tbuckley/cabot-search huggingface dataset:
Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier
Authors: Monica Corada, Fabrizio Orsenigo, Ganesh Parameshwar Bhat, Lei Liu Conze, Ferruccio Breviario, Sara Isabel Cunha, Lena Claesson-Welsh, Galina V. Beznoussenko, Alexander A. Mironov, Marco Bacigaluppi, Gianvito Martino, Mara E. Pitulescu, Ralf H. Adams, Peetra Magnusson, Elisabetta Dejana
Journal: Circulation Research (2018)

The microvasculature of the central nervous system includes the blood-brain barrier (BBB), which regulates the permeability to nutrients and restricts the passage of toxic agents and inflammatory cells. Canonical Wnt/β-catenin signaling is responsible for the early phases of brain vascularization and BBB differentiation. However, this signal declines after birth, and other signaling pathways able to maintain barrier integrity at postnatal stage are still unknown.Sox17 (SRY [sex-determining region Y]-box 17) constitutes a major downstream target of Wnt/β-catenin in endothelial cells and regulates arterial differentiation. In the present article, we asked whether Sox17 may act downstream of Wnt/β-catenin in inducing BBB differentiation and maintenance.Using reporter mice and nuclear staining of Sox17 and β-catenin, we report that although β-catenin signaling declines after birth, Sox17 activation increases and remains high in the adult. Endothelial-specific inactivation of Sox17 leads to increase of permeability of the brain microcirculation. The severity of this effect depends on the degree of BBB maturation: it is strong in the embryo and progressively declines after birth. In search of Sox17 mechanism of action, RNA sequencing analysis of gene expression of brain endothelial cells has identified members of the Wnt/β-catenin signaling pathway as downstream targets of Sox17. Consistently, we found that Sox17 is a positive inducer of Wnt/β-catenin signaling, and it acts in concert with this pathway to induce and maintain BBB properties. In vivo, inhibition of the β-catenin destruction complex or expression of a degradation-resistant β-catenin mutant, prevent the increase in permeability and retina vascular malformations observed in the absence of Sox17.Our data highlight a novel role for Sox17 in the induction and maintenance of the BBB, and they underline the strict reciprocal tuning of this transcription factor and Wnt/β-catenin pathway. Modulation of Sox17 activity may be relevant to control BBB permeability in pathological conditions.
Real-World Outcomes of Older Patients with Primary Central Nervous System Lymphoma (PCNSL): Methotrexate Dose Intensity and Combination with Cytarabine Correlate with Response and Survival
Authors: Nicolas Martinez-Calle, Edward Poynton, Alia Alchawaf, Shireen Kassam, Matthew Horan, Mark Rafferty, Phillipa Kelsey, Gemma Scott, Stephanie Bruce, Hannah Buckley, Sophie Jones, Yeong Jer Lim, Ngu Loretta, David Lewis, Thankamma Ajithkumar, Dominic J. Culligan, Clare Rowntree, Josh Wright, Pamela McKay, Samih Fourali, Toby A. Eyre, Jeffrey Smith, Wendy Osborne, Deborah Yallop, Kim Linton, Christopher P. Fox, Kate Cwynarski
Journal: Blood (2018)
Effect of chemotherapy on the progress in colorectal cancer survival in the past two decades.
