tbuckley/cabot-search huggingface dataset:
Abstract 122: Compression-Induced Ventilation Volumes Decrease with Chest Compression Depth and Prolonged CPR
Authors: Simone Ordelman, Paul Aelen, Paul van Berkom, Gerrit J Noordergraaf
Journal: Circulation (2014)

Introduction: Compression-induced ventilation may aid gas exchange during CPR. We hypothesized that the amount of gas moving in and out of the lungs depends on chest compression depth. Methods: VF was induced in five female, anesthetized and intubated pigs of about 30 kg. After 30 seconds of non-intervention time, chest compressions were started and maintained at a rate of 100 compressions per minute. Every two minutes chest compression depth was altered, resulting in 14 minutes of CPR with a depth sequence of 4 cm, 3 cm, 4 cm, 5 cm, 5.5 cm, 5 cm and 4 cm. Ventilations were performed manually with a bag-valve device 10 times per minute during continuous chest compressions by a dedicated expert. Airway flow was measured at the end of the endotracheal tube. Compression-induced ventilation was determined from the periods between the manual ventilations. The average compression-induced minute ventilation volume was determined over the last minute of each two minute period of CPR at each specific chest compression depth. Results: The compression-induced ventilation volume in the first period of CPR at 4 cm of depth was 1.6 ± 0.9 L/min (about 4% of total ventilation volume). The figure shows how the compression-induced ventilation volume decreases with increasing chest compression depth, relative to this initial value. CPR with a chest compression depth of 4 cm was performed three times in each pig, and the corresponding compression-induced ventilation volumes decreased with time. This suggested that there might be just a time effect (e.g. atelectasis). However, the final compression depth of 4 cm resulted in larger compression-induced ventilation volumes than the preceding 5 cm and 5.5 cm compression depths, indicating that the decreased volume over time could not purely be a time effect, but must also be an effect of the depth. Conclusion: In conclusion, compression-induced ventilation volume appears to decrease with deeper chest compressions as well as with prolonged CPR.
Biomarkers and clinical outcomes in COPD: a systematic review and meta-analysis
Authors: Jilles M Fermont, Katya L Masconi, Magnus T Jensen, Renata Ferrari, Valéria A P Di Lorenzo, Jacob M Marott, Philipp Schuetz, Henrik Watz, Benjamin Waschki, Hana Müllerova, Michael I Polkey, Ian B Wilkinson, Angela M Wood
Journal: Thorax (2019)

Background Conventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease. Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance. Objective To assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD. Methods We systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results Shorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality. Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC. Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation. Few studies examined associations with musculoskeletal measures. Conclusion Findings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD. Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation. Trial registration number CRD42016052075.
PD-1 Overexpression in Richter's Transformation (RT) and Aggressive Chronic Lymphocytic Leukemia (CLL) after Progression on Ibrutinib Increases Bcl-2 Expression Via Akt/mTOR Pathway
Authors: Sutapa Sinha, Tammy Price-Troska, Shulan Tian, Charla R Secreto, Xiaosheng Wu, Timothy G. Call, Rong He, Sameer A. Parikh, Saad S. Kenderian, Jose F. Leis, Huihuang Yan, Karen L Rech, Minetta C Liu, Stephen M. Ansell, Neil E. Kay, Wei Ding
Journal: Blood (2018)
Genetic variants in tumor immune checkpoints as prognostic markers in patients (pts) with localized advanced gastric cancer (AGC).
Authors: Yu Sunakawa, Nico Benjamin Volz, Wu Zhang, Dongyun Yang, Takeru Wakatsuki, Yan Ning, Sebastian Stintzing, Stefan Stremitzer, Ana Sebio, Shinichi Yamauchi, Satoshi Matsusaka, Rita Elie El-Khoueiry, Syma Iqbal, Afsaneh Barzi, Mizutomo Azuma, Masahiko Watanabe, Wasaburo Koizumi, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

