tbuckley/cabot-search huggingface dataset:
P45 The effect of SUMO modification on hepatic differentiation from human embryonic stem cells
Authors: Z Hannoun, E Jaffray, S Greenhough, I Wilmut, J P Iredale, R T Hay, D C Hay
Journal: Gut (2010)

Introduction  Protein post translational modifications (PTMs) play an important role in many cellular processes including; transcription, apoptosis, cell cycle regulation and cytoskeleton organisation. Sumoylation is a particular PTM which affects cellular activities such as chromatin organisation, protein localisation and cell cycle regulation. SUMO is a small ubiquitin like molecule. Typically it is covalently attached to lysine residues in the ψKxE consensus sequence (K- lysine, E - glutamic acid) although ∼40% of SUMOylated proteins are modified on non-consensus sequences.  Aim  SUMO modification has been shown to be important in hESC self-renewal where one of the master regulators, Oct4, is stabilised and its degradation is inhibited by SUMOylation (Zhang  et al , 2007). We hypothesised that SUMO modification may not only regulate hESC self-renewal, but may also be required for efficient hESC differentiation. We therefore interrogated the role of SUMOylation in hESC differentiation to hepatic endoderm (HE). hESC were differentiated using our established and efficient model (Hay  et al , 2008).  Method  Cell lysates were collected at different time points throughout the differentiation and analysed by Western blotting for changes to the levels of key proteins involved in the conjugation and de conjugation of SUMO.  Results  We demonstrate that peak levels of SUMOylation were detectable in hESC populations during cellular differentiation to definitive endoderm (DE). Following commitment to DE we observed a decrease in the level of SUMO modified proteins as the cells in culture developed a hepatic fate. This corresponded with an increase in SENP 1, a SUMO specific protease. We also detected reduced levels of HNF4α, a critical regulator of hepatic status and metabolic function, as SUMOylation decreased. As a result we investigated the role of SUMO modification in HNF4α metabolism and if this process was involved in modulating HNF4α9s critical role in HE.  Conclusion  In conclusion, SUMO modification and deconjugation at critical points during cellular differentiation may regulate protein stability enhancing transcriptional activity and/or modulating subcellular localisation. As a consequence this may improve HE differentiation, viability and maturity, which are essential to the generation of high fidelity human models in culture and maybe directly applicable to other stem cell populations for example iPSCs.
Abstract 2756: Whole-exome sequencing reveals a novel germline variant in CEBPA-associated familial acute myeloid leukemia: 45-year follow-up of a large family
Authors: Anand Pathak, Katja Seipel, Alexander Pemov, Ramita Dewan, Christina Brown, Sarangan Ravichandran, Brian T. Luke, Meredith Yeager, Richard A. Gatti, Neil Caporaso, John J. Mulvihill, Lynn Goldin, Thomas Muller Pabst, Mary Lou McMaster, Douglas R. Stewart
Journal: Cancer Research (2015)

Abstract Familial acute myeloid leukemia (AML) is rare and linked to germline mutations in RUNX1 or CCAAT/enhancer binding protein-α (CEBPA). We conducted whole-exome sequencing on a large family with AML originally evaluated at NIH in 1969 and uncovered a CEBPA Q311P mutation in all tested, affected members. The Q311P variant, located in the C-terminal bZip domain of CEBPA, was predicted to be highly deleterious by in silico algorithms; the Q311 position was highly conserved among CEBPA orthologs and paralogs. This variant has not been observed in the NHLBI's Exome Sequencing Project or the Broad Institute's Exome Aggregation Consortium. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mutant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation of a promoter with a tetramer of CEBP sites, consistent with a loss-of-function mutation. In addition, there was decreased colony survival in fibroblasts with CEBPA Q311P, associated with the clinical radiosensitivity postulated in one carrier. From 45 years of follow-up, we observed incomplete penetrance (46%) of CEBPA Q311P; we did not observe other cancers or leukemias segregating with the mutation. Thus, we present a comprehensive clinical and molecular characterization of a novel AML-associated variant in CEBPA in a NCI family with nearly half a century of follow-up. This study reveals that a germline mutation in the C-terminal bZip domain can alter the ability of CEBPA to bind DNA and reduces transactivation, leading to AML, though with lower penetrance than the canonical N-terminal frameshift germline mutations. Citation Format: Anand Pathak, Katja Seipel, Alexander Pemov, Ramita Dewan, Christina Brown, Sarangan Ravichandran, Brian T. Luke, Meredith Yeager, Richard A. Gatti, Neil Caporaso, John J. Mulvihill, Lynn Goldin, Thomas Muller Pabst, Mary Lou McMaster, Douglas R. Stewart. Whole-exome sequencing reveals a novel germline variant in CEBPA-associated familial acute myeloid leukemia: 45-year follow-up of a large family. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2756. doi:10.1158/1538-7445.AM2015-2756
Clear cell sarcoma (CCR): Clinical behavior and response to chemotherapy.
Authors: S. Stacchiotti, E. Palassini, T. Negri, M. Orsenigo, R. Bertulli, C. Morosi, S. Pilotti, M. Fiore, A. Gronchi, P. G. Casali
Journal: Journal of Clinical Oncology (2010)