Authors: Irfan Jawed, Julia Wilkerson, Mauricio Emmanuel Burotto Pichun, Austin G. Duffy, Antonio Tito Fojo
Journal: Journal of Clinical Oncology (2014)

3642 Background: The past two decades have seen steady gains in the overall survival (OS) of colorectal cancer (CRC) patients. Methods: We reviewed 106 phase III and large phase II trials in CRC evaluating first and subsequent lines of therapy. Outcomes examined in the experimental (EA) and control arms (CA) included progression free survival (PFS), overall response rate (ORR), stable disease (SD), OS, and post protocol survival (PPS = OS - PFS). Results: The wealth of data provided significant correlations. The OS of EA has improved 0.76 mos/yr. Importantly OS of CA improved 0.55 mos/yr reflecting use of experimental therapies in CA in subsequent studies. A high correlation between gains in PFS and gains in OS in individual trials (p<0.001; slope=1.08) suggests within one trial PFS gains account for most OS gains. However, because PFS improved only 0.27 and 0.22 mos/yr, in EA and CA respectively, factors other than experimental and salvage therapies are needed to explain observed gains in OS over time. The discordance of OS/PFS gains over time point to important contributions from improved care and lead time bias suggested by: PPS gains of 0.43 and 0.32 mos/yr, in EA and CA respectively, accounting for large portion of OS gains despite OS improvement of only 0.11-0.13 mos/yr in 18 trials in second and subsequent lines insufficient to account for higher OS gains. As expected PFS correlates highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD emerged as an adverse outcome, OS decreasing as SD rates increase. Examination of the effect on OS of the principal drugs showed oxaliplatin, irinotecan and bevacizumab contributed significantly while capecitabine and cetuximab/panitumumab did not. Capecitabine outcome not surprising for an oral substitute of an effective drug; while cetuximab/panitumumab results likely reflect the lack of efficacy/harm in patients harboring MT KRAS tumors. Conclusions: The OS of CRC patients enrolled in trials has improved gradually over the past two decades, with contributing factors including chemotherapy but importantly also likely lead time bias and better supportive care. Meaningful progress will require novel paradigms and much better salvage therapies.
FOLFIRINOX in pancreatic cancer: Can results be reproduced outside the clinical trial setting?
Authors: Elaine M.A. Walsh, MinYuen Teo, Silvie Blaskova, Paul P. Donnellan, Maccon M. Keane, Gregory D. Leonard
Journal: Journal of Clinical Oncology (2014)

e15236 Background: 30% of patients with pancreatic cancer in Ireland receive chemotherapy. This increases to 60% in those <65 years. FOLFIRINOX is a preferred regimen for select patients with advanced pancreatic cancer and a good ECOG PS. This retrospective single institution series examines our use of FOLFIRINOX in locally advanced (LA) and metastatic disease outside of clinical trials. Methods: All patients treated with FOLFIRINOX were identified. Charts and electronic records were extensively reviewed for demographics, stage, previous treatment, schedule, toxicities, response rates, progression free (PFS) and overall survival (OS). PFS and OS were calculated from day1 of FOLFIRINOX. Results: 25 patients were treated with FOLFIRINOX from 2010-2013. Demographics are tabulated. All patients had an ECOG PS 0-2. Nine patients (36%) had prior adjuvant chemotherapy. All patients (n=25) received FOLFIRINOX as first line in the advanced setting. PFS was 3.9mos with an OS of 7mos. Those previously treated with chemotherapy had a PFS 3.2mos; OS 4.7mos. Chemo-naïve patients had a PFS 8.4mos; OS 9mos. Metastatic patients (n=21) had a PFS 3.8mos and an OS 7mos. Chemo-naïve patients (n=15) had a PFS 3.2mos; OS 4.7mos. Conroy et al previously reported PFS 6.4mos and OS 11.1mos in this group. LA patients (n=4) had a PFS of 7.7mos; OS 8.3mos. Conclusions: This retrospective series examines FOLFIRINOX in highly selected patients with LA and metastatic pancreatic cancer. Despite a young population and all patients having a good ECOG PS, our results do not match those seen in clinical trials. FOLFIRINOX is associated with a high toxicity profile; over 50% in this cohort required a dose reduction. We suggest that combination chemotherapy, whilst promising in the clinical trial setting, may not translate to routine clinical practice and not be appropriate in the metastatic setting. No. % Patients 25 100 Median age Range 57 36-71 <>Stage Metastatic LA 21 4 84 16 <>Surgery No Yes Whipples 15 10 6 60 40 24 Adjuvant Rx No Yes 16 9 64 36 Median cycles Folfirinox Range *3 patients had Rx break & re-commenced Toxicity Dose reduced Neuropathy Diarrhoea 6 1-24* 13 8 6 52 32 24
A Phase II Study of the Efficacy and Safety of Lenalidomide, Subcutaneous Bortezomib and Dexamethasone (RVD) Combination Therapy for Patients with Newly Diagnosed Multiple Myeloma: Promising Activity and Manageable Toxicity, Including in High Risk Disease
Authors: Jacob Laubach, Andrew J Yee, Jacalyn Rosenblatt, Jeffrey V Matous, Charles M. Farber, Thomas H. Openshaw, Rodrigo O. Maegawa, Michaela L. Tsai, Irene M. Ghobrial, Giada Bianchi, Bhupendra Rawal, Heidi Dipietro, Kristen Cummings, John Harran, Peter O'Gorman, Kathleen Scott, Kathleen Fitzpatrick, Jennifer Abovich, Hannah Baker, Alexandra Savell, Joshua Hansen, Paul Richardson
Journal: Blood (2018)
Which patients benefit from the inhibition of renin-angiotensin system in advanced pancreatic cancer? An exploratory analysis in 349 patients.