4018 Background: Multiple tumor immune checkpoint receptors and ligands, some of which are selectively upregulated in various types of tumors, play a role as an antitumor immune suppressor. The potential use of immune-based therapy in gastrointestinal cancers is just being realized. We examined the prognostic impact of single nucleotide polymorphisms (SNPs) in genes encoding for immune checkpoints on clinical outcome in pts with localized AGC from U.S. and Japan (JPN). Methods: Genomic DNA was extracted from blood or tissues of 161 Japanese pts (median age 68; median follow-up 4 yrs) for evaluation set and 105 U.S. pts (median age 59; median follow-up 3.3 yrs) for validation set, with localized AGC treated with surgery alone or plus adjuvant therapy (stage Ib-IV; AJCC-6th). Thirty-six functional SNPs in genes of immune checkpoints (PDCD1, CD274, CD73, IDO1, CTLA4, LAG3, ADORA2A, and FOXP3) were analyzed by PCR-based direct sequencing for association with disease-free survival (DFS) / time to recurrence (TTR) and overall survival (OS). Results: The univariate analysis showed 4 SNPs were significantly associated with DFS and OS in JPN cohort. IDO1 rs9657182 remained significant upon multivariate analysis. Any C allele of PDCD1 rs10204525 in U.S. cohort was associated with worse TTR and OS compared to T/T genotype (2.1 vs 7.0 y; HR 2.01; p=0.03, 4.1 vs 7.3 y; HR 2.46; p=0.02, respectively) as well as worse DFS and OS in JPN cohort (HR 1.61; p=0.03, HR 1.79; p=0.01, respectively) in univariate analysis. Interestingly, pts with any T allele of CD73 rs6922 in U.S. cohort had shorter OS compared to those with G/G genotype (HR 2.48; p=0.03) but longer OS in JPN cohort (HR 0.58; p=0.04) in uni- and multivariate analyses, there was no association with TTR/DFS in both cohorts. This different impact on OS reached statistical significance (p=0.002). Conclusions: Our results showed for the first time that tumor immune checkpoint SNPs may serve as a prognostic marker in pts with localized AGC and that there may be an ethnic difference in the impact on clinical outcome by genetic variants in immune checkpoints. Our data suggest that clinical trials using drugs targeting immune checkpoints should be stratified by ethnicity.
Increasing ER stress response in pemetrexed-resistant mesothelioma cells.
Authors: Yuying Luo, Harvey I. Pass, Jessica Donington, Chandra Goparaju, Claudia Canino, Mario Cioce
Journal: Journal of Clinical Oncology (2014)

7577 Background: Clinically silent progression and extraordinary resistance to therapy dictate poor survival for malignant pleural mesothelioma (MPM) patients. Current standard therapies such as antifolate (pemetrexed) treatment only minimally increase patient survival. Induction of ER-stress is a desired response of tumor cells to chemotherapy. We tested the hypothesis that butein (3,4,2',4'-tetrahydroxychalcone), a naturally occurring compound shown to counteract pemetrexed resistance in vitro and in vivo, may function by enhancing the ER-stress response of pemetrexed-treated MPM cells. Methods: MPM and benign mesothelial cells were treated with vehicle or butein, alone or in combination with pemetrexed. Levels of known ER-stress markers were evaluated by western blotting. The splicing of XBP-1, a transcription factor activated by ER-stress, was evaluated by PCR. Induction of CHOP, a main effector of ER-stress induced apoptosis was visualized and quantified by a CHOP-mCherry reporter and measured at the endogenous level by RT-qPCR. Established ER-stress inducing agents served as positive controls. Viability (vital cell count) and clonogenicity assays were used to evaluate the in vitroeffect of butein and butein + pemetrexed treatment. Results: MPM cells were resistant to pemetrexed treatment. MPM cells treated with butein demonstrated increased levels of ER-stress markers (BiP, CHOP, spliced XBP-1) as well as increased CHOP mRNA levels and promoter activation (fig.1). Moreover, butein was a stronger ER-stress inducer than pemetrexed. In line with this, viability and cytotoxicity assays revealed the potential for butein to strongly enhance the sensitivity of the mesothelioma cells to pemetrexed. Interestingly, butein treatment alone did not affect the viability of pemetrexed-sensitive hTERT transformed normal mesothelial cells (LP9). Conclusions: Butein triggers ER stress in MPM cells and may potentiate the ER-stress response of pemetrexed-treated cells. This may be one underlying mechanism for the anticancer effects of butein. Given its lack of effects on untransformed mesothelial cells, we propose that butein may be tested as an addition to the current clinically limited therapies for MPM.
Upregulation of Bcl-2 Confers Resistance to FLT3 Inhibition in FLT3-ITD AML with Secondary Acquired Mutations
Authors: Kotoko Yamatani, Yoko Tabe, Kaori Saito, Haeun Yang, Yuko Murakami-Tonami, Koya Suzuki, Weiguo Zhang, Sonoko Kinjo, Kazuho Ikeo, Kaoru Mogushi, Masaki Hosoya, Shigeo Yamaguchi, Hironori Harada, Takashi Miida, Neil P. Shah, Marina Y. Konopleva, Yoshihide Hayashizaki, Michael Andreeff
Journal: Blood (2018)
PROX: Primary resistance to oxaliplatin containing regimen in the first line treatment of metastatic colorectal carcinoma—Retrospective analysis.
Authors: Larissa Machado, Tiago Felismino, Diogo De Brito Sales, Diogo Morbeck, Amanda Karani, Lara Azevedo Diniz, Ingrid Hariman Fonseca Cunha, Virgilio Souza, Maria Dirlei Begnami, Mariana Petaccia Macedo, Dirce Maria Carraro, Celso Lopes Mello
Journal: Journal of Clinical Oncology (2018)

