tbuckley/cabot-search huggingface dataset:
The microRNA-212/132 cluster regulates B cell development by targeting Sox4
Authors: Arnav Mehta, Mati Mann, Jimmy L. Zhao, Georgi K. Marinov, Devdoot Majumdar, Yvette Garcia-Flores, Xiaomi Du, Erdem Erikci, Kamal Chowdhury, David Baltimore
Journal: The Journal of Experimental Medicine (2015)

MicroRNAs have emerged as key regulators of B cell fate decisions and immune function. Deregulation of several microRNAs in B cells leads to the development of autoimmune disease and cancer in mice. We demonstrate that the microRNA-212/132 cluster (miR-212/132) is induced in B cells in response to B cell receptor signaling. Enforced expression of miR-132 results in a block in early B cell development at the prepro–B cell to pro–B cell transition and induces apoptosis in primary bone marrow B cells. Importantly, loss of miR-212/132 results in accelerated B cell recovery after antibody-mediated B cell depletion. We find that Sox4 is a target of miR-132 in B cells. Co-expression of SOX4 with miR-132 rescues the defect in B cell development from overexpression of miR-132 alone, thus suggesting that miR-132 may regulate B lymphopoiesis through Sox4. In addition, we show that the expression of miR-132 can inhibit cancer development in cells that are prone to B cell cancers, such as B cells expressing the c-Myc oncogene. We have thus uncovered miR-132 as a novel contributor to B cell development.
Use of non invasive gas exchange to track pulmonary vascular responses to exercise in heart failure
Authors: Paul Woods, Bryan Taylor, Thomas Olson, Bruce Johnson
Journal: European Respiratory Journal (2011)

Simple metrics to quantify severity of pulmonary hypertension (PH) are lacking, particularly with exercise. Studies have suggested that end tidal CO 2  (PetCO 2 ) and ventilatory efficiency (V E /VCO 2 ) may be good indicators of the pulmonary vascular (PV) response to exercise in patients with PH. In addition, measures of PV capacitance (stroke volume/pulmonary arterial pressure, Pv CAP ) are predictive of survival in the PH population and may potentially be estimated with gas exchange. PH is common in heart failure (HF) and appears to have both passive and reactive components. However, HF is associated with a number of gas exchange abnormalities that could limit the ability of using PetCO 2  or V E /VCO 2  to estimate the presence of PH. The focus of this study was, a) determine how well non-invasive gas exchange tracks the PV response to exercise and b) test a non-invasive estimate of Pv CAP . Forty-two patients with HF (age 54±9, LVEF 20±6, NYHA class 3±1) undergoing rt.-hrt catheterization as part of a pre-transplant evaluation were studied. PV pressures (Ppa/Ppw), cardiac output and PV resistance (PVR) were obtained with simultaneous measures of gas exchange. PetCO 2  and V E /VCO 2  obtained during moderate exercise (VO 2  9±2ml/kg/mn, 37±13W) were highly correlated (r -0.95) and thus data were analyzed in tertiles according to PetCO 2  (mean 23±3, 29±2, 36±4mmHg). PVR followed a decreasing trend from low to high PetCO 2  groups (365±256, 282±162, 188±91WU, p CAP  from catheter measures was highly associated with a value estimated from O 2 pulse/(1/PetCO 2 ), (r=0.84). Non invasive gas exchange measures may represent a relatively simple way to track PV response to exercise in HF.  NIH HL71478.
Different protein expression of healthy and malignant hematopoietic stem cells
Authors: H. Lannert, T. Franz, A. Bathke, A. Lenze, R. Hofmann, V. Eckstein, A. D. Ho
Journal: Journal of Clinical Oncology (2005)

