tbuckley/cabot-search huggingface dataset:
Abstract LB-077: T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy
Authors: Patrick Raber, Rosa A. Sierra, Shuzhong Zhang, Paul Thevenot, Paulo C. Rodriguez
Journal: Cancer Research (2016)

Abstract The success of adoptive T cell-based immunotherapy (ACT) in cancer is limited in part by the accumulation of myeloid-derived suppressor cells (MDSC), which block several T cell functions, including T cell proliferation and the expression of various cytotoxic mediators. Paradoxically, the inhibition of CD8+ T cell differentiation into cytotoxic populations increased their efficacy after ACT into tumor-bearing hosts. Therefore, we aimed to test the impact of conditioning CD8+ T cells with MDSC on their differentiation potential and ACT efficacy. Our results indicate that MDSC impaired the progression of CD8+ T cells into effector populations, without altering their activation status, production of IL-2, or signaling through the T cell receptor. In addition, culture of CD8+ T cells with MDSC resulted in an increased ACT anti-tumor efficacy, which correlated with a higher frequency of the transferred T cells and elevated IFNγ production. Interestingly, activated CD62L+ CD8+ T cells were responsible for the enhanced anti-tumor activity showed by MDSC-exposed T cells. Additional results showed a decreased protein synthesis rate and lower activity of the mammalian/mechanistic target of rapamycin (mTOR) in T cells conditioned with MDSC. Silencing of the negative mTOR regulator tuberous sclerosis complex-2 in T cells co-cultured with MDSC restored mTOR activity, but resulted in T cell apoptosis. These results indicate that conditioning of T cells with MDSC induces stress survival pathways mediated by a blunted mTOR signaling, which regulated T cell differentiation and ACT efficacy. Continuation of this research will enable the development of strategies to increase ACT responses in cancer. Citation Format: Patrick Raber, Rosa A. Sierra, Shuzhong Zhang, Paul Thevenot, Paulo C. Rodriguez. T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-077.
Abstract 5230: Modulation of SF3B1 causes global intron retention and downregulation of the B-cell receptor pathway in chronic lymphocytic leukemia
Authors: Qimei Han, Jianbo Wang, Austin Y. Shull, Fang Shi, Libin Deng, Jeong-Hyeon Choi, Eun-Jeong Park, Shuo Tu, Lirong Pei, Farrukh T. Awan, Roni Bollag, Locke J. Bryan, Hong-bo Xin, Chandraiah Lagisetti, Thomas R. Webb, Victor Jin, Huidong Shi
Journal: Cancer Research (2019)

Abstract Splicing factor SF3B1 is frequently mutated in chronic lymphocytic leukemia (CLL) patients and has been suggested as a potential therapeutic target. In this study, we demonstrated that SF3B1 modulator sudemycin D6 (SD6) effectively inhibits cell growth and induces apoptosis in CLL cells. RNA sequencing analysis revealed significant increases in global intron retention in SD6-treated CLL cells. Pathway analysis of the genes associated with increased intron retention suggested that B-cell receptor (BCR) and PI3K signaling pathways were among the most important pathways being affected by SD6. The increases in intron retention were inversely correlated with decreases in mRNA and protein levels of the affected BCR/PI3K pathway molecules including BLNK, BTK, AKT, PLCγ2, and PI3Kδ. SD6 treatment also induced a time-dependent exon-skipping event in MCL-1 mRNA and resulted in significant down-regulation of another anti-apoptotic gene TRAF1, thus collectively contributing to the SD6-induced apoptosis. Furthermore, SD6 treatment can overcome the pro-survival and pro-growth signals and synergize with established CLL therapies ibrutinib, idelalisib, and venetoclax to induce apoptosis in primary CLL cells co-cultured with bone marrow stromal cells and T-cell-derived cytokines. Finally, in vivo treatment with SD6 at 10mg/kg/day for 7 days significantly inhibited the growth of xenograft tumors that were established by subcutaneous inoculation of 5×106 MEC1 CLL cells into NOD mice. Collectively, these results provide a strong rationale for the future clinical development of spliceosome modulators and potential combination therapies for the treatment of CLL. Citation Format: Qimei Han, Jianbo Wang, Austin Y. Shull, Fang Shi, Libin Deng, Jeong-Hyeon Choi, Eun-Jeong Park, Shuo Tu, Lirong Pei, Farrukh T. Awan, Roni Bollag, Locke J. Bryan, Hong-bo Xin, Chandraiah Lagisetti, Thomas R. Webb, Victor Jin, Huidong Shi. Modulation of SF3B1 causes global intron retention and downregulation of the B-cell receptor pathway in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5230.
La surveillance des maladies sexuellement transmissibles en France par des réseaux de laboratoires
Authors: V Goulet, P Sednaoui
Journal: Eurosurveillance (1998)