855 Background: The rate of primary resistance to modern first line (FL) chemotherapy regimen in the treatment of metastatic colorectal cancer (mCRC) is low. Progression Disease (PD) to FOLFOX in the FL is less than 15% in most trials. Prognostic factors associated with worse outcome in mCRC have been identified. However, primary resistance to Oxaliplatin (PROX) containing regimen is not well understood, as well as the role of salvage therapy in further lines of treatment. The aim of the study was to analyze clinical and pathological characteristics of patients with PROX. Methods: A retrospective, single center study included patients that presented PD in the first response evaluation with an Oxaliplatin containing regimen in the FL treatment of mCRC. We also evaluated the Overall Survival (OS) and progression free survival (PFS) of these patients to second and third line. Clinical and pathological variables were analyzed and correlated with (OS). Results: A total of 55 patients were inclued. Median age these cohort was 57 years. Female/Male rate was 42%/58%. Mucinous component was 27%. Right and Left colon was 27% and 66%, respectively. BRAF mutation (2/16 pts). Wild type KRAS was 44%. Synchronic metastasis was 75%. Ressection of metastasis was performed in 20%. Liver limeted disease was found in 45%. Main chemotherapy regimen containing oxaliplatin was FOLFOX (78%) in first line. Bevacizumab, Cetuximab and Panitumumab were used in 21.8%, 9%, 1.8%, respectively. OS was 9.4 months. PFS in second line 3.8 months (47 pts) and third line 3.5 months (18 pts). The only variable associated with longer survival was resection of metastasis (25.6 x 8.6 months, p=0.039). Conclusions: No clinical and pathological variable were able to predict primary resistance to Oxaliplatin containing regimen. However, we found a higher proportion of mucinous subtype. Patients submitted to resection of metastasis had almost three fold the survival of patient that did not underwent surgery. Refractory patients have a very short survival. Further lines of treatment are not able to rescue these patients. Further studies focusing in patients with primary resistance to chemotherapy in first line are needed.
Single-institution experience with autologous stem cell transplants for mantle cell lymphoma patients.
Authors: Nasheed Mohammad Hossain, Matthew R. Zibelman, Nadia Khan, Thomas R. Klumpp, Mary Ellen Martin, Michael Mark Millenson, Rushang D. Patel, Richard I. Fisher, Henry C. Fung, Patricia Lamont Kropf
Journal: Journal of Clinical Oncology (2014)

