tbuckley/cabot-search huggingface dataset:
Local Activation of p53 in the Tumor Microenvironment Overcomes Immune Suppression and Enhances Antitumor Immunity
Authors: Gang Guo, Miao Yu, Wei Xiao, Esteban Celis, Yan Cui
Journal: Cancer Research (2017)

Mutations in tumor suppressor p53 remain a vital mechanism of tumor escape from apoptosis and senescence. Emerging evidence suggests that p53 dysfunction also fuels inflammation and supports tumor immune evasion, thereby serving as an immunological driver of tumorigenesis. Therefore, targeting p53 in the tumor microenvironment (TME) also represents an immunologically desirable strategy for reversing immunosuppression and enhancing antitumor immunity. Using a pharmacological p53 activator nutlin-3a, we show that local p53 activation in TME comprising overt tumor-infiltrating leukocytes (TILeus) induces systemic antitumor immunity and tumor regression, but not in TME with scarce TILeus, such as B16 melanoma. Maneuvers that recruit leukocytes to TME, such as TLR3 ligand in B16 tumors, greatly enhanced nutlin-induced antitumor immunity and tumor control. Mechanistically, nutlin-3a-induced antitumor immunity was contingent on two nonredundant but immunologically synergistic p53-dependent processes: reversal of immunosuppression in the TME and induction of tumor immunogenic cell death, leading to activation and expansion of polyfunctional CD8 CTLs and tumor regression. Our study demonstrates that unlike conventional tumoricidal therapies, which rely on effective p53 targeting in each tumor cell and often associate with systemic toxicity, this immune-based strategy requires only limited local p53 activation to alter the immune landscape of TME and subsequently amplify immune response to systemic antitumor immunity. Hence, targeting the p53 pathway in TME can be exploited to reverse immunosuppression and augment therapeutic benefits beyond tumoricidal effects to harness tumor-specific, durable, and systemic antitumor immunity with minimal toxicity. Cancer Res; 77(9); 2292-305. ©2017 AACR.
Daratumumab Single Agent and Daratumumab Plus Pomalidomide and Dexametasone in Relapsed/Refractory Multiple Myeloma: A Real Life Retrospective Evaluation
Authors: Antonio Branca, Amy Buros, Donghoon Yoon, Larry J Suva, Niels Weinhold, Leo Rasche, Carolina Schinke, Sharmilan Thanendrarajan, Meera Mohan, Cerisse Harcourt, Faith E Davies, Frits van Rhee, Gareth J Morgan, Maurizio Zangari
Journal: Blood (2016)
Abstract 317: Physiologic Cardiac Hypertrophy in Mice Reduces mRNA Levels of Myostatin and Autophagy Genes
Authors: Graziela H Pinto, Michael E Andrades, Carolina Cohen, Nidiane C Martinelli, Santiago A Leitão, Mariana R Mendoza, Luis E Rohde, Nadine O Clausell, Andréia Biolo
Journal: Circulation Research (2015)

Myostatin and autophagy are involved in muscle growth regulation. However, there are few studies exploring their role in physiologic cardiac hypertrophy. We evaluated myostatin and autophagy in mice subjected to a swimming protocol to induce physiologic cardiac hypertrophy. Methods: Adult (8 weeks-old) male BALB/c mice ( n =52) were divided in sedentary (S) and trained (T) groups, which were evaluated in 7 (S7 or T7, initial hypertrophy) and 28 (S28 or T28, stablished hypertrophy) days after the start of the protocol. Left ventricular/tibial length ratio (LV/TL) and cardiomyocyte diameter were used to assess cardiac hypertrophy. Gene expression was evaluated by RT-qPCR, while protein expression was analyzed by western blot. Bioinformatic analysis was performed by TargetScan to predict potential miRNAs’ targets and Genemania to create an interaction network between miRNAs and genes. All results were expressed as mean ± SEM and comparisons were performed using the Student T test. Results: Myocardial hypertrophy was confirmed in trained group both by the increase in LV/TL ratio in 28 days (13%, p=0.0001) and cardiomyocyte diameter in 7 days (20%, p=0.04) and 28 days (30%, p=0.002). There was a decrease in myostatin gene expression levels in T7 compared to S7 group (0.8 ± 0.1 vs 1.2 ± 0.1, p=0.01) without changes at day 28. However, there was no difference in mTOR phosphorylation at T7, although it was increased in T28 compared to S28 (397±95 vs 90±23 AU; p=0.02). Autophagic genes showed reduced expression levels in trained groups at both time points (reductions of 19% and 10% for Lc3, 22% and 11% for P62 , 19% and 10% for Beclin1 in T7 and T28, respectively; p&lt;0.05 for all analyses compared to sedentary groups), but there was no difference at protein level. Bioinformatics analysis showed that miR-30a, - 221, -27a/b and 208a/b are possible regulators of autophagic and myostatin genes. Conclusions: Taken together, reduced myostatin during initial hypertrophy and increased mTOR phosphorylation in the established hypertrophic phenotype might favor muscular growth and reduce basal autophagy. Candidate miRNAs identified through bioinformatic analysis might regulate this process, and should be further validated in this scenario.
Hundreds of cases need reviewing after letters were shelved
Authors: Adrian O’Dowd
Journal: BMJ (2017)

