tbuckley/cabot-search huggingface dataset:
Gemcitabine/docetaxel for metastatic or locally advanced soft tissue sarcoma: A retrospective single-center experience.
Authors: Gerlinde Egerer, Patrick Wuchter, Sascha Dietrich, Johann Wilhelm Schmier, Anthony D Ho, Thomas Schmitt
Journal: Journal of Clinical Oncology (2012)

10040 Background: Soft tissue sarcoma (STS) represent a group of rare malignant tumors. Survival for patients with disseminated disease is dismal. Gemcitabine/docetaxel (GD) is a commonly used systemic 2°-line regime in this setting. Methods: Here we report on our single center experience of GD (G 900 mg/m² or 675 mg/m² d1+8 and D 100 mg/m² d8) in STS. Patients were retrospectively analysed. Restaging according to RECIST criteria of primary tumor site and metastases was performed every 3 cycles or on clinical progression. Progression-free (PFS) and overall survival (OS) were estimated using the method of Kaplan and Meier. Results: Between 2005 and 2011, 34 STS patients (male=20, female=14, median age 59 years [range 32-75]) were treated with GD at our institution. Histological subtypes comprised leiomyo- (n=13), lipo- (n=7), pleomorphic- (n=6), rhabdomyo- (n=3), synovial sarcoma (n=2), and other subtypes (n=3) with tumor grades being G1 (n=1), G2 (n=9) and G3 (n=24). Primary tumor sites included extremities (n=19), abdomen/retroperitoneum (n=10), trunk (n=3), and others (n=2). Metastases were found in lung (n=26), soft tissue/solid organs (n=12), bone (n=8) and lymph nodes (n=5). Patients had received no (n=2), 1 (n=22), 2 (n=9) or 3 (n=1) previous lines of CTX. A total number of 158 cycles was administered with a median number of 6 cycles (range 1-6) per patient. Best response by RECIST criteria after 3 cycles of treatment was PR (n=2, 6%). Disease stabilisation (SD) was achieved in further 22 subjects, resulting in a clinical benefit rate (CBR) of 70%. Median PFS and OS for the whole population were 7.7 and 15.3 months, respectively. PFS at 6 months was 62%. Patients responding to therapy had a significantly longer median PFS with 8.6 months (p &lt;0.0001; HR 33.1) and OS with 22.5 months (p&lt;0.0001; HR 20.2). Major toxicities included hand-foot syndrome (n=10), febrile neutropenia (n=7), mucositis (n=7), oedema (n=5), hematological toxicity (n=4) and polyneuropathy (n=3), leading to dose reductions in 10 patients. Conclusions: GD is an active regimen in STS with tolerable side effects. CBR was 70% after 3 cycles. Patients achieving at least SD had a significantly prolonged PFS and OS.
High Efficiency Gene Correction in Hematopoietic Cells By Template-Free Crispr/Cas9 Genome Editing
Authors: Frank Schnütgen, Duran Sürün, Joachim Schwäble, Ana Tomasovic, Ralf Kühn, Stefan Stein, Nina Kurrle, Hubert Serve, Erhard Seifried, Harald von Melchner
Journal: Blood (2016)
Abstract IA02: Mcl-1 inhibitors for the treatment of cancer
Authors: Stephen W. Fesik
Journal: Clinical Cancer Research (2017)

