tbuckley/cabot-search huggingface dataset:
Abstract 1449: <i>In vivo</i> targeted silencing of CCR1 and CCR5 repolarizes pro-tumoral myeloid cells in retinoblastoma positive neutrophils with a strong anti-tumor activity
Authors: Serena Zilio, Jennifer Vella, Adriana De La Fuente, Vincenzo Bronte, Emilia Mazza, Silvio Bicciato, Paolo Serafini
Journal: Cancer Research (2016)

Abstract Introduction: Depending on their polarization, myeloid cells can either promote or restrain tumor progression. By secreting myelopoietic factors tumours promote myeloid cells polarization toward a phenotype that provides immune protection and that stimulate neoplastic cells growth, invasiveness, and metastasis. Chemokines and their cognate receptors are thought to play a key role in myeloid cell trafficking, however, their study in vivo is hindered by their signal redundancy and integration. Methods: By taking advantage of a newly developed nanoplatform that allows the in vivo preferential transfection of tumor infiltrating myeloid cells (TIMC, aka Myeloid derived suppressor cells, MDSC, and tumor associated macrophages, TAM), we evaluated the effect of CCR-1, CCR-2, CCR-4, CCR-5 and/or CCR-7 silencing on TAMC trafficking, phenotype, and function. Results: While CCR-4 and -7 targeted silencing did not affect tumor progression, simultaneous silencing of CCR-1 and CCR-5 significantly restrained tumor growth and greatly modifies tumor micro-environment. Mechanistic in vivo and in vitro analysis surprisingly indicate that myeloid cell trafficking was not altered whereas myeloid cell polarization was. In particular, CCR-1 and CCR-5 blockade restrained MDSC differentiation and promote the accumulation of retinoblastoma positive, neutrophil-like cells with a strong tumoricidal activity. Discussion: Our data indicate that CCR-1 and CCR-5 engagement (most likely via CCL-3 and CCL-4) is necessary for the pro-tumoral polarization of myeloid cells in cancer. Our findings not only improve our understanding of myeloid cells differentiation in cancer but, also, strongly suggest that targeted inhibition of CCR1 and CCR5 on TIMC can be a new and effective anti-tumor immune-therapeutic strategy that convert pro-tumoral MDSCs into tumoricidal neutrophils. Citation Format: Serena Zilio, Jennifer Vella, Adriana De La Fuente, Vincenzo Bronte, Emilia Mazza, Silvio Bicciato, Paolo Serafini. In vivo targeted silencing of CCR1 and CCR5 repolarizes pro-tumoral myeloid cells in retinoblastoma positive neutrophils with a strong anti-tumor activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1449.
Analysis of Related Factors of Malignant Clone Burden of Patients with Myelodysplastic Syndromes
Authors: Zonghong Shao, Lanzhu Yue, Rong Fu, Huaquan Wang, Lijuan Li, Erbao Ruan, Wen Qu, Yong Liang, Guojin Wang, Xiaoming Wang, Hong Liu, Jia Song, Yuhong Wu, Limin Xing, Jun Wang, Jing Guan
Journal: Blood (2010)
Case 32-1970
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. McNeely, Cecil H. Coggins, Robert E. Scully
Journal: New England Journal of Medicine (1970)

Presentation of Case First admission. A 64-year-old woman was admitted to the hospital because of pain in the left leg.Fifteen months previously a routine physical examination revealed atrial fibrillation and a blood pressure of 150 systolic, 105 diastolic. An x-ray film of the chest showed enlargement of the heart and minimal prominence of the pulmonary vessels; no intracardiac calcification was observed. Digitalis was prescribed but was not taken. Four weeks before entry numbness and pain in the left leg developed abruptly. She was seen by a physician, who prescribed medication and rest in bed. A few days later . . .
Abstract 3179: Germline deletion of FH in hereditary leiomyomatosis and renal cell carcinoma (HLRCC)
Authors: Cathy D. Vocke, Christopher J. Ricketts, Lindsay A. Middelton, Youfeng Yang, W. Marston Linehan.
Journal: Cancer Research (2016)