Patient care and safety could easily have been compromised by a “serious” failing of a government agency to send important medical records onwards, it has emerged.

Large amounts of data on patients, including test results and diagnoses, were mistakenly put in storage between 2011 and 2016 by the NHS Shared Business Services agency before the mix up was discovered last year. Since then the vast majority of information and correspondence has now been delivered to hospitals and GP surgeries “wherever possible,” NHS England has said.

Details of the scale of the error emerged this week after the Guardian newspaper obtained documents showing that around 708 000 pieces of correspondence were undelivered over this period, though 200 000 of these were not clinically relevant.1

The data, which included copies …
The Absolute Monocyte Count at Diagnosis Could Improve the Prognostic Role of the End of Treatment 18-FDG-PET in Diffuse Large B Cell Lymphoma (DLBCL) Patients
Authors: Raffaella Marcheselli, Antonella Franceschetto, Luigi Marcheselli, Alessia Bari, Samantha Pozzi, Monica Barbolini, Virginia Rossetti, Rosaria D'Apollo, Napoleone Prandini, Stefano Sacchi
Journal: Blood (2016)
The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by downregulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression
Authors: M Abraham, S Klein, B Bulvik, H Wald, I D Weiss, D Olam, L Weiss, K Beider, O Eizenberg, O Wald, E Galun, A Avigdor, O Benjamini, A Nagler, Y Pereg, S Tavor, A Peled
Journal: Leukemia (2017)
Abstract A49: Tumor-associated interstitial flow promotes macrophage migration and pro-metastatic M2 phenotype in 3D ECM
Authors: Ran Li, Hao Xing, Tara A. Lee, Hesham Azizgolshani, Roger D. Kamm
Journal: Cancer Research (2017)

Abstract The growth of solid tumor is often accompanied by an increase in the flow of interstitial fluid (interstitial flow) from the center of the tumor to the surrounding stroma. Recent studies have shown that elevated interstitial flow can influence the migration of cancer cells and fibroblasts. Despite these findings, the effects of interstitial flow on macrophages, one of the key metastasis-promoting tumor-associated stromal cell types, have not been explored. We used microfluidic and transwell flow assays to investigate how high level of interstitial flow (~3 μm/s) often observed in tumor affect macrophage migration and protein expression. We found that interstitial flow not only enhanced macrophage migration speed, but also directed macrophages to migrate against the flow in 3D extracellular matrix. Moreover, we discovered that interstitial flow activated Akt and FAK, two kinases that are crucial for cell migration. Interestingly, interstitial flow also up-regulated macrophage expression of M2 markers Arg I and TGFβ through the activation of JAK1-STAT3/6 pathway. Finally, macrophages treated with interstitial flow were shown to have enhanced abilities to promote cancer cell migration and protrusion formation. Taken together, these results suggest that interstitial flow can promote metastasis through its effects on macrophages. Specifically, since macrophages migrate against the flow, interstitial flow, which emanates from the tumor, can act as a mechanical stimulus to recruit macrophages into tumor tissues. Moreover, interstitial flow can activate macrophages and polarize them toward pro-metastatic M2 phenotype to further promote tumor metastasis and immunosuppression. Citation Format: Ran Li, Hao Xing, Tara A. Lee, Hesham Azizgolshani, Roger D. Kamm. Tumor-associated interstitial flow promotes macrophage migration and pro-metastatic M2 phenotype in 3D ECM. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A49.
The role of CTCF and DNA methylation in telomerase hTERT gene regulation
Authors: Jean Benhattar, Stéphanie Renaud, Dmitri Loukinov, Isabelle Guilleret, Victor V. Lobanenkov
Journal: Cancer Research (2005)

