tbuckley/cabot-search huggingface dataset:
Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease
Authors: Saskia N. van der Crabben, Marije P. Hennus, Grant A. McGregor, Deborah I. Ritter, Sandesh C.S. Nagamani, Owen S. Wells, Magdalena Harakalova, Ivan K. Chinn, Aaron Alt, Lucie Vondrova, Ron Hochstenbach, Joris M. van Montfrans, Suzanne W. Terheggen-Lagro, Stef van Lieshout, Markus J. van Roosmalen, Ivo Renkens, Karen Duran, Isaac J. Nijman, Wigard P. Kloosterman, Eric Hennekam, Jordan S. Orange, Peter M. van Hasselt, David A. Wheeler, Jan J. Palecek, Alan R. Lehmann, Antony W. Oliver, Laurence H. Pearl, Sharon E. Plon, Johanne M. Murray, Gijs van Haaften
Journal: Journal of Clinical Investigation (2016)

The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood.
Clinical Significance of Positive Red Blood Cell Antibody Screen with Inconclusive Antibody Identification
Authors: Shweta Gupta, Prantesh Jain, Harsha v Poola, Sumedha Dhar, Manila Gaddh, Paul G. Rubinstein, Tareq Braik, Rosalind Catchatourian, Margaret Clare Telfer, Ram Kakaiya
Journal: Blood (2011)
Stability through variability: Homeostatic plasticity and psychological resilience [Open Peer Commentary to "A conceptual framework for the neurobiological study of resilience"]
Authors: D.J.L.G. Schutter, M. Wischnewski, H. Bekkering
Journal: Behavioral and Brain Sciences (2015)

According to Kalisch et al., adopting a cognitive positive appraisal style promotes internal bodily homeostasis and acts as a safeguard against the detrimental effects of stress. Here we will discuss results from recent noninvasive brain stimulation studies in humans to illustrate that homeostatic plasticity provides a neural mechanistic account for the positive appraisal style theory of resilience.
Abstract 2845: PRMT5-PTEN molecular pathway regulates senescence and self-renewal of Glioblastoma stem-like cells
Authors: Yeshavanth Kumar Banasavadi-Siddegowda, Luke Russell, Jianying Zhang, Vrajesh A. Karkhanis, Jaime Imitola, Robert Baiocchi, Balveen Kaur
Journal: Cancer Research (2016)

Abstract PURPOSE: Glioblastoma (GBM) represents the most common and aggressive histologic subtype among malignant astrocytoma and is associated with poor outcomes because of heterogeneous tumor cell population including mature non-stem like cell and immature stem-like cells within the tumor. Thus, it is critical to find new target-specific therapeutic modalities. Protein arginine methyltransferase enzyme 5 (PRMT5) regulates many cellular processes through its methylation activity and its overexpression in GBM is associated with more aggressive disease. Previously, we have shown that silencing of PRMT5 expression in differentiated GBM cell lines results in apoptosis and reduced tumor growth in mice. Here we report the critical role of PRMT5 in differentiated GBM non-stem-like cells (non-GSC) grown in serum and undifferentiated GBM stem-like cells (GSC) grown as neurospheres in vitro. METHODS: GSC grown in stem-cell media and non-GSC grown in serum were transfected with specified siRNAs. At appropriate time, these cells were tested for in vitro proliferation, self-renewal capacity, apoptosis, cell cycle progression, mRNA expression and protein expression. Also, using intracranial mouse xenograft, tumor forming ability of PRMT5-intacta and depleted GSC and non-GSC was determined. RESULTS: Our results uncover a very significant role for PRMT5 in GSC self-renewal capacity and proliferation. PRMT5 knockdown in non-GSC led to apoptosis, knockdown in GSC led to G1 cell cycle arrest through upregulation of p27 and hypophoshorylation of Rb protein, leading to senescence. Comparison of impact of PRMT5 on cellular signaling by Human Phospho-Kinase Array and ChIP-PCR revealed that unlike non-GSC, PRMT5 controls both AKT and ERK activity by direct repression of PTEN in GSC. In vivo transient depletion of PRMT5 decreased intracranial tumor size and growth rate in mice implanted with both primary tumor derived GSC and non-GSC. CONCLUSION: This is the first study to identify PTEN as a potential downstream target of PRMT5 and vital to support both mature and immature GBM tumor cell populations. Citation Format: Yeshavanth Kumar Banasavadi-Siddegowda, Luke Russell, Jianying Zhang, Vrajesh A. Karkhanis, Jaime Imitola, Robert Baiocchi, Balveen Kaur. PRMT5-PTEN molecular pathway regulates senescence and self-renewal of Glioblastoma stem-like cells. [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 2845.
Design of an open label, randomized, phase II study of paclitaxel and panitumumab compared to paclitaxel alone in patients with relapsed or refractory urothelial cancer.
Authors: Andrea Necchi, Luigi Mariani, Patrizia Giannatempo, Daniele Raggi, Giuseppina Calareso, Flavio Crippa, Elena Togliardi, Roberto Salvioni, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2015)

