tbuckley/cabot-search huggingface dataset:
Phenformin-induced mitochondrial dysfunction sensitizes hepatocellular carcinoma for dual inhibition of mTOR
Authors: S. Veiga, X. Ge, C. Mercer, M. Hernández-Álvarez, H. Thomas, J. Hernandez-Losa, S.R.Y Cajal, A. Zorzano, G. Thomas, S. Kozma
Journal: Annals of Oncology (2018)

Introduction: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mammalian target of rapamycin (mTOR) for the treatment of HCC. However, such inhibitors induce glycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor Phenformin could reverse both side effects, impose an energetic-stress on cancer cells and suppress HCC growth. Methods: Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and Phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated pre-clinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival. Results: We found Phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with Phenformin, was highly efficacious in controlling tumor burden. However, more striking, pretreatment with Phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival. Conclusion: Treatment of HCC cells in vitro with the biguanide Phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC.
Expansion of allogeneic NK cells with efficient antibody-dependent cell cytotoxicity against multiple tumors
Authors: Diego Sanchez-Martinez, Nerea Allende-Vega, Stefania Orecchioni, Giovanna Talarico, Amelie Cornillon, Dang-Nghiem Vo, Celine Rene, Zhao-Yang Lu, Ewelina Krzywinska, Alberto Anel, Eva M. Galvez, Julian Pardo, Bruno Robert, Pierre Martineau, Yosr Hicheri, Francesco Bertolini, Guillaume Cartron, Martin Villalba
Journal: Theranostics (2018)

Monoclonal antibodies (mAbs) have significantly improved the treatment of certain cancers.However, in general mAbs alone have limited clinical activity.One of their main mechanisms of action is to induce antibody-dependent cell-mediated cytotoxicity (ADCC), which is mediated by natural killer (NK) cells.However, most cancer patients present severe immune dysfunctions affecting NK activity.This could be circumvented by the injection of allogeneic, expanded, NK cells, which is safe.Nevertheless, despite the strong cytolytic potential of expanded NK cells against different tumors, clinical results have been poor.Methods: We thus propose the combination of allogeneic NK cells and mAbs to improve cancer treatment.We generated expanded NK cells (e-NK) with strong in vitro and in vivo ADCC response against different tumors and mediated by different therapeutic mAbs, i.e. rituximab, obinutuzumab, daratumumab, cetuximab and trastuzumab.Results: Remarkably, e-NK cells can be stored frozen and after thawing armed with mAbs.They mediate ADCC through degranulation dependent and independent mechanisms.Furthermore, they overcome some of the anti-apoptotic mechanism found in leukemic cells.Conclusion: In summary, we have established a new protocol for activation/expansion of NK cells with high ADCC activity.The use of mAbs in combination with e-NK cells could potentially improve cancer treatment.
MBCL-33. HEPATOTOXICITY DURING INDUCTION CHEMOTHERAPY, WITH OR WITHOUT HIGH-DOSE METHOTREXATE (HD-MTX), ON THE HEAD START II TRIAL FOR PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Mohammad H Abu Arja, Lubna S Mehyar, Diana S Osorio, Scott Coven, Sharon Gardner, Jonathan L Finlay
Journal: Neuro-Oncology (2018)

The incidence of hepatotoxicity has never been reported for intensive induction chemotherapy regimens for young children with primary malignant CNS tumors. We report our comprehensive review of available data on patients enrolled on the Head Start II trial 1997-2003. Retrospective chart review of patients enrolled on Head Start II (n=90); Patients with non-metastatic disease other than ATRT as the primary diagnosis (n=49) received Induction without HD-MTX. The rest received HD-MTX (age-based; 400mg/Kg or 12mg/m2); Peak serum ALT, AST and bilirubin were recorded for each cycle, as well as cycle days on which the peak levels were recorded. Additionally, all grade III/IV toxicities, including clinical sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were documented. Forty-one patients received 156 Induction cycles including HD-MTX; 53 patients received 237 Induction cycles without HD-MTX. Among patients in whom test results were available, grades III/IV elevations in ALT, AST and bilirubin were recorded in 5%, 7% and 10% of HD-MTX containing cycles respectively, whereas in 3%, 0.5% and 1% of Induction cycles without HD-MTX. Timing of mean peak elevations of ALT, AST and bilirubin did not differ among patients receiving or not receiving HD-MTX Induction cycles. There were no documented reports of grades III/IV SOS/VOD. There were no permanent or severe hepatotoxicities reported during Induction chemotherapy; however, peak transaminases were higher for patients receiving HD-MTX. These data provide a baseline from which to evaluate hepatotoxicity and incidence of SOS/VOD in the current Head Start 4 trial in which all patients received HD-MTX during Induction.
Cembrane-type diterpenoids from the South China Sea soft coral Sarcophyton mililatensis
Authors: Songwei Li, Fei Ye, Zhengdan Zhu, Hui Huang, Shuichun Mao, Yuewei Guo
Journal: Acta Pharmaceutica Sinica B (2018)

