tbuckley/cabot-search huggingface dataset:
Abstract 21376: Apo A-I Mimetic Peptides Inhibit IBD In Multiple Mouse Models
Authors: David Meriwether, Carmen Volpe, Victor Grijalva, Hanah Trost, Pallavi Mukherjee, Martin G Martin, Alan M Fogelman, Srinivasa T Reddy
Journal: Circulation (2017)

Introduction: Inflammatory bowel disease (IBD) has been linked to an increased prevalence of early stage vascular disease. ApoA-I mimetic peptides including 4F and Tg6F (6F expressed in tomatoes) are potential therapeutic agents for the treatment of inflammatory diseases. We previously reported that 4F protects against the development of IBD in a COX2-deficient and cholate-dependent mouse model of Crohn’s disease. Hypothesis: We sought to determine, a) the mechanism by which 4F inhibits IBD, b) whether 4F is protective in additional mouse models of IBD, and c) whether Tg6F could also protect against IBD. Methods: We examined the effects of cholate on changes in barrier permeability and translocation of LPS into portal vein plasma, in COX2-deficient and wild-type mice. We studied the effects of both COX2 and 4F on the pro-inflammatory response of LPS-stimulated macrophages. We investigated the effects of 4F in the IL10 -/- + piroxicam model of colitis. Finally, we examined the protective effects of Tg6F in myeloid conditional COX2 KO mice that were challenged with cholate. Results: Cholate increased both barrier permeability and the translocation of LPS into portal vein plasma equally in both COX2-deficient and wild-type mice, while only COX2-deficient mice including myeloid COX2-deficient mice subsequently developed IBD. Bone marrow derived macrophages lacking COX2 expressed 10-15 fold higher pro-inflammatory cytokines including IL1-β compared to WT macrophages, when stimulated with LPS. Both pre-treatment and co-treatment of these macrophages with 4F significantly reduced the expression of pro-inflammatory cytokines, returning them to the level of WT. 4F significantly inhibited the development of colitis in IL10 -/- mice challenged with the COX inhibitor piroxicam, as determined by colon length, colitis score, and H&amp;E score. Furthermore, Tg6F significantly protected against the development of IBD in myeloid COX2 KO mice challenged with cholate, as determined by gross pathology and H&amp;E score. Conclusions: 4F protects against IBD in the COX2-deficient mouse model, in part, by inhibiting the pro-inflammatory phenotype of COX2-deficient macrophages. Our findings suggest a novel therapeutic role for ApoA-I mimetic peptides including Tg6F in IBD.
Phase I study of combination of crizotinib (C) and dasatinib (D) in patients (pts) with advanced cancer.
Authors: Shumei Kato, Denis Leonardo Fontes Jardim, Faye M. Johnson, Vivek Subbiah, Sarina Anne Piha-Paul, Apostolia Maria Tsimberidou, Gerald Steven Falchook, Daniel D. Karp, Jennifer J. Wheler, Ralph Zinner, Filip Janku, Siqing Fu, Lakshmi Dandu, Elsa Browne, Funda Meric-Bernstam, David S. Hong
Journal: Journal of Clinical Oncology (2015)

