tbuckley/cabot-search huggingface dataset:
Tamoxifen (TAM)-induced severe hot flashes (HF): Is dose reduction (DR) a safe and effective strategy?
Authors: Clara Inkyung Lee, Peter Fox, Bavanthi Balakrishnar, Rosemary L Balleine, Bo Gao, Pamela Provan, Sally Coulter, Mark Tomlins, Christopher Liddle, Rina Hui, Mark Wong, Howard Gurney, Nicholas Wilcken
Journal: Journal of Clinical Oncology (2015)

557 Background: It is recognized that severe HF toxicity due to TAM can compromise compliance. We previously established that HF do not correlate with endoxifen level or CYP2D6genotype, though prior reports are varied on this subject. In this pilot study, we reduced TAM dose in patients with severe HF and determined whether HF were ameliorated whilst maintaining a purported therapeutic endoxifen level of > 15nM. Methods: Eighteen patients with severe HF on 20mg TAM were enrolled. CYP2D6genotype, trough level TAM and metabolites were measured. Loprinzi HF diaries were filled out before and after DR to 10mg TAM, and hot flash scores (HFS) derived. Other data collected included demographics, smoking and alcohol history, breast cancer history, previous chemotherapies, concurrent medications, menstrual history, body mass index (BMI) and other toxicities recognized to be associated with TAM. Results: At 20mg dose of TAM, baseline endoxifen levels were 24.5, 27.9, 0-91.9 nM (median, mean, range), consistent with the high variability seen in our previous 122 patient cohort. HFS at baseline were 108, 188, 4-1482 (median, mean, range). Upon dose reduction to 10mg, endoxifen levels fell to 13.2, 18.6, 0.6-71.9 nM (difference in means p = 0.056, two-tailed T test). HFS at 10mg fell to 38, 101, 5-864 (difference in means p = 0.36, two-tailed T test). Despite this lack of statistical significance, 78% of patients reported subjective improvement of hot flashes with DR. However after DR, the proportion of patients with an endoxifen level below a suggested therapeutic target of 15nM increased from 22% to 50%. HFS did not correlate with several patient characteristics including menopausal state, duration since last menstrual period and BMI (Spearman’s rank correlation coefficient). Conclusions: In this group of women selected for having significant HF, DR of TAM from 20mg to 10mg daily resulted in halving of endoxifen levels and subjective improvement of HF, however half were below a potential therapeutic level of endoxifen at the reduced dose. Therefore routine DR to ameliorate HF toxicity may not be safe unless therapeutic drug level monitoring is performed.
Targeting the Creatine Kinase Pathway in EVI1-Positive Acute Myeloid Leukemia
Authors: Alexandre Puissant, Nina Fenouille, Christopher F. Bassil, Issam Ben-Sahra, Lina Benajiba, Gabriela Alexe, Azucena Ramos, Yana Pikman, Michael R. Burgess, Qing Li, Frederic Luciano, Patrick Auberger, Ilene Galinsky, Daniel J. DeAngelo, Richard M. Stone, Archibald S. Perkins, Kevin Shannon, Michael T. Hemann, Kimberly Stegmaier
Journal: Blood (2016)
Localization of Alexa-conjugated cisplatin in cisplatin-resistant cell lines
Authors: Xing-Jie Liang, Ding-Wu Shen, Stephen M. Wincovitch, Susan H. Garfield, Michael M. Gottesman
Journal: Cancer Research (2004)

