tbuckley/cabot-search huggingface dataset:
Upfront combination therapy reduces right ventricular volumes in pulmonary arterial hypertension
Authors: Mariëlle C. van de Veerdonk, Anna E. Huis in t Veld, J. Tim Marcus, Nico Westerhof, Martijn W. Heymans, Harm-Jan Bogaard, Anton Vonk-Noordegraaf
Journal: European Respiratory Journal (2017)

In pulmonary arterial hypertension (PAH), upfront combination therapy is associated with better clinical outcomes and a greater reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) than monotherapy. NT-proBNP levels reflect right ventricular (RV) wall stress, which increases when the right ventricle dilates. This study explored the impact of upfront combination therapy on RV volumes compared with monotherapy in PAH patients. This retrospective study involved 80 incident PAH patients (New York Heart Association class II and III) who were treated with upfront combination therapy (n=35) ( i.e. endothelin receptor antagonists (ERAs) plus phosphodiesterase-5-inhibitors (PDE5Is)) or monotherapy (n=45) ( i.e. either ERAs or PDE5Is). All patients underwent right-sided heart catheterisation and cardiac magnetic resonance imaging at baseline and after 1-year follow-up. Combination therapy resulted in more significant reductions in pulmonary vascular resistance and pulmonary pressures than monotherapy. NT-proBNP was decreased by ∼77% in the combination therapy group compared with a ∼51% reduction after monotherapy (p&lt;0.001). RV volumes and calculated RV wall stress improved after combination therapy (both p&lt;0.001) but remained unchanged after monotherapy (both p=NS). RV ejection fraction improved more in the combination therapy group than in the monotherapy group (p&lt;0.001). In PAH patients, upfront combination therapy was associated with improved RV volumes.
Radioembolization with yttrium-90 resin microspheres for liver metastases of pancreatic adenocarcinoma: A retrospective multicenter analysis.
Authors: Alexander Y. Kim, Shelby Frantz, Nabeel Akhter, Jian Zhang
Journal: Journal of Clinical Oncology (2017)

e15745 Background: Patients with chemotherapy-treated metastatic pancreatic cancer typically survive for 7 to 11 months. Liver metastases from the pancreas are common and can reduce survival. Radioembolization of these metastases with Y-90 resin microspheres (Y-90 resin) may reduce tumor burden and improve prognosis, but data are limited. We report early data from a multicenter database of patients with pancreatic adenocarcinoma treated with Y-90 resin. Methods: Retrospective patient, treatment, and outcome data were entered by each site (Georgetown, U Maryland). Outcomes included overall survival (OS, determined with Kaplan-Meier analyses), response rate (RECIST), and adverse events (AEs; CTCAE v4.0). Results: Data from the first 24 patients (79% male, mean age 63 y [range 51-77 y]) were analyzed. ECOG status was 0 (n = 10), 1 (n = 13), and 2 (n = 1). Median (IQR) time from diagnosis to Y-90 resin was 10.2 (6.1) mo. Nine patients had extrahepatic disease. Median (IQR) dose delivered to the right (n = 14), left (n = 2), or whole (n = 8) liver was 1.36 (0.42) GBq. Y-90 resin was given concurrently with first-line chemotherapy in 12/21 patients (57%), with a minimum of 4 mo between the onset of chemotherapy and Y-90 resin treatment. Median OS was 6.0 mo (95% CI: 3.9, 12.5) from Y-90 resin and 16.7 mo (95% CI: 13.3, 26.1) from diagnosis. Five patients experienced a partial response. Most AEs were grade 1 or 2. Three patients had grade 3 AEs (abdominal distension or pain, fatigue, ascites, odynophagia, oral sores, biliary duct dilation), and 4 had grade 3 laboratory values (white blood cells, bilirubin, alkaline phosphatase, albumin). Two patients experienced grade 4 AEs, 1 with peripheral neuropathy and 1 with elevated ALT &amp; AST suggesting post-radioembolization hepatitis. Conclusions: Overall, Y-90 resin was safe, with few serious AEs. Survival in this retrospective study was promising, given the generally poor prognosis for pancreatic adenocarcinoma; however, further investigation is needed.
Superoxide Dismutase‐Loaded Porous Polymersomes as Highly Efficient Antioxidants for Treating Neuropathic Pain
Authors: Sonia Kartha, Lesan Yan, Christine L. Weisshaar, Meagan E. Ita, Vladimir V. Shuvaev, Vladimir R. Muzykantov, Andrew Tsourkas, Beth A. Winkelstein, Zhiliang Cheng
Journal: Advanced Healthcare Materials (2017)