4321  Telomerase, which is involved in the regulation of the replicative life span by its maintaining telomere length, is activated in germ and stem cells, repressed in normal somatic cells and reactivated in a large majority of tumor cells. The expression of the catalytic subunit (hTERT) represents the limiting factor for telomerase activity. The hTERT promoter region is located in a CpG island and we observed that, in a majority of telomerase-positive cells, methylation of the hTERT promoter seems necessary for its transcription (Int J Cancer 101:335-341, 2002). This correlation is in stark contrast to the general model of regulation by DNA methylation. To understand how DNA methylation can lead to hTERT gene expression, several experiments were performed which showed that: 1) Strong activation of the hTERT minimal promoter is necessary but not sufficient to hTERT activation in vivo. 2) The strong inhibitory effect of the proximal exonic region was also investigated. We demonstrated that the inhibitory effect of this region is not promoter and cell dependent. 3) This inhibition is mainly due to the chromatin insulator protein CCCTC binding factor (CTCF), which binds in two sites in the hTERT proximal exonic region. ChiP experiments revealed that CTCF binds to the unmethylated hTERT exonic region (normal telomerase-negative cells) but not to the methylated one (telomerase-positive cells). 4) In transient or even stable transfection experiments, CTCF knockdown with siRNA resulted in a significant increasing activity of hTERT promoter in luciferase reporter constructs containing the hTERT promoter and the proximal exonic region. This indicates that activation of the unmethylated hTERT gene can be achieved by inhibition of CTCF. According to our data, a new model for hTERT gene regulation could be proposed. In telomerase-negative normal tissues and in some of telomerase-negative tumors, hypomethylation of the hTERT promoter allows CTCF to bind to the proximal exonic region and leads to hTERT transcription inhibition. In contrast, in telomerase-positive samples (normal or tumor tissues), hypermethylation of the hTERT gene prevents the methylation-sensitive CTCF inhibitor to bind and thus, lead to a weak but significant level of hTERT transcription.
AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program
Authors: Xuebiao Wu, Xiaoli Li, Qiang Fu, Qianhua Cao, Xingyu Chen, Mengjie Wang, Jie Yu, Jingpei Long, Jun Yao, Huixin Liu, Danping Wang, Ruocen Liao, Chenfang Dong
Journal: The Journal of Experimental Medicine (2017)

Basal-like breast cancer (BLBC) is associated with high-grade, distant metastasis and poor prognosis. Elucidating the determinants of aggressiveness in BLBC may facilitate the development of novel interventions for this challenging disease. In this study, we show that aldo-keto reductase 1 member B1 (AKR1B1) overexpression highly correlates with BLBC and predicts poor prognosis in breast cancer patients. Mechanistically, Twist2 transcriptionally induces AKR1B1 expression, leading to nuclear factor κB (NF-κB) activation. In turn, NF-κB up-regulates Twist2 expression, thereby fulfilling a positive feedback loop that activates the epithelial-mesenchymal transition program and enhances cancer stem cell (CSC)-like properties in BLBC. AKR1B1 expression promotes, whereas AKR1B1 knockdown inhibits, tumorigenicity and metastasis. Importantly, epalrestat, an AKR1B1 inhibitor that has been approved for the treatment of diabetic complications, significantly suppresses CSC properties, tumorigenicity, and metastasis of BLBC cells. Together, our study identifies AKR1B1 as a key modulator of tumor aggressiveness and suggests that pharmacologic inhibition of AKR1B1 has the potential to become a valuable therapeutic strategy for BLBC.
Peptide Libraries to CMV Antigens Predict Levels of Cytotoxic Function of CMV-Specific CTL Populations in PBMC from HSCT Recipients.
Authors: Don J. Diamond, Madeva Sharma, Ghislaine Gallez-Hawkins, Joy Martinez, Anne E. Franck, Ricardo Spielberger, John A. Zaia, Stephen J. Forman, Simon F. Lacey
Journal: Blood (2005)
Different Clinical Results with the Use of Different Dosing Schedules of Azacitidine in Patients with Myelodysplastic Syndrome Managed in Community-Based Practice: Effectiveness and Safety Data From the Spanish Azacitidine Compassionate Use Registry.
Authors: Regina Garcia, Dunia de Miguel, Alicia Bailen, José Ramón González, MD, Guillermo Sanz, Jose F Falantes, Rafael Andreu, Mar Tormo, Rafael F Duarte, Antonio Figueredo
Journal: Blood (2009)
ADP-Induced Whole Blood Aggregometry and Platelet-Associated Thrombin Generation (TG) In Essential Thrombocythemia (ET) and Polycythemia Vera (PV) Patients
Authors: Marina Panova-Noeva, Marina Marchetti, Annamaria Leuzzi, Laura Russo, Guido Finazzi, Alessandro Rambaldi, Tiziano Barbui, Hugo Ten Cate, Anna Falanga
Journal: Blood (2010)
Abstract 81: Beta-catenin Loss-of-function in Cardiac Fibroblasts Attenuate Cardiac Fibrosis After Transverse Aortic Constriction in Mice
Authors: Fuli Xiang, Min Fang, Katherine Yutzey
Journal: Circulation Research (2015)

