tbuckley/cabot-search huggingface dataset:
The interferon paradox: can inhibiting an antiviral mechanism advance an HIV cure?
Authors: Steven G. Deeks, Pamela M. Odorizzi, Rafick-Pierre Sekaly
Journal: Journal of Clinical Investigation (2016)

While antiretroviral therapy (ART) has improved the quality of life and increased the life span of many HIV-infected individuals, this therapeutic strategy has several limitations, including a lack of efficacy in fully restoring immune function and a requirement for life-long treatment. Two studies in this issue of the JCI use a humanized mouse model and demonstrate that type I interferon (IFN) is induced early during HIV infection and that type I IFN-associated gene signatures persist, even during ART. Importantly, blockade of type I IFN improved immune function, reduced the HIV reservoir, and caused a delay in viral rebound after ART interruption. Together, these two studies support further evaluation of IFN blockade as a supplement to ART.
No Benefit of Adding High-Dose Melphalan (HDM) Suppported by Autologous Stem Cell Transplantation (SCT) over Treatment with Conventional Induction, HD ARAC Consolidation, and Auto SCT (Busulfan + HDM) for Acute Myelogenous Leukemia (AML) under 60: First Results of the Randomized AML 2001 Trial.
Authors: B. Lioure, A. Pigneux, C. Recher, F. Witz, T. Lamy, N. Fegueux, C.E. Bulabois, N. Ifrah, I. Luquet, D. Bouscary, N. Vey, M. Delain, J.O. Bay, P. Turlure, Jean-Luc Harousseau
Journal: Blood (2006)
Overexpression of the LEF-1 and TCF4 Transcription Factors in B-CLL: Further Evidence for a Role of the Wnt Signaling Pathway in B-CLL Biology and Leukemogenesis
Authors: Albert Gutierrez, Renee Tschumper, Jeanette Eckel-Passow, Neil E. Kay, Diane F. Jelinek
Journal: Blood (2008)
The genome and transcriptome of Japanese flounder provide insights into flatfish asymmetry
Authors: Changwei Shao, Baolong Bao, Zhiyuan Xie, Xinye Chen, Bo Li, Xiaodong Jia, Qiulin Yao, Guillermo Ortí, Wenhui Li, Xihong Li, Kristin Hamre, Juan Xu, Lei Wang, Fangyuan Chen, Yongsheng Tian, Alex M Schreiber, Na Wang, Fen Wei, Jilin Zhang, Zhongdian Dong, Lei Gao, Junwei Gai, Takashi Sakamoto, Sudong Mo, Wenjun Chen, Qiong Shi, Hui Li, Yunji Xiu, Yangzhen Li, Wenteng Xu, Zhiyi Shi, Guojie Zhang, Deborah M Power, Qingyin Wang, Manfred Schartl, Songlin Chen
Journal: Nature Genetics (2016)

Songlin Chen, Manfred Schartl, Qingyin Wang, Deborah M. Power and colleagues analyze the genome of the Japanese flounder and its transcriptome dynamics during metamorphosis. They report a role for thyroid hormone and retinoic acid signaling, as well as phototransduction pathways, in the regulation of craniofacial asymmetry. Flatfish have the most extreme asymmetric body morphology of vertebrates. During metamorphosis, one eye migrates to the contralateral side of the skull, and this migration is accompanied by extensive craniofacial transformations and simultaneous development of lopsided body pigmentation1,2,3,4,5. The evolution of this developmental and physiological innovation remains enigmatic. Comparative genomics of two flatfish and transcriptomic analyses during metamorphosis point to a role for thyroid hormone and retinoic acid signaling, as well as phototransduction pathways. We demonstrate that retinoic acid is critical in establishing asymmetric pigmentation and, via cross-talk with thyroid hormones, in modulating eye migration. The unexpected expression of the visual opsins from the phototransduction pathway in the skin translates illumination differences and generates retinoic acid gradients that underlie the generation of asymmetry. Identifying the genetic underpinning of this unique developmental process answers long-standing questions about the evolutionary origin of asymmetry, but it also provides insight into the mechanisms that control body shape in vertebrates.
Tackling Bet v 1 and associated food allergies with a single hybrid protein
Authors: Heidi Hofer, Claudia Asam, Michael Hauser, Birgit Nagl, Josef Laimer, Martin Himly, Peter Briza, Christof Ebner, Roland Lang, Thomas Hawranek, Barbara Bohle, Peter Lackner, Fátima Ferreira, Michael Wallner
Journal: Journal of Allergy and Clinical Immunology (2016)