A highly efficient antioxidant is developed by encapsulating superoxide dismutase (SOD) within the aqueous interior of porous polymersomes. The porous polymersomes provide a permeable membrane that allows free superoxide radicals to pass into the aqueous interior and interact with the encapsulated antioxidant enzyme SOD. In vivo studies in the rat demonstrate that administration of SOD‐encapsulated porous polymersomes can prevent neuropathic pain after nerve root compression more effectively than treatment with free antioxidant enzyme alone.
Trifluridine tipiracil (TAS 102) in patients with stage IV pretreated colorectal neoplasm: an experience from Rimini City Hospital
Authors: Claudio Ridolfi, Emiliano Tamburini, Britt Rudnas, Manuela Fantini, Stefano Cascinu, Luca Frassineti Giovanni, Rossana Berardi, Lucia Stocchi, Carlotta Santelmo, Luisa Nicoletti Stefania Vittoria, Giusi Giacomini, Davide Tassinari
Journal: Annals of Oncology (2017)
Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer
Authors: Brian S. Finkelman, Mary Putt, Teresa Wang, Le Wang, Hari Narayan, Susan Domchek, Angela DeMichele, Kevin Fox, Jennifer Matro, Payal Shah, Amy Clark, Angela Bradbury, Vivek Narayan, Joseph R. Carver, W.H. Wilson Tang, Bonnie Ky
Journal: Journal of the American College of Cardiology (2017)
A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer.
Authors: Daniel Peter Petrylak, Raymond P. Perez, Jingsong Zhang, David C. Smith, Joseph D. Ruether, Srikala S. Sridhar, Randeep S. Sangha, Joshua Michael Lang, Elisabeth I. Heath, Jaime R. Merchan, Elaina M. Gartner, Rong Chu, Banmeet Anand, Fernando Doñate, Lynnae Jackson, Jeffrey Adams, Amal Melhem-Bertrandt, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2017)