2597 Background: Although C and D both demonstrate activity resistance can develop. Preclinical studies demonstrated that activation of MET requires c-SRC. We hypothesized that a c-SRC inhibitor (D), in combination with a MET inhibitor (C), may overcome resistance and demonstrate activity. This study is the first in-human attempt to combine C and D. Methods: This is a 2 arm concurrent phase I study (3+3) to determine the safety of oral C and D (Table). Arm A: C fixed at 250mg BID with escalation of D. Arm B: D was fixed at 140mg QD with escalation of C. Endpoints included MTD, DLT, RP2D at least 10 evaluable pts at MTD of each arm and response (RECIST 1.1). Results: 47 pts were enrolled. Median age was 59 yrs (16- 76), 3 median prior therapies (1 - 11). Most common cancers were prostate (21%) and sarcoma (19%). 27 pts in Arm A were enrolled. 10 pts were not evaluable: consent withdrawal (n=3) primarily for G2 AEs, missed doses <15% (n=7) primarily for early progression. Among 17 pts evaluable for DLT/AE (dose level [DL] 1 [n=13], DL2 [n=4]), 7 pts (41%) had at least one G3 drug-related AE with diarrhea (n=3) the most common AE. 2/4 pts had DLTs at DL2 (all G3; dehydration, infection, nausea, vomiting [n=1 each]). We expanded Arm A DL1 to determine the MTD with 1/13 pts with DLT (G3 esophageal pain). Arm B, 20 pts were enrolled. 6 pts were not evaluable: consent withdrawal (n=1), missed doses (n=5). Among 14 pts evaluable for DLT/AE (DL1 [n=10], DL2 [n=4]), 5 pts (36%) had at least one G3 drug-related AE with fatigue (n=3) being the most common. 2/4 pts had DLT at DL2 (G3 renal failure, G3 fatigue, G3 anorexia [n=1 each]). We expanded Arm B DL1 to determine the MTD with 2/10 pts with DLT (G3 fatigue [n=2]). Based on number of DLTs in the MTDs of each arm, our preliminary RP2D is DL1 on Arm A. 2 pts had PR (prostate [-34%] and uterine carcinosarcoma [-27%]) and 2 pts had SD ≥ 6 months (NSCLC [10.1] and melanoma [(+)14.4]). Conclusions: Preliminary RP2D for the combination is C (250mg PO BID) + D (50 mg QD). Responses have been observed and specific tumor and molecular expansions are ongoing. Clinical trial information: NCT01744652. Arm A Crizotinib 250 mg BID Dasatinib (mg) DL 1 50 QD DL 2 70 QD DL 3 100 QD DL 4 120 QD DL 5 140 QD Clinical trial information: NCT01744652. Arm B Dasatinib 140 mg QD Crizotinib (mg) DL 1 250 QOD DL 2 200 QD DL 3 250 QD DL 4 200 BID DL 5 250 BID
Preclinical development of an oral anti- <i>Wolbachia</i> macrolide drug for the treatment of lymphatic filariasis and onchocerciasis
Authors: Mark J. Taylor, Thomas W. von Geldern, Louise Ford, Marc P. Hübner, Kennan Marsh, Kelly L. Johnston, Hanna T. Sjoberg, Sabine Specht, Nicolas Pionnier, Hayley E. Tyrer, Rachel H. Clare, Darren A. N. Cook, Emma Murphy, Andrew Steven, John Archer, Dominique Bloemker, Franziska Lenz, Marianne Koschel, Alexandra Ehrens, Haelly M. Metuge, Valerinne C. Chunda, Patrick W. Ndongmo Chounna, Abdel J. Njouendou, Fanny F. Fombad, Robert Carr, Howard E. Morton, Ghaith Aljayyoussi, Achim Hoerauf, Samuel Wanji, Dale J. Kempf, Joseph D. Turner, Stephen A. Ward
Journal: Science Translational Medicine (2019)

An oral macrolide drug targeting the bacterial endosymbiont, Wolbachia , shows efficacy against filarial nematodes in preclinical animal models.
Abstract P422: Accelerometer-Determined Sedentary Time and Physical Activity Across Employment Status Categories in CARDIA
Authors: Tyler D Quinn, Kelley Pettee Gabriel, Juned Siddique, David Aaby, Kara Whitaker, Abbi Lane-Cordova, Steve Sidney, Barbara Sternfield, Bethany Barone Gibbs
Journal: Circulation (2019)