10096 Background: CCR is a rare sarcoma with a high metastatic potential, characterized by a specific translocation involving the EWS gene or abnormalities in chromosomes 22 and 8. Anecdotal responses to dacarbazine, vincristine + antracycline + ciclophosphamide, interferon-alpha, and, more recently, Met-inhibitors and sunitinib were reported. Methods: We retrospectively reviewed all cases of CCR surgically treated at our Institution (INT) from 1989 to 2009. Diagnosis was confirmed by morphology, immunophenotyping and FISH. Clinical characteristics were analyzed, focusing on response to chemotherapy (CT). Overall survival (OS) was calculated from time of diagnosis and from time of distant metastasis for the whole series. Local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and OS for the subgroup of pts (Sub1) who received primary surgery at INT were also considered. Results: 35 pts were identified (M/F:18/17, age: median/range 45/20-79 yrs; status at the time of first operation at INT: primary/local relapse/distant relapse 20/9/7). EWSR1 rearrangement was detected in 49% of pts. All EWSR1 negative pts, but one, showed trisomy of chromosome 8 accompanied by gain of chromosome 22. Median follow-up was 15 mos (IQ-range 10-32 mos). The 5/10-year OS was 52/28% (median 91 mos). None of the metastatic pt was alive at 5 yrs (median OS 6 mos). In Sub1 the 5/10-year OS and DRFS were respectively: 58/43% (median 91 mos), 55/41% (median 87 mos). No pt had a local relapse. The overall incidence of metastases in Sub1 was 35% (7 pts). 11 pts received CT for progressive advanced disease. All of them received front-line CT with doxorubicin + dacarbazine ± ifosfamide, with 2 RECIST PR, 3 SD and 6 PD at 3 months; in all pts the PR/SD lasted <6 mos. Further treatments included high-dose ifosfamide (5 pts), with 1 PR lasting 3 mos; gemcitabine ± taxotere (2 pts), with 1 PR (ongoing, confirmed at 4 mos) and 1 SD; trabectedin (1 pt), with PD. Conclusions: This series confirms the aggressive behavior of CCR. Doxorubicin/dacarbazine based CT regimens are active, but responses are short-lasting. A response to gemcitabine was observed. New medical options are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
Hypomethylating Agent Azacitidine Induces FoxP3 Negative HLA-G Expressing Immunoregulatory T Cells
Authors: Panagiota Stamou, Angeliki Vittoraki, Dimitra Kokkinou, Anne-Lise De Lastic, Panagiotis Zikos, Alexandros Spyridonidis
Journal: Blood (2013)
Long-Term Results of Bone Marrow Transplantation for Thalassemia Major in Pescara.
Authors: Paolo Di Bartolomeo, Stella Santarone, Erminia Di Bartolomeo, Antonio Nicolucci, Paola Olioso, Pasqua Bavaro, Gabriele Papalinetti, Paolo Di Carlo, Glauco Torlontano
Journal: Blood (2004)
Herpes Zoster and the Risk of Stroke in Patients With Autoimmune Diseases
Authors: Leonard H. Calabrese, Fenglong Xie, Huifeng Yun, Kevin L. Winthrop, John W. Baddley, Cassandra Calabrese, Jeffrey R. Curtis
Journal: Arthritis & Rheumatology (2016)