106 Background: Enfortumab vedotin, an antibody–drug conjugate, delivers monomethyl auristatin E to tumors expressing Nectin-4, which is overexpressed in metastatic urothelial cancer (mUC). Methods: This Phase I study (NCT02091999) enrolled patients (pts) with solid tumors, including pts with mUC, treated with ≥1 prior chemotherapy regimen. All pts received different dose levels of IV enfortumab vedotin (0.5, 0.75, 1, 1.25 mg/kg) once weekly for 3 out of 4 wks. Nectin-4 expression was determined by IHC on archival tumor specimens and quantified by histochemical scoring (H-score). Primary endpoint was tolerability; secondary endpoint was antitumor activity assessed every 8 wks per RECIST v1.1. Results: As of 3 Jan 2017, 68 pts with mUC (46 M/22 F; median age, 67 yr [range: 41–84]) had been treated. Of these, 62% received ≥2 prior therapies in the metastatic setting and 40% had prior immune checkpoint inhibitor (CPI) therapy. In these pts, Nectin-4 expression was high and prevalent (median H-score, 280 [range: 32–300]). Treatment-related adverse events (TRAEs) were reported in 58 pts (85%); diarrhea, fatigue, nausea, and pruritus were TRAEs reported in ≥25% of pts. Most TRAEs were grade ≤2 in severity; 19 pts (28%) experienced a TRAE of grade ≥3. The most common grade ≥3 AEs (occurring in ≥5 pts), regardless of attribution to treatment, were urinary tract infection (10%) and hypophosphatemia (9%). No treatment-related deaths have occurred. Sixty pts had ≥1 post-baseline assessment. Antitumor activity was observed across the dose range; overall response rate (ORR) was 40% (95% CI: 27.6–53.5) for all evaluable pts (n = 60), 46% (95% CI: 25.6–67.2) in pts with prior CPI exposure (n = 24), and 44% (95% CI: 19.8–70.1) in pts with metastasis to the liver (n = 16). Complete responses were noted in 3 pts at doses ≥1 mg/kg. Median treatment duration was 26 wks (range: 5.1–64.6), median duration of response was 18 wks (95% CI: 8.4–40.1), and median progression-free survival was 17 wks (95% CI: 15.1–23.3). Study enrollment is ongoing. Conclusions: Enfortumab vedotin demonstrated a favorable tolerability profile with encouraging antitumor activity in heavily pretreated mUC, including pts for whom CPIs have failed. Clinical trial information: NCT02091999.
Abstract P325: Novel Insights in Transcriptome Remodeling Associated with Heart Failure Revealed by Deep RNA Sequencing
Authors: Chen Gao, Jae-Hyung Lee, Shuxun Ren, Guangdun Peng, Robb MacLellan, Jau-nian Chen, Grace (Xinshu) Xiao, Yibin Wang
Journal: Circulation Research (2011)

The complexity of transcriptome and proteome is contributed by alternative splicing of RNA. Altered RNA splicing is also implicated in many human diseases including cancer. However, little knowledge is available about the scope of alternative splicing at whole genome level in heart diseases and even less about the mechanisms underlying the regulation of mRNA splicing in response to pathological injury in heart. In order to investigate the key alternative splicing events associated with cardiac pathogenesis, we used high-throughput RNA-Seq to profile total transcriptome in mouse heart failure induced by pressure-overload. From preliminary data, we identified &gt;1000 novel exons that have not been reported in any published database. Many of the novel exons are detected in genes with potential importance in cardiac gene regulation and signal transduction. In addition, we have also identified a significant number of differentially expressed exons between normal and diseased hearts, supporting the notion that differential RNA splicing is associated with the onset of heart failure. Interestingly, the differential splicing events observed in failing hearts were also detected in neonatal mouse hearts, suggesting that differential RNA splicing is a part of the “fetal” gene expression program in diseased hearts. Furthermore, we have also validated some of these changes in human heart failure samples, supporting the clinic relevance of these findings. In summary, this study suggests that development of heart failure is associated with alternative RNA splicing events at genome level. Further studies on the functional consequences of differential RNA splicing and the underlying regulatory mechanisms in heart will advance our understanding to this important disease.
Tackling doping in sport: a call to take action on the <i>dopogenic</i> environment
Authors: Susan H Backhouse, Claire Griffiths, Jim McKenna
Journal: British Journal of Sports Medicine (2017)

Widespread allegations of doping in sport consistently make front page news. The findings of an independent commission for the WADA1 underscore the importance of moving beyond a focus on individual athletes to concurrently address individual, social and environmental factors in anti-doping policy and practice (socioecological perspective).