Authors: Yousuke Nakai, Hiroyuki Isayama, Kei Saito, Naminatsu Takahara, Takashi Sasaki, Hirofumi Kogure, Natsuyo Yamamoto, Kenji Hirano, Hideaki Ijichi, Keisuke Tateishi, Minoru Tada, Kazuhiko Koike
Journal: Journal of Clinical Oncology (2014)

e15216 Background: We previously reported that the inhibition of renin-angiotensin system (RAS) prolongs survival in advanced pancreatic cancer (APC) receiving gemcitabine (GEM) (Br J Cancer. 2010;103:1644-8). However, a subsequent phase 2 trial of GEM and candesartan in patients (pts) with advanced pancreatic cancer failed to demonstrate additional effects of candesartan (Invest New Drugs. 2013;31:1294-9). Therefore, we conducted this analysis to explore subgroups who benefit from the addition of ACEI or ARB. Methods: Pts receiving chemotherapy for APC were retrospectively studied. Kaplan-Meier method was used to calculate PFS and OS. A Cox proportional hazard analysis for PFS and OS was performed to evaluate the prognostic factors in pts receiving ACEI/ARB. Results: Between 2001 and 2013, 349 pts (median age 66 yo, 58% male, 45% PS=0, 33% locally advanced, 52% diabetic and median CA19-9 536 u/mL) received GEM-based chemotherapy: GEM alone 210, GEM+erlotinib 12, GEM+candesartan 28, GEM+S-1 62, GEM+S-1+LV 37 pts. ACEI and ARB were used in 19 and 90 pts. Smoking status was 23% current smokers, 29% ex-smokers and 48% non-smokers. Response rate was 9%, PFS 5.4 months and OS 11.2 months in the total cohort. PFS was 5.5 vs. 5.0 months (p=0.212) and OS was 12.1 vs. 10.9 months (p=0.400) with vs. without ACEI/ARB. A Cox proportional hazard analysis for PFS and OS according to age, gender, PS, diabetes or CA19-9 did not show significant differences with and without ACEI/ARB. Hazard ratios for PFS and OS in pts taking ACEI/ARB were 0.49(95%CI, 0.30-0.80, p=0.003 for interaction) and 0.70(0.45-1.10, p=0.254 for interaction) in locally advanced diseases and 0.64(0.45-0.93, p=0.035 for interaction) and 0.61(0.42-0.89, p=0.005 for interaction) in non-smokers, suggesting these subgroups might benefit from ACEI/ARB. Conclusions: Our exploratory analysis suggested that the inhibition of RAS in GEM-based chemotherapy might improve clinical outcomes in APC without distant metastasis or without a history of smoking.
An international, multicenter, randomized, double-blind phase III study of maintenance belagenpumatucel-l in non-small cell lung cancer (NSCLC): Updated analysis of patients enrolled within 12 weeks of completion of chemotherapy.
