tbuckley/cabot-search huggingface dataset:
Ranjit Chandra: how reputation bamboozled the scientific community
Authors: Caroline White
Journal: BMJ (2015)

Generating a protective humoral immune response requires proper B cell activation. Ligation of the BCR increases the level of reactive oxygen intermediates (ROI). While they have been implicated in oxidative stress, recent studies suggest ROI act as secondary messengers facilitating normal cellular function. Our focus is on the mechanisms by which ROI control B cell function. Following BCR ligation in vitro, the levels of the first oxidation product of cysteine, sulfenic acid, increased in the proteome. Using 5,5-dimethyl-1,3-cyclohexanedione (dimedone), a compound that covalently reacts with sulfenic acid to prevent further oxidation or reduction, we determined reversible cysteine sulfenic acid formation is critical for sustained tyrosine phosphorylation, calcium flux, and proliferation of B cells. To address the role of ROI in vivo, lymphocytic choriomeningitis virus (LCMV) infected mice were treated with Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), a superoxide dismutase mimetic, from days 0-8 postinfection. On day 38, LCMV specific IgG antibody secreting cells (ASC) were 5-fold lower in the bone marrow. In contrast, the number of LCMV specific memory B cells was unaffected. The ASC decrease was not detected when mice were only treated from days 0-4 or 4-8 postinfection or during secondary viral infection. These data demonstrate ROI and reversible cysteine sulfenic acid formation are critical to B cell function and differentiation.
Effects of the SLCO1B1 *1 and SLCO1B1 *5 polymorphisms on IL-6 and IL-10 levels in patients under pravastatin treatment prior to inguinal hernia repair
Authors: Martha Irazema Cárdenas-Rojas, Ivan Delgado-Enciso, Luz Margarita Baltazar-Rodríguez, José Guzmán-Esquivel, Mario Ramírez-Flores
Journal: International Journal of Surgery (2016)
An unusual cause of odynophagia
Authors: Catherine Moreman, Shivkumar Budihal, Sukhbir Ubhi, John de Caestecker, Cathy J Richards
Journal: Gut (2015)

A 45-year-old man presented with odynophagia, felt in the region of the upper chest. Upper GI endoscopy was normal and proton pump inhibitor therapy ineffective. Oesophageal function tests showed no reflux on 24 h pH monitoring; manometry revealed ineffective oesophageal motility (low-amplitude peristalsis) thought to explain his symptoms. He re-presented 6 years later with worsening odynophagia; repeat endoscopy showed a 1 cm nodule in the proximal oesophagus at 24 cm from the incisor teeth. Endoscopic biopsies showed features of low-grade adenocarcinoma of mucinous/tubular type. He was referred to the network upper GI cancer multidisciplinary team and a decision was made for further endoscopic assessment, after staging CT and positron emission tomography scans did not identify the tumour or any metastases; endoscopic ultrasound (EUS) was not performed. …
Idarubicin and high-dose cytarabine in the treatment of refractory and relapsed acute lymphoblastic leukemia
Authors: F Giona, A M Testi, S Amadori, G Meloni, M Carotenuto, L Resegotti, R Colella, P Leoni, A M Carella, P Grotto
Journal: Annals of Oncology (1990)
Randomized study of growth factors post-peripheral-blood stem-cell transplant: neutrophil recovery is improved with modest clinical benefit.
Authors: G Spitzer, D R Adkins, V Spencer, F R Dunphy, P J Petruska, W S Velasquez, C E Bowers, N Kronmueller, R Niemeyer, W McIntyre
Journal: Journal of Clinical Oncology (1994)

PURPOSE To evaluate the clinical value of growth factors (GFs) with peripheral-blood stem cells (PBSC) collected following mobilization with GFs, we randomized patients to receive or not to receive GFs following transplant. PATIENTS AND METHODS Thirty-seven patients were apheresed after receiving the combination of granulocyte colony-stimulating factor (G-CSF) with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses of 10 micrograms/kg/d and 5 micrograms/kg/d, respectively, for 6 days before apheresis and during a median of 4 days of collections. One day after the infusion of autologous marrow and PBSC, patients were randomly assigned to receive no GFs or a combination of G-CSF (7.5 micrograms/kg/d) and GM-CSF (2.5 micrograms/kg/d), both as a 2-hour intravenous (i.v.) infusion twice per day until the neutrophil count was greater than 1,500/microL. RESULTS The median days to recovery to an absolute neutrophil count (ANC) of 100/microL (9 v 11.5, P = .0005), 500/microL (10 v 16, P = .0004), or 1,000/microL (12 v 21, P = .0008) was shortened with the use of GFs, post-PBSC infusion. In addition, the duration of hospitalization was shorter (19 v 21 days, P = .0112) in the arm receiving GFs post-PBSC infusion. There was no significant difference between the two study arms in the duration of fever, documented septic episodes, or RBC or platelet transfusion requirements. CONCLUSION Despite faster neutrophil recovery and shortened duration of hospitalization with GFs administered after PBSC transplantation, the measured clinical variables of febrile days, septic episodes, and transfusion requirements were similar between the study arms. The use of GFs post-PBSC transfusion is associated with a modest clinical benefit.
Abstract 16802: Gender Match Does Not confer Survival Advantage in Pediatric Heart Transplantion
Authors: Lee Tosi, Nancy Halnon, Myke Federman, Daniella Markovic, Rick Harrison
Journal: Circulation (2011)