Eight cembrane-type diterpenoids, namely, (+)-(6R)-6-hydroxyisosarcophytoxide (1), (+)-(6R)-6-acetoxyisosarcophytoxide (2), (+)-17-hydroxyisosarcophytoxide (3), sarcomililatins A-D (4-7), and sarcomililatol (8), were isolated from the soft coral Sarcophyton mililatensis collected from Weizhou Island, Guangxi Autonomous Region, together with 2 known related analogues, (+)-isosarcophytoxide (9) and (+)-isosarcophine (10). The structures of these compounds were elucidated by a combination of detailed spectroscopic analyses, chemical methods, and comparison with reported data. The absolute configuration of compound 1 was established by the modified Mosher׳s method, while the absolute configurations of compounds 4 and 5 were assigned by electronic circular dichroism (ECD) spectroscopy and that of compound 8 was established by time-dependent density functional theory electronic circular dichroism (TD-DFT ECD) calculation. In in vitro bioassays, compound 9 displayed significant cytotoxicity against the human cancer cell lines human promyelocytic leukemia cells (HL-60) and human lung adenocarcinoma cells (A-549) with IC50 values of 0.78±0.21 and 1.26±0.80 μmol/L, respectively. Compounds 4 and 9 also showed moderate inhibitory effects on the TNFα-induced Nuclear factor kappa B (NF-κB, a therapeutical target in cancer) activation, showing IC50 values of 35.23±12.42 and 22.52±4.44 μmol/L, respectively.
Combination of Asiatic Acid and Naringenin Modulates NK Cell Anti-cancer Immunity by Rebalancing Smad3/Smad7 Signaling
Authors: Guang-Yu Lian, Qing-Ming Wang, Patrick Ming-Kuen Tang, Shuang Zhou, Xiao-Ru Huang, Hui-Yao Lan
Journal: Molecular Therapy (2018)

Transforming growth factor β1 (TGF-β1) plays a promoting role in tumor growth via a mechanism associated with hyperactive Smad3 and suppressed Smad7 signaling in the tumor microenvironment. We report that retrieving the balance between Smad3 and Smad7 signaling with asiatic acid (AA, a Smad7 inducer) and naringenin (NG, a Smad3 inhibitor) effectively inhibited tumor progression in mouse models of invasive melanoma (B16F10) and lung carcinoma (LLC) by promoting natural killer (NK) cell development and cytotoxicity against cancer. Mechanistically, we found that Smad3 physically bound Id2 and IRF2 to suppress NK cell production and NK cell-mediated cytotoxicity against cancer. Treatment with AA and NG greatly inhibited Smad3 translation and phosphorylation while it restored Smad7 expression, and, therefore, it largely promoted NK cell differentiation, maturation, and cytotoxicity against cancer via Id2/IRF2-associated mechanisms. In contrast, silencing Id2 or IRF2 blunted the protective effects of AA and NG on NK cell-dependent anti-cancer activities. Thus, treatment with AA and NG produced an additive effect on inactivating TGF-β1/Smad3 signaling, and, therefore, it suppressed melanoma and lung carcinoma growth by promoting NK cell immunity against cancer via a mechanism associated with Id2 and IRF2.
Simplified versus standard regimen for focal radiofrequency ablation of dysplastic Barrett's oesophagus: a multicentre randomised controlled trial
Authors: Roos E Pouw, Hannah T Künzli, Raf Bisschops, Carine M Sondermeijer, Arjun D Koch, Paul Didden, Anniek W Gotink, Erik J Schoon, Wouter L Curvers, Jacques J G H M Bergman, Bas L A M Weusten
Journal: The Lancet. Gastroenterology & hepatology (2018)
Radiation therapy in locally distributed inoperable cancer of the stomach without the symptoms of obstruction
Authors: S. Lukmonov, O. Usmanov, K. Madatov, M. Ismailov, U. Kurbankulov, U. Allazarov
Journal: Annals of Oncology (2018)