Authors: Lyudmila Bazhenova, Giuseppe Giaccone, John J. Nemunaitis, Erzsébet Juhász, Rodryg Ramlau, Michel M van den Heuvel, Rohit Lal, David Dunlop, Edward B. Garon, Quincy S. Chu, Minish Mahendra Jain, Ewa Carrier, Steven Moses, Daniel Shawler, Habib Fakhrai
Journal: Journal of Clinical Oncology (2014)

8056 Background: Belagenpumatucel-L (Lucanix) is a therapeutic vaccine comprised of 4 TGF-β2 antisense gene-modified, irradiated, allogeneic NSCLC cell lines. Methods: The trial enrolled patients (pts) without progression after completion of frontline chemotherapy (IIIA-42, IIIB/IV-490). Pts were randomized 1:1 between 4 and 17.4 weeks (w) from the end of frontline chemotherapy. Pts were treated until disease progression or withdrawal. The primary endpoint was overall survival (OS). Secondary endpoints were PFS, RR and safety. Results: 532 pts were enrolled (270 vaccine and 262 placebo), 57% adenocarcinoma (non-SCC), 27% squamous (SCC). Median OS results and safety profile of belagenpumatucel-L was previously reported. A predefined Cox regression demonstrated that the time elapsed between the end of frontline chemotherapy and randomization had a significant impact on survival outcomes (p=0.002). 318 (59.8%) of pts were randomized within 12 w of the completion of chemotherapy (IIIA=13, IIIB/IV=305, 162 vaccine, 143 placebo). Pts with pretreatment radiation (XRT) enrolled within 12 w had median OS of 40.1 m (belagenpumatucel-L) vs. 10.3 m (placebo) (HR 0.45, p=0.014). Median OS of pts treated with concurrent XRT and enrolled within 12 w was not reached (belagenpumatucel-L) and 10.3 m (placebo) (HR 0.34, p=0.04). Conclusions: Although,trial did not meet its predefined end point, a non-statistically significant increase in OS was observed in several subsets of pts who began belagenpumatucel-L within 12 w of the completion of frontline chemotherapy. These data support another Phase III trial with IIIB/IV patients to be randomized within 12 weeks of the completion of frontline chemotherapy. Clinical trial information: 00676507. Stage/time from randomization (< 12 w) N Median OS (m) P HR Belagenpumatucel-L Placebo All 318 20.7 13.3 0.092 0.77 IIIB/IV 305 20.7 13.3 0.083 0.76 IIIB 83 24.7 13.4 0.303 0.71 IV 230 19.7 12.7 0.165 0.76 IIIB/IV SCC 78 20.7 12.3 0.092 0.58 IIIB/IV non-SCC 227 22.3 16.4 0.189 0.66
Microbiome Analytics of the Gut Microbiota in Patients With Juvenile Idiopathic Arthritis: A Longitudinal Observational Cohort Study
Authors: E. H. Pieter van Dijkhuizen, Federica Del Chierico, Clara Malattia, Alessandra Russo, Denise Pires Marafon, Nienke M. ter Haar, Silvia Magni‐Manzoni, Sebastiaan J. Vastert, Bruno Dallapiccola, Berent Prakken, Alberto Martini, Fabrizio De Benedetti, Lorenza Putignani
Journal: Arthritis & Rheumatology (2018)

To assess the composition of gut microbiota in Italian and Dutch patients with juvenile idiopathic arthritis (JIA) at baseline, with inactive disease, and with persistent activity compared to healthy controls.In a multicenter, prospective, observational cohort study, fecal samples were collected at baseline from 78 Italian and 21 Dutch treatment-naive JIA patients with <6 months of disease duration and compared to 107 geographically matched samples from healthy children. Forty-four follow-up samples from patients with inactive disease and 25 follow-up samples from patients with persistent activity were analyzed. Gut microbiota composition was determined by 16S ribosomal RNA-based metagenomics. Alpha- and β-diversity were computed, and log ratios of relative abundance were compared between patients and healthy controls using random forest models and logistic regression.Baseline samples from Italian patients showed reduced richness compared to healthy controls (P < 0.001). Random forest models distinguished between Italian patient baseline samples and healthy controls and suggested differences between Dutch patient samples and healthy controls (areas under the curve >0.99 and 0.71, respectively). The operational taxonomic units (OTUs) of Erysipelotrichaceae (increased in patients), Allobaculum (decreased in patients), and Faecalibacterium prausnitzii (increased in patients) showed different relative abundance in Italian patient baseline samples compared to controls after controlling for multiple comparisons. Some OTUs differed between Dutch patient samples and healthy controls, but no evidence remained after controlling for multiple comparisons. No differences were found in paired analysis between Italian patient baseline and inactive disease samples.Our findings show evidence for dysbiosis in JIA patients. Only patient/control status, age, and geographic origin appear to be drivers of the microbiota profiles, regardless of disease activity stage, inflammation, and markers of autoimmunity.