e19523 Background: Mantle cell lymphoma (MCL) is a type of B cell non-Hodgkin’s lymphoma that can often have an aggressive clinical course. Treatment generally consists of conventional induction chemotherapy regimens followed by consolidation with autologous stem cell transplant (ASCT) if appropriate. ASCT has also been utilized in relapsed disease. Methods: We queried our core database to analyze the clinical cases of the 24 consecutive patients with a diagnosis of MCL, all of whom underwent ASCT at our institution between August 1995 and December 2013. Results: The median age at transplant was 57.5 (range 24-68) with a marked male predominance (70.1%), reflecting historical observations in MCL. Fifty percent of patients were transplanted in CR1. The most common conditioning regimen was cyclophosphamide with total body irradiation, utilized in 75.0% of patients. At the time of data collection, 14/24 (58.3%) of patients were still living, with 13/24 (54.2%) alive without disease. Furthermore, 13/24 (54.2%) were disease free at two years post-transplant, but 5/13 (38.5%) died prior to the five year post-transplant mark. Eight patients died of disease (33.3%), one died of toxicity (pneumonitis) and one died of unrelated causes (metastatic melanoma). For the fourteen patients still living, median follow-up was 1048 days (2.9 years) with four patients alive past the six year post-transplant mark. The five year actuarial overall survival was 59.2%. Progression free survival at five years was 50.2%. The transplant-related toxicity profile was manageable, similar to other institutions’ experience with ASCT. Toxicities of grade 3-4 or higher were seen in only 3 patients (diarrhea, mucositis), and one patient had grade 5 pneumonitis. Conclusions: We conclude that ASCT is an effective and tolerable treatment for transplant eligible patients with MCL.
Effect of stable knockdown of TPPP3 on H1299 cell proliferation and migration by inhibiting PI3K/AKT signal pathway.
Authors: Yintao Li, Kuanping Ye, Nan Wu, Wenbai Zhou, Renming Hu
Journal: Journal of Clinical Oncology (2014)

e22009 Background: Lung cancer is the leading cause of cancer deaths in the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Tubulin polymerization promoting protein 3 (TPPP3), a member of the TPPP family, can induce tubulin polymerization and microtubule bundling. In our previous study, it has been shown that depletion of TPPP3 by microRNA-based RNA interference inhibited cell growth, arrested cell cycles, and caused mitotic abnormalities in HeLa cells. However, the expression pattern of TPPP3 protein and its clinical significance in human NSCLC have not been well characterized to date. The purpose of this study was to explore the role of TPPP3 protein in tumorigenesis, invasion of NSCLC and the potential mechanism. Methods: Tissue microarrays from 75 NSCLC patients were immunohistochemically stained using antibody against TPPP3. Overall survival (OS) was estimated using the Kaplan-Meier method. TPPP3 protein expression in the H1299 lung cancer cells was detected by western blot. TPPP3 was interferred in H1299 cells with the siRNA or Lentiviral shRNA. After the TPPP3 was stably knocked down, cell proliferation was determined by CCK-8 and Live cell Imaging System, the migration and invasion were measured by Transwell assay, apoptosis and cell cycle was analyzed by FACS. Furthermore, we assessed tumor growth in vivo using H1299-knockdown cell xenografts in mice. Results: Patients with NSCLC expressing high levels of TPPP3 had a significantly poorer overall survival compared with those expressing low levels of TPPP3 (P=0.01). TPPP3 protein was much higher expressed by 50% in H1299 cells than A549 cells. After TPPP3 was stably knocked down in H1299 cells, cell proliferation was suppressed in vitro and in vivo, and the migration activity was decreased by transwell migration assay. Cell cycle assay by FACS demonstrated that it induced a significant G0-G1 growth arrest of H1299 cells. Furthermore, we firstly found that phosphorylated Akt (p-Akt), survivin and bcl-2 was obviously reduced in TPPP3 knockdown H1299 cells. Conclusions: TPPP3 knockdown in H1299 cells attenuates the tumor proliferating and migrating effects and could become a promising target for cancer therapy.
Toca 511 and Toca FC in patients with gastrointestinal tumors in the Toca 6 study.
Authors: Jaime R. Merchan, Derek Ostertag, Douglas J. Jolly, Dalissa Tejera, Harry E. Gruber, Jolene Shorr
Journal: Journal of Clinical Oncology (2018)