Abstract Myeloid cell leukemia 1 (Mcl-1) is a member of the Bcl-2 family of proteins that is overexpressed and amplified in a wide variety of cancers and causes resistance to many chemotherapies. Although a very promising cancer target, it exerts its activity through protein-protein interactions and is very challenging to drug with small molecules. In this presentation, I will describe the discovery of picomolar Mcl-1 inhibitors using fragment-based methods and structure-based design that show promise as therapeutic agents for the treatment of heme malignancies and solid tumors. Citation Format: Stephen W. Fesik. Mcl-1 inhibitors for the treatment of cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA02.
The challenge of HCV-retreatment after DAA-failure: real-life experience advocates for caution
Authors: V. Cento, S. Barbaliscia, V.C. Di Maio, C. Masetti, C. Minichini, C.F. Magni, V. Micheli, S. Marenco, L.A. Nicolini, B. Bruzzone, Y. Troshina, C. Baiguera, C. Dentone, V. Calvaruso, S. Paolucci, M. Melis, M. Aragri, A. Bertoli, I. Lenci, S. Landonio, M. Schiavini, L. Sticchi, T. Ruggiero, E. Polilli, V. Messina, A. Pellicelli, L. Boglione, R. Cozzolongo, M. Biolato, F. Morisco, M. Siciliano, G. Parruti, G. Barbarini, A. Craxì, S. Babudieri, M. Puoti, A. Ciancio, G. Rizzardini, N. Coppola, M. Angelico, C.F. Perno, F. Ceccherini-Silberstein
Journal: Journal of Hepatology (2017)
Erratum: Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor (Nature Genetics (1996) 12 (280-287))
Authors: R. Rozmahel, M. Wilschanski, A. Matin, S. Plyte, M. Oliver, W. Auerbach, A. Moore, J. Forstner, P. Durie, J. Nadeau, C. Bear, L. C. Tsui
Journal: Nature Genetics (1996)
Acetyl-CoA carboxylase (ACC) inhibitor GS-0976 leads to suppression of hepatic de novo lipogenesis and significant improvements in MRI-PDFF, MRE, and markers of fibrosis after 12 weeks of therapy in patients with NASH
Authors: E.J. Lawitz, F. Poordad, A. Coste, N. Loo, C.S. Djedjos, B. McColgan, C. Jia, R. Xu, R.P. Myers, G.M. Subramanian, J.G. McHutchison, M.S. Middleton, C. Sirlin, E. Nyangau, M. Fitch, K. Li, M. Hellerstein
Journal: Journal of Hepatology (2017)
<sup>Non-V600</sup><i>BRAF</i> Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer
Authors: Jeremy C. Jones, Lindsay A. Renfro, Humaid O. Al-Shamsi, Alexa B. Schrock, Andrew Rankin, Ben Y. Zhang, Pashtoon M. Kasi, Jesse S. Voss, Alexis D. Leal, James Sun, Jeffrey Ross, Siraj M. Ali, Joleen M. Hubbard, Benjamin R. Kipp, Robert R. McWilliams, Scott Kopetz, Robert A. Wolff, Axel Grothey
Journal: Journal of Clinical Oncology (2017)

Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer (CRC). Expanded mutational testing, such as next-generation sequencing (NGS), often identifies mutations with unclear clinical or prognostic implications. One such example is BRAF mutations that occur outside of codon 600 (non-V600 BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of non-V600 BRAF mutations in metastatic CRC. We pooled patients in whom non-V600 BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories. Results A total of 9,643 patients with metastatic CRC underwent NGS testing. We identified 208 patients with non-V600 BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with non-V600 BRAF mutations, compared with cancers with V600E BRAF (V600E BRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, non-V600 BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P < .001). Conclusion Non-V600 BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.
Activation of proinflammatory citokines is involved in muscle wasting in mice model of carbon tetrachloride induced liver cirrhosis
Authors: M. Giusto, L. Barberi, F. Di Sario, E. Rizzuto, C. Nicoletti, F. Ascenzi, A. Renzi, N. Caporaso, G. D’Argenio, E. Gaudio, A. Musarò, M. Merli
Journal: Journal of Hepatology (2017)
Abstract A05: An in vivo model reveals a role for Argonaute 2 in oncogenic KRAS driven pancreatic cancer initiation
Authors: Sunita Shankar, Jean Tien, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Arul M. Chinnaiyan
Journal: Cancer Research (2017)

Abstract Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we recently identified an interaction between RAS and Argonaute 2 (AGO2), the core component of the RNA silencing machinery exerting translational control of mRNA transcripts. RAS and AGO2 co-sediment and co-localize in intracellular endomembrane bound organelles. The AGO2 N-terminal domain directly binds the KRAS Switch II region, irrespective of GDP/GTP bound to RAS. Functionally, we observed that AGO2 was required for maximal oncogenic KRAS levels and AGO2 knock-down attenuates cell proliferation in mutant KRAS-dependent cells. Intriguingly, AGO2 mediated microRNA processing (RISC activity) was attenuated in cancer cells expressing mutant KRAS compared to those expressing wild type RAS. Yet, these initial investigations using cell line models do not reveal a clear role for AGO2 in KRAS driven oncogenesis. Therefore, we probed the role of AGO2 in the well-established pancreatic ductal adenocarcinoma (PDAC) mouse model driven by oncogenic KRAS. Towards this end, we generated LSL-KrasG12D; Pft1a Cre; AGO2flox/flox (KCA) mice. Preliminary analysis (8-10 weeks of age) suggests that compared to LSL-KRASG12D (KC) mice, homozygous loss of AGO2 results in increased KRAS driven Acinar to Ductal Metaplasia (ADM) phenotype considered as precursors of PanIN (pancreatic intraepithelial neoplasia) and PDAC. This mirrors the phenotype of loss of Dicer, another microRNA processing enzyme, in the same model further reinforcing a role for microRNAs in restraining KRAS oncogenic programs. Yet unlike Dicer, loss of AGO2 alone did not cause any gross or histological changes in the development of the mouse pancreata. In an effort to understand the underlying mechanisms that are regulated by AGO2, we also studied the activated levels of a variety of signaling molecules in pancreata obtained from different genotypes. Using both Western blot and Immunohistochemical analyses, we demonstrate a previously unknown and critical role for AGO2 in KRAS-MAPK signaling pathway. Together our data from the in vivo mouse model suggests that AGO2 is an important regulator of KRAS signaling and oncogenic KRAS alters the translational machinery through its interaction with AGO2. Citation Format: Sunita Shankar, Jean Tien, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Arul M. Chinnaiyan. An in vivo model reveals a role for Argonaute 2 in oncogenic KRAS driven pancreatic cancer initiation. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A05.
<i>hSRBC</i> promoter CpG island hypermethylation as resistant predictive biomarker of oxaliplatin based chemotherapy in metastasic colorectal cancer patients.
Authors: Catia Moutinho, Anna Martinez-Cardus, Cristina Santos, Valentín Navarro-Perez, Eva Martinez-Balibrea, Albert Abad Esteve, Ramon Salazar, Manel Esteller
Journal: Journal of Clinical Oncology (2013)

