan Gong, David L. Brautigan, Stephen R. Plymate, Cynthia C.T. Sprenger, William K. Oh, Alice C. Levine, Alexander Kirschenbaum, John P. Sfakianos, Rosalie Sears, Analisa DiFeo, Yiannis Ioannou, Michael Ohlmeyer, Goutham Narla, Matthew D. Galsky
Journal: Cancer Research (2018)

Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that are more difficult to treat nearly always occur due to aberrant reactivation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth-inhibitory effects of reengineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A, which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small-molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable with enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment.Significance: A novel class of small-molecule activators of the tumor suppressor PP2A, a serine/threonine phosphatase that inhibits many oncogenic signaling pathways, is shown to deregulate the phosphoproteome and to destabilize the androgen receptor in advanced prostate cancer. Cancer Res; 78(8); 2065-80. ©2018 AACR.
Improving the prognosis of patients with severely decreased glomerular filtration rate (CKD G4+): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Authors: Kai-Uwe Eckardt, Nisha Bansal, Josef Coresh, Marie Evans, Morgan E. Grams, Charles A. Herzog, Matthew T. James, Hiddo J.L. Heerspink, Carol A. Pollock, Paul E. Stevens, Manjula Kurella Tamura, Marcello A. Tonelli, David C. Wheeler, Wolfgang C. Winkelmayer, Michael Cheung, Brenda R. Hemmelgarn, Ali K. Abu-Alfa, Shuchi Anand, Mustafa Arici, Shoshana H. Ballew, Geoffrey A. Block, Rafael Burgos-Calderon, David M. Charytan, Zofia Das-Gupta, Jamie P. Dwyer, Danilo Fliser, Marc Froissart, John S. Gill, Kathryn E. Griffith, David C. Harris, Kate Huffman, Lesley A. Inker, Kitty J. Jager, Min Jun, Kamyar Kalantar-Zadeh, Bertrand L. Kasiske, Csaba P. Kovesdy, Vera Krane, Edmund J. Lamb, Edgar V. Lerma, Andrew S. Levey, Adeera Levin, Juan Carlos Julián Mauro, Danielle M. Nash, Sankar D. Navaneethan, Donal O’Donoghue, Gregorio T. Obrador, Roberto Pecoits-Filho, Bruce M. Robinson, Elke Schäffner, Dorry L. Segev, Bénédicte Stengel, Peter Stenvinkel, Navdeep Tangri, Francesca Tentori, Yusuke Tsukamoto, Mintu P. Turakhia, Miguel A. Vazquez, Angela Yee-Moon Wang, Amy W. Williams
Journal: Kidney International (2018)

Patients with severely decreased glomerular filtration rate (GFR) (i.e., chronic kidney disease [CKD] G4+) are at increased risk for kidney failure, cardiovascular disease (CVD) events (including heart failure), and death. However, little is known about the variability of outcomes and optimal therapeutic strategies, including initiation of kidney replacement therapy (KRT). Kidney Disease: Improving Global Outcomes (KDIGO) organized a Controversies Conference with an international expert group in December 2016 to address this gap in knowledge. In collaboration with the CKD Prognosis Consortium (CKD-PC) a global meta-analysis of cohort studies (<i>n</i> = 264,515 individuals with CKD G4+) was conducted to better understand the timing of clinical outcomes in patients with CKD G4+ and risk factors for different outcomes. The results confirmed the prognostic value of traditional CVD risk factors in individuals with severely decreased GFR, although the risk estimates vary for kidney and CVD outcomes. A 2- and 4-year model of the probability and timing of kidney failure requiring KRT was also developed. The implications of these findings for patient management were discussed in the context of published evidence under 4 key themes: management of CKD G4+, diagnostic and therapeutic challenges of heart failure, shared decision-making, and optimization of clinical trials in CKD G4+ patients. Participants concluded that variable prognosis of patients with advanced CKD mandates individualized, risk-based management, factoring in competing risks and patient preferences.
Correlation of PD-L1 expression with p16<sup>INK4A</sup> expression in nonoropharyngeal head and neck squamous cell carcinoma.
Authors: San-Chi Chen, Peter Chang, Hsiao-Jung Wang, Shyh-Kuan Tai, Pen-Yuan Chu, Muh-Hwa Yang
Journal: Journal of Clinical Oncology (2017)