TPS4570 Background: The paradigm shift in the treatment of urothelial cancer (UC) is perceived by the oncology community as a long-standing medical need under multiple aspects. For patients (pts) with advanced disease and who have failed chemotherapy attempts, no FDA-approved agent is still available. One plausible target in UC is the Epidermal Growth Factor Receptor (EGFR). Strong expression of EGFR is found in 50% of advanced UC and it is associated with a more aggressive phenotype. Signals of activity of anti-EGFR agents combined with chemotherapy have been observed. Methods: Pts will receive paclitaxel (TXL) and will be randomly assigned 2:1 to also receive Panitumumab or not until disease progression, unacceptable toxicity, or withdrawal of consent. The doses of the study drugs will be as follows: panitumumab 6 mg/Kg IV every 14 days and TXL 80 mg/m2 IV on days 1, 8 and 15 of a 28 day cycle. Pts will undergo computed tomography (CT) and positron emission tomography (PET)/CT scan at baseline and q2 months. The primary endpoint will be progression-free survival (PFS). It is foreseen an accrual of 120 patients, 80 + 40 in the two arms, corresponding to 114 disease progressions or deaths. This is the number of events necessary to yield 90% power of a one-sided logrank test at the 5% significance level in case of an improvement in PFS from a median of 2.5 months (H0) to a median of 4.5 months (H1), corresponding to a 44% hazard rate reduction in the experimental arm compared to control. Computations were done taking into account an annual 10% drop out rate and the use of O’Brien-Fleming type efficacy and futility stopping rules at the interim analysis, to be performed when 51 (50%) of the expected number of events will be recorded. Eligibility will include diagnosis of metastatic UC and failure of 1 or 2 chemotherapy regimens. A relapse within 6 months of a perioperative chemotherapy will be counted as one line. Pharmacodynamic analyses are planned on pre- and post- tissue samples and will include molecular alterations of EGFR/RAS pathways. The trial is currently open to accrual (registered with EudraCT, number 2014-000857-35). Clinical trial information: 2014-000857-35.
Abstract 1583: SRI31215, a novel inhibitor of oncogenic HGF/MET signaling
Authors: Benjamin Y. Owusu, Phanindra K. Venukadasula, Robert A. Galemmo, Lidija Klampfer
Journal: Cancer Research (2016)

