tbuckley/cabot-search huggingface dataset:
Ibrutinib in previously treated chronic lymphocytic leukemia patients with autoimmune cytopenias in the RESONATE study
Authors: M Montillo, S O'Brien, A Tedeschi, J C Byrd, C Dearden, D Gill, J R Brown, J C Barrientos, S P Mulligan, R R Furman, F Cymbalista, C Plascencia, S Chang, E Hsu, D F James, P Hillmen
Journal: Blood Cancer Journal (2017)

Autoimmune cytopenias occur in up to 10% of patients during the course of chronic lymphocytic leukemia (CLL), with autoimmune hemolytic anemia (AIHA) the most common, followed by immune-mediated thrombocytopenia (ITP). 1,2These disorders may occur at any time during disease course and depend on complex interactions between the malignant clone, impaired T-cell function, microenvironment and the immune system.2][3] Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase (BTK), is indicated by the US FDA for the treatment of patients with CLL/small lymphocytic lymphoma (SLL), including patients with 17p deletion, and allows for treatment without chemotherapy.In addition to BTK, ibrutinib targets members of the Tec kinase family, ITK and TEC, and TXK which may impact immune function. 4To address the impact of ibrutinib on CLL-associated AIHA/ITP, we retrospectively analyzed data from patients in the phase 3 RESONATE study comparing ibrutinib versus ofatumumab in previously treated CLL, including patients with history of ongoing complications of AIHA and/or ITP. 5 History of AIHA and/or ITP was collected as complications of CLL, including status at study entry (ongoing/resolved), from 386 patients who received study treatment for this analysis (n = 195 ibrutinib; n = 191 ofatumumab).Per the study protocol, AIHA was defined by at least one marker of hemolysis (indirect bilirubin above the upper limit of normal (ULN) not due to liver disease, increased lactate dehydrogenase (above ULN) without alternative etiology, or increased absolute reticulocytes (above ULN) or bone Both AIHA and ITPOngoing at study entry, n (%) 8 (4.1%) 6 (3.1%)Abbreviations: AIHA, autoimmune hemolytic anemia; ITP, immune-mediated thrombocytopenia.a AIHA reported as a grade 3/4 event in one patient.b ITP reported as a grade 3/4 event in both patients.
E-cadherin loss has a permissive but not active role in gastric cancer
Authors: Anita K. Dunbier, Parry J. Guilford
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2863 

Hereditary diffuse gastric cancer (HDGC) is a cancer predisposition syndrome caused by germline mutation of CDH1 , the gene encoding E-cadherin. CDH1 mutation carriers are predominantly affected by diffuse, poorly differentiated gastric cancer, although increased susceptibility to lobular breast cancer is also observed. For gastric cancer to develop in HDGC patients, expression of normal E-cadherin must be abrogated. However, the mechanisms through which this loss contributes to the development of gastric cancer are poorly understood. E-cadherin has been categorised as a tumour-suppressor on the basis of its ability to suppress invasion, yet the association of germline mutation of E-cadherin with HDGC and putative links to the Wnt signalling pathway have suggested that the protein could also play a role in tumour initiation. To investigate the consequences of E-cadherin loss in gastric cancer, in vitro and in vivo models of E-cadherin loss were studied using cDNA microarray analysis. Firstly, a gastric cancer cell line which does not express E-cadherin was stably transfected to generate cells which express E-cadherin in an inducible manner. RNA harvested at a range of different post-treatment timepoints after induction and following decay of the protein and was analysed on 30000-gene spotted cDNA arrays. In the second part of the study, gene expression profiles in sporadic gastric tumours were examined. Tumours were classified as having low, medium or high CDH1 expression and genes which correlated with CDH1 expression level were identified. Analysis of these two models of E-cadherin action suggested that the effects E-cadherin in gastric cancer are felt at the level of cell and tissue structure, rather than signalling and proliferation. Notably, expression of proliferative-associated genes including targets of the Wnt signalling pathway were unaffected by E-cadherin. Overall, these results suggest that loss of E-cadherin is necessary, but not sufficient for the development of gastric tumours in HDGC patients. Together with other recent findings in the field, this study supports a model in which reduction of the level of functional E-cadherin in the gastric epithelia of HDGC patients leads to pre-malignant lesions. For these lesions to progress to symptomatic gastric cancer further genetic events are necessary, suggesting that the role of E-cadherin in gastric cancer is permissive rather than active.
Commentary: Five changes to future proof the NHS
Authors: Alan Milburn
Journal: BMJ (2017)

