tbuckley/cabot-search huggingface dataset:
Measurement of Hemoglobin A<sub>1c</sub> in Patients With Sickle Cell Trait—Reply
Authors: Mary E. Lacy, Gregory A. Wellenius, Wen-Chih Wu
Journal: JAMA (2017)

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A Chemical Perspective of Pharmacology and Toxicology
Authors: Arthur K. Cho
Journal: The Annual Review of Pharmacology and Toxicology (2018)

My chemical training provided a somewhat different perspective of biolo-gical problems, in the problem itself and approaches to its solution. I was fortunate to have in my laboratory postdocs and students who shared this perspective and used appropriate tools to address problems in amphetamine pharmacology and air pollution toxicology. These apparently disparate areas of research shared two chemical reactions: prooxidant-based generation of reactive oxygen and formation of covalent bonds between electrophiles and biological nucleophiles. This article is an attempt to summarize that research and to identify those individuals who made the contributions.
Sacred cows: The accelerating pace of change
Authors: James Willis
Journal: BMJ (1998)

Geronte: It seems to me you are locating them wrongly: the heart is on the left and the liver is on the right. Sganarelle: Yes, in the old days that was so, but we have changed all that, and we now practise medicine by a completely new method. Act II, scene 4, Le Medecin Malgre Lui by Moliere

Once upon a time (it’s all changed now) everyone knew a song called The Vicar of Bray.1 The words—suitable, somehow, in their buccolic, 17th century way, for Christmas—highlight the absurdity of our belief that our era is uniquely prone to change.

As King James succeeded King Charles, followed by King William, Queen Anne, and finally King George, the Vicar of Bray swung back and forth, left and right, Protestant and Catholic, Whig and Tory, to cling to his living. Like Euripides’ Trojan women being carried across the Aegean to slavery, the ceaseless incursions of rapacious Vikings into Medieval Britain, and the recent obliteration of great tracts of Bangladesh and Nicaragua by storms, the six verses of The Vicar of Bray provide a chronicle of what to us in our tolerant, disease-immunised, risk-insured, pension-squirrelled, and air-bag-protected world would be unthinkable disruption.
Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder
Authors: Julie R. Larsen, Louise Vedtofte, Mathilde S. L. Jakobsen, Hans R. Jespersen, Michelle I. Jakobsen, Camilla K. Svensson, Kamuran Koyuncu, Ole Schjerning, Peter S. Oturai, Andreas Kjaer, Jimmi Nielsen, Jens J. Holst, Claus T. Ekstrøm, Christoph U. Correll, Tina Vilsbøll, Anders Fink-Jensen
Journal: JAMA Psychiatry (2017)

Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects.
Retinoblastoma (Rb) protein expression in triple-negative breast cancer.
Authors: Jaymin M Patel, Vanda Torous, Michele R Hacker, Tessa Nalven, Judy Ellen Garber, Brian Michael Alexander, Larissa Janeen Lee, Laura C. Collins, Stuart J. Schnitt, Nadine M. Tung
Journal: Journal of Clinical Oncology (2017)

