tbuckley/cabot-search huggingface dataset:
Prospective evaluation of perceived barriers to medication adherence by patients on oral antineoplastics.
Authors: Benyam Muluneh, Maurice Alexander, Allison Mary Deal, Meredith Deal, Janell Markey, Jennifer Neal, Stephen A. Bernard, John Valgus, Lynn G. Dressler
Journal: Journal of Clinical Oncology (2012)

6042 Background: Appropriate use of oral antineoplastics (OA), especially those with a food-effect, is a challenge for patients and clinicians. Patient adherence is essential to optimize outcomes, minimize toxicity, minimize bias in clinical trials, and reduce health care costs. As the use of OA grows, due to the narrow therapeutic margin, it is critical to understand the barriers to patient adherence. The purpose of this study was to analyze cancer patients’ use of OAs and identify opportunities to improve patient adherence. Methods: We developed and tested a 30-question survey to address frequency and reasons for reducing/skipping doses; sources of information for OA use; perceived importance of food-drug effects, and ease of understanding directions on vial label. Surveys, consisting of Likert scale and multiple choice questions, were distributed to adult cancer patients on OAs at the UNC Cancer Hospital clinics. Results: Seventy-seven patients taking OAs with CML, RCC, breast cancer, and GI tumors completed the survey with a response rate of 97%. This was a well-educated population with 71% having completed some college; 54% female and 58% older than 50 years. Forty-three percent of patients taking drugs with a significant food-drug effect (sorafenib, pazopanib, lapatinib, imatinib, nilotinib, and capecitabine) did not think about the last time they ate before taking their OA and 23% did not know that their OA had a food-drug effect. In addition, 21% of patients indicated they intentionally skipped/cut back on their OAs and 38% of those did not inform their physician. Although 97% reported no difficulty reading instructions on drug vial, nearly 20% had some difficulty understanding the directions. Conclusions: There are three main barriers associated with appropriate use of OAs: confusion or misunderstanding about the timing of drug with food; reducing/stopping drug without informing MD; and difficulty understanding directions on the drug vial label. A multipronged integrated approach involving the pharmacist, physician and nurse is needed to optimize communication of directions for optimal OA use.
Oncogenic Ras Isoforms Signaling Specificity at the Membrane
Authors: Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Journal: Cancer Research (2017)

How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and N-Ras) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity. There are two major pathways in oncogenic Ras-driven proliferation: MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. All membrane-anchored, proximally located, oncogenic Ras isoforms can promote Raf dimerization and fully activate MAPK signaling. So why the differential statistics of oncogenic isoforms in distinct cancers and what makes KRas so highly oncogenic? Many cell-specific factors may be at play, including higher
AZA-MS: a novel multiparameter mass spectrometry method to determine the intracellular dynamics of azacitidine therapy in vivo
Authors: A Unnikrishnan, A N Q Vo, R Pickford, M J Raftery, A C Nunez, A Verma, L B Hesson, J E Pimanda
Journal: Leukemia (2017)

The cytidine analogue, 5-azacytidine (AZA; 5-AZA-cR), is the primary treatment for myelodysplastic syndrome and chronic myelomonocytic leukaemia. However, only ~50% of treated patients will respond to AZA and the drivers of AZA resistance in vivo are poorly understood. To better understand the intracellular dynamics of AZA upon therapy and decipher the molecular basis for AZA resistance, we have developed a novel, multiparameter, quantitative mass spectrometry method (AZA-MS). Using AZA-MS, we have accurately quantified the abundance of the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA and the cytoplasm within the same sample using nanogram quantities of input material. We report that although AZA induces DNA demethylation in a dose-dependent manner, it has no corresponding effect on RNA methylation. By applying AZA-MS to primary bone marrow samples from patients undergoing AZA therapy, we have identified that responders accumulate more 5-AZA-CdR in their DNA compared with nonresponders. AZA resistance was not a result of impaired AZA metabolism or intracellular accumulation. Furthermore, AZA-MS has helped to uncover different modes of AZA resistance. Whereas some nonresponders fail to incorporate sufficient 5-AZA-CdR into DNA, others incorporate 5-AZA-CdR and effect DNA demethylation like AZA responders, but show no clinical benefit.
Risk of cardiac rhythm disturbances and aortic regurgitation in different spondyloarthritis subtypes in comparison with general population: a register-based study from Sweden
Authors: Karin Bengtsson, Helena Forsblad-d’Elia, Elisabeth Lie, Eva Klingberg, Mats Dehlin, Sofia Exarchou, Ulf Lindström, Johan Askling, Lennart T H Jacobsson
Journal: Annals of the Rheumatic Diseases (2017)