England’s care system is at an inflection point. Demands are rising and performance is deteriorating. Siren voices are once again sounding the death knell of a “free at the point of use” NHS. They miss the point. What needs to change is not how it is funded but its level of resources and how it is organised. Change is necessary not only to respond to shifting patterns of demography and disease but to harness the benefits of advances in precision medicine, genomics, and data …
IL-2, IL-7, IL-15 and IL-6 Induce Differential Activation of Naive and Memory T Cell Subsets
Authors: Masahiro Hirakawa, Tiago R Matos, Edouard Forcade, Kathy S. Wang, Eduardo L Espada, Jennifer Whangbo, Carol G Reynolds, Marie J Chammas, Kazuyuki Murase, Jerome Ritz
Journal: Blood (2015)
Human CD34+ Cells Expressing Membrane-Bound Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Exert a Potent Anti-Lymphoma Effects by Targeting Tumor Vasculature.
Authors: Carmelo Carlo-Stella, Cristiana Lavazza, Arianna Giacomini, Daniela Sia, Loredana Cleris, Massimo Di Nicola, Paolo Longoni, Marco Milanesi, Michele Magni, Marco Righi, Maura Francolini, Annunziata Gloghini, Anna Guidetti, Antonino Carbone, Alessandro M. Gianni
Journal: Blood (2007)
A mouse model of MYCN-driven retinoblastoma reveals MYCN-independent tumor reemergence
Authors: Nan Wu, Deshui Jia, Breanna Bates, Ryan Basom, Charles G. Eberhart, David MacPherson
Journal: Journal of Clinical Investigation (2017)

The most frequent focal alterations in human retinoblastoma are mutations in the tumor-suppressor gene retinoblastoma (RB) and amplification of the oncogene MYCN. Whether MYCN overexpression drives retinoblastoma has not been assessed in model systems. Here, we have shown that Rb inactivation collaborates strongly with MYCN overexpression and leads to retinoblastoma in mice. Overexpression of human MYCN in the context of Rb inactivation increased the expression of MYC-, E2F-, and ribosome-related gene sets, promoted excessive proliferation, and led to retinoblastoma with anaplastic changes. We then modeled responses to MYCN-directed therapy by suppressing MYCN expression in MYCN-driven retinoblastomas. Initially, MYCN suppression led to proliferation arrest and partial tumor regression with loss of anaplasia. However, over time, retinoblastomas reemerged, typically without reactivation of human MYCN or amplification of murine Mycn. A subset of returning retinoblastomas showed genomic amplification of a Mycn target gene encoding the miR cluster miR-17~92, while most retinoblastomas reemerged without clear genetic alterations in either Mycn or known Mycn targets. This Rb/MYCN model recapitulates key genetic driver alterations seen in human retinoblastoma and reveals the emergence of MYCN independence in an initially MYCN-driven tumor.
CXCR3 Is Required for the Efficient Recruitment of Bone Marrow-Resident Memory T Cells to Inflamed Tissues,
Authors: Robbert van der Voort, Claudia Brandao, Thomas J. Volman, Viviènne Verweij, Klaas van Gisbergen, Bao Lu, Craig Gerard, Martijn A. Nolte, Harry Dolstra
Journal: Blood (2011)
IL7 Administration in Humans Results in Preferential Expansion of Naive and Memory CD4+ &amp; CD8+ T Cells with a Relative Decrease in Regulatory T-Cells (T-Regs).
Authors: Claude Sportes, Michael Krumlauf, Rebecca Babb, Ladan Foruraghi, Janine Daub, Daniele Avila, Catherine Chow, Hua Zhang, Kevin Chua, Terry Fry, Sarfraz Memon, Frances Hakim, Thomas Fleisher, Margaret Brown, Julie Engel, Renaud Buffet, Michel Morre, Ronald Gress, Crystal Mackall
Journal: Blood (2006)
Lead-in Stage Results of a Pivotal Trial of SL-401, an Interleukin-3 Receptor (IL-3R) Targeting Biologic, in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) or Acute Myeloid Leukemia (AML)
Authors: Kendra L. Sweet, Naveen Pemmaraju, Andrew A Lane, Anthony S. Stein, Sumithira Vasu, William Blum, David A. Rizzieri, Eunice S. Wang, Eric K. Rowinsky, Michael Szarek, Christopher L. Brooks, Sarah Disalvatore, David Liu, Madeleine Duvic, Jonathan D. Schwartz, Marina Konopleva
Journal: Blood (2015)
Factors influencing survival in inflammatory breast cancer.
Authors: Julie A. Cupp, Diane Liu, Yu Shen, Naoto T. Ueno, Ricardo H. Alvarez, Mariana Chavez-Mac Gregor, Wendy A. Woodward, Takahiro Kogawa, Gildy Babiera
Journal: Journal of Clinical Oncology (2014)