1097 Background: Expression of Rb, the protein product of the RB tumor suppressor gene, is required for cyclin D kinase (CDK) 4/6 inhibition in luminal breast cancers. Triple negative breast cancers (TNBC) frequently exhibit Rb loss and are thus believed to be poor candidates for CDK4/6 inhibition. However, the features associated with Rb loss in TNBC are poorly-defined. We aimed to assess whether TNBC that express the androgen receptor (AR) and resemble a more luminal subtype retain Rb more often than other TNBC. Methods: To assess the frequency and correlates of Rb expression in TNBC, we stained tissue microarrays (TMAs) containing 180 Stage I-III TNBC, 71 with germline BRCA1 mutations ( BRCA1+) and 109 without BRCA1 mutation (sporadic), using a mouse monoclonal antibody to human Rb (clone G3-245, BD Biosciences). Assessment of tumor size, histologic type, grade, lymphovascular invasion and lymph node status were assessed on histologic review. The TMAs, containing three 0.6mm cores/tumor, had been previously stained for AR, CK5/6, CK14 and EGFR. Log-binomial regression was used to calculate risk ratios (RR). Results: Fifty percent of TNBC were Rb-positive (Rb+; ≥10% nuclei staining) of which 84.4% had &gt; 50% nuclei staining. Among TNBC that were Rb-negative, 76.6% had &lt; 1% nuclei staining for Rb. AR expression (≥10% nuclei staining) was more common in Rb+ than Rb-negative TNBC (16.7% vs 4.5%; p = 0.01). In addition, Rb expression was significantly more common among sporadic than BRCA1+ TNBC (59.6% vs 35.2%, p = 0.001). Compared with Rb-negative TNBC, Rb+ tumors were associated with older age (mean 48.7 vs 45.7 years; p = 0.06) and lower histologic grade (grade 1 or 2: 9.2% vs 2.2%; p = 0.05). No other clinical or pathologic features were significantly associated with Rb status. In a multivariable model, both AR expression (RR, 1.65; 95% CI, 1.31-2.08) and lack of BRCA1 mutation (RR, 1.63; 95% CI, 1.17-2.29) significantly predicted for Rb expression among TNBC. Conclusions: Sporadic TNBC is significantly more likely to be Rb+ than BRCA1+ TNBC. Among TNBC, AR expression significantly predicts for Rb expression. These results suggest clinically relevant biomarkers that may predict for Rb expression and potential targeted therapies in TNBC.
Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study.
Authors: John C. Byrd, Peter Hillmen, Susan Mary O'Brien, Jacqueline Claudia Barrientos, Nishitha M. Reddy, Steven Coutre, Constantine S. Tam, Stephen P. Mulligan, Ulrich Jäger, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Patrick Thornton, John M. Pagel, Jan Andreas Burger, Jeffrey Alan Jones, Sandra Dai, Remus N. Vezan, Danelle Frances James, Jennifer R. Brown
Journal: Journal of Clinical Oncology (2017)

7510 Background: Ibr, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is FDA-approved for all pts with CLL/SLL. We report updated safety and efficacy results with up to 4 y follow-up from the ph III RESONATE trial of ibr vs ofatumumab (ofa). Methods: Pts had ≥1 prior therapy. Pts received 420 mg ibr PO until PD or ofa up to 24 wks. At interim analysis (median 9 mo follow-up), the DMC declared superiority of ibr vs ofa for PFS and OS, and ibr access was recommended for all ofa pts. Long-term follow-up efficacy endpoints are per investigator assessment. Ofa pts were censored at crossover for OS. Results: 391 pts were randomized to receive ibr (n = 195) or ofa (n = 196). Median age was 67 y (40% ≥70 y); 57% had Rai stage III/IV. With median follow-up of 44 mo (53 mo max) for ibr arm, PFS was significantly longer for ibr vs ofa (median NR vs 8 mo, [HR 0.133; P&lt; 0.0001]; 3-y PFS 59% vs 3%) with significant benefit across subgroups. PFS with ibr for del11q subgroup trended to have the most favorable outcome; however, PFS was not statistically different for pts with del17p or del11q or without these FISH abnormalities. At analysis, with the majority of pts (68%) randomized to ofa crossing over to ibr, OS was longer for ibr vs ofa (median OS NR for either arm). The OS rate for ibr at 3 y was 74%. ORR for ibr was 91% with CR/CRi rates (now 9%) increasing over time. Baseline cytopenias improved with extended ibr therapy for hemoglobin (85%), platelet (95%), and absolute neutrophil counts (95%). AE profile of ibr was consistent with previous reports. Major hemorrhage, Gr ≥3 atrial fibrillation, and Gr ≥3 hypertension occurred in 6%, 6%, and 8% of pts, respectively, over a follow-up of up to 4 y. Incidence of most Gr ≥3 AEs decreased from y 1 vs y 2-3: neutropenia- 18% vs 8%; pneumonia- 11% vs 4%; atrial fibrillation- 4% vs 2%, respectively. Discontinuations were most frequently PD (27%) and AE (12%). At analysis, 90 ibr pts (46%) continue ibr on study. Conclusions: Long-term treatment with ibr in this international ph III RESONATE study is tolerable and continues to show sustained PFS and OS regardless of high-risk cytogenetics. Ph III results in relapsed del17p and del11q pts compare favorably to prior ph II reports. Clinical trial information: NCT01578707.
Secukinumab is superior to fumaric acid esters in treating patients with moderate-to-severe plaque psoriasis who are naive to systemic treatments: results from the randomized controlled PRIME trial
Authors: M. Sticherling, U. Mrowietz, M. Augustin, D. Thaçi, N. Melzer, C. Hentschke, J. Kneidl, C. Sieder, K. Reich
Journal: British Journal of Dermatology (2017)