1218  Resistance to cisplatin, one of the most widely used anticancer chemotherapeutic agents, is a major clinical problem. The exact mechanism of cisplatin resistance is still unknown. In KB-CP-r cells, multidrug resistance is accompanied by decreased accumulation of platinum compounds and membrane protein mislocalization, which is caused mainly by a defect of plasma membrane protein recycling as shown by pulse-chase labeling and pulse-chase biotinylation analysis. We have hypothesized that the mislocalization of a cisplatin-binding protein or proteins is responsible for the decreased drug uptake. To study distribution of cisplatin in parental and KB-CP-r cells, a fluorescent platinum compound, Alexa Fluo-546 cisplatin, was used. Using digital fluorescence confocal microscopy, the fluorescent cisplatin was readily internalized by the parental KB-3-1 cells and localized throughout the cells after 2 hours. In contrast, only punctate cytoplasmic staining was observed in KB-CP-r cells after incubation, with little or no fluorescence observed in the nucleus. In parental cells, Alexa-546 cisplatin entered cells partially by pinocytosis similar to that seen with Dextran-10, after which it localized in the Golgi apparatus as detected by colocalization with NBD-C6-ceramide, followed by nuclear localization. The overall fluorescence accumulated in the cells decreased in the KB-CP-r cells compared with sensitive KB-3-1 cells, as observed by Flow Cytometry (FACS) and confocal fluorescence microscopy, consistent with decreased uptake of the platinum complex in KB-CP-r cells. To identify the punctate compartment in which Alexa-488 cisplatin localized in CP-r cells, we examined cell extracts by iodixanol gradient centrifugation. As detected by antibodies to Alexa-488, the fluorescent cisplatin was mostly in a low density membrane fraction in both sensitive and resistant cells. Some Alexa-488 cisplatin binding proteins (CBPs) were not labeled in KB-3-1 cells after treatment with 10mg/ml cisplatin, suggesting specific labeling. We conclude that failure of appropriate trafficking of cell membrane binding protein(s) for cisplatin may result in resistance to cisplatin in cultured cancer cells, presumably because putative CP-r cell surface receptors/ transporters/ channels are not properly located on the cell surface in these cells.
Mathematical Modeling of Tumor–Tumor Distant Interactions Supports a Systemic Control of Tumor Growth
Authors: Sebastien Benzekry, Clare Lamont, Dominique Barbolosi, Lynn Hlatky, Philip Hahnfeldt
Journal: Cancer Research (2017)

Interactions between different tumors within the same organism have major clinical implications, especially in the context of surgery and metastatic disease. Three main explanatory theories (competition, angiogenesis inhibition, and proliferation inhibition) have been proposed, but precise determinants of the phenomenon remain poorly understood. Here, we formalized these theories into mathematical models and performed biological experiments to test them with empirical data. In syngeneic mice bearing two simultaneously implanted tumors, growth of only one of the tumors was significantly suppressed (61% size reduction at day 15,
Clinical Joint Outcome after Joint Bleeds in Patients with Von Willebrand Disease Is Comparable to Moderate and Severe Hemophilia A Despite Fewer Joint Bleeds
Authors: Karin PM van Galen, Merel Timmer, Piet de Kleijn, Frank W.G. Leebeek, Roger E.G. Schutgens, Kathelijn Fischer, Eveline Mauser-Bunschoten
Journal: Blood (2016)
Serum Vitamin D and Risk of Breast Cancer within Five Years
Authors: Katie M. O’Brien, Dale P. Sandler, Jack A. Taylor, Clarice R. Weinberg
Journal: Environmental Health Perspectives (2017)