Objective Herpes zoster (HZ) is an opportunistic infection caused by varicella‐zoster virus and observed with increasing frequency in patients receiving immunosuppressive therapies. The literature has suggested that the risk of stroke may increase shortly after HZ, but little is known about this association in patients with autoimmune diseases, who are at increased risk of both zoster and stroke. Methods Medicare data from January 1, 2006 through December 31, 2013 were used to identify patients with autoimmune diseases. The outcome of interest was hospitalized stroke. The hypothesis tested was that the incidence of stroke immediately following HZ is increased compared to the incidence of stroke at later time points. Secondary analyses included assessment of the impact of antiviral therapy on subsequent stroke, as well as the influence of varicella‐zoster virus–related complications on stroke incidence. Results The crude incidence of stroke ranged from a high of 2.30 per 100 patient‐years (95% confidence interval [95% CI] 0.96–5.52) within 90 days of HZ in patients who had HZ‐related cranial nerve complications and did not receive treatment to a low of 0.87 per 100 patient‐years (95% CI 0.75–1.02) at 366–730 days in those without complication who received antiviral treatment. After multivariable adjustment for multiple stroke‐related factors, the overall incidence rate ratio (IRR) for stroke in the first 90 days after HZ was 1.36 (95% CI 1.10–1.68) compared to stroke occurring at 366–730 days after HZ. The risk was greater for patients with zoster and cranial nerve complications (IRR 2.08 [95% CI 0.99–4.36]). Prompt antiviral therapy was associated with lower incidence of subsequent stroke (IRR 0.83 [95% CI 0.70–0.98]). Conclusion In patients with autoimmune diseases, incident HZ was associated with as much as a 2‐fold increased risk of stroke in the subsequent few months. These data underscore the urgency of developing strategies for reducing the risk of varicella‐zoster virus.
Therapeutic Inhibition of the MDM2–p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas
Authors: Felipe Nör, Kristy A. Warner, Zhaocheng Zhang, Gerson A. Acasigua, Alexander T. Pearson, Samuel A. Kerk, Joseph I. Helman, Manoel Sant'Ana Filho, Shaomeng Wang, Jacques E. Nör
Journal: Clinical Cancer Research (2016)

Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the antitumor effect of a novel small-molecule inhibitor of the MDM2-p53 interaction (MI-773) combined with cisplatin in patient-derived xenograft (PDX) ACC tumors.Experimental Design: Therapeutic strategies with MI-773 and/or cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A, -2B, -5, -6) in vitro The effect of therapy on the fraction of cancer stem cells (CSC) was determined by flow cytometry for ALDH activity and CD44 expression.Results: Combined therapy with MI-773 with cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-xL, and active caspase-9 upon MI-773 treatment. Both single-agent MI-773 and MI-773 combined with cisplatin decreased the fraction of CSCs in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a postsurgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (P = 0.0097).Conclusions: Collectively, these data demonstrate that therapeutic inhibition of MDM2-p53 interaction by MI-773 decreased the CSC fraction, sensitized ACC xenograft tumors to cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2-p53 interaction. Clin Cancer Res; 23(4); 1036-48. ©2016 AACR.
Notes from the Field: Varicella Outbreak Associated with Riding on a School Bus — Muskegon County, Michigan, 2015
Authors: Douglas E. Hoch
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