Secukinumab is a fully human antibody that neutralizes interleukin‐17A. It has significant efficacy and a favourable safety profile in moderate‐to‐severe plaque psoriasis and psoriatic arthritis. To compare secukinumab with fumaric acid esters (FAEs) in a randomized controlled trial. In this 24‐week, randomized, open‐label, multicentre study with blinded assessment, patients with moderate‐to‐severe plaque psoriasis, naive to systemic treatments, were randomized to receive secukinumab 300 mg subcutaneously or oral FAEs. The primary end point was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75 response) at week 24, and missing patients were considered responders if they were responders at the time of dropout. In total 202 patients were randomized and 200 were treated with at least one dose. Outcomes at week 24 were available for 147 and imputed for 53 patients. Discontinuations were mostly due to adverse events, which occurred more frequently in the FAE group (1·9% vs. 33·0%). At week 24, significantly more patients receiving secukinumab compared with FAEs achieved PASI 75 response (89·5% vs. 33·7%, P < 0·001), PASI 90 response (81·0% vs. 28·4%, P < 0·001) and Dermatology Life Quality Index 0 or 1 response (71·4% vs. 25·3%, P < 0·001). Secukinumab demonstrated superior efficacy to FAEs in patients with psoriasis over a 24‐week period.
Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction
Authors: Constantine D. Troupes, Markus Wallner, Giulia Borghetti, Chen Zhang, Sadia Mohsin, Dirk von Lewinski, Remus M. Berretta, Hajime Kubo, Xiongwen Chen, Jonathan Soboloff, Steven Houser
Journal: Circulation Research (2017)

Rationale: Pathological increases in cardiac afterload result in myocyte hypertrophy with changes in myocyte electrical and mechanical phenotype. Remodeling of contractile and signaling Ca 2+ occurs in pathological hypertrophy and is central to myocyte remodeling. STIM1 (stromal interaction molecule 1) regulates Ca 2+ signaling in many cell types by sensing low endoplasmic reticular Ca 2+ levels and then coupling to plasma membrane Orai channels to induce a Ca 2+ influx pathway. Previous reports suggest that STIM1 may play a role in cardiac hypertrophy, but its role in electrical and mechanical phenotypic alterations is not well understood. Objective: To define the contributions of STIM1-mediated Ca 2+ influx on electrical and mechanical properties of normal and diseased myocytes, and to determine whether Orai channels are obligatory partners for STIM1 in these processes using a clinically relevant large animal model of hypertrophy. Methods and Results: Cardiac hypertrophy was induced by slow progressive pressure overload in adult cats. Hypertrophied myocytes had increased STIM1 expression and activity, which correlated with altered Ca 2 + -handling and action potential (AP) prolongation. Exposure of hypertrophied myocytes to the Orai channel blocker BTP2 caused a reduction of AP duration and reduced diastolic Ca 2+ spark rate. BTP2 had no effect on normal myocytes. Forced expression of STIM1 in cultured adult feline ventricular myocytes increased diastolic spark rate and prolonged AP duration. STIM1 expression produced an increase in the amount of Ca 2+ stored within the sarcoplasmic reticulum and activated Ca 2+ /calmodulin-dependent protein kinase II. STIM1 expression also increased spark rates and induced spontaneous APs. STIM1 effects were eliminated by either BTP2 or by coexpression of a dominant negative Orai construct. Conclusions: STIM1 can associate with Orai in cardiac myocytes to produce a Ca 2+ influx pathway that can prolong the AP duration and load the sarcoplasmic reticulum and likely contributes to the altered electromechanical properties of the hypertrophied heart.
Abstract NTOC-091: INVOLVEMENT OF TIE–1 TYROSINE KINASE RECEPTOR IN CHEMO–RESISTANCE: POTENTIAL OF TIE1 AS A NOVEL THERAPEUTIC TARGET
Authors: Masumi Ishibashi, Masafumi Toyoshima, Mahy Egiz, Xuewei Zhang, Junko Minato, Shogo Shigeta, Kazuyuki Kitatani, Nobuo Yaegashi
Journal: Clinical Cancer Research (2017)