Background: Vitamin D is an environmental and dietary agent with known anticarcinogenic effects, but protection against breast cancer has not been established. Objective: We evaluated the association between baseline serum 25-hydroxyvitamin D [25(OH)D] levels, supplemental vitamin D use, and breast cancer incidence over the subsequent 5 y of follow-up. Methods: From 2003–2009, the Sister Study enrolled 50,884 U.S. women 35–74 y old who had a sister with breast cancer but had never had breast cancer themselves. Using liquid chromatography–mass spectrometry, we measured 25(OH)D in serum samples from 1,611 women who later developed breast cancer and from 1,843 randomly selected cohort participants. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of developing breast cancer using Cox proportional hazards models. Results: We found that 25(OH)D levels >38.0 ng/mL were associated with a 21% lower breast cancer hazard (highest versus lowest quartile: adjusted HR=0.79; CI: 0.63, 0.98). Analysis of the first 5 y of follow-up for all 50,884 Sister Study participants showed that self-reported vitamin D supplementation ≥4 times/wk was associated with an 11% lower hazard [HR=0.89 (CI: 0.81, 0.99)]. These associations were particularly strong among postmenopausal women [HR=0.72 (CI: 0.57, 0.93) and HR=0.83 (CI: 0.74, 0.93), respectively]. Conclusions: In this cohort of women with elevated risk, high serum 25(OH)D levels and regular vitamin D supplement use were associated with lower rates of incident, postmenopausal breast cancer over 5 y of follow-up. These results may help to establish clinical benchmarks for 25(OH)D levels; in addition, they support the hypothesis that vitamin D supplementation is useful in breast cancer prevention. https://doi.org/10.1289/EHP943
Endoscopic treatment of gastrointestinal non variceal acute bleeding using an over-the-scope-clip (OTSC) device: a case series
Authors: R. Manta, G. Galloro, B. Mangiavillano, E. Dabizzi, L. Pasquale, A. Arezzo, H. Bertani, M. Manno, G. Olivetti, G. Bassotti, R. Conigliaro
Journal: Gut (2012)
Considering the impact of pregnancy on the natural history of hidradenitis suppurativa
Authors: P. Perng, J.G. Zampella, G.A. Okoye
Journal: British Journal of Dermatology (2017)

Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory skin disease that disproportionately affects women of childbearing age. Yet, little has been written about the impact of pregnancy on the natural history of HS. It has been postulated that apocrine-gland activity diminishes in pregnancy, accounting for symptom remission.

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Reply to Londhe <i>et al.</i>: CAPTURE: A Screening Tool for Chronic Obstructive Pulmonary Disease or Obstructive Airway Disease?
Authors: Fernando J. Martinez, MeiLan Han, Nancy Leidy, Barry Make, David M. Mannino, Stephen I. Rennard, Byron M. Thomashow, Barbara P. Yawn
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Tophaceous Gout of the Lumbar Spine Mimicking Malignancy on FDG PET/CT
Authors: Qian Zhao, Aisheng Dong, Yushu Bai, Yang Wang, Changjing Zuo
Journal: Clinical Nuclear Medicine (2017)

A 46-year-old man with over a 10-year history of gout complained of progressive bilateral buttock pain with numbness of legs for 4 months. Serum uric acid level was elevated. Lumbar radiographs showed decreased density of the bilateral L4-L5 facet joints. CT showed lytic lesions of the facet joints with hyperdense periarticular lesions. Enhanced MRI showed marked enhancement of these lesions. FDG PET/CT showed avid FDG uptake of the bony and periarticular lesions with SUVmax of 16.8. A decompressive posterior lumbar laminectomy with periarticular lesion resection was performed. Histopathologic findings of the periarticular lesions were consistent with tophaceous gout.
Abstract 15537: E2F1 Suppresses Fibrosis Through Serine-threonine Kinase Receptor Associated Protein (Strap)
Authors: Dauren Biyashev, Chan Boriboun, Junlan Zhou, Gangjian Qin
Journal: Circulation (2014)

Background: E2F1 is best studied in cell-cycle control and cancer biology. Recently, we have disclosed a novel function of E2F1 that suppresses TGF-beta signaling pathway; however the underlying molecular mechanisms and physiological significance of this regulation remains unknown. Methods and Results: In a proteomics approach, Flag-tagged Smad3 protein was overexpressed in the embryonic fibroblasts (MEF) isolated from wild-type (WT) and E2F1-null (E2F1-KO) mice, and the Smad3-interacting proteins were isolated by co-immunoprecipitation and identified by mass spectrometry. Notably, the serine-threonine kinase receptor-associated protein (Strap) was found associated with Smad3 in WT MEFs, but not in E2F1-KO MEFs. This is important because Strap has been shown as inhibitor of canonical TGF-beta signaling pathway by interacting with both TGF-beta receptor I and Smad7 to interfere with Smad2/3 activation. When analyzed by Western blotting, we found that the expression of Strap was significantly higher in WT MEFs than in E2F1-KO MEFs, and similar results were obtained in the cardiac and lung tissues of WT and E2F1-KO mice. Remarkably, both bleomycin and Ang II treatments resulted in a significantly greater degree of lung fibrosis in E2F1-KO mice than in WT mice. Conclusion: Our results suggest that E2F1 suppresses tissue fibrosis through Strap expression and Strap-mediated repression of canonical TGF-beta signaling pathway.
Population pharmacokinetics (popPK) and exposure-response (ER) analyses bridge J-ALEX to the global population with an alectinib (ALC) 600mg bid dosing regimen.
Authors: Joy C. Hsu, Felix Jaminion, Elena Guerini, Tomohiro Tanaka, Sophie Golding, Bogdana Balas, Ali Hassan Zeaiter, Peter N. Morcos, Nicolas Frey
Journal: Journal of Clinical Oncology (2017)