Abstract Constitutive activation of MET signaling, frequently observed in cancer, triggers signaling by AKT, ERK 1/2 and STAT3, and promotes survival, proliferation, migration and invasion of cancer cells. Accordingly, MET amplification or overexpression of its ligand, hepatocyte growth factor (HGF), are associated with tumor aggressiveness, resistance to therapy and poor prognosis in many cancer patients. Cancer cells can secrete HGF which triggers autocrine HGF/MET signaling, however, fibroblasts are the predominant source of HGF and activate MET expressed on tumor cells in a paracrine manner. Cancer cells and fibroblasts secrete HGF as an inactive precursor, pro-HGF. A crucial step in the regulation of HGF/MET signaling is the proteolytic processing of the inactive precursor, pro-HGF, to its active form by one of the three serine proteases, matriptase, hepsin or HGF activator (HGFA). This is the rate-limiting step in the HGF/MET signaling pathway, controlled by the inhibitors of HGF activation, hepatocyte growth factor activator inhibitors 1 and 2 (HAI-1/2). We synthesized a novel small molecule, SRI31215, a triplex inhibitor of matriptase, hepsin and HGFA, mimicking the biological activity of HA1-1/2. We confirmed that SRI31215 inhibits the proteolytic activation of pro-HGF and blocks HGF-induced MET activation and signaling by AKT, ERK 1/2 and STAT3. SRI31215 blocked fibroblast-induced epithelial-to-mesenchymal transition (EMT) and prevented scattering and migration of cancer cells. Finally, we demonstrated that SRI31215 sensitized HGF-producing colon cancer cells to epidermal growth factor receptor inhibitors (EGFRi) and inhibited fibroblast-mediated, HGF-dependent, resistance to EGFRi in colon cancer. Thus, SRI31215 blocks signaling between cancer cells and fibroblasts and inhibits the tumor-promoting activity of cancer associated fibroblasts. Taken together, our data demonstrate that inhibitors of HGF activation, such as SRI31215, represent a novel approach to curb the growth and metastatic spread of tumor cells that are addicted to HGF/MET signaling and to overcome primary and acquired resistance to EGFR-targeted therapy. Citation Format: Benjamin Y. Owusu, Phanindra K. Venukadasula, Robert A. Galemmo, Lidija Klampfer. SRI31215, a novel inhibitor of oncogenic HGF/MET signaling. [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 1583.
Avelumab (MSB0010718C; anti-PD-L1) in combination with axitinib as first-line treatment for patients with advanced renal cell carcinoma.
Authors: James M. G. Larkin, Michael S. Gordon, Fiona Thistlethwaite, Paul D. Nathan, Brian I. Rini, Marcella Martignoni, Michael Shnaidman, Chiara Chiruzzi, Alessandra Di Pietro, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2016)

TPS4580 Background: Targeted agents have improved outcomes in advanced renal cell carcinoma (aRCC), but patients (pts) inevitably develop resistance. Programmed death-1 receptor ligand (PD-L1) is a key therapeutic target in the reactivation of the immune response against multiple cancers, including RCC. Avelumab* is a fully human IgG1 anti-PD-L1 antibody showing clinical activity in several tumor types. Axitinib is a receptor tyrosine kinase inhibitor (TKI) indicated for treatment of aRCC after failure of one prior systemic therapy; axitinib also shows clinical activity as a first-line (1L) therapy. In recent trials, anti-PD-1/TKI combinations have shown promising clinical efficacy in aRCC, and preliminary data suggest better tolerability for the combination with axitinib. This open-label, multicenter, dose-finding study (NCT02493751) evaluates the novel combination of avelumab + axitinib as 1L therapy in pts with aRCC. Methods: The primary objective for this global phase Ib study is to assess safety and tolerability of avelumab + axitinib, defined by dose-limiting toxicities, and determine the maximum tolerated dose (MTD). Eligibility criteria include: histologically confirmed aRCC with a clear cell component, archival or fresh tumor biopsy, ECOG PS 0-1, no prior immunotherapy, and no prior systemic therapy for aRCC. Up to 55 pts will receive avelumab (10 mg/kg or 5 mg/kg as a 1h IV infusion Q2W) + axitinib (5 mg or 3 mg orally BID) in dose-finding and dose-expansion parts and treatment will be given until confirmed disease progression, unacceptable toxicity, withdrawal, or study termination. Other objectives include assessment of objective tumor response (RECIST 1.1), disease control, progression-free survival, OS, duration of response, time to response, pharmacokinetics, pharmacodynamics, immunogenicity, tumor tissue biomarkers, and safety (NCI-CTCAE v4.03). Enrollment began in Oct 2015. A phase 3 trial of avelumab + axitinib vs sunitinib monotherapy as 1L treatment of aRCC is planned. *Proposed INN. Clinical trial information: NCT02493751.
Fracking is linked to asthma increase, study finds
Authors: Anne Gulland
Journal: BMJ (2016)

Fracking—a controversial method of extracting gas from the ground—is associated with an increased risk of asthma exacerbation, a study published by JAMA Internal Medicine has found.1