Abstract OBJECTIVES: Platinum-resistance is one of the most challenging difficulties in the treatment of ovarian cancer patients. To overcome this problem, we have explored a target molecule which can conquer platinum-resistance of ovarian cancer cells utilizing a functional genomics approach. MATERIALS AND METHODS: High-throughput functional siRNA screening was designed to target 6550 genes in cisplatin-resistant A2780 CP ovarian cancer cells. Cell viability was assessed by luminescent cell viability assay. After identifying a candidate molecule, cisplatin uptake was determined by atomic absorption spectrometry. DNA damages were determined by the western blotting and immunofluorescent staining using γH2AX antibodies. RESULTS: Through a functional screening, receptor tyrosine kinase TIE 1 was identified as a top candidate gene, of which inhibition give rise to enhancement of cisplatin sensitivity in ovarian cancer cells. Conversely, over-expression of TIE 1 gene significantly decreased susceptibility to cisplatin-induced cell death without affecting cisplatin uptake. DNA damages induced by cisplatin was significantly suppressed in TIE 1 over-expressed cells, raising novel potential mechanisms of TIE 1 in nucleotide excision repair system that removes chemicals adduct to DNA. In addition, over-expression of TIE 1 increased the expression of XPC, which is responsible for nucleotide excision repair. CONCLUSION: We have identified TIE 1 as a molecular target to overcome platinum-resistance in ovarian cancer cells. TIE 1 contribute platinum- resistance in ovarian cancer cells by promoting XPC-dependent DNA repairing system. Citation Format: Masumi Ishibashi, Masafumi Toyoshima, Mahy Egiz, Xuewei Zhang, Junko Minato, Shogo Shigeta, Kazuyuki Kitatani, Nobuo Yaegashi. INVOLVEMENT OF TIE–1 TYROSINE KINASE RECEPTOR IN CHEMO–RESISTANCE: POTENTIAL OF TIE1 AS A NOVEL THERAPEUTIC TARGET [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-091.
Abstract NTOC-093: SYNTHETIC LETHAL APPROACHES TO TARGET ARID1A DEFICIENT OVARIAN CANCERS
Authors: Saira Khalique, Chris T. Williamson, Helen Pemberton, Patty T. Wai, Malini Menon, Rachel Brough, Andri Leonidou, Barrie Peck, Susana Banerjee, Rachael C. Natrajan, Christopher J. Lord
Journal: Clinical Cancer Research (2017)

Abstract Epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy in the Western world. Ovarian clear cell carcinoma (OCCC), a distinct histological subtype, has a notably poor prognosis in the advanced setting compared to patients with high-grade serous ovarian cancer (HGSOC). Understanding why these patients have a poor outcome may be due to the underlying genetic drivers and their response to treatment. Dysregulation of the SWI/SNF complex is one of the most commonly occurring defects in solid cancers. Mutations in ARID1A (AT-rich interactive domain-containing protein 1A), a gene that encodes for BAF250A, forming part of the SWI/SNF chromatin remodeling complex, rarely occur in HGSOC but are common in ovarian clear cell carcinomas. The vast majority of these are loss of function frameshift or nonsense mutations, resulting in loss of protein function. In addition, loss of ARID1A expression in tumour specimens has been associated with a shorter progression free survival and chemoresistance in ovarian clear cell carcinoma (OCCC). Despite the understanding that ARID1A defects are associated with tumourigenesis, targeted therapy approaches that exploit this deficiency have not as yet been developed. Our aims were to identify ways of targeting ARID1A deficient tumours by performing a large-scale functional genomics screen to identify actionable synthetic lethal effects. Using a high-throughput combination drug screen with a plate library of 80 compounds and a phase 1 compound, in isogenic ARID1A null and wild type HCT116 cells, we have identified candidate therapeutic approaches to targeting ARID1A mutant tumours that could be assessed in proof of concept clinical trials. We have undertaken subsequent high throughput drug screens in isogenic ARID1A null and wild type MCF10A cells that in we have identified a series of novel synthetic lethal effects. Assessment of this combinatorial approach in in vivo models of ARID1A mutant cancers is now underway. In conclusion, we have identified clinically actionable combinatorial approaches that may provide additional therapeutic benefit for ARID1A deficient patients. Citation Format: Saira Khalique, Chris T. Williamson, Helen Pemberton, Patty T. Wai, Malini Menon, Rachel Brough, Andri Leonidou, Barrie Peck, Susana Banerjee, Rachael C. Natrajan and Christopher J. Lord,. SYNTHETIC LETHAL APPROACHES TO TARGET ARID1A DEFICIENT OVARIAN CANCERS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-093.
Survival by HER2 receptor status in stage IV breast cancer: SEER 2010-2012.
Authors: Alexandra Thomas, Seema Ahsan Khan, Charles Lynch, Mary Chen Schroeder
Journal: Journal of Clinical Oncology (2017)