Comparison of CD22 Expression between Baseline, End of Treatment, and Relapse Among Patients Treated with Inotuzumab Ozogamicin Who Responded and Subsequently Relapsed in Two Clinical Trials
Authors: Hagop M. Kantarjian, Wendy Stock, Ryan D. Cassaday, Daniel J. DeAngelo, Elias J. Jabbour, Susan M. O'Brien, Matthias Stelljes, Tao Wang, Katherine F Liau, Kevin Nguyen, Barbara Sleight, Erik Vandendries, Alexander Neuhof, A. Douglas Laird, Anjali S. Advani
Journal: Blood (2018)
Memory CD8+ T Cells Use Cell-Intrinsic Lipolysis to Support the Metabolic Programming Necessary for Development
Authors: David O’Sullivan, Gerritje J.W. van der Windt, Stanley Ching-Cheng Huang, Jonathan D. Curtis, Chih-Hao Chang, Michael D. Buck, Jing Qiu, Amber M. Smith, Wing Y. Lam, Lisa M. DiPlato, Fong-Fu Hsu, Morris J. Birnbaum, Edward J. Pearce, Erika L. Pearce
Journal: Immunity (2018)
Elevated WBP2 Expression in HER2-positive Breast Cancers Correlates with Sensitivity to Trastuzumab-based Neoadjuvant Therapy: A Retrospective and Multicentric Study
Authors: Shin-Ae Kang, Jye Swei Guan, Hock Jin Tan, Tinghine Chu, Aye Aye Thike, Cristina Bernadó, Joaquín Arribas, Chow Yin Wong, Puay Hoon Tan, Mihir Gudi, Thomas Choudary Putti, Joohyuk Sohn, Swee Ho Lim, Soo Chin Lee, Yoon Pin Lim
Journal: Clinical Cancer Research (2018)

Trastuzumab-based chemotherapy has shown remarkable clinical benefits for patients with HER2-positive breast cancer. However, treatment regimens involving trastuzumab had little or no effect for a subset of patients. Preliminary studies revealed WW-binding protein 2 (WBP2), an oncogenic transcription coactivator, to be coamplified with HER2 in 36% of HER2-positive breast cancers. We hypothesize that WBP2 regulates and correlates with the response of HER2-positive breast cancer to trastuzumab.The coexpression of WBP2 and HER2 in breast tumors was validated using IHC. The role and mechanism of WBP2 in regulating breast cancer response to trastuzumab was elucidated using in vitro, patient-derived xenograft and murine xenograft models. A multicenter retrospective study involving 143 patients given neoadjuvant trastuzumab-based chemotherapy was conducted to determine whether WBP2 expression correlates with pathologic complete response (pCR).Elevated expression of WBP2 significantly enhanced breast cancer's response to trastuzumab by augmenting trastuzumab-induced HER2 downregulation and cell-cycle arrest via inhibition of cyclin D expression. High level of WBP2 correlated with better pCR (67.19%) compared with low WBP2 level (26.58%). The highest response was observed in subgroups of patients with high WBP2-expressing tumors also aged below 50 years (77.78%) or were premenopausal in status (73.33%). Retrospectively, WBP2 demonstrated sensitivity of 80% to 81% and specificity of 76.5% to 80% in discriminating between patients showing pCR and non-pCR.WBP2 expression correlates with the response of HER2-positive breast cancer to trastuzumab-based neoadjuvant chemotherapy.
Population-based analysis of mortality over time in endometrial cancer.