6636 Background: Proteome analysis is a direct measurement of proteins in terms of their presence and relative abundance in a defined system. Different states of a cell can be compared and specific qualitative and quantitative protein changes can be identified. We focused our proteom-investigations on the comparison and differences between healthy and malignant hematopoietic stem cells. Methods: Mononuclear cells were isolated by a standard Ficoll-Hypaque gradient separation method from healthy donors, as well as from patients with CD34+ acute myeloic leukemia. An Auto-MACS (Miltenyi) and FACS Vantage SE cell sorter (Becton Dickinson) was used to highly enrich (>99%) CD34+ cells fractions. Sample preparation, determination of protein concentrations, 2D-gel-electrophoresis with a 1D-separation isoelectric focusing with immobilized pH gradient strips (17cm), 2D-separation with SDS-PAGE were performed and described in Proteome Works System (BioRad). Sypro ruby stained gels were used for protein identification by Q-TOF sequencing. Results: 1.) The pattern of the CD34+ fractions from healthy and malignant stem cells are complex and show >1000 protein spots (dependent on protein concentration) in silver stain using PDQuest. 2.) The most dominant 150 protein spots were definitely characterized by Q-TOF analyses. A sample of identified spots and their functional groups are specified: 1. Cytosketeletal proteins: tubulin, actin, profilin, tropomyosin. 2. Signaling proteins: enolase, rho GDP dissociation inhibitor 2, glutathione S transferase, nucleophosmin. 3. Metabolism: phosphoglycerate kinase I, glyceraldehyde-3P-dehydrogenase. 4. Protein folding: heat shock proteins (HSP 60, HSP70c), molecular chaperones (GRP78). Conclusions: Proteomics is a highly effective method to describe the gen-expression and the cell biology of healthy and malignant stem cells on real protein transcription. Our preliminary results show that cell cycle determining chaperones (folding of other protein and responsible for their functional activation or deactivation) are dominantly expressed. Different protein expression between healthy and malignant stem cells may result to new prognosis factors and/or new therapeutic targets. No significant financial relationships to disclose.
A phase I study of biweekly docetaxel as salvage chemotherapy in advanced gastric cancer.
Authors: Y. Kimura, H. Yano, H. Taniguchi, K. Danno, T. Kanoh, T. Ohnishi, T. Tono, Y. Nakano, T. Monden, S. Imaoka
Journal: Journal of Clinical Oncology (2010)

e14607 Background: Docetaxel is active for gastric cancer. However, grade 4 neutropenia occurs in the majority of patients with a dose of 60 mg/m2 every 3 weeks in Japan. To find a more convenient and tolerable schedule than the triweekly schedule, we conducted a dose escalation study of biweekly docetaxel. This dose escalation study investigated the maximal tolerated dose (MTD) and the recommended dose (RD). Methods: Patients with advanced gastric cancer who had received more than one prior chemotherapy regimen were enrolled between April 2004 and March 2007. This study was designed to evaluate escalated dose of docetaxel starting at 35 mg/m2 (level 1) (n = 3) given every two weeks. The dose was escalated to 40 mg/m2 (level 2) (n = 3), 45 mg/m2 (level 3) (n = 3) and 50 mg/m2 (level 4) (n = 6) in a stepwise fashion. Results: Fifteen patients completed at least two cycles of therapy. Three episodes of grade 3 neutropenia occurred in all patients and grade 4 neutropenia was seen at dose level 4 in all 6 patients. No grade 3 or 4 thrombocytopenia and anemia was observed. Grade 3 AST/ALT elevation (n = 1) and grade 3 stomatitis (n = 1) were noted at level 4. No other grade 3 or 4 nonhematologic toxicity was observed. The definition of dose-limiting toxicities of this docetaxel schedule are grade 4 neutropenia, grade 3 AST/ALT elevation and grade 3 stomatitis at level 4. Conclusions: The MTD of docetaxel when administrated by this biweekly schedule was 50 mg/m2 and the RD was 45 mg/m2. Biweekly administration of docetaxel may provide a better tolerated and efficacious use of this drug. Phase II study of this regimen is underway. No significant financial relationships to disclose.
Influence of the vascular endothelial growth factor-A (VEGF-A) 936C&gt;T germinal polymorphism on tumoral VEGF-A expression in head and neck cancer patients (HNCP)
Authors: M. Etienne-Grimaldi, J. L. Formento, M. Francoual, G. Pagès, C. Onesto, E. Chamorey, O. Dassonville, G. Poissonnet, G. Milano
Journal: Journal of Clinical Oncology (2007)