On December 3, 2015, Public Health-Muskegon County (PHMC) in Michigan was notified by a local kindergarten-grade 2 school that a student aged 8 years (the index patient) had been sent home because of a rash suspected to be varicella (chickenpox); the rash had not been observed the previous day. Investigation by PHMC revealed that the student was one of five siblings in household A, none of whom had a history of having received any immunizations. During the preceding month the index patient's two older siblings (aged 12 years and 25 years) and two younger siblings (twins, aged 4 years) had been excluded from other schools in this rural district because of rashes that also were suspected to be varicella. Investigators also learned that a parent in household A had received a physician diagnosis of herpes zoster (shingles) nearly 7 weeks earlier, on October 20, after having been evaluated for a painful, unilateral trunk rash that had begun 3 days earlier, and for which acyclovir was prescribed. PHMC could not confirm whether any advice regarding prevention of possible transmission of varicella zoster virus to susceptible contacts was provided. The other children in household A had rash onsets on November 3, November 18 (two children), and November 22. The index patient rode a school bus and was the first student on and the last off each day; none of the index patient's four siblings attended the same school or rode on the same school bus as the index patient. Public health investigators subsequently linked three more cases in children to sharing the same school bus as the index patient.
Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial
Authors: Ludwig Kappos, Douglas L Arnold, Amit Bar-Or, John Camm, Tobias Derfuss, Bernd C Kieseier, Till Sprenger, Kristin Greenough, Pingping Ni, Tomohiko Harada
Journal: The Lancet Neurology (2016)
Prostate-Specific Antigen Failure and Risk of Death Within Comorbidity Subgroups Among Men With Unfavorable-Risk Prostate Cancer Treated in a Randomized Trial
Authors: Nicholas J. Giacalone, Jing Wu, Ming-Hui Chen, Andrew Renshaw, Marian Loffredo, Philip W. Kantoff, Anthony V. D’Amico
Journal: Journal of Clinical Oncology (2016)

Purpose Physicians sometimes make management recommendations on the basis of early results from randomized controlled trials (RCTs) relating to reduced prostate-specific antigen (PSA) failure, yet whether this early end point is associated with all-cause mortality (ACM), particularly in men with competing risks, is unknown. Using a validated metric in men treated within the context of an RCT, we aimed to determine whether PSA failure is associated with the risk of ACM stratified by comorbidity score. Patients and Methods Between 1995 and 2001, 206 men with localized (T1b to 2b) intermediate- and high-risk prostate cancer (PC) were randomly assigned to receive radiation therapy or radiation therapy and 6 months of ADT. Cox regression analyses were performed to evaluate whether PSA failure modeled as a time-dependent covariate was associated with an increased risk of ACM among men with Adult Comorbidity Evaluation-27–defined no or minimal versus moderate-to-severe comorbidity adjusting for age, PC prognostic factors, and treatment. Results After a median follow-up of 16.62 years, 156 men (76%) died, 29 of whom (19%) died as a result of PC. PSA failure was associated with an increased ACM risk among men with no or minimal (adjusted hazard ratio, 1.59; 95% CI, 1.03 to 2.46; P = .04), but not moderate or severe comorbidity (adjusted hazard ratio, 1.75; 95% CI, 0.76 to 3.99; P = .19). Conclusion Recommending treatment on the basis of reduced PSA failure observed from early results of RCTs is unlikely to prolong survival in men with moderate-to-severe comorbidity but may prolong survival in men with no or minimal comorbidity, providing evidence to support discussing the early results with these men.
Outcomes for elderly advanced stage non-small cell lung cancer (NSCLC) patients (pts) treated with bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P): Analysis of Eastern Cooperative Oncology Group (ECOG) 4599 study
Authors: S. S. Ramalingam, S. E. Dahlberg, C. J. Langer, R. Gray, C. P. Belani, J. R. Brahmer, A. Sandler, J. H. Schiller, D. H. Johnson
Journal: Journal of Clinical Oncology (2007)