e14609 Background: Resistance acquisition to chemotherapeutic agents is one of the main problems that come up during cancer treatment. hSRBC is a tumor suppressor gene whose inactivation has been associated with malignant tumor progression. In a previous work, we investigated the influence of hSRBC promoter methylation alterations in oxaliplatin (OXA) resistance acquisition by using a CRC “in vitro” model, detecting an hSRBC promoter hypermethylation in OXA–resistant derived cells when compared with the sensitive counterpart. These results were validated by functional analyses in the same model. Taking this into account, our aim in the present work is to determine the role of hSRBC methylation status as a potential biomarker of OXA resistance, in metastatic CRC patients, treated at first line with fluouropirimidines plus OXA based chemotherapy. Methods: hSRBC promoter hypermethylation was analyzed in DNA extracted from paraffin embebbed tissue of 111 metastatic CRC tumors by using Methylation Specific PCR. Methylation data was correlated to overall response (OR) and progression free survival (PFS) by using F-Fisher test and Kaplan-Meyer Survival curves respectively. A multivariate analysis was carried out by Cox regression. p-values under 0.05 were considered statistic significant. Results: Two independent cohorts of stage IV CRC tumors were included. Twenty-two out of 111 patients received radical surgery for metastasis, that became to be a positive prognostic factor (p-value = 0.04). Gene hypermethylation was detected in a 33% of cases. Although OR was not associated with hSRBC methylation, we observed a significant correlation between hypermethylation of gene and a worse PFS in patients without metastasis surgery (Log Rank; p-value = 0.04). Conclusions: Remarkably, hSRBC promoter hypermethylation is associated with worse PFS in metastatic CRC patients. We suggest hSRBC methylation status as a predictive biomarker of OXA-based treatment outcome in metastatic CRC patients. However, further studies are warranted in order to elucidate the clinical application of these findings.
Efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin (RBV) in hepatitis C virus genotype 1- infected patients with compensated cirrhosis and multiple comorbidities
Authors: R.C. Popa, C. Mihai, A. Trifan, C. Stanciu, L. Gheorghe, S. Iacob, V. Arama, I. Rogoveanu, M. Diculescu, A. Goldis, S. Bataga, A. Seicean, L. Sandulescu, R. Nastase, V. Molagic, C. Brisc, M. Curescu, C.C. Prelipcean
Journal: Journal of Hepatology (2017)
INCLUDING THE COPENHAGEN ADDUCTION EXERCISE IN THE FIFA 11+ PROVIDES MISSING ECCENTRIC HIP ADDUCTION STRENGTH EFFECT: A RANDOMISED CONTROLLED TRIAL
Authors: Joar Harøy, Kristian Thorborg, Per Hölmich, Andreas Serner, André Bjørkheim, Linn E Rolstad, Roald Bahr, Thor Einar Andersen
Journal: British Journal of Sports Medicine (2017)