Introduction: To assess the overall survival (OS) of patients with "asymptomatic" LAIGC in the groups of CRT and CT according to a randomized study. Methods: Patients with LAIGC without signs and threats of dysphagia were selected from a randomized study aimed at comparing chemoradiation (CRT) and chemotherapy (СT), from 2015 to 2017 on the basis of the Department of Oncology and Radiology of the Tashkent Medical Academy. Twenty-nine patients with LAIGC with tumors localized in the body and antrum sections of the stomach were selected: 15 of them received CRT, 14 - HT. In the CRT group, treatment was started with a remote radiation therapy, which was carried out from two counter figured fields in the traditional fractionation mode to a total dose of 50-64 Gy. Chemotherapy included cisplatin 100 mg/m 2 per day + 5-fluorouracil 1000 mg/m 2 24-hour infusion from 1 to 5 days, every 28 days, 4-6 courses. Overall survival was assessed by the Kaplan-Mayer method using a log-rank test. The relationship between the risk of death in a single-factor and multivariate analysis was calculated using Cox's regression. All calculations were carried out using the statistical software package Stata 13.0 (College Station, Texas 77845 USA). Results: Treatment groups were well balanced by baseline characteristics. In the distribution by sex, age, ECOG status, the severity of the concomitant pathology, trial laparotomy, gastroenteroanastomosis, the size of the primary tumor, lymph node involvement, stage of the process, tumor localization, histological variant, no statistically significant differences were found. At the time of analysis, the median time of follow-up was 52.0 (standard deviation, SD 6.9) months, 25 patients died. All four living patients - from the group of CRT (3 with localization of the tumor in the body of the stomach). Median OS, 1-and 3-year OS were 13 (95% confidence interval (CI) 4-20) vs. 20 (95% CI 7-43) months, 57% (95% CI 28-78%) vs. 80% (95% CI 50-93%) and 0% vs. 33% (95% CI 12-56%), log rank χ2 = 4.7, p = 0.029 in the CT and CRT groups, respectively. The ratio of the risk (RR) of death from any cause with the use of CRT was reduced to 0.39 (95% CI 0.17-0.94). Conclusion: Adding RT to the standard used for LAIGC of chemotherapy leads to an improvement in the overall survival of patients in the absence of symptoms of dysphagia. A small number of observations, however, does not allow to consider the advantage of CRT as proven and requires more observations in phase III of the randomized trial. The reserves of improving the effectiveness of treatment are conformal irradiation techniques and simultaneous CRT.
HGG-09. DECISION MAKING IN THE FACE OF INCURABLE HIGH GRADE GLIOMAS: A QUALITATIVE ANALYSIS
Authors: Ashley F Lanzel, Katharine E Brock, Abby R Rosenberg, Justin N Baker, Amy E Caruso Brown, Ann Mertens, Rebecca Pentz, Karen Wasilewski-Masker
Journal: Neuro-Oncology (2018)

For children/young adults with incurable high grade gliomas (HGGs), oncologists strive to align therapy with goals of care. Ethical challenges can arise around decision making for care. Qualitatively evaluate factors impacting longitudinal decision making for patients with HGGs, their families and oncologists. English-speaking patients ages 0-21 with diffuse intrinsic pontine glioma, glioblastoma multiforme, or secondary HGG were eligible. Key decision making visits (e.g. MRI reviews) and patient/parent semi-structured interviews were serially audio-recorded. Oncologist questionnaires were obtained. Transcribed audio-recordings were coded with inter-rater reliability assessment. Constant comparison analysis continued with MAXQDA until thematic saturation. Of 34 eligible patients, 22 were approached; 15 participated; 1 withdrew upon transferring care. Mean age: 9.9 years (SD 5.9); 71% male, 50% Caucasian, 29% African American, 14% Hispanic, and 7% Asian. On average, 4 encounters (2.5 hours)/patient were recorded. Parent/patient interview themes included: 1) hope (for cure, time, quality of life), 2) physician recommendations, 3) support systems (family, community, social media), 4) food (as cancer etiology, intervention) 5) finances (personal, research funding), 6) communication (with providers, family, community), 7) death, and 8) God (beliefs, prayer, existential questions). Oncologists desired prolonged quality of life, while patients/families transitioned to that hope from hope for a cure. Decisions are multifactorial for patients with HGGs as families balance optimism about treatment efficacy with poor prognosis. Acknowledging families’ shifting hopes allows for changes in goals and shared decision making.
Estimating the probability of OSA in the spinal cord injury population: specific tools are still needed
Authors: Dan Adler, Jean-Paul Janssens
Journal: Thorax (2018)