7535 Background: PC administered in combination with bevacizumab extends survival for advanced non-squamous NSCLC pts. Based on SEER data, elderly pts (age ≥70 years) represent &gt;50% of all new cases of lung cancer and present unique therapeutic challenges. The ECOG 4599 database was analyzed to compare the outcomes in elderly pts treated with PCB vs. PC alone. Methods: Pts ≥ 70 years at study entry constituted the elderly cohort. Each arm (PCB vs. PC) and age group (≥70 vs. &lt;70) was compared with respect to baseline pt characteristics, response rate (RR), progression-free survival (PFS), survival and toxicity. Results: Out of 850 eligible pts, 26% (N=224) were ≥ 70 years of age (1.6% ≥ 80 years). Median age for the elderly was 74 yrs; 44% were ≥ 75 yrs. Baseline characteristics of the elderly cohort were similar to the younger group except for a higher proportion of males (62% vs. 52%, P = 0.005). For the elderly pts, there was a trend towards superior response rate (29% vs. 17%, P = 0.067) and median PFS (5.9 mos vs. 4.9 mos, P = 0.063) with PCB when compared to PC, though there was no difference in overall survival (PCB = 11.3 mos; PC = 12.1 mos; P = 0.4). Grades 3–5 toxicities (CTC version 2.0) were noted in 87% of elderly pts treated with PCB compared to 61% with PC (P &lt; 0.001). Treatment-related death rates with PCB vs. PC were 6.3% vs. 1.8% (NS) for the elderly. Febrile neutropenia (6% vs. 0.9%), proteinuria (8% vs. 0) and hypertension (6% vs. 0.9%) were more common with PCB than PC among the elderly. When compared to younger pts, the elderly experienced more neutropenia (34% vs. 22%), bleeding (7.9% vs. 3.2%), proteinuria (7.9% vs. 1.3%), muscle weakness (7.9% vs. 2.2%) and motor neuropathy (3.5% vs. 0.6%) with PCB. Conclusions: The proportion of elderly patients in ECOG 4599 is the highest recorded among ECOG phase III studies for advanced NSCLC. Increased toxicity with the addition of bevacizumab in those ≥ 70 yrs may have contributed to the absence of survival benefit for PCB vs PC, but this observation is limited by its post-hoc, retrospective nature. No significant financial relationships to disclose.
Spending and Quality of Care for Medicare Beneficiaries in Massachusetts—Reply
Authors: J. Michael McWilliams, Bruce E. Landon, Michael E. Chernew
Journal: JAMA (2013)

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Cell therapy with EBV-specific cytotoxic T-lymphocytes for patients with nasopharingeal carcinoma.
Authors: P. Comoli, S. Secondino, L. F. Licitra, R. Schiavo, I. Schiavetto, A. Gurrado, L. Locati, P. Pedrazzoli, F. Locatelli, S. Siena
Journal: Journal of Clinical Oncology (2010)

2509 Background: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related malignancy expressing a restricted set of viral antigens. The outcome of patients with NPC failing conventional radiochemotherapy is poor, the median overall survival of patients receiving second line treatments being less than two years. Hence, there is a need for alternative therapies capable of improving survival and associated with reduced toxicity. Methods: Since 2001, we have implemented a T-cell therapy program for patients with NPC failing conventional treatment. We have treated 27 patients with disease resistant/relapsing after >2 lines of radiochemotherapy in two sequential trials of cell therapy with autologous EBV-specific cytotoxic T-lymphocytes (CTL). In detail, EBV CTL (4 escalating doses to a maximum of 8×107 CTL/dose in the first trial, or 2 doses of 3-4 × 108 CTL in the second trial) were administered in patients without or with preceding lymphoablative chemotherapy and followed by low-dose recombinant human interleukin-2 (rhIL-2). The proportion of patients achieving response or stable disease lasting at least 3 months (RECIST criteria), as well as immunologic correlates of effective treatment, were evaluated. Results: Overall, the objective control of disease was 57%, with 6/27 patients showing complete (n=1), partial (n=4), and minimal (n=1) responses, and 10/27 disease stabilization (median duration 7 months). No severe adverse events were observed after cell therapy; 4 patients showed an inflammatory reaction at the tumor site. The use of preparative chemotherapy and increased CTL dose did not influence outcome. Importantly, patients showing response to cell therapy showed the emergence of EBV LMP2 antigen-specific T-cells in their peripheral blood. Conclusions: EBV-specific CTL therapy is safe and associated with clinical benefit in patients with advanced NPC refractory to standard therapies. The use of CTL with higher specificity for the EBV subdominant antigens expressed by the tumor, such as LMP2, at an earlier stage of disease, could further implement the strategy and ameliorate the outcome of patients with relapsing/refractory NPC. No significant financial relationships to disclose.
Role Of Maternal Immunization Against Low Frequency Human Platelet Antigens (LFHPA) In Neonatal Alloimmune Thrombocytopenia (NAIT)
Authors: Julie A. Peterson, Maria Gitter, Daniel W. Bougie, Shannon Pechauer, Kathleen Hopp, Brad Pietz, Aniko Szabo, Brian R. Curtis, Janice McFarland, Richard H. Aster
Journal: Blood (2013)