Background The FIFA 11+ was developed as a complete warm-up programme to prevent injuries in football players. Although reduced hip adduction strength is associated with groin injuries, none of the exercises included in the FIFA 11+ specifically target hip adduction strength. Objective To investigate the effect on eccentric hip adduction strength of the FIFA 11+ warm-up programme with or without the Copenhagen Adduction exercise. Design Randomised controlled trial. Setting U19 elite male football teams. Participants We recruited 45 eligible players from two teams. Per-protocol analyses were performed, with 12 players excluded due to low compliance (&lt;67% of sessions completed). Interventions Players were randomized into two groups; one group was asked to carry out the standard FIFA 11+ program, while another group was asked to carry out the FIFA 11+, but to replace the Nordic Hamstring exercise with the Copenhagen Adduction exercise. Both groups performed the intervention three times weekly for 8 weeks. Players completed eccentric strength and sprint testing before and after the intervention. Main Outcome Measurements Eccentric hip adduction strength (Nm/kg). Results Between-group analyses showed that there was a significant difference in the change in eccentric hip adduction strength of 0.32 Nm/kg (10.1%) (p=0.006) on the left side and 0.24 Nm/kg (7.2%) (p=0.046) on the right side in favour of the group performing the Copenhagen Adduction exercise. There was no within-group change in eccentric hip adduction strength in the group that did not perform the Copenhagen adduction exercise (left side: −0.03 Nm/kg (−0.8%) p=0.79, right side: −0.02 Nm/kg (−0.7%) p=0.78). Conclusions Including the Copenhagen Adduction exercise to the FIFA 11+ programme increases eccentric hip adduction strength, while the standard FIFA 11+ programme does not. We therefore suggest adding the Copenhagen Adduction exercise to the FIFA 11+ to potentially prevent groin problems.
An open-label single-arm, phase II trial of zalutumumab, a human monoclonal anti-EGFR antibody, in patients with platinum-refractory squamous cell carcinoma of the head and neck.
Authors: Vassiliki Saloura, Ezra E.W. Cohen, Lisa F. Licitra, Salem Billan, Jose Dinis, Steen Lisby, Thomas Christoph Gauler
Journal: Journal of Clinical Oncology (2013)

6065 Background: Treatment for patients with platinum-refractory metastatic squamous cell carcinoma of the head and neck (SCCHN) is limited. Cetuximab has been approved in the US in this patient population based on a phase II trial that demonstrated 13% response rate (RR) and 5.9 months median OS. A recently conducted phase III trial of zalutumumab, a human monoclonal IgG1k antibody against EGFR, versus best supportive care showed significant increase in PFS. Here, we present the results of a companion phase II trial in the same patient population. Methods: Patients with platinum-refractory recurrent or metastatic SCCHN received weekly infusions of zalutumumab starting at a loading dose of 8mg/kg. The dose was then reduced to 4mg/kg and individually titrated by increments of 4mg/kg every 2 weeks based on skin rash evaluation up to a maximum of 16mg/kg aiming at a grade 2 skin rash. Primary objective was OS. The analysis was based on the intent-to-treat principle and OS was estimated using the Kaplan-Meier method. Results: Between January 2008 till August 2011 90 patients were enrolled in 57 centers in the United States, Europe and South America. 23% of patients had WHO PS 2 and 74% had distant relapse metastases. Grade 3-4 adverse events (AEs) related to zalutumumab were observed in 19% of the patients and included skin rash (5%), hypomagnesemia (4%) and pneumonitis (1%). Infusion-related reactions occurred in 33% of patients. The frequency of all-cause grade 3-4 AEs was 62% and included infections (14%), gastrointestinal disorders (12%), hypokalemia (6%), dyspnea (9%) and anemia (6%). Two deaths secondary to cardiac arrest in a patient with history of myocardial infarction, and respiratory acidosis in a patient with a pleural effusion and hypomagnesemia were deemed related to zalutumumab. CR was observed in one (1%) patient and PR in four (5%) patients. The median PFS was 8.6 weeks (95% CI [8.0, 10.4]) and the estimated median OS was 5.3 months (95% CI [4.1, 7.1]). Conclusions: Zalutumumab showed reasonable efficacy in platinum-refractory recurrent or metastatic SCCHN patients and dosing titration based on skin rash evaluation was feasible. Clinical trial information: NCT00542308.
Coronary Plaque Characterization in Psoriasis Reveals High-Risk Features That Improve After Treatment in a Prospective Observational Study
Authors: Joseph B. Lerman, Aditya A. Joshi, Abhishek Chaturvedi, Tsion M. Aberra, Amit K. Dey, Justin A. Rodante, Taufiq Salahuddin, Jonathan H. Chung, Anshuma Rana, Heather L. Teague, Jashin J. Wu, Martin P. Playford, Benjamin A. Lockshin, Marcus Y. Chen, Veit Sandfort, David A. Bluemke, Nehal N. Mehta
Journal: Circulation (2017)