6050 Background: VEGF-A is a potent inducer of endothelial cell growth and tumor neo-vascularisation. We previously reported that tumoral VEGF-A expression is linked to overall survival in HNCP (Onesto et al. Br J Cancer 2006). The present purpose was to extend this study by analyzing VEGF-A gene polymorphisms since functional VEGF-A polymorphisms associated with serum VEGF-A and risk of cancer have been described. Methods: VEGF-A polymorphisms in position (relative to translation initiation) −2578C&gt;A (promoter region), − 1498T&gt;C (promoter region), −634G&gt;C (5’UTR) and 936C&gt;T (3’UTR) were analyzed (PCR-RFLP) in tumoral genomic DNA from 49 Caucasian HNCP (34 men, 15 women; 16 T1-T2, 33 T3-T4; 31% N0). Tumoral VEGF-A expression was measured with an ELISA kit. Results: Genotype distributions agreed with those predicted by the Hardy-Weinberg equilibrium. A linkage disequilibrium was observed between −2578C&gt;A and −634G&gt;C (p&lt;0.001) as well as between −2578C&gt;A and −1498T&gt;C (p&lt;0.001). Of note, tumoral VEGF-A expression was influenced by the 936C&gt;T polymorphism, with a median at 540 pg/mg in CT+TT patients (N = 5) versus 940 pg/mg in CC patients (N = 44) (p = 0.064). VEGF-A expression was not related to any other polymorphisms. None of the analyzed polymorphisms was linked to node involvement or to tumor size. Unlike tumoral VEGF-A expression, the analyzed genotypes were not related to patient survival. Conclusions: In addition to the known influence of tumor hypoxia, the present data suggest that the 936C&gt;T polymorphism can modulate tumoral VEGF expression, with the presence of the T allele associated with decreased VEGF-A expression. Determination of this germinal polymorphism may thus provide an easily accessible test that deserves further investigation as a potential factor to aid anti-angiogenic treatment selection. No significant financial relationships to disclose.
Phase I first-in-human study of the polo-like kinase-1 selective inhibitor, GSK461364, in patients with advanced solid tumors
Authors: D. Olmos, A. Allred, R. Sharma, A. Brunetto, D. Smith, S. Murray, D. Barker, A. Taegtmeyer, J. de Bono, S. Blagden
Journal: Journal of Clinical Oncology (2009)

3536 Background: Polo-like kinase-1 (Plk1), part of a family of highly conserved serine-threonine kinases, has multiple roles in mitotic progression, is over-expressed and also associated with poor prognosis in some tumor types. GSK461364 is a potent and selective ATP-competitive inhibitor of Plk1 (Ki 2.2nM) with demonstrated antiproliferative activity in vitro and in vivo. Methods: Adult patients (pts) with relapsed/refractory advanced solid tumors with performance status of 0–2 and adequate organ function were eligible. Sequential cohorts of 2–6 patients each received escalating doses of GSK461364 administered as a 4h intravenous infusion (Schedule [Sch] 1: D1,8,15 q28 or Sch 2: D1,2,8,9,15,16 q28). Primary objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSK461364. Secondary objectives included preliminary evaluation of anti-tumor activity. Results: 27 pts (20 male, 7 female) were evaluated. Four dose levels, 50mg (n = 2), 100 mg (n = 3), 150 mg (n = 3) and 225 mg (n = 8) were evaluated in Sch 1. Three dose levels, 25 mg (n = 2), 50 mg (n = 2) and 100 mg (n = 7) were evaluated in Sch 2. Dose-limiting toxicities (DLTs) observed were Gr 4 sepsis, in Sch 1 at 225 mg dose, Gr 4 pulmonary embolism (PE) and Gr 4 neutropenia &gt;7d in Sch 2, both at 100 mg dose. Other Sch 1 adverse events (AEs) with a maximum grade ≥3 were fatigue and anemia (both, n = 2), pleuritic pain, pelvic pain, abdominal discomfort, constipation, vomiting, neutropenia, and deep vein thrombosis (all, n = 1). Other Sch 2 AEs with a maximum grade ≥3 were PE, renal failure, thrombocytopenia, and catheter-related infection (all n = 1). The most common adverse events (AEs) regardless of attribution, Sch and dose level were phlebitis (n = 9), fatigue (n = 9), nausea (n = 7), anemia (n = 6), anorexia (n = 6), diarrhea (n = 6), and infusion site reaction (n = 5). Preliminary PK data indicate that AUC and Cmax were proportional across doses; mean values were CLs ∼72–85L/hr, Vss ∼550–1200L and t1/2 ∼11.5hr. Phospho-histone H3, a marker of mitotic arrest, was detected, in circulating tumor cells, 24 hrs after first dose. Stable disease &gt;5m has been observed in 2 esophageal cancer pts. Conclusions: Dose escalation continues in Sch1, Sch2 has been expanded at 75mg. An MTD has not yet been defined. [Table: see text]
Intensive induction chemotherapy (CT) without methotrexate (MTX) in adult patients with localized osteosarcoma (LO): Updated results of the Institut Gustave Roussy phase II trial
Authors: H. Assi, M. C. Le Deley, G. Missenard, P. Terrier, C. Le Péchoux, S. Bonvalot, D. Vanel, J. B. Meric, T. Tursz, A. Le Cesne
Journal: Journal of Clinical Oncology (2004)