The authors said that this was the first study to look at the links between fracking and asthma. To date, most health concerns have centred on groundwater contamination as a by-product of the procedure, which involves drilling 2000-3000 m down into the ground and then 600-3000 m across. A high pressure water mixture is …
Abstract 1569: IL6 mediated inflammatory loop reprograms normal to highly metastatic cancer stem cells at pre-HCC liver in β2SP+/- mice
Authors: Abhisek Mitra, Xueqing Xia, Lopa Mishra, Shulin Li
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC), the second-leading cause of cancer-related death world-wide, displays overexpression of the pro-inflammatory cytokine interleukin6 (IL6) and inhibition of transforming growth factor β (TGF-β) in its early phase. We aimed to identify the dynamics of liver immune cells under inflammatory conditions and to characterize early-phase tumor-initiating cells to comprehend aberrant molecular pathway(s) in HCC progression in a TGF-β disrupted murine model (β2SP+/-). Methods: Chronic inflammation was induced in wild-type (WT) and β2SP+/- mice by hydrodynamic injection of IL6 (pIL6) encoding Sleeping Beauty transposons twice per month for 3 months. Liver stem cells were isolated by using CD133 antibody at the end of third month and cultured with suitable supplements. Results: Culturing of stem cells enriched from WT and β2SP+/- mice treated with pIL6 showed that the stem cells derived from β2SP+/- mice were highly tumorigenic and metastatic in immune-deficient mice. Staining of these cells with EMT markers Twist and Slug were found in the nucleus. Immunophenotyping suggested that pIL6 treatment induced significant expansion and pro-inflammatory phenotypes of liver NKT and suppressed MDSCs in the β2SP+/- mice compared with WT to generate tumorigenic stem cells. By using numerous pharmacological inhibitors to identify aberrant molecular signaling event(s), we discovered constitutively activated nuclear factor κB (NF-κB) in these cancer stem cells (CSCs). Upon stable knockdown of NF-κB in the CSCs, both EMT phenotype and metastatic ability decreased significantly both in vitro and in vivo. Furthermore, screening of putative kinase(s) that could phosphorylate NF-κB identified that TGF-β activated kinase-1 (TAK-1) directly phosphorylated NF-κB. Staining of HCC tissue specimens showed that CD133+ liver stem cells expressed constitutively activated NF-κB. Conclusions: Collectively, our data suggest that IL6, highly expressed in 40% HCC patients, can be considered an initiation driver to develop metastatic CSCs by constitutively activated TAK1-NFκB pathway at pre-HCC stage. Citation Format: Abhisek Mitra, Xueqing Xia, Lopa Mishra, Shulin Li. IL6 mediated inflammatory loop reprograms normal to highly metastatic cancer stem cells at pre-HCC liver in β2SP+/- mice. [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 1569.
Abstract 2352: Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allow their intratumoral delivery and an improved tumor-growth inhibition
Authors: Jean-Baptiste Marchand, Patricia Kleinpeter, Laetitia Fend, Christine Thioudellet, Michel Geist, Nathalie Sfrontato, Véronique Koerper, Renée Brandely, Dominique Villeval, Karola Rittner, Nathalie Silvestre, Philippe Erbs, Laurence Zitvogel, Eric Quemeneur, Xavier Preville
Journal: Cancer Research (2016)

Abstract We report here the successful vectorization of a hamster monoclonal IgG (namely J43) recognizing the murine Programmed cell death-1 (mPD-1) in Western Reserve (WR) oncolytic vaccinia virus. Three forms of mPD-1 binders have been inserted in the virus: whole antibody (mAb), Fragment antigen-binding (Fab) or single-chain variable fragment (scFv). MAb, Fab and scFv were produced and assembled with the expected patterns in supernatants of cells infected by the recombinant viruses. The 3 purified mPD-1 binders were able to block the binding of mPD-1 ligand to mPD-1 in vitro. Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant WR-mAb was injected intratumorally (IT) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after IT injection was up to 1900-fold higher than the level obtained after a subcutaneous (SC) injection (i.e. without tumor) confirming the virus tropism for tumoral cells and/or that tumoral microenvironment allows virus escape from immune surveillance. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after IT injection of WR-mPD-1, than after IT administration of 10 μg of J43. Interestingly, in the MCA 205 tumor model, WR-mPD-1 (both mAb and scFv) induced a therapeutic control of tumor growth similar to unarmed WR combined to systemically administered J43 and superior to that provided by an unarmed WR. These results pave the way for next generation of oncolytic vaccinia armed with immunomodulatory therapeutic proteins such as mAbs. New generation of oncolytic vaccinia virus that will express several transgenes simultaneously may also be designed with the goal of providing to the patients enhanced therapeutic/toxicity ratio. Citation Format: Jean-Baptiste Marchand, Patricia Kleinpeter, Laetitia Fend, Christine Thioudellet, Michel Geist, Nathalie Sfrontato, Véronique Koerper, Renée Brandely, Dominique Villeval, Karola Rittner, Nathalie Silvestre, Philippe Erbs, Laurence Zitvogel, Eric Quemeneur, Xavier Preville. Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allow their intratumoral delivery and an improved tumor-growth inhibition. [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 2352.
Metastatic lymph node ratio as an independent prognostic factor in stage III gastric cancer after D2 nodal dissection.
Authors: Jieer Ying, Cong Li, Yigong Zhang, Qi Xu
Journal: Journal of Clinical Oncology (2016)