Background: Psoriasis, a chronic inflammatory disease associated with an accelerated risk of myocardial infarction, provides an ideal human model to study inflammatory atherogenesis in vivo. We hypothesized that the increased cardiovascular risk observed in psoriasis would be partially attributable to an elevated subclinical coronary artery disease burden composed of noncalcified plaques with high-risk features. However, inadequate efforts have been made to directly measure coronary artery disease in this vulnerable population. As such, we sought to compare total coronary plaque burden and noncalcified coronary plaque burden (NCB) and high-risk plaque (HRP) prevalence between patients with psoriasis (n=105), patients with hyperlipidemia eligible for statin therapy under National Cholesterol Education Program-Adult Treatment Panel III guidelines (n=100) who were ≈10 years older, and healthy volunteers without psoriasis (n=25). Methods: Patients underwent coronary computed-tomography angiography for total coronary plaque burden and NCB quantification and HRP identification, defined as low attenuation (&lt;30 hounsfield units), positive remodeling (&gt;1.10), and spotty calcification. A consecutive sample of the first 50 patients with psoriasis was scanned again 1 year after therapy. Results: Despite being younger and at lower traditional risk than patients with hyperlipidemia, patients with psoriasis had increased NCB (mean±SD: 1.18±0.33 versus 1.11±0.32, P =0.02) and similar HRP prevalence ( P =0.58). Furthermore, compared to healthy volunteers, patients with psoriasis had increased total coronary plaque burden (1.22±0.31 versus 1.04±0.22, P =0.001), NCB (1.18±0.33 versus 1.03±0.21, P =0.004), and HRP prevalence beyond traditional risk (odds ratio, 6.0; 95% confidence interval, 1.1–31.7; P =0.03). Last, among patients with psoriasis followed for 1 year, improvement in psoriasis severity was associated with improvement in total coronary plaque burden (β=0.45, 0.23–0.67; P &lt;0.001) and NCB (β=0.53, 0.32–0.74; P &lt;0.001) beyond traditional risk factors. Conclusions: Patients with psoriasis had greater NCB and increased HRP prevalence than healthy volunteers. In addition, patients with psoriasis had elevated NCB and equivalent HRP prevalence as older patients with hyperlipidemia. Last, modulation of target organ inflammation (eg, skin) was associated with an improvement in NCB at 1 year, suggesting that control of remote sites of inflammation may translate into reduced coronary artery disease risk.
Blood-test based assessment of liver fibrosis, but not transient elastography, is less accurate in NAFLD patients of South Asian compared to White ethnicity
Authors: S. De Silva, W. Li, P. Kemos, J.H. Brindley, R. Feakins, J. Chinaleong, S. Samsuddin, G.R. Foster, W.K. Syn, W. Alazawi
Journal: Journal of Hepatology (2017)
Red meat consumption is linked to higher risk of death from most major causes
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Eating red meat increases the likelihood of dying from most major causes while eating white meat instead reduces the risk, a cohort study of more than half a million people published in The BMJ suggests.1

The chances of dying from cancer, heart disease, respiratory disease, stroke, diabetes, infections, kidney disease, or liver disease all increased in line with red meat consumption. The only protective effect of eating red meat was on the risk of dying from Alzheimer’s disease, although the researchers said that it was difficult to draw conclusions from this finding because of the complicated relation between diet and dementia.

The strongest association with red meat …
Effect of metformin on the effects of TKI on human lung carcinoma cells harboring KRAS or EGFR-T790M mutation.
Authors: Yongsheng Wang, Yu Ma, Dan Li, Fuchun Guo
Journal: Journal of Clinical Oncology (2012)

e18051 Background: K-ras and egfr-T790M mutation show primary and acquired resistance to EGFR-TKI in non-small cell lung cancer, respectively. The antidiabetic drug metformin has been associated with a decreased incidence and a better prognosis of lung cancer. The affects of metformin on the EGFR-TKI resistance in non-small cell lung cancer remain unknown. Methods: The effects of metformin on EGFR-TKI were investigated in k-ras mutant A549 cells, and egfr-T790M mutant H1975 cells both in virto and in vivo. The proliferation and apoptosis were tested. The underlying mechanisms were also analyzed. Results: Our data showed metformin significantly enhanced the inhibition activity of gefitinib both in A549 and H1975 cells in vitro. At the molecular level, metformin inhibited multiple signaling including LKB1-AMPK-S6K, PI3K-AKT and Raf-MEK-MAPK in a dose-dependent manner. Furthermore, the increased tumor inhibitions were observed in nude mice models of A549 (P&lt;0.05)and H1975 (P&lt;0.01). Conclusions: Metformin can increase the effects of EGFR-TKI in lung adenocarcinoma harboring K-ras and egfr-T790M mutation. Our study may provide a new strategy to overcome the EGFR-TKI resistance in NSCLC.