9020 Background: High dose MTX in adult patients (pts) with LO is highly toxic. We have designed in 1995 an intensive protracted regimen without MTX (API-AI regimen) in LO Methods:. Preliminary results were reported at ASCO 2001. The 3-yr event-free survival (EFS) compared favorably with those obtained with HDMTX CT regimen in pediatric population (Le Cesne, ECCO 11). Briefly good responders (≥95% necrosis) (GR) received 2 other API courses (c) and poor responders (PR) a salvage regimen of etoposide and ifosfamide. Results: from March 1993 to March 2000, 32 adult pts with LO (male/female : 19/13) with a median age of 21 yrs, [range 15–49], were included in the study. 126 c (API-AI) of CT were administered (median 3,94 c/pt, range 3 to 5). The planned protocol was given in 75% of pts, 16% received only 3 c for hematologic toxicity (T), and 10% received 5 c due to delay surgery. The median delay between each c of CT was 15 days (range 12–32). All pts received the fixed dose. All but 3 pts had a limb sparing surgery performed 10.3 weeks (median) after the first CT c (range 8–15). T was mainly haematological with febrile neutropenia, grade 4 neutropenia and thrombocytopenia observed in 34%, 69% and 35% of pts respectively. There were no renal and cardiac T. There were 15 GR (47%) and 17 PR (53%). The median follow-up was now 64 months [30–115]. The 5-yr EFS and overall survival (OS) were 65% [48–79%] and 69% [50–83%]. Two pts developed hemopathy: 1 AML5 in a PR with concomitant relapse and 1 MDS in a GR. Until december 2003, two pts with GR exhibited a distant relapse and one died from secondary hemopathy. The 5-yr EFS and OS for pts with GR were 79% [54–93%] and 85% [59–96%]. Eight of the pts with PR experienced relapse. The 5-yr EFS and OS for pts with PR were 52% [30–74%] and 56% [32–77%]. Conclusions: despite the haematological T, these results compare favorably with those observed with previous induction CT containing MTX in adult pts treated in our institution (Le Cesne, ASCO 98). These promising results had to be corroborated by an ongoing national multicenter coordinated by the French Sarcoma Group. No significant financial relationships to disclose.
Phase II randomized trial of MEK inhibitor pimasertib or placebo combined with gemcitabine in the first-line treatment of metastatic pancreatic cancer.
Authors: Eric Van Cutsem, Manuel Hidalgo, Igor Bazin, Jean-Luc Canon, Elena Poddubskaya, Nebojsa Manojlovic, Michele Milella, Dejan Radenkovic, Chris Verslype, Wei Guo, Lars Damstrup, Pascal Hammel
Journal: Journal of Clinical Oncology (2015)