39 Background: The expression of PD-L1 expression is important for tumor cells to evade the immune system. The level of its expression and its correlation to disease prognosis is unclear in non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC). Methods: A retrospective clinicopathologic analysis was performed for 106 non-OPHNSCC patients diagnosed during the period from 2007 to 2014. We made tissue arrays from the paraffin-embedded non-OPHNSCC samples obtained from the patients, and studied PD-L1 and p16 INK4A expression by immunohistochemistry. Systemic inflammatory factors including C-reactive protein, serum white blood cell, neutrophil, monocyte, and lymphocyte count were also analyzed to study the correlation. Results: We found that PD-L1 was overexpressed in 32.1% (34/106) and p16 INK4A in 20.8% (22/106) of the patients who were studied. The expression of PD-L1 was associated with p16 INK4A expression ( p &lt; 0.01), but was not associated with the level of systemic inflammatory factors. No significant prognostic values of PD-L1, p16 INK4A , or other clinicopathologic factors were found except tumor stage (stage I/II vs. III/IV, p=0.03). Conclusions: This study demonstrates the correlation between PD-L1 and p16 INK4A in non-OPHNSCC, which may provide important information for designing the clinical trials of anti-PD1/PDL1 treatment in head and neck cancer patients. [Table: see text]
Abstract 11918: The Interplay of Ethnicity and Education With the American Heart Association’s Life’s Simple 7 Metrics: The Baptist Health South Florida Employee Study
Authors: Oluseye Ogunmoroti, Sankalp Das, Ovie Utuama, Adnan Younus, Maribeth Rouseff, Don Parris, Henry Guzman, Ziyad Ben Taleb, Raed Bahelah, Chukwuemeka U. Osondu, Ehimen Aneni, Muhammad Aziz, Ebenezer Oni, Thinh Tran, Wasim Maziak, Theodore Feldman, Arthur Agatston, Emir Veledar, Salim S. Virani, Khurram Nasir
Journal: Circulation (2015)

Background: Healthcare disparities are a major public health concern. It is known that ethnicity and educational status independently predict health outcomes. Higher numbers of the American Heart Association's (AHA) ideal Life’s Simple 7 metrics (LS7) are associated with better cardiovascular health. In this study, we investigated the interplay of ethnicity and education on the attainment of ideal cardiovascular health (ICH) among employees of Baptist Health South Florida (BHSF), a large nonprofit health care organization. Methods: The data collected during BHSF annual voluntary wellness examination included age, gender, race, ethnicity and education. We assessed cardiovascular health using the LS7 metrics. Components of the LS7 metrics (smoking, physical activity, body mass index, diet, total cholesterol, blood pressure, and blood glucose) were categorized into ideal, intermediate and poor, according to AHA criteria. Study participants who met 6-7 ideal metrics were considered to have attained ICH. Results: The study population consisted of 9056 individuals (Mean age 43 ± 12 years, 74% women). Among employees with postgraduate education, 12% of white employees met the ideal for 6-7 LS7 metrics, 15% for Hispanic and 4% for Black employees. For employees with college degrees, the prevalence of 6-7 ideal LS7 metrics was 14%, 16% and 8% for white, Hispanic and black employees respectively (Figure). Overall, the odds of meeting 6-7 ideal LS7 metrics was lower for Hispanic and black employees compared to white employees of similar education (Table). These differences were especially large in those with high school education or less. Conclusion: Minorities are at an increased risk of poor cardiovascular health particularly those with the lowest educational achievement. Comprehensive workplace wellness programs that target these groups will improve cardiovascular health and employee productivity, in addition to saving health care costs.
Study Limitations in HLA-Mismatched Microtransplant in Older Patients Newly Diagnosed With Acute Myeloid Leukemia—Reply
Authors: Hui-Sheng Ai, Mei Guo, Nelson J. Chao
Journal: JAMA Oncology (2018)

In Reply We appreciate Dr Gale's interest in our recent article in JAMA Oncology.1 He raised 2 important questions: (1) There were no controls. (2) There was concern about patient selection in the older subject cohorts. We agree.
Indoor mould exposure assessment with an EIA for mould extracellular polysaccharides (EPS) in house dust.
Authors: G. Doekes, B. van der Sluis, F.M. van Leusden, L.M. Wijnands, R. van Strien, A.P. Verhoeff, J. Douwes, B. Brunekreef
Journal: Allergy (1995)
147P Clinical testing of ctDNA from NSCLC patients using A 17-gene liquid biopsy mutation panel
Authors: D.A. Eberhard, J. Bennett, D. Davison, C. Hammond, A. Petty, J. Pluenneke, A. Dei Rossi, G. Alexander, D. Paragas, M. Lopatin
Journal: Journal of Thoracic Oncology (2018)
The effect on quality of life via bio-mimetic hormone replacement therapy for breast cancer patients.
Authors: TS Wiley, Jason T. Haraldsen
Journal: Journal of Clinical Oncology (2017)