Allergy vaccines should be easily applicable, safe, and efficacious. For Bet v 1-mediated birch pollen and associated food allergies, a single wild-type allergen does not provide a complete solution.We aimed to combine immunologically relevant epitopes of Bet v 1 and the 2 clinically most important related food allergens from apple and hazelnut to a single hybrid protein, termed MBC4.After identification of T cell epitope-containing parts on each of the 3 parental allergens, the hybrid molecule was designed to cover relevant epitopes and evaluated in silico. Thereby a mutation was introduced into the hybrid sequence, which should alter the secondary structure without compromising the immunogenic properties of the molecule.MBC4 and the parental allergens were purified to homogeneity. Analyses of secondary structure elements revealed substantial changes rendering the hybrid de facto nonreactive with patients' serum IgE. Nevertheless, the protein was monomeric in solution. MBC4 was able to activate T-cell lines from donors with birch pollen allergy and from mice immunized with the parental allergens. Moreover, on immunization of mice and rabbits, MBC4 induced cross-reactive IgG antibodies, which were able to block the binding of human serum IgE.Directed epitope rearrangements combined with a knowledge-based structural modification resulted in a protein unable to bind IgE from allergic patients. Still, properties to activate specific T cells or induce blocking antibodies were conserved. This suggests that MBC4 is a suitable vaccine candidate for the simultaneous treatment of Bet v 1 and associated food allergies.
Febrile neutropenia in adjuvant docetaxel and cyclophosphamide (TC) with prophylactic pegfilgrastim in patients with breast cancer: A retrospective analysis.
Authors: N. Ngamphaiboon, P. P. Advani, T. L. O'Connor, F. O. Ademuyiwa, E. G. Levine, G. Riebandt, E. B. Kossoff
Journal: Journal of Clinical Oncology (2011)

1134 Background: US Oncology Research Trial 9735 reported that TC improved overall survival when compared to AC in early stage breast cancer (BC). Despite 61% grade 3-4 neutropenia in TC arm, only 5% of patients developed febrile neutropenia (FN), and this study did not use prophylactic GCSF. TC has risen in popularity, particularly in older patients or in those where an anthracycline is contraindicated. Other studies examining the toxicity of TC have reported an incidence of FN between 25-46%. One study reported that when prophylactic GCSF was added to the TC regimen, FN decreased from 25% to 6.3%. Though prophylactic GCSF support during TC is not yet recommended in standard guidelines, it has been adopted in clinical practice. We reviewed our institutional experience with prophylactic pegfilgrastim (PEG) and the TC regimen. Methods: Patients treated with adjuvant TC and PEG at Roswell Park Cancer Institute were identified through the pharmacy database between 5/2006-7/2010. Patient characteristics, co-morbidities, and Charlson Co-morbidity Index (CCI) were abstracted. Endpoints included incidence of FN, hematologic toxicities (defined by CTCAE V.4), relative dose intensity (RDI), delay, dose reduction, hospitalization, and discontinuation of TC. Docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 were given on day 1 of a 21-day/cycle for a planned 4 cycles. PEG 6 mg was administered on day 3 of each cycle in all patients. Results: 101 women with median age of 56 years (range 27-79) were identified. 23% of patients were ≥65 at diagnosis. 80 patients (79%) had CCI 0-1. 8 patients developed FN (8%). Grade 3-4 neutropenia and anemia were reported in 10 (10%) and 3 (3%). TC was discontinued due to toxicity in 16 patients (16%). Dose reductions occurred in 6 (6%), delay in 6 (6%), and hospitalization in 17 (17%). Administration of docetaxel and cyclophosphamide with RDI ≥85% was achieved in 83 (82%) and 86 (85%) patients respectively. Conclusions: Despite prophylactic PEG, the incidence of FN was 8%, which is consistent with other studies. Primary prophylactic growth factor support should be strongly considered in breast cancer patients who receive adjuvant TC chemotherapy.
Basoluminal and luminal phenotypes in triple-negative breast cancer: Immunohistochemical profiling and survival.
Authors: H. Sinn, Z. Elsawaf, J. L. Bermejo, S. Aulmann, J. Rom, A. Schneeweiss
Journal: Journal of Clinical Oncology (2011)