738 Background: The aim of this study was to evaluate the prognostic impact of metastatic lymph node ratio (MLR) in stage III gastric cancer after D2 dissection, and to assess the value of MLR for adjuvant chemotherapy. Methods: A total of 87 patients who underwent radical resection with D2 lymphadenectomy between December 2007 and March 2014 was enrolled in this study. Survival was determined by Kaplan-Meier method and survival curves were assessed by log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. Results: The median age of patients was 60 (range:21 to 83) with a male to female ratio of 2. 83 patients have undergone total gastrectomy (95.4%) and 4 subtotal gastrectomy (4.6%). 57 patients received chemotherapy, including 24 neoadjuvant chemotherapy and 33 adjuvant chemotherapy. All chemotherapy regimens have contained Flouropyrimidines (5-FU or capecitabine). There were only 5 patients received single-agent 5-FU or capecitabine as chemotherapy regimen, while 52 patients received combined-chemotherapy. The median total retrieved lymph node was 35 (range:10 to 104) and the median metastatic lymph nodes was 8 (range: 0 to 71). MLR was classified into 4 groups as follows: Group 1(MLR = 0), Group 2(MLR &lt; 0.1), Group 3(MLR = 0.1-0.25), Group 4(MLR &gt; 0.25). After a median follow-up of 28 months, the median PFS of group 1-4 was 37.1m, 35.9m, 31.5m and 16.9m, respectively (p = 0.025). The median PFS was significantly different in subgroups: 39.2m in low group (MLR &lt; 0.25) with adjuvant chemotherapy, 36.4m in low group without chemotherapy, 17.2m in high group (MLR &gt; 0.25) with chemotherapy and 11.5m in high group without chemotherapy (p = 0.012). The MLR was retained as an independent prognostic factor in multivariable analysis. Conclusions: After R0 resection with D2 lymphadenectomy for stage III gastric cancer, MLR can be a more effective and prognostic indicator. Patients with high MLR may most benefit from adjuvant treatments.
Part 7.2: Management of Cardiac Arrest
Journal: Circulation (2005)

Part 7.2: Management of Cardiac ArrestF our rhythms produce pulseless cardiac arrest: ventricular fibrillation (VF), rapid ventricular tachycardia (VT), pulseless electrical activity (PEA), and asystole.Survival from these arrest rhythms requires both basic life support (BLS) and advanced cardiovascular life support (ACLS).The foundation of ACLS care is good BLS care, beginning with prompt high-quality bystander CPR and, for VF/pulseless VT, attempted defibrillation within minutes of collapse.For victims of witnessed VF arrest, prompt bystander CPR and early defibrillation can significantly increase the chance for survival to hospital discharge.In comparison, typical ACLS therapies, such as insertion of advanced airways and pharmacologic support of the circulation, have not been shown to increase rate of survival to hospital discharge.This section details the general care of a patient in cardiac arrest and provides an overview of the ACLS Pulseless Arrest Algorithm.
Case 38-1964
Authors: Gerald F. Winkler, Edward P. Richardson
Journal: New England Journal of Medicine (1964)

Presentation of CaseA sixty-one-year-old woman was admitted to the hospital because of progressive dizziness.She had had difficulty in walking for three months. She had first noticed unsteadiness while walking down a corridor, when she found it necessary to hold on to the wall, and thereafter experienced increasing unsteadiness on turning or descending stairs. She described "head spinning" on turning or getting up rapidly but stated that the environment did not move. When she lay back on the table during examination in a physician's office shortly before admission she had the feeling that she might fall off.Ten years . . .