344 Background: In metastatic pancreatic cancer (mPaCa), KRAS mutations lead to constitutive activation of the MAPK pathway in the vast majority of cases. Pimasertib (Pim) is a selective, non-competitive MEK 1/2 inhibitor with potent antitumor activity in preclinical models with constitutive MAPK activation. Methods: Following a phase I, dose-finding part to the trial, 88 patients (pts) with mPaCa were randomized 1:1 to receive Pim 60 mg BID (A, 44 pts) or placebo (B, 44 pts) in combination with weekly gemcitabine (Gem) 1000 mg/m 2 (7 of 8 wks in cycle 1, then 3 of 4 wks in subsequent cycles), in a phase II setting (NCT01016483). The primary endpoint was progression-free survival (PFS). Response rate (RR), overall survival (OS) and safety were secondary endpoints. Biomarker analysis was an exploratory endpoint. Results: Pt characteristics were balanced (median age 63.5 yrs, males 56%, stage IV at initial diagnosis 75%) except for PS 0, which was more frequent in arm A (59 vs 41%). Time on treatment was longer in arm B (10.6 vs 8.0 wks). A higher proportion of pts in arm A discontinued treatment during the first 4 wks (31 vs 19%), predominantly due to adverse events (AEs) and PD. Median PFS was 3.7 mo in arm A and 2.8 mo in arm B (HR=0.883, 95% CI: 0.549–1.42; p=0.608). No statistically significant differences were observed between arms for OS (median 7.3 mo in arm A vs 8.3 mo in arm B) and RECIST 1.0 RR (9.1% in both arms). Grade ≥3 thrombocytopenia (20.0 vs 0%), vomiting (15.6 vs 4.8%), fatigue (15.6 vs 7.1%), stomatitis (13.3 vs 0%) and diarrhea (11.1 vs 2.4%) were more common in arm A. Typical allosteric MEK inhibitor-related AEs, such as all grade retinal detachment (24.4%) and creatine phosphokinase elevation (20.0%), were observed almost exclusively in arm A. KRAS mutational status did not influence PFS or OS. Conclusions: The primary study endpoint was not met; secondary endpoints did not suggest clinically meaningful differences between arms, except for selected toxicities observed more frequently with the combination of Gem and Pim. The outcome does not support further development of this combination in the first-line setting in mPaCa. Pim is currently in development in other solid tumors. Clinical trial information: NCT01016483.
Phase I evaluation of the weekly 24 hour intravenous administration of aviscumine, a recombinant ribosome-inactivating protein, in patients with refractory solid tumors
Authors: P. Schöffski, I. Breidenbach, O. Bolte, J. Krauter, S. Zilz, K. Wilhlelm-Ogunbiyi, H. Lentzen
Journal: Journal of Clinical Oncology (2004)

3106 Background Aviscumine is a recombinant E.coli-derived type II ribosome-inactivating protein with potent antitumor activity in vitro and in vivo. The drug targets terminal a2–6-sialylated structures (CD75s). In a previous Phase I study (EORTC 16002), the drug exhibited a short t½ after 1 h i.v. infusion. Methods In the current Phase I study, Aviscumine was therefore administered weekly as a 24 h central i.v. infusion in patients (pts) with refractory solid tumors to determine safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and PK. Pts had histologically or cytologically verified disease, were =18 yrs old, had an ECOG PS =2 and adequate bone marrow, liver and renal function. DLT was any non-hematological gr 3–4 toxicity (CTC version 2.0), ANC below 500/ml for =7 days, febrile neutropenia or thrombocytopenia °4. MTD was defined as dose where >20% of pts had DLT in cycle 1. Results Since February 2003, 11 pts (8 male, 3 female) were enrolled. Median age was 63 yrs (41–77). Tumor types included colorectal cancer (7), soft tissue sarcoma (2), renal cell (1) and pancreatic cancer (1). Median no. of cycles was 2 (1–4+). Based on previous experience the starting dose was 6 μg/kg. DLTs were increases in liver enzymes in 2 pts at the starting dose. The protocol was amended and re-opened at 4 μg/kg for another 3 pts. No DLTs were observed with this dose. 5 μg/kg were tolerated well in 4+ pts. 1 patient, previously exposed to mistletoe extracts, had a hypersensitivity reaction on day 1 of cycle 1 and was replaced. The study is ongoing to enrol a total of 6 evaluable pts on the dose level of 5 μg/kg. In 2 pts at doses below 6 μg/kg increases of γGT >50 U/l >baseline were observed (already gr 3 at baseline). The only other toxicity >gr 1 in >1 pt was increased urinary frequency (4 pts). Best response (RECIST) was stable disease in 4 pts for 2–4+ cycles. PK analysis revealed plasma levels in the theoretically active range (>2 ng/ml) during the 24 h infusion. Conclusions The prolonged i.v. administration of Aviscumine was well tolerated and feasible. The recommended dose for further clinical trials will most likely be 5 μg/kg. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration VISCUM AG VISCUM AG VISCUM AG
&lt;italic&gt;Brief Communication:&lt;/italic&gt; Argyrophilic Carcinoids in Two Syrian Hamsters (&lt;italic&gt;Mesocricetus auratus&lt;/italic&gt;)
Authors: Lucia J. Dunham, Katharine C. Snell, Harold L. Stewart
Journal: JNCI Journal of the National Cancer Institute (1975)