1098 Background: Triple negative breast cancer (TNBC), one of the major subgroups of breast cancer, is frequently characterized by the expression basal cytokeratins. We have investigated the characteristics and patient survival of basal, luminal, and mixed type TNBC. Methods: The expression of basal and luminal cytokeratins (CK5/6, CK7, CK14, CK18, CK19), and other biomarkers (Ki-67, p53, p16, EGFR, c-KIT, bcl2, WT1, vimentin) was determined by immunohistochemistry on TMA sections from 142 TNBCs diagnosed in a single institution. Expression data were subjected to unsupervised cluster analysis and compared regarding clinicopathologic data and patient survival (med. follow-up 52.7 months). Results: Basal markers were positive in 68% of tumors, with frequent coexpression of luminal markers (basoluminal phenotype, 57%) and only 11% showed a pure basal phenotype. A pure luminal phenotype was seen in 27% of cases and 5% were immature (belonging to neither phenotype). These four groups differed significantly with respect to proliferation rates (median Ki-67 for pure basal 80%, basoluminal 45%, luminal 30%, and immature 50%). Expression of p16, EGFR, and CD117 was increased in the basal and immature groups. Luminal and basoluminal phenotypes were associated with better tumor differentiation and less lymphocytic infiltrate. Hierarchical unsupervised cluster analysis on the expression of all 13 immunohistochemical markers identified four clusters with the main distinguishing feature being their intermediate filament expression. 5-year overall survival rates were higher for pure basal and immature clusters (93.5% and 87.5%) than rates for luminal and basoluminal clusters (71.5% and 73.5%, p 0.016). This classification remained a significant predictor of survival in a multivariate Cox model that also included tumor stage, grade, and lymph node status with an estimated hazard ratio of 0.26 (95% CI: 0.09 - 0.72) for the basal and immature clusters combined. Conclusions: Triple negative breast cancers can be classified into four distinct clusters based on biomarker expression. These clusters show specific clinicopathological features and decreased survival in the basoluminal and luminal clusters.
Treatment (trx) patterns of angiogenesis inhibitors in patients (pts) with metastatic renal cell carcinoma (mRCC) in Ireland.
Authors: R. S. McDermott, P. P. Donnellan, J. McCaffery, S. P. Sarda, C. Korves, A. Luka, R. Wei, M. Neary, R. Hanley, M. S. Duh
Journal: Journal of Clinical Oncology (2011)

383 Background: This study evaluated rates of trx modifications and reasons for these changes among pts treated with angiogenesis inhibitors in Irish clinical practice. Methods: Data from medical records were retrospectively reviewed at 3 large oncology centers in Ireland for mRCC pts who were ≥ 18 years and received sunitinib (SU) (n=54), sorafenib (n=9), bevacizumab (n=6), or temsirolimus (n=7) as first-line trx from 1/1/2005 to 8/31/2010. Proportions of pts with trx discontinuation (d/c), interruption, or dose change, and reasons for modifications and time to modifications were determined. Results: Due to small sample sizes in other groups, only results for SU are summarized. 1.9% of pts had prior cytokine therapy. Median first-line trx duration for SU was 8.7 months (mo), while median progression-free survival was 13.8 mo. 87% of patients treated with first-line SU experienced adverse events (AEs); 18.5% experienced grade 3/4 AEs. AEs led to trx modifications in 42.6% of pts. 94.4% of pts started trx on 50 mg QD 4/2 dosing; 33.3% of them were dose reduced to 37.5 mg QD 4/2 with median time to reduction 2.7 mo. Among pts who discontinued trx, 31.6% discontinued within 18 weeks (w) (15.8% within 0-6 w, 7.9% in 7-12 w, and 7.9% in 13-18 w). Among pts who discontinued trx within 18 w, 66.7% discontinued due to AEs. Conclusions: Over three-quarters of SU pts experienced trx modifications, more than half due to AEs. About 24% of txt discontinuations occurred within the first two cycles. This real-world practice study suggests that treatment tolerability is a challenge for physicians in the clinical care of mRCC pts. [Table: see text] [Table: see text]
Graft-Versus-Host Disease Following Myeloablative Busulfan Plus Fludarabine and Busulfan Plus Cyclophosphamide For Allogeneic Hematopoietic Stem Cell Transplantation In Acute Myeloid Leukemia In First Complete Remission
Authors: Qifa Liu, Hui Liu, Daihong Liu, Yongrong Lai, Jing Sun, Chaoyang Song, Yu Zhang, Yang Xiao, Fen Huang, Hongsheng Zhou, Zhiping Fan, Xutao Guo, Danian Nie, Guopan Yu, Xiaojun Huang
Journal: Blood (2013)
Impaired prohormone processing: a grand unified theory for features of Prader-Willi syndrome?
Authors: Joseph Polex-Wolf, Giles S.H. Yeo, Stephen O’Rahilly
Journal: Journal of Clinical Investigation (2016)