Background: Cardiac fibrosis increases myocardium stiffness, impairs cardiac function and contributes to heart failure. Activated fibroblasts produce excessive extracellular matrix leading to fibrosis and impaired cardiac function. Pathologically activated canonical Wnt signaling has been implicated in the pulmonary-, renal-, dermal- and liver fibrosis as well as in scarring after myocardial infarction. We hypothesize that Wnt/β-catenin signaling contributes to cardiac fibroblast (CF) activation and β-catenin loss-of-function (βLOF) in CFs reduces fibrosis and preserves cardiac function. Methods and Results: The role of Wnt/β-catenin signaling in CF activation was studied using in vitro CF culture and in vivo genetic manipulation. Postnatal (P)0, P8 and P60 CFs were isolated and cultured. Wnt1 treatment significantly activated CFs, while Wnt inhibition (XAV) completely blocked Wnt1-induced CF activation as determined by αSMA staining. Interestingly, XAV also partially abrogated CF activation induced by TGFβ. In vivo, PeriostinMerCreMer (Pn) or Tcf21MerCreMer (T21) mice were crossbred with βLOF and ROSAmTmG. At baseline, CFs were labeled by T21 but minimal activity was observed with Pn. Accumulation of CFs labeled by Pn or T21 Cres was observed in myocardium 8 weeks after TAC. Inducible CF-specific βLOF transgenic mice (Pn-βLOF or T21-βLOF) were subjected to transverse aortic constriction (TAC) or sham surgeries. βLOF was induced post-surgery via tamoxifen. In sham-operated mice, no difference in cardiac function or morphology was observed between βLOF and control mice. In mice subjected to TAC, cardiac function, as measured by echocardiography, was significantly improved, and the interstitial and peri-vascular fibrosis, as well as heart weight to tibia length ratios, were significantly reduced in the βLOF group, compared to controls, 8 weeks after TAC. Thus, induction of βLOF in CFs after TAC leads to improved cardiac performance, decreased fibrosis, and reduced maladaptive cardiac remodeling. Conclusions: βLOF in CFs inhibits myo-fibroblast activation, reduces cardiac fibrosis and preserves cardiac function in TAC induced cardiac injury.
A Phase 3 Randomized Placebo (PBO)-Controlled Double-Blind Trial of Darbepoetin Alfa in the Treatment of Anemia in Patients with Low or Intermediate-1 (Int-1) Risk Myelodysplastic Syndromes (MDS)
Authors: Uwe Platzbecker, Argiris Symeonidis, Esther N. Oliva, Jeroen S. Goede, Michel Delforge, Jiri Mayer, Borhane Slama, Sejal Badre, Eduard Gasal, Bhakti Mehta, Janet Franklin
Journal: Blood (2016)
Abstract P3-13-18: Technical skill of surgical residents may affect margin status of breast conserving operations
Authors: IK Komenaka, B Djenic, C-H Hsu, J Nodora, L Winton, M Bouton, ME Martinez
Journal: Cancer Research (2017)