Authors: Michael Joseph Eblan, Ronald C. Chen, Laura H. Hendrix, Ellen Jones
Journal: Journal of Clinical Oncology (2014)

5605 Background: Endometrial cancer is the most common gynecologic malignancy in developed countries. In this population-based study, we analyzed mortality over a 25-year period. Methods: 62513 patients in the Surveillance, Epidemiology & End Results (SEER) database diagnosed with endometrial cancer between 1980 and 2005, with at least 5 years’ follow-up, were included. Cases with multiple malignancies or secondary endometrial cancer were excluded. Multivariate analysis examined factors associated with all-cause mortality (ACM) and cancer-specific mortality (CSM) using Cox proportional hazards model and Fine-Gray competing risk model, respectively. Results: There were 10886 deaths from endometrial cancer and 10184 from other causes. ACM and CSM decreased in more recent years (Table). Older age at diagnosis, black race, advanced stages, higher grade and sarcoma histology were associated with increased hazards for ACM and CSM. Receipt of total hysterectomy, external beam radiation therapy (EBRT) and implant were associated with decreased ACM. Conclusions: When accounting for patient, diagnostic and treatment factors, ACM and CSM have decreased over time for endometrial cancer. However, racial disparity in mortality outcomes persists. Factors associated with ACM and CSM. ACM HR (p) CSM HR (p) Year of diagnosis (REF=2000-2005) 1995-1999 1990-1994 1980-1989 1.06* 1.19* 1.13 (0.12) 1.05 (0.11) 1.17* 1.52* Age at diagnosis (REF=85+) 80-84 75-79 70-74 65-69 60-64 50-59 <50 0.74* 0.55* 0.38* 0.27* 0.21* 0.13* 0.08* 0.88 (0.04) 0.82* 0.73* 0.67* 0.60* 0.44* 0.33* Race (REF=White) Black Other Unknown 1.41* 0.94 (0.06) 0.52* 1.24* 0.96 (0.42) 0.45* Stage (REF=Unstaged) Local Regional Distant 0.74* 1.66* 4.00* 0.50* 1.66* 4.02* Grade (REF=I) II III IV Unknown 1.29* 2.12* 2.36* 1.62* 2.12* 4.30* 4.53* 3.05* Histology (REF=Type 2) Type I AdenoCa Sarcoma 0.82* 1.41* 0.70* 1.53* Surgery (REF=Total Hysterectomy) Subtotal Hysterectomy Radical Hysterectomy None 1.44* 1.08 (0.64) 3.29* 1.47* 1.09 (0.67) 2.40* Radiation (REF=None) Implant EBRT EBRT + Implant 0.81* 0.98 (0.24) 0.85* 0.83* 1.19* 1.06 (0.13) Also controlled for marital status, regional income and education level, urban/rural, SEER region and lymph node dissection. *p value <.0.
Activity of the Wee1 inhibitor MK1775 plus cytarabine in AML through interference with DNA repair capacity at the DNA level.
Authors: Raoul Tibes, Leena Chaudhuri, Nanna Hansen, Devora Delman, James Bogenberger
Journal: Journal of Clinical Oncology (2014)

7106 Background: Cytarabine (AraC) resistance is a fundamental characteristic of refractory/relapsed AML. In previous RNAi screens we identified WEE1 kinase as top candidate target whose inhibition sensitized to AraC in AML. The WEE1 inhibitor MK1775 potently synergized with AraC ex vivo and in vitro and clinical trials are in preparation. However, a mechanistic understanding has remained elusive. Methods: In siRNA rescue screens of 44 genes involved in WEE1 and DNA damage repair (DDR) pathway regulation were conducted and below described experiments conducted. Results: Several RNAi hits converged on DDR repair genes with a focus on the MRN (MRE11, Rad51, NBS1) complex. Interfering with MRN complex members significantly altered the response of AML cells to combined AraC+MK1775 vs. single agent MK1775 or AraC. Unexpectedly the ATM-CHEK1 pathway was not activated, and Homologous recombination (HR)-mediated repair was compromised as shown by a DR-GFP expression vector. Consistently other HR markers decreased as well. The cell cycle was globally dysregulated by slower S-phase kinetics (progression), an expected abrogated G2/M checkpoint as well as de-regulated DNA replication origin formation and firing as evidenced by Cdt1 and Mus81. As a consequence high-single and double strand breaks (H2AX) occurred with early mitotic entry (increased phospho-histone H3) induced by AraC + MK1775 vs. single agents. Changes were followed by massive induction of apoptosis, with specific anti-apoptotic members decreasing and pro-apoptotic BH3 members increasing. Finally, AraC+MK1775 dramatically reduced colony formation vs. single agent MK1775 or even high-dose AraC incubations indicating a stem cell targeting combination, which was p53 independent. Conclusions: Herein we propose combined AraC+MK1775 as a potent AML regimens by directly interfering with DDR via compromising the MRN complex with subsequent reduced HR, early abortive mitotic entry subsequent massive ÒdefaultÓ apoptosis, in a p53 independent manner. These data provides a rationale to clinically evaluate AraC+MK1775 in patients with AML, points towards a mechanistic understanding as well as offers suggestions for biomarkers.