Prader-Willi syndrome (PWS) is a complex disorder that manifests with an array of phenotypes, such as hypotonia and difficulties in feeding during infancy and reduced energy expenditure, hyperphagia, and developmental delays later in life. While the genetic cause has long been known, it is still not clear how mutations at this locus produce this array of phenotypes. In this issue of the JCI, Burnett and colleagues used a comprehensive approach to gain insight into how PWS-associated mutations drive disease. Using neurons derived from PWS patient induced pluripotent stem cells (iPSCs) and mouse models, the authors provide evidence that neuroendocrine PWS-associated phenotypes may be linked to reduced expression of prohormone convertase 1 (PC1). While these compelling results support a critical role for PC1 deficiency in PWS, more work needs to be done to fully understand how and to what extent loss of this prohormone processing enzyme underlies disease manifestations in PWS patients.
All Trans-Retinoic Acid (ATRA) in Combination with PPAR-g Ligand Synergistically Enhances Inhibition of Cell Growth and Induction of Tumor Suppressor PTEN in Leukemic Cells.
Authors: Jinny Park, Young-Rae Lee, Hyun-Jaung Shim, Jae-Young Kwak, Chang-Yeoul Yim, Eun-Kyung Song, Myung-Kwan Han, Jin-Woo Park, Hye-Won Rho, Sang-Young Lee, Jong-Suk Kim
Journal: Blood (2004)
Two-year PSA outcomes after cesium prostate brachytherapy.
Authors: R. Smith, B. L. Jacobs, S. Beriwal, R. M. Benoit
Journal: Journal of Clinical Oncology (2011)

92 Background: Given the long natural history of prostate cancer, long term follow up is needed to definitively know the efficacy of a new treatment, in this case 131 Cs brachytherapy. However, it is also important to report on short term outcomes to ensure that this treatment is on course to provide equivalent outcomes as compared to existing treatment options. This reports two year PSA outcomes in men undergoing prostate brachytherapy with cesium 131 at a single institution. Methods: All patients who underwent prostate brachytherapy with 131 Cs and had at least 24 months of follow up were included in this study. Results are reported for the total cohort and stratified by risk group as well as treatment received (monotherapy, combination therapy, or trimodal therapy). The Phoenix definition was used to define biochemical disease free survival (bDFS). Outcomes were analyzed using descriptive statistics. Results: 115 patients underwent prostate brachytherapy with 131 Cs and had at least 24 months of follow up. Fifty two (45.2%) patients were classified as low risk, 52 (45.2%) were intermediate risk, and 11 (9.6%) were high risk. Eighty one patients were treated with prostate brachytherapy as monotherapy, including six patients who received androgen-deprivation therapy (ADT) in combination with their brachytherapy. Twenty five patients received combination therapy, and 9 patients received trimodal therapy. Specifics of bDFS rates and PSA data are reported in the table. Of the 115 patients four had biochemical recurrence. Two patients died during the study period, both due to causes other than prostate cancer, and one patient was unwilling to obtain a PSA at the 24 month follow up time point. Conclusions: The first 115 patients who have undergone prostate brachytherapy with 131 Cs at our institution have a bDFS rate of 96.4% 24 months after their procedure. With the very important caveat that only short term results are reported, 131 Cs appears to be on course to achieve results comparable to those achieved with iodine 125 ( 125 I) and palladium 103 ( 103 Pd). [Table: see text] No significant financial relationships to disclose.
Activity of toremifene in sporadic desmoid-type fibromatosis.
Authors: M. Fiore, C. Colombo, S. Radaelli, P. Prestianni, R. Sanfilippo, C. Morosi, F. Perrone, S. Stacchiotti, P. G. Casali, A. Gronchi
Journal: Journal of Clinical Oncology (2011)