e20616 Background: J-ALEX showed superiority of ALC 300mg BID vs crizotinib (CRIZ) in Japanese ALK inhibitor naïve ALK-positive NSCLC patients (pts). PopPK and ER analyses were used to bridge J-ALEX data to the global population to confirm the appropriateness of ALC 600mg BID dose, used in global trials. Methods: The previous popPK analysis (Hsu et al, ASCO 2016) was updated to include PK data from J-ALEX and the ongoing global ALEX study to confirm any significant covariates influencing PK of ALC and major metabolite, M4, using Bayesian feedback analysis. ER analyses from J-ALEX (n=96) investigated the relationship between ALC and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis and key safety events using logistic regression. Results: The popPK models previously developed for pts who have progressed on, or are intolerant to CRIZ were able to adequately predict ALC and M4 PK in J-ALEX and ALEX. Body weight remained the only significant covariate influencing ALC and M4 PK. Administration of ALC 600mg BID in the global population ensures that ALC and M4 exposures across the body weight range are not inferior to those seen in Japanese pts receiving ALC 300mg BID, while lower doses would result in lower exposures. CPH analysis demonstrated a statistically significant relationship between ALC exposure and PFS in J-ALEX such that one third of pts in J-ALEX may benefit from a higher exposure of ALC (Table). ALC 600mg BID ensures the distribution of achieved exposures maximize the expected PFS benefit while lower ALC exposures could result in reduced efficacy. No significant exposure-safety relationships were identified in J-ALEX consistent with previous analyses conducted following ALC 600mg BID. Conclusions: ALC 600mg BID is the appropriate dose in the global ALK inhibitor naïve population. Clinical trial information: JapicCTI-132316. [Table: see text]
Is It Time to Change the Type 2 Diabetes Treatment Paradigm? Yes! GLP-1 RAs Should Replace Metformin in the Type 2 Diabetes Algorithm
Authors: Muhammad Abdul-Ghani, Ralph A. DeFronzo
Journal: Diabetes Care (2017)