Prolonged sedentary behavior and insufficient physical activity is a common activity profile, especially in modern workplaces. Describing activity profiles by employment status groups could identify target populations for sedentary and activity intervention. Methods: This cross-sectional analysis of Year 20 CARDIA data (2005-6), included participants who had valid accelerometry data (≥4 days with ≥10 hours), reported occupational status, and were not currently a student (n=2,068). Uniaxial accelerometry data (ActiGraph 7164) were expressed in 60 second epochs and summarized as: average counts per minute (cpm) and time spent (min/day) in prolonged sedentary behavior (≥30 continuous minutes, SED ≥30 ), less than 30-minute bouts of sedentary behavior of (SED &lt;30 ), light physical activity (LPA), less than 10-minute bouts of moderate-to-vigorous physical activity of (MVPA &lt;10 ), and bouted MVPA (≥10 minutes, MVPA ≥10 ) using Freedson cutpoints. Employment status was self-reported as full-time, part-time, unemployed/looking for work, keeping house, or raising children. Omnibus group differences were analyzed using ANCOVA adjusted for sex, race, age, education, wear time, center, and BMI. Least square means of activity time across groups were calculated and standardized to population average wear time (14.8 hours). Results: Figure 1 shows activity profiles of employment groups rank ordered by cpm. Cpm and most types of activity differed modestly but significantly across employment groups, except for MVPA ≥10 . Unemployed participants had the highest cpm, the most MVPA ≥10 and SED ≥30 , but the least SED &lt;30 . Participants working part-time had the most MVPA &lt;10 . Full-time workers had the least LPA. Those raising children had the least SED ≥30 and MVPA ≥10 , but the most LPA. Participants keeping house had the least cpm and MVPA &lt;10 . Conclusions: Public health intervention programing could consider differences in activity profiles across employment status groups.
Role of robot assisted retroperitoneal lymph node dissection in metastatic malignant mesothelioma of the tunica vaginalis: Case series.
Authors: Kassem Faraj, Haidar Abdul-Muhsin, Anojan Navaratnam, Kyle Rose, Thai Huu Ho, Alan Haruo Bryce, Parminder Singh, Scott Cheney, Mark D. Tyson, Erik P. Castle
Journal: Journal of Clinical Oncology (2019)

536 Background: The management of malignant mesothelioma of the tunica vaginalis of the testes (MMTVT) is not clearly defined, though retroperitoneal lymph node dissection has been reported as a diagnostic and potentially therapeutic option. Herein we present our experience with robot assisted retroperitoneal lymph node dissection (RARPLND) in a series of patients with MMTVT. Methods: The Mayo Clinic cancer registry was queried from 1972-present for all patients who had a diagnosis of MMTVT. Six patients were identified, five of whom were treated with RPLND, where four underwent RARPLND. Data was collected on pertinent demographic, preoperative, perioperative, postoperative outcomes and follow-up oncological data. Results: In five patients who underwent RPLND, the median age was 50 years (IQR 34-51), median BMI was 26.9 (IQR 26.4-30.6). Four patients originally presented with right sided symptomatic hydroceles, while one presented with right sided chronic epididymitis. Orchiectomy (one simple, two inguinal radical) was performed in three patients and hydrocelectomy in the other two patients prior to presentation. Preoperative cross-sectional imaging, including PET-CT scan in three patients, was negative for lymphadenopathy or metastasis. RARPLND was performed in 4/5 (80%) cases and concomitant hemiscrotectomy in 4/5 (80%) cases. Full bilateral template was performed in three patients and right modified template was performed in the remaining two. Median lymph node yield was 29 (IQR 22-32) and median blood loss was 275 cc (IQR 200-300). Positive retroperitoneal lymph nodes were found in 3/5 (60%) cases. Final margins of hemiscrotectomy were negative in all four cases. All patients who underwent RARPLND were discharged home on postoperative day one. One patient received four cycles of adjuvant Cisplatin and Pemetrexed. Mean follow-up was 27 months (range 2-47). No patients recurred. Conclusions: MMTVT is a very rare malignancy with high potential for retroperitoneal lymph node dissemination. Regardless of the approach, RPLND may provide both a diagnostic and therapeutic benefit, with the robotic approach affording a potentially expedited recovery.
Covariate Adjusted Indirect Treatment Comparison (ITC) of Glasdegib Plus Low Dose Ara-C Versus a Hypomethylating Agent for Acute Myeloid Leukemia Patients Ineligible for Intensive Chemotherapy
Authors: Gabriel Tremblay, Bhakti Arondekar, Geoffrey Chan, Anastasiya Shor, Anna Forsythe, Su Yun
Journal: Blood (2017)
Abstract MP13: Comparative Effectiveness of Direct Oral Anticoagulants and Warfarin on Risk of Bleeding Resulting in Hospitalization Among Venous Thromboembolism Patients
Authors: Pamela L Lutsey, Neil A Zakai, Richard F MacLehose, Faye L Norby, Rob F Walker, Nicholas S Roetker, Terrence J Adam, Alvaro Alonso
Journal: Circulation (2018)