10033 Background: Hormoneal therapy is one of the most common conservative approaches to desmoid-type fibromatosis (DF). Tamoxifene has been so far the preferred compound. Anecdotal cases treated by Toremifene (T) have also been described. Its mechanism of action is not completely understood, but a possible role in regulating the level of TGF-β and its receptors has been suggested. Aim of the study was to further investigate the feasibility and activity of T in DF. Methods: All consecutive patients affected by sporadic DF, either primarily or secondarily treated with T on a named basis, were prospectively collected. Indication for therapy were either progressive disease and/or pain. Drug schedule was 180 mg daily, until progression or toxicity. Disease assessment was performed by contrast-enhanced MRI or CT scan, pain evaluation by a visual analog scale (VAS) every 3 months. Response was evaluated either by RECIST and/or symptomatic relief. Results: Between 2008 and 2010, 27 patients (F/M ratio = 2.9) were treated at median age of 46.6 years (range, 27-83); 15 patients had primary DF and 12 recurrent. DFs were located in upper limb in 2 patients, thoracic girdle in 9, trunk in 12, pelvic in 2, mesentery in 2. Indication to T was severe pain in 44.4% (12/27), progressive disease in 40.7% (11/27), both in 7.4% (2/27), other in 7.4%. Early T withdrawal was needed in a young patient due to metrorrhagia; 2 more patients experienced moderate side effects, controlled by dose adjustment. RECIST best response was SD in 70.3% (19/27), PR in 22.2% (6/27), PD in 7.4% (2/27). Median TTP was 4 months for those who progressed. Symptomatic relief was achieved in 79% (11/14) of patient initially treated for severe pain with median time to benefit of 3 months. Among the subset of pre-treated patients who experienced PD on tamoxifen, 1/9 had PR after toremifene, 7/9 had SD (of which 5/7 had pain relief), 1/9 had PD. Overall 81.5% of patients got symptomatic and/or radiological response. Progression-free survival was 76% at 6 months. Conclusions: Toremifene seems active and well tolerated. Symptomatic relief is often obtained. Previous progression on tamoxifen should not be considered a contraindication to T. A formal phase II study could be conducted.
Clinical Diagnosis of Mental Disorders Before Cancer Diagnosis
Authors: Jasmina Mallet, Caroline Dubertret, Olivier Huillard
Journal: JAMA Oncology (2016)

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The active bacterial assemblages of the upper GI tract in individuals with and without <i>Helicobacter</i> infection
Authors: Christian Schulz, Kerstin Schütte, Nadine Koch, Ramiro Vilchez-Vargas, Melissa L Wos-Oxley, Andrew P A Oxley, Marius Vital, Peter Malfertheiner, Dietmar H Pieper
Journal: Gut (2016)

Patients infected with Helicobacter pylori develop chronic gastritis with a subgroup progressing to further complications. The role of microbiota from the oral cavity swallowed with saliva and either transiting the stomach or persisting in the gastric mucosa is uncertain. It is also not known whether the bacterial community differs in luminal and mucosal niches. A key question is whether H. pylori influences the bacterial communities of gastroduodenal niches.Saliva, gastric and duodenal aspirates as well as gastric and duodenal biopsies were collected during oesophagogastroduodenoscopy from 24 patients (m:9, f:15, mean age 52.2±SD 14.5 years). RNA was extracted and the V1-V2 region of the retrotranscribed bacterial 16S rRNA amplified and sequenced on the Illumina MiSeq platform.Overall, 687 bacterial phylotypes that belonged to 95 genera and 11 phyla were observed. Each individual comprised a unique microbiota composition that was consistent across the different niches. However, the stomach fluid enriched for specific microbiota components. Helicobacter spp were shown to dominate the mucosa-associated community in the stomach, and to significantly influence duodenal and oral communities.The detailed analysis of the active global bacterial communities from the five distinct sites of the upper GI tract allowed for the first time the differentiation between host effects and the influence of sampling region on the bacterial community. The influence of Helicobacter spp on the global community structures is striking.
Further Evaluation of Pro-Atherogenic and Anti-Angiogenic Effects of Nilotinib in Mice and in Patients with Ph-Chromosome+ CML
Authors: Emir Hadzijusufovic, Karin Albrecht-Schgoer, Kilian Huber, Florian Grebien, Gregor Eisenwort, Wilfried Schgoer, Christoph Kaun, Susanne Herndlhofer, Markus Theurl, Sabine Cerny-Reiterer, Gregor Hoermann, Wolfgang R Sperr, Uwe Rix, Irina Sadovnik, Bernd Jilma, Gerit Holger Schernthaner, Johann Wojta, Dominik Wolf, Giulio Superti-Furga, Rudolf Kirchmair, Peter Valent
Journal: Blood (2014)
Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease
Authors: Anamitra Ghosh, Trevor Tyson, Sonia George, Erin N. Hildebrandt, Jennifer A. Steiner, Zachary Madaj, Emily Schulz, Emily Machiela, William G. McDonald, Martha L. Escobar Galvis, Jeffrey H. Kordower, Jeremy M. Van Raamsdonk, Jerry R. Colca, Patrik Brundin
Journal: Science Translational Medicine (2016)

Mitochondrial pyruvate carrier may be a therapeutic target in Parkinson’s disease.
Disease Characteristics, Treatment Patterns, and Outcomes of Follicular Lymphoma in Patients 40 Years of Age and Younger: An Analysis from the National LymphoCare Study
Authors: Carla Casulo, Michelle Byrtek, Keith L Dawson, Xiaolei Zhou, Christopher R. Flowers, Charles M. Farber, John D Hainsworth, James R Cerhan, Brian K Link, Jonathan W Friedberg
Journal: Blood (2014)