TPS880 Background: Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to defects in innate and adaptive immune responses found in cancers that support virus replication, and the requirement for cell division for virus integration into the genome. Toca 511 spreads through tumors, stably delivering an optimized cytosine deaminase (CD) gene that converts the prodrug, Toca FC (investigational, extended-release 5-FC) into 5-FU. 5-FU kills infected dividing cancer cells and diffuses and kills surrounding cancer cells, myeloid derived suppressor cells, and tumor associated macrophages, thus reestablishing tumor immunity (Cloughesy et al. Neuro Oncol 2016). In a Phase 1 study, resected high grade glioma tumors expressed CD protein following intravenous (IV) Toca 511. 1 In animal models of metastatic colorectal cancer, IV Toca 511 infected metastatic sites, and subsequent 5-FC treatment resulted in decreased tumor size and improved survival (Yagiz et al. Mol Therapy 2015). Methods: Toca 6 is a Phase 1b, multicenter, open-label study (NCT02576665) that aims to investigate changes in immune activity after treatment with Toca 511 &amp; Toca FC in patients with solid tumors, including gastrointestinal tumors. A total of 30 patients who have advanced malignancies, including colorectal and pancreatic cancer, with molecular characteristics that may increase sensitivity to 5-FU or viral infection, or IDH1 mutated solid tumors (e.g., intrahepatic cholangiocarcinoma) will be enrolled. In these patients, Toca 511 is injected IV daily for 3 days, then intratumorally after biopsy. Oral Toca FC is started ~4 weeks later and repeated every 4-6 weeks. Changes from baseline in intratumoral immune activity (infiltrating T-cell subpopulations, B cells, monocytes) at 4 weeks after start of Toca FC are assessed. Contemporaneous peripheral blood is analyzed for effector, memory, Treg, and myeloid lineage cells. Viral RNA, DNA, and CD protein expression in tumor after IV Toca 511 are measured. Safety and efficacy will be determined. Concomitant checkpoint inhibitor therapy may be given following immune activity assessments. The study has enrolled 3 patients. Clinical trial information: NCT02576665.
Abstract 21353: Ccn5 Gene Therapy Suppresses Arrhythmias by Reversing Fibrosis in Mice With Chronic Angiotensin II Infusion
Authors: Nour Raad, Dongtak Jeong, Woo Jin Park, Fadi G Akar
Journal: Circulation (2017)

Background: Increased angiotensin II (ANG) levels elicit profibrotic effects which promote ventricular tachyarrhythmias (VT). Hypothesis: Gene delivery of the matricellular protein CCN5 ameliorates ANG related VT by reversing fibrosis. Methods: 8-10 wk old mice underwent ANG infusion (3mg/Kg/d) for 2wk after which they received 5E11 drp AAV9.CCN5 (ANGII+CCN5, n=8) or empty vector (ANGII, n=8) and were maintained for another 2wk. Optical mapping was performed in hearts that were challenged with right atrial (RA) burst trains (20Hz, 5-20 sec) to determine VT propensity. Fibrosis was assessed using trichrome staining. Results: VT was induced in 6/8 ANG, 2/8 ANG+CCN5, and 1/3 control hearts. A total of 34 trains elicited 13 VT episodes (38.4% rate) in ANG whereas 150 trains yielded only 6 episodes in ANG+CCN5 (4.0%). ANG increased the transepicardial APD gradient by causing selective APD prolongation on the RV side which was partially reversed by CCN5. No differences in the APD gradient were found between VT (+) and VT (-) hearts. Activation mapping revealed fixed lines of conduction block leading to onset of VT in ANG hearts. In contrast, RA trains caused shifting ventricular activation patterns that were normalized following the train in ANG+CCN5 (Fig). Extensive fibrotic lesions in ANG were reversed by CCN5 (Fig). Conclusions: Reversal of fibrosis by chronic CCN5 gene therapy suppresses the incidence of ANG related VT.