Background: Direct oral anticoagulants (DOACs), including rivaroxaban, dabigatran, apixaban and edoxaban, have been approved as alternatives to warfarin for the primary treatment of venous thromboembolism (VTE). However, understanding of their comparative effectiveness in practice-based populations is limited. Objective: Among anticoagulant-naïve VTE patients, estimate the association of type of oral anticoagulant (OAC) with the rate of bleeding resulting in hospitalization. Methods: Patients with VTE and prescription for an OAC were identified from the US Truven Health MarketScan® Commercial and Medicare Supplemental databases for the period from 2011-2015. Hospitalization related to bleeding events (inclusive of intracranial, gastrointestinal and other) was defined using a validated algorithm. In head-to-head comparisons, initiators of a specific OAC were matched with up to 5 initiators of the comparing OAC by age, sex, and time since database enrollment. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (95%CI) for bleeding by OAC, adjusted for age, sex, and a comorbidity propensity score (created using prevalence of 20 common diagnoses and procedures). Results: The final analysis included 83,831 VTE patients who were 49.9% female and on average (standard deviation) 59.0 (16.0) years old. Of these, the initial OAC prescribed for 2,604 was apixaban, for 1,669 dabigatran, for 28,518 rivaroxaban, and for 48,514 warfarin. A total of 1,947 bleeding events occurred over an average of 13 months. Compared to new warfarin users, risk of bleeding was lower among patients initiating apixaban [HR (95%CI): 0.55 (0.36, 0.83)] and rivaroxaban [0.80 (0.72, 0.89)], but similar among new dabigatran users [0.96 (0.72, 1.27)]. In head-to-head DOAC comparisons, relative to rivaroxaban, risk of bleeding was lower among users of apixaban [0.57 (0.36, 0.89)] but similar for users of dabigatran [1.05 (0.73, 1.51)]. Due to low numbers we did not conduct analyses of edoxaban or a head-to-head comparison of dabigatran versus apixaban. Conclusion: In this practice-based population of 83,831 patients prescribed OACs for the treatment of VTE, subsequent risk of hospitalized bleeding was lowest among those prescribed apixaban, intermediate among those prescribed rivaroxaban, and highest among those prescribed warfarin and dabigatran. These data demonstrate that differences in bleeding risk exist by DOAC. While risk factors for bleeding might impact choice of warfarin versus the DOACs, the choice between DOACs may be less likely to be based on patient conditions.
Cribriform pattern, Genomic Prostate Score, and adverse pathology at radical prostatectomy in a cohort of prostate cancer patients initially on active surveillance.
Authors: Kyle Brian Zuniga, Samuel L. Washington, Jeffry Simko, Nancy Greenland, Bradley A. Stohr, Janet E. Cowan, Imelda Tenggara, Martina Maggi, June M. Chan, Matthew R. Cooperberg, Peter Carroll
Journal: Journal of Clinical Oncology (2019)