La plupart des maladies sexuellement transmissibles (MST) sont diagnostiquees en France par les medecins liberaux (medecins generalistes, gynecologues, dermato-venerologues et urologues) bien qu’il existe sur tout le territoire des dispensaires antiveneriens (DAV) qui prennent en charge gratuitement certaines MST (gonococcie, syphilis). La reorganisation en 1985 du systeme de maladies a declaration obligatoire a limite la liste de maladies a declarer sans y inclure les MST. Celles-ci ne sont plus notifiees par les medecins liberaux et, depuis 1995, les MST diagnostiquees dans les DAV ne sont plus recueillies par les services statistiques du ministere de la sante.
Abstract 4934: Detection of HBV-host junction DNA sequences in urine of patients with hepatocellular carcinoma
Authors: Selena Lin, Evan R. Trauger, Benjamin P. Song, Ling Lan, Patrick M. Jongeneel, Emilie G. C. Thompson, Malcolm C. Hoffman, Surbhi Jain, Ting-Tsung Chang, Timothy M. Block, Wei Song, Ying-Hsiu Su
Journal: Cancer Research (2016)

Abstract Human urine has been shown to contain DNA from circulation. In this study, we aim to provide unambiguous evidence that urine contains hepatocellular carcinoma (HCC)-derived DNA, and thus can be used for detecting HCC-associated DNA markers. We used novel hepatitis B virus (HBV)-host junction sequences (HBV-JSs), created by viral integration in the human genome, as unique markers to track the HBV-integrated DNA from tumor tissues to their corresponding urine samples. An HBV DR1-2 enriched Next-Generation sequencing (NGS) assay was developed to identify the major HBV-JSs in 15 HBV-HCC tissues. Upon validation of the major HBV-JSs by Sanger sequencing, a short-amplicon PCR assay tailed for each HBV-JS was developed to test the junctions’ existence in the corresponding urine DNA. 15 major HBV-JSs were identified by the HBV DR1-2 enriched NGS assay from 15 HBV related HCC (HBV-HCC) tissues, 13 of which were validated by Sanger sequencing. By using HBV-JS specific short-amplicon junction PCR assays, we detected and confirmed six of nine HBV-JSs for which there were matching urine samples. Urine contains detectable major HBV-JSs derived from HCC, and thus can be used for liquid biopsies to study not only the complexities of HBV-JS species during chronic HBV infection and carcinogenesis, but also other HCC-related DNA modifications for the early detection of HCC and disease management. Citation Format: Selena Lin, Evan R. Trauger, Benjamin P. Song, Ling Lan, Patrick M. Jongeneel, Emilie G. C. Thompson, Malcolm C. Hoffman, Surbhi Jain, Ting-Tsung Chang, Timothy M. Block, Wei Song, Ying-Hsiu Su. Detection of HBV-host junction DNA sequences in urine of patients with hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4934.
Learn from the mistakes of care.data
Authors: Nick Mann
Journal: BMJ (2016)

Care.data’s massive potential for knowledge and research was wasted. It failed because of the poor regard people have for data accountability beyond distribution, including deductive re-identification for discriminative commercial purposes, such as assessing insurability.