1032 Background: Therapeutic advances have altered the course of once highly lethal HER2+ breast cancer (BC). We report survival in a recent population-based cohort by HER2 status, overall, and within hormone receptor(HR)+ BC. Methods: Surveillance, Epidemiology, and End Results Program data were queried to identify women diagnosed 2010-2012 with Stage IV BC as first cancer. Patients were grouped by HER2 and HR status. Kaplan Meier estimates of 3-yr observed survival (OS) were compared with log-rank tests. A multivariate cox model was fitted for the HER2+ cohort. Results: 3-yr OS for HER2+(any HR), HR+/HER- and triple-negative (TN) BC was 52.3%, 48.4% and 16.0% respectively (p&lt;0.01 HER2+(any HR) vs TNBC; p=0.20 HER2+(any HR) vs HR+/HER2-). Across registries, OS for HER2+(any HR) BC ranged from 29.2% to 61.7% (p=0.05). On Cox model, survival in HER2+(any HR) BC was associated with age 50+ (Hazard ratio (HR) 1.84, 95% CI 1.45-2.34), HR+ status (HR 0.70, 0.58-0.84), high histologic grade (HR 1.30, 0.58-0.84), surgery (HR 0.40, 0.33-0.49), separated marital status (HR 1.72, 1.4-2.13), year 2012 (HR 0.81, 0.64-1.04), and registry (varies by reference group). For HR+ BC, OS also differed by HER2 status: 55.3% for HR+/HER+ and 48.4% for HR+/HER2- (p&lt;0.01). 3-yr OS by HER2 status for women presenting with HR+ BC is shown (Table). Conclusions: Survival in de novo Stage IV HER2+ BC in the United States exceeds that in HER2- BC, with median survival &gt;3 yrs. Survival was significantly better for HR+/HER+ BC than HR+/HER- BC. Disparate OS in HER2+ BC suggest opportunities may remain to fully realize advances in HER2-directed therapy. Given recent therapeutic advances, the trend of HER2+ survival gains from 2010 to 2012 will likely continue. [Table: see text]
Association of single nucleotide polymorphisms (SNP) in STAT3 gene with hand-foot skin reaction in metastatic renal cell carcinoma patients treated with multi-kinase inhibitor.
Authors: Kazuhiro Yamamoto, Takeshi Ioroi, Kazuaki Shinomiya, Sachi Hirata, Kenichi Harada, Manabu Suno, Tatsuya Nishioka, Manabu Kume, Hiroo Makimoto, Tsutomu Nakagawa, Takeshi Hirano, Toshinori Bito, Chikako Nishigori, Hideaki Miyake, Masato Fujisawa, Midori Hirai
Journal: Journal of Clinical Oncology (2015)

e15622 Background: Signal transducer and activator of transcription (STAT) 3 has been reported to be a mediator for keratinocyte toxicity induced by molecular-targeted drugs. Our purpose was to assess the association between single nucleotide polymorphisms (SNPs) in the STAT3 gene and hand-foot skin reaction (HFSR) in metastatic renal cell carcinoma (mRCC) patients treated with multi-kinase inhibitors (MKIs). Methods: Sixty-five mRCC patients treated with MKIs (sunitinib, sorafenib, or axitinib) were genotyped for rs4796793 in the 5′ region of the STAT3 gene. We retrospectively analyzed 60 patients whose first MKI therapy lasted for more than 4 months, regardless of the presence or absence of HFSR, and who developed HFSR within 4 months before treatment failure. Results: MKIs sunitinib, sorafenib, and axitinib were given to 35, 16, and 9 patients, respectively. HFSR was observed in 46 patients. Genotypes GG, GC, and CC at rs4796793 were found in 9, 27, and 24 patients, respectively. A significant association was found between the alleles of rs4796793 and HFSR (G vs C; odds ratio (OR), 4.33; 95% confidence interval (CI), 1.80–10.45; p < 0.001). The GG genotype at rs4796793 had the highest OR compared with GC + CC genotypes (OR, 10.75; 95% CI, 2.38–48.07; p < 0.001). In time-to-event analysis, the median time to developing HFSR in patients with GC + CC genotypes at rs4796793 was 21 days whereas the median time for patients with the GG genotype was not reached in 4 months. Kaplan–Meier analysis demonstrated a statistically significant difference between the two groups (p = 0.0095) . Conclusions: SNPs in the STAT3 gene correlate with development of HFSR in mRCC patients treated with MKIs. The wild-type homozygous genotype (GG) of STAT3-associated SNP could be considered a prognostic biomarker of resistance to HFSR related to MKIs in mRCC.