Abstract Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial cancer syndrome characterized by germline mutations in the fumarate hydratase (FH) gene that encodes the enzyme responsible for conversion of fumarate to malate in the Kreb's Cycle. HLRCC is associated with the development of cutaneous and uterine leiomyomas, and a highly aggressive form of type 2 papillary kidney cancer. HLRCC renal tumors can be extremely aggressive with patients demonstrating locally advanced or disseminated disease even when associated with small tumors 1-2 cm in size. Therefore, accurate identification of the “at risk” individuals is very important. In our experience, FH point mutations are identified in 90% of individuals that are clinically diagnosed with HLRCC, while in the remainder, FH may be inactivated by deletion or other causes. Several studies have reported complete deletions of the FH gene and a few have estimated the extent of these deletions and identified the additional genes that would be lost in conjunction with FH. Interestingly, families with complete FH deletion have demonstrated cutaneous and uterine leiomyomas but no families have yet been reported with evidence of kidney cancer. A single family has been identified that demonstrates a partial deletion resulting in the loss of exon 1, and in this case kidney cancer has identified within the family. In this study, patients with suspected HLRCC hereditary kidney cancer but no germline point mutation were enrolled on an NCI-IRB approved protocol and an Agilent custom high-definition comparative genomic hybridization (CGH) array was used to identify FH gene deletions. The assay identified complete germline deletion of a single copy of FH within seven suspected HLRCC patients deletion ranging from 249kb to 4.74Mb that in all cases resulted in a minimum addition loss of the KMO, OPN3, CHML, and WDR6 genes. All results were confirmed by CLIA approved tests and a further five new patients were identified by direct CLIA testing, including a novel partial deletion. In contrast to previous reports, seven out of twelve (58.3%) patients/families in our cohort demonstrated a personal or family history of HLRCC associated Type 2 papillary kidney cancer. In conclusion, complete or partial deletion of the FH gene is an infrequent but important cause of HLRCC and has no protective effect on the incidence of HLRCC associated type 2 papillary kidney cancer. Citation Format: Cathy D. Vocke, Christopher J. Ricketts, Lindsay A. Middelton, Youfeng Yang, W. Marston Linehan. Germline deletion of FH in hereditary leiomyomatosis and renal cell carcinoma (HLRCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3179.
Abstract LB-016: Nutlin and oxaliplatin induce p53-dependent addiction to FLIP
Authors: Alexander McIntyre, Fiammetta Falcone, Patrick G. Johnston, Daniel B. Longley, Simon S. McDade
Journal: Cancer Research (2016)

Abstract Background: The tumour suppressive functions of the p53 transcription factor are inactivated through mutations or suppressed through non-mutational mechanisms in almost all cancer cells. This work focusses on identifying mechanisms through which, tumours retaining wild-type p53 evade apoptosis in response to chemotherapies and p53 agonists such as Nutlin-3A. Methods: A panel of matched p53 wild-type and deficient colorectal cancer cell line models were studied, using Nutlin-3A and oxaliplatin as direct and indirect p53 activating agents. A number of molecular (Western blots, RT-PCR), phenotypic (cell death) and genomic analyses were used to investigate the importance of p53 and its downstream transcriptional programs. Results: We demonstrate the importance of p53 in priming cancer cell sensitivity to apoptotic cell death following treatment with Nutlin-3A or oxaliplatin through activation of pro-apoptotic p53 targets, such as TRAIL-R2, Fas/CD95, PUMA and NOXA. Surprisingly, our analysis further reveals that this priming is accompanied by a parallel early p53-dependent pro-survival response that imposes a critical dependence on the caspase-8 inhibitor FLIP. Preventing FLIP up-regulation with siRNA resulted in synergistic increases in apoptosis in response to Nutlin-3A and oxaliplatin in p53 wild-type, but not p53 null cells. p53-mediated FLIP up-regulation was blocked by pharmacological inhibition of HDACs1-3 using Entinostat, which caused hyper-acetylation of the p53 C-terminus and altered transactivation of a number of other p53 apoptotic target genes. Notably, the synergy between Nutlin-3A or oxaliplatin and Entinostat was abrogated in cells over-expressing FLIP trans-genes or in cells in which caspase-8 was depleted using RNAi. Conclusion: These results uncover a p53-regulated apoptosis priming event, in which a number of key pro-apoptotic genes are upregulated in response to direct p53 agonism (Nutlin-3A) or indirect activation downstream of DNA damage (oxaliplatin). However, immediate commitment to apoptosis is prevented by the concomitant p53-mediated up-regulation of FLIP. This may be a mechanism that has evolved to allow DNA damage repair time to take place, while priming the cell to undergo apoptosis if the damage is irreparable. From a cancer therapeutics point-of-view, this work identifies FLIP upregulation in p53 wild-type cancers as a key target for overcoming resistance to direct and indirect p53 activating therapies. Citation Format: Alexander McIntyre, Fiammetta Falcone, Patrick G. Johnston, Daniel B. Longley, Simon S. McDade. Nutlin and oxaliplatin induce p53-dependent addiction to FLIP. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-016.
Case 5-1969
Authors: Frank C. Wheelock, Benjamin Castleman
Journal: New England Journal of Medicine (1969)