The development of care.data to exploit the commercial value of datasets was clearly evident in its structure. Patients’ fears about privacy were well founded.1 I …
Abstract 5046: High-throughput chemical screening for sensitization of bladder cancer to gemcitabine and cisplatin chemotherapy
Authors: Yuki Kita, Takashi Kobayashi, Norihiko Masuda, Atsuro Sawada, Yoshiyuki Matsui, Takahiro Inoue, Tomomi Kamba, Osamu Ogawa
Journal: Cancer Research (2016)

Abstract Background Gemcitabine and cisplatin chemotherapy (GC) is the current standard regimen for locally advanced and metastatic bladder cancer (BC). Despite a relatively high initial response rate, some cases do not regress (intrinsic resistance) and the remaining cases often show regrowth after initial shrinkage (acquired resistance). To identify novel therapeutic agents for overcoming these resistances, we applied a high-throughput screening of chemicals administered in combination with GC. Methods and Findings As a high-throughput screening, 2100 compounds were administered alone or in combination with GC to human BC cell lines (J82, UMUC-3). Cell viability was determined after 3-day incubation and chemicals that enhanced inhibitory effect of GC were screened. The initial screening identified 26 compounds and further validation narrowed them into the most synergistic agent disulfiram (DSF), an FDA-approved drug for alcoholism. Combination index assay showed synergistic effects of DSF with cisplatin but not with gemcitabine in J82, UMUC-3, T24, HT1197 and HT1376 cells. Co-administration of DSF significantly enhanced apoptosis by GC treatment in UMUC-3 and T24 cells, with significant increase of reactive oxygen species (ROS) production. DSF-induced apoptosis was attenuated in the presence of N-acetyl L-cysteine and Trolox, ROS scavengers. Use of DSF in combination with GC (GCD) significantly inhibited tumor growth of UMUC-3 subcutaneous xenograft on athymic mice (by 39% compared with GC alone, p = 0.02). GCD regimen was as tolerable as GC and no significant differences were observed in body weight of treated mice between the two regimen. Conclusion Repositioning of DSF to a chemotherapy sensitizer is a promising treatment strategy, which can be translated rapidly in the future. Citation Format: Yuki Kita, Takashi Kobayashi, Norihiko Masuda, Atsuro Sawada, Yoshiyuki Matsui, Takahiro Inoue, Tomomi Kamba, Osamu Ogawa. High-throughput chemical screening for sensitization of bladder cancer to gemcitabine and cisplatin chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5046.
Abstract 4746: Pharmacological characterization of BAY-876, a novel highly selective inhibitor of glucose transporter (GLUT)-1 in vitro and in vivo
Authors: Charlotte Kopitz, Luisella Toschi, Carolyn Algire, Mélanie Héroult, Anna-Lena Frisk, Kirstin Meyer, Arndt Schmitz, Eleni Lagkadinou, Heike Petrul, Iring Heisler, Roland Neuhaus, Bernd Buchmann, Herbert Himmel, Marcus Bauser, Andrea Haegebarth, Karl Ziegelbauer
Journal: Cancer Research (2016)

Abstract One hallmark of cancer is the accelerated metabolism, high energy requirements, and increased glucose uptake by the tumor cells, the latter being the first and rate-limiting step for glucose metabolism. Glucose transport into the tumor cell is mediated by facilitative high-affinity glucose transporter (GLUT) proteins. Among the 14 GLUT proteins, expression of GLUT1 in normal organs is nearly exclusively restricted to the blood brain barrier, while other GLUTs are also expressed in a wide variety of vital organs such as liver and heart. Interestingly, GLUT1 expression is highly regulated by hypoxia-inducible factor (HIF)-1α, a key driver of tumor progression. In line with this finding, GLUT1 over-expression was found to be associated with tumor progression and poor overall survival in various tumor indications. Consequently, GLUT1 represents a potential target for cancer treatment. Therefore, we have developed a highly-selective GLUT1 inhibitor, namely BAY-876, with selectivity over GLUT2, 3, and 4 of 4700-, 800-, and 135-fold, respectively. We here show for the first time the pharmacological characterization of BAY-876, comprising inhibition of glucose-uptake, anti-proliferative activity in vitro, and anti-tumor efficacy in vivo in models of different tumor indications in monotherapy as well as first results on the combinability of BAY-876. Furthermore, at the therapeutic dose, BAY-876 treatment did not show any relevant finding on the behavior of treated mice in the Irwin test, assuming no or only minor effects on brain function. In conclusion, BAY-876 is the first GLUT1-selective inhibitor which reduces glucose uptake and growth of tumor cells with sufficient tolerability at the efficacious dose in preclinical models. Citation Format: Charlotte Kopitz, Luisella Toschi, Carolyn Algire, Mélanie Héroult, Anna-Lena Frisk, Kirstin Meyer, Arndt Schmitz, Eleni Lagkadinou, Heike Petrul, Iring Heisler, Roland Neuhaus, Bernd Buchmann, Herbert Himmel, Marcus Bauser, Andrea Haegebarth, Karl Ziegelbauer. Pharmacological characterization of BAY-876, a novel highly selective inhibitor of glucose transporter (GLUT)-1 in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4746.
Bortezomib-Doxorubicin-Dexamethasone (BDD) for Reversal ofAcute Light Chain Induced Renal Failure (ARF) in MultipleMyeloma (MM). Results from a Phase II Study
Authors: H. Ludwig, Z. Adam, Roman Hájek, R. Greil, F. Keil, N. Zojer, J. Thaler, H. Gisslinger, A. Lang
Journal: Blood (2008)
Patient-Specific Mutation-Derived Tumor Antigens As Targets for Cancer Immunotherapy in Multiple Myeloma
Authors: Deepak Perumal, Alessandro Lagana', Alex Rubinsteyn, John P Finnigan, Pei-Yu Kuo, Violetta V Leshchenko, Ajai Chari, Hearn Jay Cho, Sundar Jagannath, Joel Dudley, Jeff Hammerbacher, Eric Schadt, Nina Bhardwaj, Samir Parekh
Journal: Blood (2015)
Abstract 1573: The progesterone analogue, Norgestrel, impairs tumor immunity and promotes metastatic breast cancer progression
Authors: Tomas Dalotto Moreno, Gabriel Adrian Rabinovich, Mariana Salatino
Journal: Cancer Research (2016)