The concept of such a complex interactive system has successfully generated positive behaviour change in other domains. Many sports physicians will be familiar with the Foresight Report,2 the UK’s most comprehensive investigation into obesity and its causes. This report highlighted that many obesity risk factors emerge from multiple contexts and interact to place individuals at risk. Building on this, researchers and policy makers are increasingly engaging with the idea that ‘whole systems’ create the deep harm associated with obesity and this has spawned the term ‘obesogenic environment’.3 

Appreciating the equivalent complexity of doping in sport, we define a ‘dopogenic environment’ to acknowledge the sum of influences produced by the surroundings, opportunities and conditions that promote anti-doping rule violations (ADRVs). Local level factors …
Tribalism in Medicine—Us vs Them
Authors: Rebekah Mannix, Joshua Nagler
Journal: JAMA Pediatrics (2017)

Today, while having lunch in the cafeteria, it happened. Three men asked to join the far end of our table and their proximity, combined with their increasingly animated conversation, made eavesdropping inevitable. That, and the fact that "they" were unknowingly talking about "us."
Comparison of recurrent and nonrecurrent breast cancer patients undergoing AE37 peptide vaccine therapy.
Authors: Erika J Schneble, Sonia A. Perez, John S. Berry, Alfred F Trappey, Tim Vreeland, Diane F. Hale, Alan K. Sears, Guy T. Clifton, Eric von Hofe, Alexandros Ardavanis, Nathan M. Shumway, Sathibalan Ponniah, Michael Papamichail, George Earl Peoples, Elizabeth Ann Mittendorf
Journal: Journal of Clinical Oncology (2014)

613 Background: We are conducting a Phase II clinical trial of the HER2 peptide vaccine AE37 (MHC Class II binding) for the prevention of breast cancer recurrence in disease-free, node-positive or high-risk node-negative patients (pts). In this analysis, we compare disease features and immunologic responses (IR) between vaccinated recurrent (vR) pts and vaccinated non-recurrent (vNR) pts. Methods: After completion of standard of care therapy, pts with any level of HER2 expression (IHC1-3+) who were randomized to the vaccine group received AE37+GM-CSF in 6 monthly intradermal inoculations during the primary vaccine series (PVS) followed by four boosters every 6 months. Ex vivo IR was measured by T-cell proliferation using thymidine incorporation and expressed in mean counts per minute (cpm) ±SEM at R0 and as the average of multiple time points after the PVS and throughout the booster series (R). In vivo IR was measured by delayed type hypersensitivity (DTH) immediately before (R0) and after the PVS (R6). Data was compared using student’s t-test and Fisher’s exact as appropriate. Results: Of 298 enrolled and randomized pts, 153 have been vaccinated. For this analysis, 5 patients were excluded for second malignancies leaving 14 vR and 134 vNR available for analysis. Demographics between vaccinated pts were compared with vR exhibiting a higher percentage of node positive (85.7% v 61.9%, p=0.07) disease. vR pts displayed significantly weaker proliferation than nVR pts (R0: 912±254 v 1954±350, p=0.02; R: 4463±764 v 6803±391, p=0.01). DTH between vR and vNR revealed a significantly lower initial DTH response (R0: 1.09±0.78 v 2.80±0.71mm, p<0.05), but similar post PVS DTH (R6: 33.3±9.1 v 28.9±2.0mm, p=0.68). Conclusions: Comparison of vR and vNR pts demonstrates that vR have more advanced disease as well as a consistently weaker intrinsic anti-HER2 immunity as measured in vivo and ex vivo at baseline. The factors responsible for the diminished endogenous immune response and reduced amplification in these pts will require further studies in larger patient populations. Of particular interest would be the response in HER2 non-overexpressing and triple negative pts, both of which appear to derive a greater benefit from AE37. Clinical trial information: NCT00524277.
A Practice-Based Evaluation of Distress Screening Protocol Adherence and Medical Service Utilization
Authors: Brad Zebrack, Karen Kayser, Deborah Bybee, Lynne Padgett, Laura Sundstrom, Chad Jobin, Julianne Oktay
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: This study examined the extent to which cancer programs demonstrated adherence to their own prescribed screening protocol, and whether adherence to that protocol was associated with medical service utilization. The hypothesis is that higher rates of service utilization are associated with lower rates of adherence to screening protocols. Methods: Oncology social workers at Commission on Cancer–accredited cancer programs reviewed electronic health records (EHRs) in their respective cancer programs during a 2-month period in 2014. Rates of overall adherence to a prescribed distress screening protocol were calculated based on documentation in the EHR that screening adherence and an appropriate clinical response had occurred. We examined documentation of emergency department (ED) use and hospitalization within 2 months after the screening visit. Results: Review of 8,409 EHRs across 55 cancer centers indicated that the overall adherence rate to screening protocols was 62.7%. The highest rates of adherence were observed in Community Cancer Programs (76.3%) and the lowest rates were in NCI-designated Cancer Centers (43.3%). Rates of medical service utilization were significantly higher than expected when overall protocol adherence was lacking. After controlling for patient and institutional characteristics, risk ratios for ED use (0.82) and hospitalization (0.81) suggest that when overall protocol adherence was documented, 18% to 19% fewer patients used these medical services. Conclusions: The observed associations between a mandated psychosocial care protocol and medical service utilization suggest opportunities for operational efficiencies and costs savings. Further investigations of protocol integrity, as well as the clinical care models by which psychosocial care is delivered, are warranted.
Abstract 306: Mitochondrial Aldehyde Dehydrogenase, A Therapeutic Target In Post-myocardial Infarction Heart Failure In Diabetes
Authors: Suresh Palaniyandi, Vishal Mali, Jiang Xu, Xiao-Ping Yang
Journal: Circulation Research (2013)