Objectives To describe the incidence of atrioventricular (AV) block II–III, atrial fibrillation (AF), pacemaker implantation (PM) and aortic regurgitation in patients with ankylosing spondylitis (AS), undifferentiated spondyloarthritis (uSpA) and psoriatic arthritis (PsA) compared with the general population (GP) and with each other. Methods A prospective nationwide study with cohorts of patients with AS (n=6448), PsA (n=16 063) and uSpA (n=5190) and a GP (n=2 66 435) cohort, identified in 2001–2009 in the Swedish National Patient and Population registers. Follow-up began on 1 January 2006 and ended at event, death, emigration or 31 December 2012. Age-standardised and sex-standardised incidence rates and hazard ratios (HRs) were calculated. Results The highest incidence rates were noted for AF (5.5–7.4 events per 1000 person-years), followed by PM (1.0–2.0 events per 1000 person-years). HRs for AV block, AF, PM and aortic regurgitation were significantly increased in AS (HRs 2.3, 1.3, 2.1 and 1.9), uSpA (HRs 2.9, 1.3, 1.9 and 2.0) and PsA (HRs 1.5, 1.5, 1.6 and 1.8) compared with the GP cohort. The highest HRs were seen for AV block in male uSpA (HR 4.2) and AS (HR 2.5) compared with GP. Compared with PsA, significantly increased HRs were noted for PM (HR 1.5) in AS and for AV block (HR 1.8) in uSpA. Conclusions Patients with SpA are at increased risk of aortic regurgitation, cardiac rhythm disturbances and, as a probable consequence, also PM. Particularly for AF, the most common arrhythmia, increased caution is warranted, whereas AV block should be looked for especially in men with AS or uSpA.
Extramural venous invasion on pretreatment MRI and surgical pathology: Is there a role in predicting prognosis in rectal cancer?
Authors: Sophia C. Kamran, Hamed Kordbacheh, Vinit Baliyan, Theodore S. Hong, Avinash Kambadakone
Journal: Journal of Clinical Oncology (2017)

e15165 Background: Extramural venous invasion (EMVI) describes tumor cells invading the veins beyond the muscularis propria and has been previously recognized as a predictor for survival and disease recurrence in rectal cancer. EMVI is generally diagnosed on pathology after surgical resection. Pretreatment MRI has been proposed as a surrogate imaging biomarker for recognition of EMVI. Our objective is to study the prognostic significance of EMVI in rectal cancers based on pretreatment MRI imaging to determine its correlation with overall survival (OS), local recurrence (LR), and distant metastases (DM). We also compare MRI-detected EMVI to EMVI detected on pathology to evaluate correlation. Methods: In this ongoing study, records of rectal cancer patients with a pretreatment staging MRI diagnosed between 2004-2015 were retrospectively reviewed (n = 180). Pretreatment rectal MRIs were evaluated for different imaging characteristics, including EMVI. The endpoint of OS was calculated using the Kaplan-Meier method and compared with a log-rank test. A p&lt; 0.05 was considered significant. Cox proportional hazard ratios for LR and DM were generated using clinical, imaging, and pathologic characteristics. Results: Most patients were male (63%) with a median age at diagnosis of 63 years (28.5-95.2). Eighty percent of patients received neoadjuvant chemoradiation (nCRT) followed by surgery and adjuvant chemotherapy (AC); 20% received nCRT followed by surgery. A pathologic complete response was achieved in 17% of patients. Median survival was 48.5 months (2.6-145.2); five-year OS was 85%. The receipt of AC improved OS (HR 0.40, CI 0.2-0.9). Of 70 patients with EMVI noted on the pretreatment MRI, 22 (31%) had EMVI on pathology (p = 0.05). EMVI on MR was not found to be prognostically significant for OS, LR, or DM. EMVI on pathology was found to be significant for DM (HR 3.74, CI 1.8-8.0). Conclusions: Preliminary results show that pretreatment MR-detected EMVI was not found to be predictive for OS, LR, or DM, but pathologically-detected EMVI was found to be a predictor for DM. Further analysis of the relationship between this surrogate imaging biomarker on post-CRT MRI and outcomes is ongoing.
Survival gains needed to justify the side effects of treatment for localized prostate cancer
Authors: M. T. King, R. Viney, I. Hossain, D. Smith, E. Savage, M. R. Stockler, B. Armstrong
Journal: Journal of Clinical Oncology (2009)