Most treatment guidelines, including those from the American Diabetes Association/European Association for the Study of Diabetes and the International Diabetes Federation, suggest metformin be used as the first-line therapy after diet and exercise. This recommendation is based on the considerable body of evidence that has accumulated over the last 30 years, but it is also supported on clinical grounds based on metformin’s affordability and tolerability. As such, metformin is the most commonly used oral antihyperglycemic agent in the U.S. However, based on the release of newer agents over the recent past, some have suggested that the modern approach to disease management should be based upon identification of its etiology and correcting the underlying biological disturbances. That is, we should use interventions that normalize or at least ameliorate the recognized derangements in physiology that drive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, it is argued that therapeutic interventions that target glycemia but do not correct the underlying pathogenic disturbances are unlikely to result in a sustained benefit on the disease process. In our field, there is an evolving debate regarding the suggested first step in diabetes management and a call for a new paradigm. Given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative below that precedes the counterpoint narrative, Drs. Abdul-Ghani and DeFronzo provide their argument that a treatment approach for type 2 diabetes based upon correcting the underlying pathophysiological abnormalities responsible for the development of hyperglycemia provides the best therapeutic strategy. Such an approach requires a change in the recommendation for first-line therapy from metformin to a GLP-1 receptor agonist. In the counterpoint narrative that follows Drs. Abdul-Ghani and DeFronzo’s contribution, Dr. Inzucchi argues that, based on the medical community’s extensive experience and the drug’s demonstrated efficacy, safety, low cost, and cardiovascular benefits, metformin should remain the “foundation therapy” for all patients with type 2 diabetes, barring contraindications. —William T. Cefalu Chief Scientific, Medical &amp; Mission Officer, American Diabetes Association
03.04 Serum and synovial concentration of calprotectin in rheumatoid arthritis patients
Authors: Russka Shumnalieva, Tsvetelina Velikova, Darina Kachakova, Simeon Monov, Kalina Tumangelova-Yuzeir, Dobroslav Kyurkchiev, Rasho Rashkov
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Abstract</h3> Calprotectin is a 36 kDa protein released from activated leukocytes during bacterial infection or inflammation. It is potentially a more sensitive biomarker of disease activity in rheumatoid arthritis (RA) as it directly reflects the local inflammation in the joints rather than systemic inflammatory activity. <h3>Objective</h3> The aim of our study was to compare the systemic and local concentrations of calprotectin in RA and osteoarthritis (OA) patients and to establish a possible systemic and local biomarker for RA disease activity and severity. <h3>Material and methods</h3> Concentrations of calprotectin were compared between matched serum and synovial fluid (SF) samples from 20 RA and 15 OA patients by using HK325 Human Calprotectin ELISA kit (Hycult biotech, USA). 16 healthy donors were used as controls. <h3>Results</h3> Serum concentration of calprotectin was higher in RA compared to OA (344.25 ng/ml versus 209.33 ng/ml, p=0.002) and HCs (188.13 ng/ml, p=0.000) and there was a significant difference of its concentration between the three studied groups (p&lt;0.001). Within the RA group levels of calprotectin were higher in SF compared to serum (p=0.000) and showed moderate correlation (r=0.595, p=0.006). The highest serum and SF concentration of calprotectin in RA was found in patients with disease duration between 7 and 24 months. The systemic concentration of calprotectin was higher in patients with positive rheumatoid factor type IgG and IgA and the local concentration of calprotectin was higher in patients with mild compared to moderate degree of synovial hypertrophy found by MSUS (p=0.025). Patients on corticosteroids had lower systemic and local concentration of calprotectin (p=0.027 and p=0.002, respectively). <h3>Conclusions</h3> Systemic and local calprotectin levels correlate with clinical, immunological and instrumental assessments of disease activity and joint inflammation and disease under treatment. Calprotectin could be used as a possible biomarker for monitoring the disease activity and severity of RA. Larger sets are needed to confirm the diagnostic and prognostic accuracy of calprotectin in RA. <h3>Acknowledgement</h3> The study was supported by Grant 61/2015 from Medical University-Sofia, Bulgaria
Long‐term effects: Galectin‐1 and specific immunotherapy for allergic responses in the intestine
Authors: L.‐T. Yang, Q. Shu, X.‐Q. Luo, Z.‐Q. Liu, S.‐Q. Qiu, J.‐Q. Liu, H.‐J. Guo, L.‐J. Li, M.‐G. Li, D.‐B. Liu, L.‐X. Xia, Z.‐G. Liu, P.‐C. Yang
Journal: Allergy (2017)