Patients with high spinal cord injury (SCI) and tetraplegia have a remarkably high prevalence of sleep-disordered breathing (SDB). Most reports describe obstructive sleep apnoeas (OSAs) and hypopnoeas in this population.1 2 OSA impairs health-related quality of life (HRQL) in tetraplegic subjects and is associated with cognitive dysfunction, with repercussions mainly on attention, concentration, memory and learning skills.3 4 Changes in upper airways (UA) in SCI may increase the risk of OSA syndrome (OSAS): increased passive UA collapsibility,5 greater volume of soft palate and lateral pharyngeal walls, increased nasal resistance and nasal congestion.6 7 Breathing at lower volumes may also contribute to the higher prevalence of OSAS in this population.2 8 Coexistent traumatic brain injury, sleep position and medication (opioids, baclofen and benzodiazepines) can affect breathing during sleep with an additional burden of central events9 or nocturnal hypoventilation. It is quite possible that central events are underestimated in available publications because hypopnoeas are most often not specified as being central or obstructive as proposed by the American Academy of Sleep Medicine (AASM) 2012 guidelines.10 Despite the high prevalence of SDB and SDB-related symptoms in SCI, adherence to Continuous Positive Airways Pressure (CPAP) is poor: symptomatic patients treated with SDB by CPAP have a long-term adherence to treatment of 50%–63%.2

Polysomnography (PSG) is the gold standard for the diagnosis of OSA. However, transportation of the patient for in-laboratory PSG may be as complicated as providing unattended portable PSG in a long-term facility. Providing a simple pragmatic alternative to PSG was therefore the main goal for the study by Graco and colleagues published in  Thorax .11 The authors describe the performance of a disease-specific two-stage screening tool for moderate to severe OSAS (defined as apnea-hypopnea index (AHI) >21/hour) in tetraplegic patients with SCI, developed using an existing database of …
Motivation to Participate in PTSD Research
Authors: Walton T. Roth, Stefan G. Hofmann
Journal: JAMA (2018)

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Afatinib restrains K-RAS–driven lung tumorigenesis
Authors: Herwig P. Moll, Klemens Pranz, Monica Musteanu, Beatrice Grabner, Natascha Hruschka, Julian Mohrherr, Petra Aigner, Patricia Stiedl, Luka Brcic, Viktoria Laszlo, Daniel Schramek, Richard Moriggl, Robert Eferl, Judit Moldvay, Katalin Dezso, Pedro P. Lopez-Casas, Dagmar Stoiber, Manuel Hidalgo, Josef Penninger, Maria Sibilia, Balázs Győrffy, Mariano Barbacid, Balázs Dome, Helmut Popper, Emilio Casanova
Journal: Science Translational Medicine (2018)

K-RAS –mutated lung adenocarcinomas depend on ERBB signaling, and pan-ERBB inhibitors impair K-RAS–driven lung tumorigenesis.
Feedback-informed treatment versus usual psychological treatment for depression and anxiety: a multisite, open-label, cluster randomised controlled trial
Authors: Jaime Delgadillo, Kim de Jong, Mike Lucock, Wolfgang Lutz, Julian Rubel, Simon Gilbody, Shehzad Ali, Elisa Aguirre, Mark Appleton, Jacqueline Nevin, Harry O'Hayon, Ushma Patel, Andrew Sainty, Peter Spencer, Dean McMillan
Journal: The Lancet Psychiatry (2018)
Comparison of prognosis after hepatic resection of hepatocellular carcinoma between intermediate stage tumor and early stage tumor
Authors: J. Arita, T. Kokudo, N. Akamatsu, J. Kaneko, T. Ishizawa, K. Hasegawa
Journal: Annals of Oncology (2018)