113 Background: Many treatments for breast cancer block the estrogen receptors to reduce the risk of relapse. However, this treatment results in massive changes to the normal hormonal milieu. When the normal rhythmic hormonal patterns are disrupted, either through treatment or normal menopause, women typically experience a multitude of harsh symptoms with little affect on relapse rate. We set out to examine and evaluate the effects of estrogen (E2) and progesterone (P4) treatments via a bio-mimetic bio-identical hormone replacement therapy (BBHRT). We theorized, through the analysis of physiological and clinical literature, that the use BBHRT in the normal physiological pattern of reproductive women will lead to an increase of overall well-being and better quality of life for post-treatment and menopausal women, but does not increase their risk of breast cancer. Methods: E2 and P4 control over 9,000 different gene products and a disruption of these processes can lead to an increase in illnesses of aging including cancer. Through an evaluation of current literature, we theorize that a BBHRT approach utilizing E2 and P4 in a bio-mimetic manner to restore a woman’s body to normal hormonal levels can be achieved through twice-daily transdermal applications of hormonal creams with peaks in serum levels on days 12 and 21. The proposed method uses compounded, bio-identical hormones dosed to mimic the female reproductive cycle. Results: While this is a proposed clinical study, it is expected that women will experience resolution of menopausal and post-treatment symptoms, including better sleep, decreased migraines and incontinence, increased focus, and increased libido. By restoring the normal hormonal rhythm, it is anticipated that the body’s natural response elements will help restore both quality of life and well being, while also protecting from possible relapse. Conclusions: We propose a method to provide better quality of life and well being for women through BHRT that combines the use of E2 and P4 in a manner that mimics a woman’s normal reproductive levels. While a small long-term study of this method has shown promising results, we conclude that further, most detailed studies are still needed.
Diagnosing Acute Mountain Sickness–Reply
Authors: Tinh-Hai Collet, David Meier, Claudio Sartori
Journal: JAMA (2018)

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Neonatal Hypoglycemia Following Diet-Controlled and Insulin-Treated Gestational Diabetes Mellitus
Authors: Daphne N. Voormolen, Leon de Wit, Bas B. van Rijn, J. Hans DeVries, Martijn P. Heringa, Arie Franx, Floris Groenendaal, Marije Lamain-de Ruiter
Journal: Diabetes Care (2018)

To assess the risk of neonatal hypoglycemia following diet-controlled and insulin-treated gestational diabetes mellitus (GDM) and how it relates to birth weight.Prospective cohort study included term neonates born after GDM from January 2013 through December 2015 at the University Medical Center Utrecht (Utrecht, the Netherlands). Routine screening of neonatal blood glucose levels was performed at 1, 3, 6, 12, and 24 h after birth. Main outcome measures were neonatal hypoglycemia defined as blood glucose ≤36 mg/dL (severe) and ≤47 mg/dL (mild).A total of 506 neonates were included, born after pregnancies complicated by GDM treated either with insulin (22.5%) or without insulin (77.5%). The incidence of mild and severe hypoglycemia was similar in the insulin-treated and diet-controlled groups (33 vs. 35%, P = 0.66; and 20 vs. 21%, P = 0.79). A birth weight >90th centile was seen in 17.2% of all infants. Although children with a birth weight >90th centile had the highest risk for hypoglycemia, the vast majority of hypoglycemia (78.6%) was detected in those with a birth weight <90th centile. Over 95% of all hypoglycemia occurred within 12 h after birth.Routine screening for neonatal hypoglycemia following pregnancies complicated by GDM reveals high incidence of both mild and severe hypoglycemia for both diet-controlled and insulin-treated GDM and across the full range of birth weight centiles. We propose routine blood glucose screening for neonatal hypoglycemia within the first 12 h of life in all neonates after GDM, irrespective of maternal insulin use or birth weight.
Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial
Authors: H.-G. Wirsching, G. Tabatabai, U. Roelcke, A.F. Hottinger, F. Jörger, A. Schmid, L. Plasswilm, D. Schrimpf, C. Mancao, D. Capper, K. Conen, T. Hundsberger, F. Caparrotti, R. von Moos, C. Riklin, J. Felsberg, P. Roth, D.T.W. Jones, S. Pfister, E.J. Rushing, L. Abrey, G. Reifenberger, L. Held, A. von Deimling, A. Ochsenbein, M. Weller
Journal: Annals of Oncology (2018)

BackgroundThe addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT → TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population.Patients and methodsARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses.ResultsMedian PFS was longer in arm A than in arm B (7.6 and 4.8 months, P = 0.003), but OS was similar (12.1 and 12.2 months, P = 0.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, P = 0.014) and proneural gene expression (HR 0.29, P = 0.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for age <70 years (HR 0.52, P = 0.018) and Karnofsky performance score 90%–100% (HR 0.51, P = 0.026). Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS (HR 1.73, P = 0.076).ConclusionEfficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients. Molecular biomarkers may identify patients with preferential benefit from bevacizumab.Clinical trial registration numberNCT01443676.
Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial
Authors: Milton Packer, Brian Claggett, Martin P Lefkowitz, John J V McMurray, Jean L Rouleau, Scott D Solomon, Michael R Zile
Journal: The Lancet Diabetes & Endocrinology (2018)
HER2 gene amplification and protein overexpression in uterine clear cell carcinoma and its implications in targeted immunotherapy.
Authors: Jain Zhou, William R. Sukov, Jodi M Carter, J. Kenneth Schoolmeester
Journal: Journal of Clinical Oncology (2017)