Mast cell activation interferes with the effects of allergen-specific immunotherapy (SIT). Galectin-1 (Gal-1) is capable of regulating immune cells' functions. This study tests the hypothesis that administration of Gal-1 promotes and prolongs the efficacy of SIT via suppressing mast cell activation.An intestinal allergy mouse model was developed. The coadministration of SIT and Gal-1 on suppression of the allergic responses, prevention of mast cell activation, and generation of antigen-specific regulatory T cells (Treg) in the intestine was observed in sensitized mice.The coadministration of Gal-1 and SIT markedly suppressed the allergic responses in the mouse intestine vs the use of either SIT alone or Gal-1 alone. The Gal-1 binds to the IgE/FcɛRI complexes on the surface of mast cells to prevent mast cell activation during SIT. Gal-1 promoted the SIT-generated allergen-specific Tregs in the intestine of sensitized mice. Coadministration of Gal-1 and SIT significantly enhanced the efficacy of immunotherapy in suppressing allergic responses in the intestine, which lasted for at least for 12 months.Long-term effects of specific immunotherapy on intestinal allergy can be achieved with Gal-1/SIT therapy by inhibiting mast cell activation and facilitating Treg development.
Phase 1/2 KEYNOTE-051 study of pembrolizumab (pembro) in pediatric patients (pts) with advanced melanoma or a PD-L1<sup>+</sup> advanced, relapsed, or refractory solid tumor or lymphoma.
Authors: Birgit Geoerger, Hyoung Jin Kang, Michal Yalon-Oren, Lynley V. Marshall, Catherine Vezina, Alberto S. Pappo, Theodore Willis Laetsch, Antonio Sergio Petrilli, Rupert Handgretinger, Jacek Toporski, Julia Glade-Bender, Wayne Nicholls, Elizabeth Fox, Steven G. DuBois, Margaret Macy, Susan Lerner Cohn, Kumudu Pathiraja, Scott J. Diede, Scot Ebbinghaus, Navin R. Pinto
Journal: Journal of Clinical Oncology (2017)

10525 Background: In phase 1 of the KEYNOTE-051 study (NCT02332668), the 2 mg/kg Q3W approved adult dose of pembro was also determined to be the pediatric recommended phase 2 dose. In phase 2, presented herein, we further evaluated this dose in pediatric pts with advanced cancer. Methods: Children aged 6 mo to &lt; 18 y with advanced melanoma or a PD-L1 + advanced, relapsed or refractory solid tumor or lymphoma, measurable disease per RECIST v1.1, and performance score ≥50 using Lansky Play or Karnofsky scales received pembro 2 mg/kg Q3W for 35 cycles or until confirmed disease progression per immune-related RECIST by investigator review, intolerable toxicity, or pt/investigator decision to discontinue. Tumor imaging was performed every 8 wk for the first 6 mo, then every 12 wk thereafter. AEs were graded by NCI CTCAE v4.0. Key efficacy endpoints were ORR, disease control rate (DCR), and PFS per RECIST v1.1 by investigator and OS. Results: Of 369 pts prescreened, 364 were evaluable for PD-L1 expression; of these, 121 (33.2%) were PD-L1 + . 66 pts were enrolled; median follow-up was 2.5 mo (range, 0.2-18). As of the data cutoff (Nov 7, 2016), 23 (34.8%) pts were still on treatment. Median age was 13 y (range, 1-17), 77.3% had metastatic disease, and 34.8% had ≥3 prior lines of therapy for recurrent/metastatic disease. Primary diagnoses were non-CNS solid tumors (n = 45), CNS tumors (n = 16), and lymphoma (n = 5). 5 (7.6%) pts had grade 3-4 treatment-related AEs (TRAEs), most commonly neutropenia (n = 2). No treatment-related deaths occurred; 1 pt discontinued for a TRAE (grade 3 AST increased). 1 pt each with Hodgkin lymphoma, adrenocortical carcinoma, mesothelioma, and glioblastoma had partial response for an ORR of 6.1% (95% CI, 1.7-14.8); 7 (10.6%) pts had stable disease for a DCR of 16.7% (95% CI, 8.6-27.9). Median PFS and OS were 1.8 mo and 9.2 mo, respectively; 12-mo PFS was 10.2% and OS was 40.5%. Potential effects of pembro on the developing immune system (eg, T and B cells, vaccinated antibodies) will also be presented. Conclusions: Pembro showed low toxicity and warrants further study to determine activity in select pediatric tumors. Enrollment in KEYNOTE-051 is ongoing. Clinical trial information: NCT02332668.