Introduction: Despite that patients with intermediate stage hepatocellular carcinoma (HCC), i.e., "4 or more tumors" or "2-3 tumors more than 3 cm in size" without vascular tumor thrombus or extrahepatic metastasis, are candidate for sorafenib according to the BCLC staging system, most of such patients undergo hepatic resection, transcatheter chemoembolization, or radiofrequency ablation. This mono-centric retrospective study assesses the long-term results after hepatic resection for the intermediate stage HCC comparing with that for patients with early or very early stage HCC. Methods: Patients without extrahepatic metastasis or macroscopic vascular invasion undergoing radical hepatic resection between October 1994 and December 2015 were classified into the following 4 categories. A: early or very early stage, i.e., Single tumor within 5 cm and 2-3 tumors within 3 cm, B1: Single tumor over 5 cm, B2: 2-3 tumors over 3 cm, B3: 4 or more tumors. Overall survival were compared among the 4 groups and prognostic factors were analyzed. Results: A total of 1030 patients were included. The patient number and the median ICG-R15 value were 606 Pts and 14.1% in Group A, 198 Pts and 11.1% in Group B1, 158 Pts and 14.6% in Group B2, and 68 Pts and 12.3% in Group B3. In Group A, 296 Pts had single tumor, 51 Pts had 2 tumors, and 18 Pts had 3 tumors. The median tumor size was 7.2 cm in Group B1. The median tumor size was 5.2 cm in Group B2, and 119 Pts had 2 tumors and 39 Pts had 3 tumors. The median tumor size was 3.9 cm (1-17 cm) in Group B3, and 31, 11, 7, and 19 patients had 4, 5, 6, 7 or more tumors, respectively. The 5-year OS rate of all 1030 patients was 65.1%, and those of Group A, B1, B2, B3 were 71.7%, 63.7%, 52.4%, and 36.8%, respectively. The OS of Group A was better than that of Group B1-3 (5y-OS rate: 55.2%). However, that of Group A was not significantly better than that of Group B1. On the other hand, significant difference of OS was seen between Group B1 and B2, and between Group B2 and B3. Among the patients in Group B3, who had the poorest prognosis, serum AFP value > 50 ng/mL was found as the only independent prognostic factor after multivariate analysis of OS using Cox proportional hazard model (HR = 1.93, 95%CI 1.04-3.56), and the 5-year OS rate of the patients with serum AFP value < = 50 in Group B3 was 47.3% and comparable with Group B2. Conclusion: Among patients with intermediate stage HCC, patients with single tumor over 5 cm show similarly fair prognosis. Patients with 2-3 tumors over 3 cm also show acceptable prognosis. Patients with 4 or more tumors may be candidate for hepatic resection if serum AFP value is 50 or less.
LGG-06. MODIFIED CARBOPLATIN AND VINCRISTINE CHEMOTHERAPY IN PEDIATRIC BRAIN STEM LOW-GRADE GLIOMAS
Authors: Jingjing Ge, Cheng Li, Zhimeng Gao, Fengjun Xue, Junping Zhang
Journal: Neuro-Oncology (2018)

To analyze the response and toxicity of updated carboplatin and vincristine (CV) chemotherapy regimen in pediatric low-grade gliomas (LGGs) of the brain stem. We modified the traditional CV regimen by increasing the carboplatin dose or combining with a new antiangiogenetic drug named recombinant human endostatin (rh-ES). 10 children who had low-grade gliomas (LGGs) of the brain stem and received modified CV regimen from August 2014 to August 2016 were reviewed. Carboplatin was administrated at a dose of 200~300 mg/m2 and vincristine was 1.5 mg/m2 (maximum dose of 2 mg). Three cases out of ten received modified carboplatin and vincristine combining rh-ES. 5 patients had objective response (1 had a complete response and 4 got a partial response). 2 got a minor response and 3 got stable diseases. All the patients’ diseases were effectively controlled. The median time for response was 3 (1.5-8) months. Two of three recurrent children had an objective response. All the three cases with carboplatin, vincristine and rh-ES chemotherapy regimen had objective response. Hematologic toxicity was common. The incidence of severe neutrocytopenia, decreased hemoglobin and thrombocytopenia was 8.8%, 5.3% and 1.5%, respectively. Modified CV regimen by increasing carboplatin dose or combining with a new antiangiogenetic drug of rh-ES could improve the effect of CV regimen, and would be helpful to quickly relieve the brain stem dysfunction by shortening the time for response in the pediatric newly diagnosed or recurrent brain stem LGGs. These modified regimens were relatively well tolerated.