Development of heart failure (HF) and pathological remodeling occurs after myocardial infarction (MI). However, in diabetic patients the prognosis is far worse. Hyperglycemia leads to accumulation of reactive aldehydes like 4-hydroxy-2 nonenal (4-HNE) in the heart. 4-HNE impairs cellular function and causes organ damage by forming adducts with critical proteins. In this study, we hypothesized that 1) 4-HNE-induced impairment of mitochondrial aldehyde dehydrogenase (ALDH) i.e. ALDH2 contributed to myocardial ischemia-induced HF in diabetes mellitus (DM) and 2) pharmacological activation of ALDH2 by Alda-1 prevent post-MI cardiac damage in DM. To test these hypotheses, first 8-week old C57BLC/6J male mice were injected with streptozotocin (STZ) (150 mg/Kg). After 8 weeks of STZ, mice were infused with isoproterenol (Iso) (45 mg/Kg) for 2 weeks by mini pumps to induce chronic myocardial ischemia and HF. Cardiac dysfunction was assessed in conscious mice by echocardiography periodically until sacrifice (16 weeks after STZ). We had normal control (Con), DM control (DM), DM + Iso and non-diabetic Iso control (Iso) with n 6 in each group. Fractional shortening (FS) was reduced in DM + Iso group (47 ± 1.2%) compared to Con (53 ± 0.9 %) and DM (55 ± 1.6 %) P&lt;0.01, but not with Iso (49 ± 1.4%). Decrease in myocardial ALDH2 activity and increase in 4-HNE adduct formation in ALDH2 and mitochondrial damage were observed in DM + Iso at various degrees compared to Con, DM and Iso. Increased cardiac fibrosis was also recorded in DM + Iso (4 ± 0.4%) relative to Con (1 ± 0.2%; P&lt;0.001), DM (2 ± 0.1%; P&lt;0.05) and Iso (2.4 ± 0.3%; P&lt;0.01). In the treatment protocol, DM + Iso group were treated with Alda-1 (10mg/kg/day) from weeks 12 to 16. Alda-1 ameliorated cardiac damage in DM as evident from enhanced FS (55 ± 3.5%; P&lt;0.01) and reduced fibrosis. Besides improving ALDH activity Alda-1 also attenuated 4-HNE adduct formation on ALDH2 and mitochondrial damage. Myocardial levels of ALDH2 activity was lower in diabetic patients with cardiomyopathy (50% reduction; P&lt;0.007). Finally, we conclude that activation of ALDH2 ameliorates HF in diabetic mice and which has a potential to be developed as a therapeutic strategy for HF in diabetic patients.
Direct endoscopic biopsy for subepithelial tumor larger than 20 mm after removal of overlying mucosa
Authors: Hwan Kang Dae, Woong Choi Cheol, Wook Kim Hyung, Jin Kim Su, Seok Nam Hyeong, Gon Ryu Dae, ho Choi Seung, Woo Yeo Chang, Jin Kwon Byung, Hwan Ko Ji
Journal: Annals of Oncology (2017)
Modernizing Research Regulations Is Not Enough: It's Time to Think Outside the Regulatory Box
Authors: Suzanne M. Rivera, Kyle B. Brothers, R. Jean Cadigan, Heather L. Harrell, Mark A. Rothstein, Richard R. Sharp, Aaron J. Goldenberg
Journal: The American Journal of Bioethics (2017)