Presentation of CaseA fifty-year-old man was admitted to the hospital because of pain in the foot.He had been in good health until nine months previously, when he began to experience crampy pain in the right calf after walking fast for a half mile; the pain was relieved by resting. Two weeks before entry he dropped a desk on the right great toe, which became dusky and cyanotic, with hemorrhage extending into the foot. Subsequently, the foot and distal portion of the leg became increasingly dusky, mottled and cold.There was no history of hypertension, diabetes or irregular heart . . .
Abstract 3108: PD-L1 expressing circulating tumor cells (CTCs) in patients with head and neck squamous cell carcinoma (HNSCC)
Authors: Areti Strati, George Koutsodontis, Ilias Angelidis, Clarence Sasaki, Margaritis Avgeris, Amanda Psyrri, Evi S. Lianidou
Journal: Cancer Research (2016)

Abstract Background: Predictive biomarkers for response to anti-PD1 therapy are lacking. Because therapy with checkpoint inhibitors is cost intensive, noninvasive tools for prediction of responders are of major interest. Methods: The “Liquid Biopsy’’in head and neck squamous cell carcinoma (HNSCC) project involved the isolation of Circulating Tumor Cells (CTC) from patients with HNSCC at baseline, at different time points during treatment and at relapse. Herein, we assessed gene expression of PD-L1 on CTCs in a prospective fashion in a cohort of locally advanced inoperable HNSCC patients treated with curative intent (n = 61), in a second cohort of recurrent/metastatic HNSCC patients (n = 18) and in 20 healthy individuals, used as normal controls. For the quantification of PD-L1mRNA in CTCs, we developed a highly sensitive, specific, and robust RT-qPCR assay that was firstly analytically validated prior to its application in HNSCC patients. Results: In patients with locally advanced disease, 54/61(88.5%) samples were evaluable for CTCs at baseline. Twenty four samples were obtained after induction chemotherapy (IC) and 34(55.7%) at the end of concurrent chemo-radiation. At baseline 22/54(40.7%) pts were found to be positive for PD-L1 overexpression, at the post-IC samples 12/24(50%) patients were positive for PD-L1overexpressionand at the end of treatment, 11/34 (32.4%) patients were positive for PD-L1 overexpression. Patients with PD-L1 positive CTCs at the end of treatment had shorter progression-free survival (PFS) (p = 0.011) and overall survival (OS) (p = 0.004). Multivariate analysis showed that PD-L1 overexpression in patients at the end of treatment was independent prognostic factor of PFS (HR = 2422.4; p = 0.014) and OS (HR = 32.23; p = 0.014). Five R/M patients were found to be positive for PD-L1 out of the 18 (27.8%) at baseline. Conclusions: We demonstrate for the first time that detection of PD-L1+ CTCs at the end of treatment in patients with locally advanced disease is associated with shorter PFS and OS. Serial PD-L1 expression assessment has potential to select and monitor pts for PD-1 checkpoint inhibitors. These data support testing of PD-1 inhibitors in the adjuvant setting in patients with locally advanced HNSCC in whom PD-L1 positive CTCs are detected at the end of treatment. Citation Format: Areti Strati, George Koutsodontis, Ilias Angelidis, Clarence Sasaki, Margaritis Avgeris, Amanda Psyrri, Evi S. Lianidou. PD-L1 expressing circulating tumor cells (CTCs) in patients with head and neck squamous cell carcinoma (HNSCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3108.
Abstract 2739: Carnosic acid induces cell cycle arrest of B16F10 cells and synergizes with carmustine and lomustine <i>in vitro</i> and <i>in vivo</i>
Authors: Kun-I Lin, Chih-Chien Lin, Ming-Feng Chen, Chang-Han Chen, Li-Yen Shiu
Journal: Cancer Research (2016)