Abstract The immune system is responsible for recognition and elimination of cancer cells. Tumors, however, can elicit different evasive mechanisms that contribute to immune escape Thus, understanding the immunosuppressive pathways that hamper tumor immunity is critical for the identification of novel therapeutic targets. Progestin-containing hormonal supplementation (as hormone replacement therapy or contraceptive) has been associated with an increase in the risk of breast cancer incidence and recurrence. Moreover, progesterone, as a natural hormone, generally impairs cellular immune responses responsible of preventingfetal rejection during pregnancy. We postulated that progestins and in particular the widely used contraceptive Norgestrel may impair tumor immunity and foster immunosuppressive tumor microenvironments. We injected Balb/c mice with the triple-negative 4T1breast tumor,, and treated them with a Norgestrel releasing depot for 30 days. Norgestrel-treated mice displayed a higher frequency of suppressive regulatory T cells (Tregs) in draining lymph nodes and tumors which displayed a CD4+CD25+Foxp3+CD44+ phenotype. Accordingly, norgestrel-treated mice showed greater number of exhausted PD1+ Tim-3+ CD8 T cells in the tumor microenvironment. Furthermore, in vitro exposure to Norgestrel also promoted differentiation and expansion of Tregs which activated the mTOR pathway assessed by phosphorylation of S6 ribonucleoprotein. These effects could not be prevented by the progesterone nuclear receptor antagonist, Zk 230211, suggesting that Norgestrel acts preferentially through membrane progesterone receptors. Although no significant difference regarding tumor growth could be observed, Norgestrel-treated mice showed greater number of lung metastasis. Mechanistically, Norgestrel-driven Treg cells showed increased expression of RANKL, a protein involved in breast cancer development and progression. Our results identify a novel progestin-mediated tumor-promoting mechanism and indicate caution onthe use of Norgestrel-supplementation therapies. Our findings suggest that Norgestrel may impair tumor immunity, thereby promoting metastatic dissemination of breast cancer cells. Citation Format: Tomas Dalotto Moreno, Gabriel Adrian Rabinovich, Mariana Salatino. The progesterone analogue, Norgestrel, impairs tumor immunity and promotes metastatic breast cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1573.
Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance).
Authors: Ghassan K. Abou-Alfa, Donna Niedzwieski, Jennifer J. Knox, Andreas Kaubisch, James Posey, Benjamin R. Tan, Petr Kavan, Rakesh Goel, John J. Murray, Tanios S. Bekaii-Saab, Vincent Channing Tam, Lakshmi Rajdev, Robin Kate Kelley, Abby Siegel, Jennifer Balletti, James J. Harding, Lawrence HOWARD Schwartz, Richard M. Goldberg, Monica M. Bertagnolli, Alan P. Venook
Journal: Journal of Clinical Oncology (2016)