We are a multidisciplinary collaborative made up of bioethicists, social scientists, clinicians, and lawyers whose work focuses on the ethical challenges posed by a networked approach to bioreposit...
Oncogenic miR-210-3p promotes prostate cancer cell EMT and bone metastasis via NF-κB signaling pathway
Authors: Dong Ren, Qing Yang, Yuhu Dai, Wei Guo, Hong Du, Libing Song, Xinsheng Peng
Journal: Molecular Cancer (2017)

The primary issue arising from prostate cancer (PCa) is its high prevalence to metastasize to bone, which severely affects the quality of life and survival time of PCa patients. miR-210-3p is a well-documented oncogenic miRNA implicated in various aspects of cancer development, progression and metastasis. However, the clinical significance and biological roles of miR-210-3p in PCa bone metastasis remain obscure. miR-210-3p expression was evaluated by real-time PCR in 68 bone metastatic and 81 non-bone metastatic PCa tissues. The biological roles of miR-210-3p in the bone metastasis of PCa were investigated both in vitro by EMT and Transwell assays, and in vivo using a mouse model of left cardiac ventricle inoculation. Bioinformatics analysis, real-time PCR, western blot and luciferase reporter analysis were applied to discern and examine the relationship between miR-210-3p and its potential targets. RT-PCR was performed to identify the underlying mechanism of miR-210-3p overexpression in bone metastasis of PCa. Clinical correlation of miR-210-3p with its targets was examined in human PCa and metastatic bone tissues. miR-210-3p expression is elevated in bone metastatic PCa tissues compared with non-bone metastatic PCa tissues. Overexpression of miR-210-3p positively correlates with serum PSA levels, Gleason grade and bone metastasis status in PCa patients. Upregulating miR-210-3p enhances, while silencing miR-210-3p represses the EMT, invasion and migration of PCa cells in vitro. Importantly, silencing miR-210-3p significantly inhibits bone metastasis of PC-3 cells in vivo. Our results further demonstrate that miR-210-3p maintains the sustained activation of NF-κB signaling via targeting negative regulators of NF-κB signaling (TNF-α Induced Protein 3 Interacting Protein 1) TNIP1 and (Suppressor Of Cytokine Signaling 1) SOCS1, resulting in EMT, invasion, migration and bone metastasis of PCa cells. Moreover, our results further indicate that recurrent gains (amplification) contribute to miR-210-3p overexpression in a small number of PCa patients. The clinical correlation of miR-210-3p with SOCS1, TNIP1 and NF-κB signaling activity is verified in PCa tissues. Our findings unravel a novel mechanism for constitutive activation of NF-κB signaling pathway in the bone metastasis of PCa, supporting a functional and clinical significance of epigenetic events in bone metastasis of PCa.
Crystal Structure of CC Chemokine Receptor 5 (CCR5) in complex with high potency HIV entry inhibitor 5P7-CCL5
Authors: Y Zheng, L Qin, G.W Han, M Gustavsson, T Kawamura, R Abagyan, R.C Stevens, Cherezov, I Kufareva, T.M. Handel
Journal: Immunity (2017)