136 Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer associated with poor prognosis, characterized by rapidly growing mass, skin changes, and regional adenopathy. The objective of this study was to determine if delay in treatment influenced survival in IBC patients. Methods: A prospective IBC database identified 93 women with stage III IBC who received care at MD Anderson from 2007 - 2012 and were retrospectively reviewed. All patients received neoadjuvant chemotherapy followed by surgery, unless progression of disease was noted, and postmastectomy radiation. Impact of time from onset of symptoms to chemotherapy or to surgery on overall survival (OS) and progression free survival (PFS) were evaluated after adjusting for the baseline covariates in the Cox model. Results: A majority of patients were white (77.4%) with an average age of 54 years. Average days from onset of symptoms to first chemo is 95 (range 16 – 387) and to surgery is 283 (range 184 – 585). Four patients had progression while on chemo. There were 14 deaths with median follow up of 2.6 years from diagnosis. In univariate analysis, delay in treatment, &gt; 90 days from onset of symptoms to chemo, did not affect OS or PFS. Obtaining negative margins was statistically significant for OS and PFS measured from first chemo (p=0.005 and p=0.007). Positive HER-2 status was associated with longer PFS time from chemo (p=0.02, log-rank test) and from surgery (p=0.009). Positive progesterone receptor (PR) was found to be statistically significantly associated with longer OS time from chemo (p=0.01) and from surgery (p=0.03). Clinical and imaging response to chemo were associated with better OS (p=0.007 and p=0.005) and pathologic response was marginally associated with improved OS and PFS (p=0.07 and p=0.06), both measured from surgery. In multivariate Cox model, adjusting for PR or HER2, days from onset of symptoms to chemo or surgery did not have significant impact on OS or PFS. Conclusions: While traditionally delay diagnosis and treatment is considered one of the factors associated with poor prognosis, our study suggests otherwise. However, due to such rapid progression of disease, early diagnosis is still important in the overall management of patients diagnosed with IBC.
Gene Mutations Detected by Whole-Exome Sequencing and Recurrent Cytogenetic Abnormalities Are Independent Events in Multiple Myeloma
Authors: Hervè Avet-Loiseau, Graham R Bignell, Cheng Li, Florence Magrangeas, Thierry Facon, Michel Attal, Kenneth C. Anderson, Peter Campbell, Stephane Minvielle, Nikhil C. Munshi, Andrew Futreal
Journal: Blood (2011)
MNGO-07PROGNOSTIC FACTORS ASSOCIATED WITH OUTCOME OF CONSERVATIVE MANAGEMENT OF INTRACRANIAL MENINGIOMAS; A THREE-DIMENSIONAL VOLUMETRIC STUDY
Authors: Jin-Deok Joo, Chae-Yong Kim, Jung Ho Han, Young-Hoon Kim, Min Mi Lee
Journal: Neuro-Oncology (2015)