Abstract Carnosic acid (CA), one of the purified components of rosemary, has shown anti-inflammatory, chemo-preventive, and anticancer activities. In this study, we treated melanoma cell line B16F10 with CA and detected the anticancer effects. After 24-hour treatment, CA decreased cell proliferation rate, wound healing activity, and inhibited colony formation of B16F10. Additionally, CA induced G0/G1 cell cycle arrest, up-regulated p21 expression, and down-regulate cyclin E, cyclin D and CDK4 expression. Carmustine (BCNU) and Lomustine (CCNU) are used in clinical treatment of melanoma. To assay the combinational effects of CA and BCNU or CCNU, B16F10 cells were treated with CA, BCNU, CCNU alone, or CA combined with BCNU or CCNU. Our results showed, BCNU and CCNU arrested cell cycle at G2/M phase after 24-hour treatment. Dramatically, CA enhenced BCNU- and CCNU-induced cell cycle arrest at G2/M phase, and decreased cyclin B1 and p-CDK1 expresion. In the in vivo xenograft model, B16F10 cells (5×105) were inoculated subcutaneously in C57BL/6 mice, and the tumor grew for one week. The mice were divided into six groups and provided different treated strategies: control, CA (50 mg/kg) alone, BCNU (50 mg/kg) alone, CCNU (25 mg/kg) alone, CA combined with BCNU, and CA combined with CCNU. After two-week treatment, compared with control group, CA had better treated effects than BCNU or CCNU. Compared with CA, BCNU or CCNU treatment alone, the combined strategies inhibited the tumor growth in melanoma mice model more effectively. Furthermore, BCNU and CCNU treatment in melanoma mice caused high values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). However, CA significantly decreased AST and ALT values caused by BCNU and CCNU in combined trestment group. Therefore, CA is more safe and effective than BCNU and CCNU, and the combined treatment strategies of CA and BCNU or CCNU result in an increased antitumor efficacy. CA may be suitable for translation to future clinic. Citation Format: Kun-I Lin, Chih-Chien Lin, Ming-Feng Chen, Chang-Han Chen, Li-Yen Shiu. Carnosic acid induces cell cycle arrest of B16F10 cells and synergizes with carmustine and lomustine in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2739.
A multicenter, randomised, phase III trial comparing fixed dose versus toxicity-adjusted dose of cisplatin + etoposide in advanced SCLC patients. The STAD-1 trial.
Authors: Alessandro Morabito, Gennaro Daniele, Adolfo G. Favaretto, Virginio Filipazzi, Antonio Rossi, Vittorio Gebbia, Federico Castiglione, Luigi Cavanna, Evaristo Maiello, Giuseppe Valmadre, Raffaele Costanzo, Anna Manzo, Laura Bonanno, Elena Piazza, Paolo Maione, Gianfranco Mancuso, Massimo Di Maio, Maria Carmela Piccirillo, Ciro Gallo, Cesare Gridelli
Journal: Journal of Clinical Oncology (2015)

7505 Background: Classic dosing of chemotherapy does not account for pts’ variability and some pts could be underdosed. We tested whether toxicity-adjusted dosing of chemotherapy was more active than classic dosing in advanced SCLC pts. (ClinicalTrials.gov NCT00526396). Methods: Advanced chemonaïve SCLC pts, aged ≤ 75, ECOG PS < 2, were randomised to either control (fixed-dose cisplatin/etoposide: C 80mg/m2, d1 + E 100mg/m2,d1-3, q3w) or experimental arm (toxicity-adjusted CE where, in absence of toxicity, dose of both agents were escalated according to the table). Primary endpoint was the objective response rate (ORR) according to RECIST 1.0. 160 pts were required based on 80% power, 2-sided α = 0.05; ≥ 80% ORR in the experimental vs ≤ 60% ORR in the standard arm. Results: 161 patients were randomly assigned either to standard (n = 81) or experimental arm (n = 80). Two patients withdrew the consent immediately after the randomisation, one in each arm, and were excluded from the analysis. Median age was 64, most of the patients were males (72%), had PS1 (55%), had not been pre-treated with RT (89%) and did not show brain metastases (75%). A median number of 6 chemotherapy cycles was administered in both the arms. The ORR was 54% and 57% in the control and the experimental arms (p = 0.75). With 44 mos of median follow up, median PFS was 6.0 mos in the control arm and 5.6 mos in the experimental arm (HR = 1.02; 95% CI: 0.73-1.43, p = 0.90), whilst median OS was 9.6 mos and 9.2 mos in the control and experimental arm (HR = 1.01, 95% CI: 0.71-1.42; p = 0.97). Six patients died while on treatment, one in the control arm and 5 in the experimental one. Among grade 3-4 toxicities, neutropenia (p = 0.005) and fatigue (p = 0.04) were significantly more frequent in the experimental arm. Conclusions: As expected, toxicity-adjusted dosing increases side-effects. However, it does not improve the ORR, nor does prolong PFS or OS in advanced SCLC patients. Clinical trial information: NCT00526396. C (mg/m2) E (mg/m2) Level –2 stop stop Level –1 60 (-25%) 80 (-25%) Level 0 (starting dose) 80 100 Level +1 100 (+20%) 120 (+20%) Level +2 110 (+10%) 120 (-) Level +3 110 (-) 135 (+12.5%) Level +4 120 (+9%) 135 (-) Level +5 120(-) 150 (+11%)
Abstract 2964: An anti-CD20 extracellular antibody-drug conjugate for the treatment of B-cell malignancies
Authors: James R. Prudent, Chad A. Hall, David J. Marshall, John Murphy, Scott Harried
Journal: Cancer Research (2016)