Abstract Background: Quality of patient care and surgical outcomes have come under increased scrutiny. Numerous other studies have examined outcomes at teaching hospitals compared to non-teaching hospitals. The most important factor to determine early success of breast conservation is the attainment of pathologically negative margins. Few studies, however, have examined the effect of teaching residents on margin status. The current study was performed to evaluate the effect teaching residents on margin status after lumpectomy. Methods: Retrospective review of all patients from July 2006-June 2015 was evaluated. A resident was usually considered the primary surgeon. If the resident was unavailable or unprepared to operate, the attending surgeon was the primary surgeon. As part of the routine evaluation of surgical residents, technical ability was classified as satisfactory or unsatisfactory for level of training. All evaluations of the technical ability of the residents were completed prior to the collection of the current data. The effect of surgical residents' participation and their technical ability to perform lumpectomy was evaluated to determine if there was an effect on margin status. Logistic regression analysis was performed to adjust for clinical variables known to affect margin status. Results: Of 292 patients, 15% of patients had positive margins. The attending surgeon has positive margin rate of 10.7% vs 16% for Residents (p = 0.32).When technical skill evaluation was included, Residents with unsatisfactory technical skills had positive margin rate of 27% compared to 10.2% for residents with satisfactory skills (p = 0.002). In multivariate logistic regression analysis, operating surgeon remained significantly associated with positive margins. Operations done by residents with satisfactory technical skills or attending surgeon were less likely to have positive margins than those done by residents with unsatisfactory technical skills (OR 0.39, 95% CI 0.22-0.86; p = 0.03). Patients who underwent preoperative chemotherapy were also less like to have positive margins (OR 0.40, 95% CI 0.18-0.91); p = 0.04). In patients with at least 2 years of followup (mean follow up of 48 months) breast cancer specific survival was 94% and 2% had local recurrences as a first event. Conclusions: Technically ability of residents may affect margin status after lumpectomy. With the increased use of surgical outcomes to measure quality of care in medicine, the importance of teaching surgical residents needs to be considered in future quality of care evaluation. Citation Format: Komenaka IK, Djenic B, Hsu C-H, Nodora J, Winton L, Bouton M, Martinez ME. Technical skill of surgical residents may affect margin status of breast conserving operations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-18.
A Novel Grading System of Lower Gastrointestinal Acute Graft-Versus-Host Disease At Disease Onset Predicts Response to Therapy and Non-Relapse Mortality
Authors: Andrew C. Harris, James L.M. Ferrara, Joel K. Greenson, Thomas M. Braun, Ernst Holler, Takanori Teshima, John E. Levine, Sung W.J. Choi, Elisabeth Huber, Karin Landfried, Koichi Akashi, Mark T. Vander Lugt, Pavan Reddy, Alice Chin, Qing Zhang, Samir Hanash, Sophie Paczesny
Journal: Blood (2011)
Elimination of FVIII-Specific B Cells By Immunotoxins Comprised of a Single FVIII Domain Fused to Pseudomonas Exotoxin a
Authors: Kerstin Brettschneider, Anja Schmidt, Joerg Kahle, Aleksander Orlowski, Diana Stichel, Karin Becker-Peters, Sonja Neimanis, Christine Heller, Thomas Klingebiel, Dirk Schwabe, Christoph Koenigs
Journal: Blood (2016)
Effect of Magnesium Oxide Supplementation on Nocturnal Leg Cramps
Authors: Noga Roguin Maor, Mordechai Alperin, Elena Shturman, Hassan Khairaldeen, Moran Friedman, Khaled Karkabi, Uzi Milman
Journal: JAMA Internal Medicine (2017)

Magnesium supplements are widely marketed for prophylaxis of nocturnal leg cramps (NLC) despite no evidence of significant benefit.To determine whether magnesium oxide is better than placebo for NLC prophylaxis.A randomized, double-blind, placebo-controlled clinical trial of 2 weeks eligibility screening followed by 4 weeks of treatment was conducted in northern Israel, from February to October 2013. An intention-to-treat data analysis was performed from March 22, 2014, to April 17, 2016. We used a volunteer sample of community-dwelling individuals experiencing NLC, 21 years or older, with 4 or more documented episodes of NLC during 2 weeks of screening.Capsules containing either magnesium oxide or a similar-looking placebo to be taken orally, once daily at bedtime for a period of 4 weeks.The primary outcome was the difference in the mean number of NLC per week between the screening and treatment phases. Secondary outcomes included severity and duration of NLC, quality of life, and quality of sleep.Of the 166 volunteers, 72 (43%) were excluded, of whom 15 declined to participate and 57 did not meet the inclusion criteria. Of the 94 individuals (39% male; mean [SD] age, 64.9 [11.1] years) randomly assigned to magnesium oxide (48) or placebo (46), 6 did not complete the study protocol (3 in each group). Mean (SD) change of NLC was -3.41 (4.05) (from 7.84 [5.68] to 4.44 [5.66]) and -3.03 (4.53) (from 8.51 [5.20] to 5.48 [4.93]) per week in the magnesium oxide and placebo groups, respectively, a difference between groups of 0.38 (0.48) NLC per week (P = .67 in an intention-to-treat analysis). There were no between-group differences in the severity and duration of NLC, quality of life, or quality of sleep.Oral magnesium oxide was not superior to placebo for older adults experiencing NLC. The decrease in the mean number of NLC per week, from the screening to the treatment phase in both groups, is probably a placebo effect that may explain the wide use of magnesium for NLC.clinicaltrials.gov Identifier: NCT01709968.