5119 Background: Men diagnosed with localized prostate cancer face difficult treatment decisions. Evidence about the relative survival benefit of treatment options is lacking or piecemeal. Side-effects can vary widely with treatment, affecting some fundamental aspects of quality of life (QOL). Little is known about patients’ views of the relative tolerability of these side-effects or the survival gains needed to justify them. Methods: QOL data were collected prospectively 3 years post-diagnosis in a population-based cohort of men treated for localized prostate cancer (n=1642); these data were used to identify common side-effect profiles. A patient preference survey was conducted in a subset (n=357, stratified by treatment); hypothetical treatment alternatives were described in terms of side-effects and survival. Random parameter logit models were estimated. We adapted the concept of compensating variation from welfare economics to derive a parameter function for the value of changes in QOL in terms of survival time; i.e., the survival gains needed to justify persistent side-effects. Bootstrap confidence intervals (CI) were constructed. Results: The table shows the survival gains needed for a range of common treatment profiles, relative to the base case of active surveillance (in which men typically experienced mild loss of libido and mild fatigue). For example, radical prostatectomy often resulted in severe impotence and mild urinary leakage; men required an extra 8.0 months (95% CI 7.4–8.7) of life to make this worthwhile. Generally, urinary dysfunction and bowel symptoms were considered the least tolerable, hormonal symptoms and fatigue came next, and sexual dysfunction was considered relatively benign. This pattern was relatively consistent across treatment groups. Conclusions: These results highlight the need for better evidence about the actual survival benefits of alternative treatments. They also help to target supportive care to optimize patient QOL after treatment for localized prostate cancer. [Table: see text] No significant financial relationships to disclose.
Down-regulation of tumor suppressor, KiSS-1, in human prostate cancer cells and prostate tumours by hepatocyte growth factor/scatter factor (HGF/SF)
Authors: Gaynor Davies, Malcolm D. Mason, Tracey A. Martin, Chris Parr, Gareth Watkins, Jane Lane, Wen G. Jiang
Journal: Cancer Research (2004)

2674  Semaphorins are a family of conserved secreted and transmembrane proteins. Originally described as chemo-repellants of the nervous system, semaphorins have various important roles throughout development. Semaphorins mediate several important signaling pathways that regulate cell migration, apoptosis, angiogenesis, and invasion of normal and cancerous cells by acting through the transmembrane plexin receptor. Class 3 semaphorins, are a subfamily of secreted semaphorins. More is known about their function in cancer than other semaphorins, however the published data are still quite limited. Semaphorin 3A (sema3A) under normal conditions is in balance with vascular endothelial growth factor isoform 165 (VEGF165). VEGF165 is an important regulator of angiogenesis leading to increased invasion and metastasis of many cancers. Sema3A inhibits VEGF165 activity leading to decreased invasion and increased apoptosis. Semaphorin 3B (sema3B) is a mediator of p53 induced apoptosis and is often deleted in metastatic cancers. Semaphorin 3C has a different cellular effect than other class 3 semaphorins and leads to increased cisplatin resistance and increased invasion of some cancers. Little is known about the function of semaphorin 3E (sema3E), although it has cellular responses similar to sema3A. Relatively little information is available on the function of class 3 semaphorins in prostate cancer. The purpose of this study was to determine the expression profile class 3 semaphorins, plexins, and downstream mediators, as well as the expression of other semaphorin classes in tumorigenic and nontumorigenic prostate cells. We found that the mRNA for class 3 semaphorins is expressed in prostate cancer cell lines PC-3, DU145, LNCaP, as well as in non-tumorigenic cell lines BPH-1 and normal prostate epithelial (PRE) cells. Also by comparing expression levels of the semaphorins and their related proteins, several semaphorins were differentially regulated between prostate cancer cells and non-tumorigenic cells. Sema3A, sema3B, and sema3E were over-expressed in PC-3 and LNCaP cells compared to non-tumorigenic cell lines BPH-1 and PRE cells. In DU145 cells sema3E was over-expressed, while sema3B was under-expressed compared to the above non-tumorigenic cell lines. The noticeable differences in over-expression of the semaphorins, between DU145 and PC-3 cells, might provide an explanation of why PC-3 cells are more invasive. However, since many of the class 3 semaphorins, according to published literature, function like tumor-suppressors when over-expressed, the exact role that semaphorins have in the progression of prostate cancer and regulation of invasion and apoptosis is not clear. This is the subject of our continuing research. (Support in part by grant #RO1CA77604 from NIH and grant number DAMD17-00-017 from the Department of the Army).
Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond
Authors: C S Chim, S K Kumar, R Z Orlowski, G Cook, P G Richardson, M A Gertz, S Giralt, M V Mateos, X Leleu, K C Anderson
Journal: Leukemia (2017)

Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.
The novel Group A Streptococcus antigen SpnA combined with bead-based immunoassay technology improves streptococcal serology for the diagnosis of acute rheumatic fever
Authors: Paulina Hanson-Manful, Alana L. Whitcombe, Paul G. Young, Polly E. Atatoa Carr, Anita Bell, Alicia Didsbury, Edwin A. Mitchell, P. Rod Dunbar, Thomas Proft, Nicole J. Moreland
Journal: Journal of Infection (2017)
Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog
Authors: Ulrike Hövelmann, Britta Væver Bysted, Ulrik Mouritzen, Francesca Macchi, Daniela Lamers, Birgit Kronshage, Daniél Vega Møller, Tim Heise
Journal: Diabetes Care (2017)

OBJECTIVE Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS In this single-center, randomized, double-blind trial, 58 patients with type 1 diabetes received single subcutaneous injections of 0.1, 0.3, 0.6, or 1.0 mg dasiglucagon or 0.5 or 1.0 mg GlucaGen in a state of hypoglycemia (blood glucose target 55 mg/dL) induced by an intravenous insulin infusion. RESULTS Dasiglucagon demonstrated a dose-dependent and rapid increase in plasma concentrations, reaching a maximum at ∼35 min with a half-life of ∼0.5 h. Dasiglucagon rapidly increased plasma glucose (PG) by ≥20 mg/dL (9–14 min) to PG ≥70 mg/dL (within 6–10 min), similar to GlucaGen, but with a longer-lasting and greater effect on PG. All patients on both treatments reached these end points within 30 min (predefined success criteria). Both treatments were well tolerated. Nausea was the most frequent adverse event, occurring at a similar rate (44–56%). CONCLUSIONS Dasiglucagon was well tolerated and showed an early PD response similar to that of GlucaGen at corresponding doses, suggesting comparable clinical effects of the two glucagon formulations. Dasiglucagon has the potential to become an effective and reliable rescue treatment for severe hypoglycemia in a ready-to-use pen.
Abstract 11107: Efficacy and Safety of Intensive Statin Therapy for Hypercholesterolemic Patients With Bioprosthetic Aortic Valve Replacement for Aortic Valve Stenosis
Authors: Yoshihisa Morimoto, Takaki Sugimoto, Hiroki Arase
Journal: Circulation (2014)

Objectives: Intensive rather than standard statin therapy has been proven to be superior in improving cardiovascular outcome, whereas the effects of intensive statin therapy on inflammation and lipoprotein biomarkers are not well defined. The purpose of this study was to validate the efficacy of intensive statin therapy for hypercholesterolemic patients with bioprosthetic aortic valve replacement for aortic valve stenosis. Methods: In this study, we performed a single-center, randomized, single-blind clinical trial. A total of 30 hypercholesterolemic patients with bioprosthetic aortic valve replacement were enrolled and randomly divided into two groups [intensive-dose rosuvastatin therapy (target LDL-C level: 70 mg/dl) and standard-dose rosuvastatin therapy (target LDL-C level: 120 mg/dl). Evaluation variables, including changes in serum lipid profile, aortic valve area, and E/e’ representing left ventricular diastolic function, from baseline to years 1 and 2, were used to compare the benefits of these two statin therapies. Results: At baseline, there were no differences between the two groups, including in LDL-C level (intensive 121+/-27 vs. standard 118+/-31, n.s.), aortic valve area (intensive 1.58+/-0.47 vs. standard 1.54+/-0.42, n.s.), and E/e’ (intensive 19+/-20 vs. standard 20+/-10, n.s.). After 2 years of treatment, improvements of LDL-C level (intensive 75+/-11 vs. standard 95+/-10, p&lt;0.001), aortic valve area (intensive 1.63+/-0.24 vs. standard 1.43+/-0.32, n.s.), and E/e’ (intensive 16+/-6 vs. standard 23+/-8, p&lt;0.05) were all better in the intensive group. Conclusions: Compared with standard statin therapy, long-term intensive-dose statin appears to be safe and lowered the LDL-C level significantly, further improved left ventricular diastolic function, and preserved bioprosthetic aortic valve.