BACKGROUND: Despite asymptomatic meningiomas are typically dealt with ‘wait and see’ policy, data to predict which meningioma patients will fail to respond to conservative management are lacking. METHODS: Between 2003 and 2012, 178 patients with 205 meningiomas were managed with clinical and radiographical follow up for two years or longer without any kind of therapeutic intervention. Data were analyzed according to age, sex, tumor location, symptoms, initial tumor diameter, calcification, MR imaging intensity, and edema.3-dimensional volumetric analysis was also conducted in 205 meningiomas. RESULTS: Among 205 meningiomas, 156 meningiomas (76%) were maintaining clinico-radiographic observation but 49 (24%) meningiomas eventually had treatment after two years or longer period of clinico-radiological observation. The median tumor volume in treated patient group was 4.64cc initially, and 7.62cc just prior to the treatment with a mean follow-up of 45.9 months. The median tumor volume in untreated patient group was 1.96cc initially and 2.77cc at the end of observation with a mean follow-up of 54.8 months. The annual tumor growth rate was 0.93cc/year in treated group, and 0.03cc/year in untreated group. Kaplan-Meier analysis and Cox proportional hazards regression with Binary logistic regression analysis revealed that tumor growth rate not less than 1cc/yr (hazard ratio [HR] 9,705, 95% CI 3.91–24.73, p < 0.001) and the absence of calcification (HR 3.015, 95% CI 1.32-6.88, p < 0.0009) were factors associated with cessation of observation. CONCLUSIONS: Although the authors could obtain variable results depending on the measurement method, the data demonstrate that meningiomas characterized by volumetric tumor growth not less than 1cc/year and absence of calcification have high likelihood of undergoing treatment ultimately.
Identification and Characterization of a Hematopoietic Stem Cell Niche in Spleen
Authors: Takuo Mizukami, Isao Hamaguchi, Kazuya Takizawa, Madoka Kuramitsu, Haruka Momose, Seishiro Naito, Atsuko Masumi, Seiji Okada, Kazunari Yamaguchi
Journal: Blood (2008)
Selegiline, or the problem of early termination of clinical trials
Authors: M. M B Breteler
Journal: BMJ (1998)

Parkinson's disease is the second most common neurodegenerative disorder, after dementia. About 1.4% of people aged 55 years or over have Parkinson's disease,1 and because of the aging of Western populations the absolute number of patients is rapidly increasing. Until now, treatment has been mainly symptomatic, but much effort is being put into developing neuroprotective agents that may stop progression or even cure the disease. Clearly, unrecognised adverse effects of such treatments may potentially affect large numbers of patients and any suggestion of such effects needs thorough investigation.

Selegiline has probably become the most controversial drug in Parkinson's disease during the past decade. Its presumed efficacy was initially ascribed to neuroprotection due to inhibition of monoamine oxidase-B, then to a symptomatic effect, and more recently again to neuroprotection, this time due to inhibition of apoptosis. The greatest controversy, however, occurred because selegiline caused the early termination of the intervention arms of two large multicentre studies—for completely different reasons. In the DATATOP study of the US Parkinson Study Group subjects randomised to receive selegiline did better than those randomised to placebo or tocopherol in that they reached the endpoint (start of levodopa treatment) significantly later.2 In …
Increased BACE1-AS long noncoding RNA and β-amyloid levels in heart failure
Authors: Simona Greco, Germana Zaccagnini, Paola Fuschi, Christine Voellenkle, Matteo Carrara, Iman Sadeghi, Claudia Bearzi, Biagina Maimone, Serenella Castelvecchio, Konstantinos Stellos, Carlo Gaetano, Lorenzo Menicanti, Fabio Martelli
Journal: Cardiovascular Research (2017)

Antisense long noncoding RNAs (ncRNAs) are transcripts emerging from the opposite strand of a coding-RNA region and their role in heart failure (HF) is largely unknown. Additionally, HF and Alzheimer's disease (AD) share several non-genetic effectors and risk factors. We investigated the regulation of the β-secretase-1 (BACE1) gene and of its antisense transcript BACE1-AS in ischaemic HF.BACE1 and BACE1-AS expression was measured in left ventricle biopsies from 18 patients affected by non-end stage ischaemic HF and 17 matched controls. The levels of both transcripts were increased in HF patients. Likewise, both transcripts increased also in a mouse model of ischaemic HF, and their expression was directly correlated. BACE1-AS was expressed by all cardiac cell types and BACE1-AS up- or down-modulation in cultured cardiomyocytes and endothelial cells induced a concordant regulation of the cognate BACE1 transcript. Interestingly, BACE1 increase also induced the intracellular accumulation of its product β-amyloid. In keeping with these findings, higher BACE1 protein and β-amyloid peptide levels were also observed in HF. Moreover, increased β-amyloid 1-40 was also found in the plasma of HF patients. Transcriptomic changes of BACE1-AS overexpressing and β-amyloid 1-40 treated cells were largely overlapping and indicated changes of relevant biological process such as 'cell cycle and proliferation', 'apoptosis', and 'DNA repair' as well as 'TGFβ-, TNFα-, p38-, EGFR-signalling', suggesting a potential maladaptive role of the BACE1-AS/BACE1/β-amyloid axis. Accordingly, the administration of β-amyloid peptides decreased the cell viability in endothelial cells and in both human IPS-derived and mouse cardiomyocytes. Moreover, both β-amyloid treatment and BACE1-AS overexpression increased endothelial cell apoptosis, and this effect was prevented by BACE1 silencing.Given the neurotoxic role of β-amyloid in AD, dysregulation of the BACE1/BACE1-AS/β-amyloid axis might be relevant in HF pathogenesis, further implicating ncRNAs in the complex scenario of proteotoxicity in cardiac dysfunction.
Advancing access and equity: the vision of a new generation in cancer control
Authors: André M Ilbawi, Elizabeth Ayoo, Afsan Bhadelia, Runcie C W Chidebe, Temidayo Fadelu, Cristian A Herrera, Han Win Htun, Nauman Arif Jadoon, Oluwafunmilola W James, Leana May, Mauricio Maza, Mellany Murgor, Yetty M Nency, Chukwuma Oraegbunam, Mandi Pratt-Chapman, Xiaojian Qin, Danielle Rodin, Neha Tripathi, Zoe Wainer, Mei Ling Yap
Journal: The Lancet Oncology (2017)
International Exchange and American Medicine
Authors: Katrina Armstrong, Mark E. Anderson, John M. Carethers, Joseph Loscalzo, Michael S. Parmacek, Robert M. Wachter, Mark L. Zeidel
Journal: New England Journal of Medicine (2017)