88 Background: A growing body of literature suggests that the presence of cribriform pattern (CP) in prostate biopsy specimens portends worse outcomes. Furthermore, CP tumors have been found to harbor a myriad of genomic alterations associated with more aggressive disease. We sought to examine the association between CP and Genomic Prostate Score (GPS) and how this association helps predict adverse pathology (AP) at radical prostatectomy (RP) in patients initially managed with active surveillance (AS). Methods: Using the UCSF Urologic Outcomes Database (UODB), we identified 180 AS patients who underwent GPS testing and subsequently RP. Biopsy specimens were re-reviewed centrally to confirm Gleason grade. AP was defined as GS ≥ 4+3, pT3/4, or pN1 on surgical pathology. Clinical and demographic characteristics were compared by CP status using t-tests and chi-squared tests. Cox proportional hazards regression was performed to identify factors associated with AP after adjusting for age, PSA density (log), percentage of positive biopsy cores, biopsy source (UCSF versus outside), and year of diagnosis. Additional models included the base covariates plus presence of CP, GPS, and both CP and GPS. Results: For the cohort, mean age was 60.7 years (SD 7.1) with median PSA of 5.3 ng/ml (interquartile range, IQR 4.2-6.9) at diagnosis. Median PSAD was 0.14 (IQR 0.10-0.20). Among 180 patients, 27 (15%) had CP at biopsy. Mean GPS was significantly higher in CP+ compared to CP- patients (35, SD 12.7 versus 27, SD13.7, p &lt; 0.01), and a greater proportion of CP+ patients had AP compared to CP- (59% versus 54%, p &lt; 0.01). On multivariate analysis, CP was associated with AP (HR 1.9, 95% CI 1.1-3.4, p = 0.02), but significance was lost after adjusting for GPS (p = 0.19). Conclusions: The presence of CP at biopsy was statistically significantly associated with higher GPS. While both were associated with AP at RP, CP was not associated with AP independent of GPS, suggesting an interaction or commonality between these factors not previously explored.
Lymphoedema of lower limbs in systemic lupus erythematosus
Authors: Junna Ye, Zhuochao Zhou, Jialin Teng, Chengde Yang
Journal: BMJ (2019)

A 36 year old woman presented with two weeks of bilateral widespread swelling, weakness, numbness, and redness of the legs, three months of knee joint pain, and a malar rash (fig 1).



Fig 1 

On examination, both legs were warm and tender and she had reduced motor …
Abstract MP40: Higher Intakes of Animal Protein Helps Maintain Functional Status and Grip Strength in Older Adults in the Framingham Offspring Study
Authors: Mengjie Yuan, Richard T Pickering, Martha R Singer, Margaret L Bradlee, Lynn L Moore
Journal: Circulation (2019)