192 Background: An exploratory analysis of a randomized phase II study in HCC comparing doxorubicin (D) alone to doxorubicin plus sorafenib (D+S) showed a significant improvement in overall survival favoring D+S (JAMA, 2011). The results appeared promising compared to the historic outcomes seen in the pivotal sorafenib (S) trials. CALGB 80802 was designed to determine if D+S improved survival compared to S alone. Methods: Patients with histologically proven advanced HCC, no prior systemic therapy and Child-Pugh A were randomized to receive D 60 mg/m 2 every 21 days plus S 400 mg PO twice daily (D+S) or S alone. For bilirubin ≥ 1.3x normal, D and S doses were halved. D was maxed out at 360 mg/m 2 . The study was stratified by extent of disease (locally advanced; metastatic), the primary endpoint was overall survival (OS); and secondary endpoint progression-free survival (PFS). The final analysis was to occur when 364 events were observed among 480 total patients, with 90% power to detect a 37% increase in median OS (10.7 to 14.7 months; 1-sided α = 0.05). Results: The Alliance DSMB halted the study after accrual of 346 patients (173 on each of D+S and S) when a futility boundary was crossed at a planned interim analysis. With 107 events in each arm, median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5 months (95% CI 7.4-14.3) for S with a hazard ratio (HR) 1.06 (95% CI 0.8-1.4) for D+S vs. S. Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1), respectively (HR = 0.90, 95% CI 0.72-1.2). There were 38 deaths on treatment: 18 on D+S and 20 on S. Among these 8 [sepsis (1), dysphagia (1), pneumonia (1), cardiac (2), hepatic failure (2), and not otherwise specified (1)] on D+S, and 3 [fatigue (1), hepatic failure (1), and a secondary malignancy (1)] on S, were at least possibly related to treatment. A maximum grade 3 or 4 only hematologic adverse events (AE) occurred in 37.8% of patients on D+S and 8.1% of patients on S. Non-hematologic AEs were comparable, in 63.6% and 61.5% of patients, respectively. Conclusions: The addition of D to S resulted in higher toxicity and did not improve OS or PFS. The S median OS of about 10 months is consistent with previous reports. NCI Grant U10CA180821 Clinical trial information: NCT01015833.
Higher Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability Is Associated With Lower Cognitive Performance, Lower Cerebral Blood Flow, and Greater White Matter Hyperintensity Load in Older Subjects
Authors: Roelof A.J. Smit, Stella Trompet, Behnam Sabayan, Saskia le Cessie, Jeroen van der Grond, Mark A. van Buchem, Anton J.M. de Craen, J. Wouter Jukema
Journal: Circulation (2016)

Recently, it was shown that intraindividual variation in low-density lipoprotein cholesterol (LDL-C) predicts both cerebrovascular and cardiovascular events. We aimed to examine whether this extends to cognitive function and examined possible pathways using a magnetic resonance imaging substudy.We investigated the association between LDL-C variability and 4 cognitive domains at month 30 in 4428 participants of PROSPER (PROspective Study of Pravastatin in the Elderly at Risk). Additionally, we assessed the association of LDL-C variability with neuroimaging outcomes in a subset of 535 participants. LDL-C variability was defined as the intraindividual standard deviation over 4 postbaseline LDL-C measurements, and all analyses were adjusted for mean LDL-C levels and cardiovascular risk factors.Higher LDL-C variability was associated with lower cognitive function in both the placebo and pravastatin treatment arms. Associations were present for selective attention (P=0.017 and P=0.11, respectively), processing speed (P=0.20 and P=0.029), and memory (immediate recall, P=0.002 and P=0.006; delayed recall, P=0.001 and P≤0.001). Furthermore, higher LDL-C variability was associated with lower cerebral blood flow in both trial arms (P=0.031 and P=0.050) and with greater white matter hyperintensity load in the pravastatin arm (P=0.046). No evidence was found for interaction between LDL-C variability and pravastatin treatment for both cognitive and magnetic resonance imaging outcomes.We found that higher visit-to-visit variability in LDL-C, independently of mean LDL-C levels and statin treatment, is associated with lower cognitive performance, lower cerebral blood flow, and greater white matter hyperintensity load.