Abstract Purpose: CD20 is known to be a therapeutic antibody drug target as it is expressed on the surface of most B-cell neoplasms. Here, we assessed the anti-tumor activity of EDC9, a novel extracellular drug conjugate composed of Rituximab (a well know and FDA approved anti-CD20 monoclonal antibody) conjugated to a steroidal glycoside via a long, flexible and stable linker. Experimental Design: The anti-cancer activity and safety of EDC9 were examined and compared to Rituximab using in vitro and in vivo techniques. Results: We found that EDC9 showed picomolar cytotoxic activity that was independent of effector functions and exhibited cytotoxic activity through a mechanism that was dependent on CD20 expression, as cells not expressing CD20 were resistant and Rituximab alone could compete with EDC9, rendering it inactive. After 72 hours of EDC9 treatment at levels between 100 and 200 picomolar, no cells were determined to be viable by CellTiter-Glo or high definition phase contrast imaging. Importantly, when compared on the basis of toxicity to PBMC, EDC9 was found not to be more toxic than Rituximab and the activity of EDC9 was dependent on specific steroid chemistry. In a tumor xenograft model, EDC9 provided complete long-term remission of diffuse large B-cell human lymphoma line SU-DHL-8 tumors, while Rituximab alone did not. Conclusion: These results support efforts to further evaluate EDC9 (a novel CD20 specific antibody drug conjugate) and may lead to phase I clinical trials in patients with certain B-cell related malignancies. Citation Format: James R. Prudent, Chad A. Hall, David J. Marshall, John Murphy, Scott Harried. An anti-CD20 extracellular antibody-drug conjugate for the treatment of B-cell malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2964.
Connecting the Dots
Authors: Edward Lau, Karol E. Watson, Peipei Ping
Journal: Circulation (2016)

Connecting the DotsFrom Big Data to Healthy Heart R ising capacity to measure extensive arrays of biological parameters has ushered in an era of biomedical big data.As massive datasets from large cohorts become the norm, the discipline of data science has emerged to tackle data-driven problems at the intersection of biomedical research and patient care.We introduce several sources of cardiovascular big data and discuss the importance of maximizing participation in data-driven knowledge production models. WHAT ARe BIg DATA?Every day, our world produces a staggering 2.5 quintillion (10 18 ) bytes of data, including a steadily increasing amount of data from health care and biomedicine.The whole-genome sequence of a patient can reach 100 gigabytes (10 11 bytes) in size, whereas a cardiology division may perform >1000 echocardiograms per month, totaling >200 gigabytes of data.The term biomedical big data has been coined to describe healthcare and biomedical datasets that reach remarkable scale, volume, or complexity.Four biomedical big data sources are of particular interest to cardiovascular biomedicine:• Functional phenotypes: Demographics, hemodynamics, electrocardiography, echocardiograms, and imaging data are pouring in from large cohorts such as from among the ≈11 500 cardiac-related studies that are listed by ClinicalTrials.gov.Popular personal fitness-tracking devices likewise have created a deluge of mobile health data (eg, heart rate, physical activities, lifestyle) awaiting exploitation.The ability to extract features from phenotypic data and to identify complex interrelationships offers tremendous potential to enhance diagnoses and to improve care.• Molecular profiles: Large-scale omics data on genes, transcripts, proteins, and metabolites can now be acquired in large studies, in the clinic, or even commercially and may be integrated with functional data to allow a better understanding of disease pathogenesis.For example, the National Center for Biotechnology Information Database of Genotypes and Phenotypes alone lists >2000 molecular and functional datasets from >250 cardiovascular studies, including the Framingham Heart Study, the Jackson Heart Study, and other National Institutes of Health-sponsored cohort studies.Collection of even more omics data from cardiovascular cohorts is being promoted by funding agencies, for example, the National Heart, Lung, and Blood Institute X01 funding mechanism for "Omics Phenotypes of Heart, Lung, and Blood Disorders."• Medical records: Patient electronic medical records abound with physician's notes, billing codes, laboratory test results, and other valuable information on disease, treatment, and epidemiology that may be mined for association studies and predictive modeling on prognosis and drug responses.