Introduction: Dietary protein has been shown to prevent age-related functional decline and strength loss, but few studies have examined the separate effects of animal and plant proteins on these outcomes. Hypothesis: We hypothesized that animal protein might provide greater protection against strength loss and functional decline than plant protein in older adults (aged ≥ 50 years) in the Framingham Offspring Study (FOS). Methods: Dietary protein was assessed using 3-day diet records at exams 3 and 5 in the prospective FOS; intakes were adjusted for body weight using the residual method. Functional status scores (median follow-up 17.3 years) was derived from standardized questionnaires at exams 5-9, while grip strength (median follow-up 10.3 years) was measured by hand-held dynamometer at exams 7-9. Multivariable analyses included Cox proportional hazards modeling, repeated-measures mixed models, and analysis of covariance to adjust for sex, age, education, percent of calories from saturated fats, and physical activity. Models for animal protein were adjusted for plant protein intake and vice versa. Results: Subjects were categorized into 3 categories of sex-specific intakes of animal protein (&lt;50, 50-&lt;70, and ≥70 g/day for men; &lt;45, 45-&lt;65, and ≥65 g/day for women) and plant protein (&lt;20, 20-&lt;26 and ≥26 g/day for men; &lt;17, 17-&lt;22, and ≥22 g/day for women). At the end of follow-up, those with the highest (vs. lowest) animal protein intakes maintained the highest functional status levels (functional score: 20.4 vs.19.0, respectively p=0.0036). Similar results were observed for plant proteins (20.2 vs.18.4 for highest vs. lowest intakes, p ≤.0001). In stratified analyses, higher intakes of both animal and plant proteins, especially in combination with higher levels of activity, were associated with greater preservation of functional status over time. Among more sedentary individuals, dietary protein alone (from both animal and plant sources) protected against functional decline over time (p=0.0015 and p=0.0008 for animal and plant protein, respectively). For grip strength, however, only animal protein protected against decline over 10.3 years (change in grip strength: -0.41 vs. -0.60 kg/yr for highest vs. lowest intakes in men, p=0.0273; -0.15 vs. -0.29 kg/yr for highest vs. lowest intakes in women, p=0.0487). Higher plant protein intake was not associated preservation of grip strength over time. Conclusions: Higher intakes of both animal and plant protein were protective of self-reported functional status in these analyses while only animal protein was associated with the preservation of grip strength among older adults.
Who benefits from liver-directed therapy (LDT) for colorectal liver metastases (CRLM)? Development of a prognostic model.
Authors: Kaihong Mi, Michael J. McNamara, Paul Elson, Shiva Shrotriya, Katherine Glass, Cristiano Quintini, Federico Aucejo, Eren Berber, Alok A. Khorana
Journal: Journal of Clinical Oncology (2015)

e17745 Background: LDT is an emerging but expensive treatment modality in patients with CRLM. It remains unclear, however, how to identify patients most likely to benefit from this approach, leading to significant variation in practice patterns. We evaluated prognostic factors, an existing risk score and developed a model predictive of outcomes in this setting. Methods: We conducted a retrospective cohort study in patients who underwent surgical resection and/or radiofrequency ablation (RFA) between 2/2006 and 2/2014 at Cleveland Clinic. Clinical, pathologic, and outcome data were collected by electronic medical records review. Overall survival (OS) was the primary endpoint and summarized by the Kaplan-Meier. The logrank test and Cox proportional hazards models were used. Results: The study population comprised 214 patients. Median age was 60 years (range 27-88) and 58% were male.Primary site was colon, recto-sigmoid, and rectal in 64%, 7%, and 28%, respectively and 59% presented synchronous CRLM. Wedge resection and segmentectomy (49%) were the most commonly employed surgical procedures, and 33% underwent RFA. Median OS was 43.8 month. In univariate analysis, CEA ≥ 10 ng/mL (p = 0.002) and age ≥ 70 years (p = 0.02) were associated with worsened OS. The number ( ≥ 4 vs < 4), size ( > 5cm vs ≤ 5cm), margin status, and distribution of metastases (uni- vs bi-lobar) were not associated with OS. The MSKCC-CRS score was not significantly associated with OS (p = 0.07). Multivariate analysis confirmed age [ ≥ 70 vs < 70, Hazard ratio (HR) 2.07 (1.33- 3.20), p = 0.001] and CEA [ ≥ 10 vs < 10 ng/mL, HR 1.79 (1.14 – 2.81), p = 0.01] association with OS. By combining the 2 factors and counting number of poor risk features (PRF), 3 prognostic groups were defined: favorable (0 PRF, 33%), intermediate (1 PRF, 55%), and unfavorable (2 PRF, 12%) with median OS of 58.4, 41.2, and 28.7 months, respectively. Conclusions: Patients with CRLM and a favorable risk profile, based on CEA and age, appear to derive substantial benefit from LDT. Further studies validating this simple prognostic model are necessary before clinical utilization for patient selection.