of title 3, United States Code, and to protect the American people from terrorist attacks by foreign nationals admitted to the United States, it is hereby ordered as follows:Section 1. Purpose.The visa-issuance process plays a crucial role in detecting individuals with terrorist ties and stopping them from entering the United States.Perhaps in no instance was that more apparent than the terrorist attacks of September 11, 2001, when State Department policy prevented consular officers from properly scrutinizing the visa applications of several of the 19 foreign nationals who went on to murder nearly 3,000 Americans.And while the visa-issuance process was reviewed and amended after the September 11 attacks to better detect would-be terrorists from receiving visas, these measures did not stop attacks by foreign nationals who were admitted to the United States.Numerous foreign-born individuals have been convicted or implicated in terrorism-related crimes since September 11, 2001, including foreign nationals who entered the United States after receiving visitor, student, or employment visas, or who entered through the United States refugee resettlement program.Deteriorating conditions in
Impact of Mandibular Advancement Therapy on Endothelial Function in Severe Obstructive Sleep Apnea
Authors: Frédéric Gagnadoux, Jean-Louis Pépin, Bruno Vielle, Vanessa Bironneau, Frédérique Chouet-Girard, Sandrine Launois, Nicole Meslier, Jean-Claude Meurice, Xuan-Lan Nguyen, Audrey Paris, Pascaline Priou, Renaud Tamisier, Wojciech Trzepizur, François Goupil, Bernard Fleury
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Endothelial dysfunction, a major predictor of late cardiovascular events, is linked to the severity of obstructive sleep apnea (OSA).Objectives: To determine whether treatment with mandibular advancement device, the main alternative to continuous positive airway pressure, improves endothelial function in patients with severe OSA.Methods: In this trial, we randomized patients with severe OSA and no overt cardiovascular disease to receive 2 months of treatment with either effective mandibular advancement device or a sham device. The primary outcome, change in reactive hyperemia index, a validated measurement of endothelial function, was assessed on an intention-to-treat basis. An embedded microsensor objectively measured treatment compliance.Measurements and Main Results: A total of 150 patients (86% males; mean [SD] age, 54 [10] yr; median [interquartile range] apnea–hypopnea index, 41 [35–53]; mean [SD] Epworth sleepiness scale, 9.3 [4.2]) were randomized to effective mandibular advancement device (n = 75) or sham device (n = 75). On intention-to-treat analysis, effective mandibular advancement device therapy was not associated with improvement of endothelial function compared with the sham device. Office and ambulatory blood pressure outcomes did not differ between the two groups. Effective mandibular advancement device therapy was associated with significant improvements in apnea–hypopnea index (P < 0.001); microarousal index (P = 0.008); and symptoms of snoring, fatigue, and sleepiness (P < 0.001). Mean (SD) objective compliance was 6.6 (1.4) h/night with the effective mandibular advancement device versus 5.6 (2.3) h/night with the sham device (P = 0.006).Conclusions: In moderately sleepy patients with severe OSA, mandibular advancement therapy reduced OSA severity and related symptoms but had no effect on endothelial function and blood pressure despite high treatment compliance.Clinical trial registered with www.clinicaltrials.gov (NCT 01426607).