Argyrophilic carcinoids were found in 2 Syrian hamsters (Mesocricetus auratus). A solitary neoplasm was located in the glandular stomach of a 25.5-month-old animal that had ingested for 12 months laboratory chow to which arecoline and calcium hydroxide [Ca(OH)2] had been added. In the other hamster, a primary carcinoid of the pancreas had metastasized to the mesenteric lymph nodes and liver; this was in a 22-month-old animal that had ingested for 16 months chow containing added snuff and Ca(OH)2. It is not known whether the carcinoids were spontaneous or induced by the treatment. Argyrophilic carcinoids have previously been reported in only one other rodent species, Mastomys (Praomys) natalensis.
Abstract 18836: Drug Delivery Strategies Employing Angioplasty Balloons for Treatment of Atherosclerosis
Authors: Lee-Chun Su, Roshni Iyer, Hao Xu, Varsha Sundaresan, Primana Punnakitikashem, Jian Yang, Subhash Banerjee, Kytai T Nguyen
Journal: Circulation (2013)

Introduction: Conventional treatments of atherosclerosis including angioplasty and stenting have adverse drawbacks like restenosis and thrombosis. Recent research on drug eluting balloons show that anti-restenotic drugs delivered at the atherosclerotic lesion via angioplasty balloons are eliminated through circulation. Our goal is therefore to provide a sustained and targeted drug release at the diseased site via paclitaxel loaded Urethane doped polyester (UPE) nanoparticles (NPs) eluting balloons. Materials and Methods: Paclitaxel-loaded UPE NPs were fabricated and characterized by dynamic light scattering, SEM and TEM. These nanoparticles were coated onto the balloon surface by either Layer by Layer (LbL) electrostatic or hydrogel (acrylic acid) coatings. NP loading was optimized by studying various parameters like incubation saturation and coating efficiency. SEM micrographs were acquired to visualize the coatings and the loaded nanoparticles. Finally, rat arteries were harvested and NP delivery via angioplasty balloons to the arterial lumen ex vivo was investigated. Results and Discussion: UPE NPs had an average size of 300 nm and zeta potential of -28.5 mV. NP loading reached saturation at 24h and 16h, allowing over 65% and 80% of UPE NPs to be loaded for LbL and hydrogel, respectively. Moreover, ex vivo NP retention results revealed that a higher rate of NPs can be delivered to the arterial wall by the hydrogel coating compared to LbL coating. It was also noted that coating materials (LbL and hydrogel coating) and UPE NPs were non-toxic to human vascular endothelial cells. Conclusion: Our results conclude that LbL nanoparticle loading, although considered as a well-established procedure, provides a comparatively low loading efficiency and NP transfer than that obtained by the hydrogel technique. However, it is difficult to obtain a uniform hydrogel coating consisting of NPs on the balloon surface. If successful, these techniques can provide a means for delivering drug loaded nanoparticles to the atherosclerotic lesion locally.