29 Background: Uterine clear cell carcinoma (UCCC) is a high-grade endometrial carcinoma. The current treatment is hysterectomy with post-operative chemotherapy and/or radiation. The 5-year disease free survival remains dismal for UCCC with 65% for early-stage and 54% for advanced stage disease. In addition, UCCC may be more resistant to chemotherapy or radiation therapy than the endometrioid subtype. The aim of the current study is to investigate the HER2 gene amplification status in UCCC and its role for targeted therapy in UCCC. Methods: Twenty-nine cases of UCCC were retrieved from surgical pathology archives of Mayo Clinic at Rochester between 2011 and 2015. All cases except one case were hysterectomy specimens. The blocks contain the most characteristic morphology of UCCC were selected and corresponding paraffin sections were subjected to fluorescent in situ hybridization for amplification of HER2 gene (Hercept, Abbott Molecular) and parallel immunohistochemical (IHC) study. Results: A total of 9 (of 29; 31%) UCCCs showed HER2 amplification and 4 (of 29; 14%) were considered equivocal for HER2 amplification by FISH. A total of 3 (10%) tumors showed 3+ HER2 overexpression while 11 (38%) UCCCs showed 2+ HER2 overexpression, 9 (31%) showed 1+ expression with the remaining cases showing no expression of HER2. Importantly, we observed significant intratumoral heterogeneity with regard to HER2 expression. Comparing the results of IHC with HER2 gene status as determined by FISH, 2 (66%) of the 3 cases that showed 3+ HER2 expression also showed amplification for HER2 by FISH, while 1 (33%) was equivocal for HER2 amplification. Of the 11 tumors that showed 2+ HER2 expression, 6 (55%) were amplified by FISH and 1 (9%) was equivocal. Conclusions: This is the largest number of UCCC cases that has been studied on the HER2 amplification and corresponding protein overexpression. Our results indicate that the HER2 overexpression is common in UCCCs and is frequently associated with HER2 amplification. These results also suggest that targeted adjuvant therapy with trastuzumab-based immunotherapy should be evaluated in patients with UCCC showing HER2 protein overexpression or HER2 gene amplification.
Poisoning by Dinitro-Ortho-Cresol
Authors: P. L. Bidstrup, D. J. H. Payne
Journal: BMJ (1951)

POISONING BY DINITRO-ORTHO-CRESOL CJOUR of D.N.O.C. in the blood following application of D.N.O.C. to the skin.This change has not been demon- strated after administration of D.N.O.C. by mouth.Study of the fatal cases of D.N.O.C. poisoning described by Bidstrup and Payne (1951) support the hypothesis advanced in this paper, that in human beings D.N.O.C. acts as a cumulative poison. SummaryFive volunteers received 75 mg. of D.N.O.C. by mouth daily for five or seven days.It is absorbed through the alimentary canal, and its presence can be demonstrated in the blood.Doses of the order of 1 mg.per kg.result in concentrations of from 15 to 20 ug. per g. of blood after three to five days.After this concentration has been attained additional doses appear to cause temporary high concentrations associated with symptoms.Forty days after the last dose of D.N.O.C. by mouth i to 1.5 yg. per g.D.N.O.C. was still present in the blood.D.N.O.C. is excreted slowly, the amount appearing unchanged in the urine being of the order of 1 to 2% of that given.Symptoms of lassitude, headache, and rmalaise may appear after 350 to 500 mg. of D.N.O.C. has been administered and when the concentration in the blood is of the order of 20 Mg. per g. of blood.Exercise has the effect of increasing the blood level, but large quantities of liquid cause.no apparent changes.Small quantities of D.N.O.C. were absorbed from the skin and caused an increase in the concentration of D.N.O.C. in the blood.The relationship of blood concentrations of D.N.O.C. to physiological effects is discussed.D.N.O.C. is shown to act as a cumulative poison in human.beings.
Probable Sexually Transmitted Zika Virus Infection in a Pregnant Woman
Authors: Arnaud Desclaux, Xavier de Lamballerie, Isabelle Leparc-Goffart, Alice Vilain-Parcé, Frédéric Coatleven, Hervé Fleury, Denis Malvy
Journal: New England Journal of Medicine (2018)

Challenging Diagnosis of Zika Virus Infection Zika virus infection is associated with birth defects. This letter describes the challenging diagnosis of Zika virus infection in a pregnant woman.