Background: In adult heart transplant recipients, a survival advantage for male recipients with donor-recipient gender match has been shown. We determined if similar effects of recipient gender, donor gender, and donor-recipient mismatch exist in pediatric heart transplantation. Methods: We reviewed the United Network for Organ Sharing (UNOS) database for 3630 first time heart transplant recipients younger than age eighteen years transplanted between January 1994 and May 2008. We determined mortality rates based on recipient gender, donor gender, and donor recipient gender match with and without adjustment for known risk factors, including presence of congenital heart disease, assist device, race, donor or recipient age, era, elevated bilirubin or creatinine, mechanical ventilation, and dialysis. Results: Female recipients (F) had increased mortality compared to male recipients (M) with adjusted hazard ratio (HR) = 1.27 (1.12-1.44, p &lt; .001). Donor gender had no effect on mortality. Gender mismatch conferred no survival disadvantage for male recipients with adjusted HR = 1.09 (0.92-1.29, p= .330) nor female recipients with HR= 1.12 (0.93-1.36, p=0.330). The largest survival effect was between M to M and M to F groups (HR=1.38; 1.17-1.63, p&lt; .001). However, 5 year conditional survival was similar between all groups (M to M, F to F, M to F, F to M) (log rank p =.1077 for 30 day and p=.0595 for 1 year survivors). Conclusion: In pediatric heart transplant recipients, unlike adult patients, gender match does not confer survival advantage. Female recipients have increased mortality compared to male recipients. Gender specific recipient risk factors post transplant should be investigated.
Central nervous system metastases after trastuzumab therapy in patients with breast cancer
Authors: H. Daw Sr., A. Muslimani, M. Ahluwalia, M. Kundranda
Journal: Journal of Clinical Oncology (2006)

10747 Background: trastuzumab (Tz), a humanized anti-HER-2/neu antibody, has been shown to improve survival in patients with HER2-positive breast cancer. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. Here we report 4 cases of HER-2 positive advanced breast cancer patients who developed BM while on TZ therapy. Cases: all 4 patients were treated initially with a combination of taxane-trastuzumab followed by maintenance trastuzumab. Tumors were classified as HER-2 over expressing if they were scored 3+ by immunohistochemistry or showed amplification by fluorescence in situ hybridization. Mean age at diagnosis was 48. Mean duration of trastuzumab therapy prior to BM was 20 months. All patients had achieved a complete remission of extracranial disease at the time of BM diagnosis. Mean number of intracranial lesions as determined by magnetic resonance imaging was 4. Treatment included radiosurgery, surgical resection, whole brain radiation, temozolomide, high dose methotrexate, thalidomide and in one patient, intra-arterial chemotherapy. All 4 patients are alive at the date of last follow-up (median =3 years) after BM diagnosis. Conclusions: this report suggests that patients who develop BM after trastuzumab can have a relatively long survival rate. The importance of a multidisciplinary approach to these patients cannot be overemphasized. Development of BM on TZ therapy does not represent resistance to TZ, but instead likely reflects the inability of TZ to cross the brain-blood barrier. Further research in this area is needed to optimize management while minimizing late effects. In this regard, alternatives to whole brain radiation should continue to be studied. In addition, the role of prophylactic cranial irradiation and the search for drugs that target HER-2 and cross the blood-brain barrier should be investigated. No significant financial relationships to disclose.
Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: A GCIG and EORTC-GCG study.
Authors: Ignace B. Vergote, Florence Joly, Dionyssios Katsaros, Corneel Coens, Alexander Reinthaller, Marcia Hall, Christopher B. Steer, Nicoletta Colombo, Anne Lesoin, Antonio Casado, Edgar Petru, John Green, Martin Buck, Isabelle Laure Ray-Coquard, Annamaria Ferrero, Laure Favier, Nicholas Reed, Herve Curve, Antonio Jimeno, Eric Pujade-Lauraine
Journal: Journal of Clinical Oncology (2012)

LBA5000 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis
Authors: Michael P. Curry, Jacqueline G. O’Leary, Natalie Bzowej, Andrew J. Muir, Kevin M. Korenblat, Jonathan M. Fenkel, K. Rajender Reddy, Eric Lawitz, Steven L. Flamm, Thomas Schiano, Lewis Teperman, Robert Fontana, Eugene Schiff, Michael Fried, Brian Doehle, Di An, John McNally, Anu Osinusi, Diana M. Brainard, John G. McHutchison, Robert S. Brown, Michael Charlton
Journal: New England Journal of Medicine (2015)

As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase.We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin.Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).
Phase II trial of preoperative bevacizumab (Bev), irinotecan (I), cisplatin (C), and radiation (RT) in esophageal adenocarcinoma: Preliminary safety analysis
Authors: D. Ilson, M. Bains, N. Rizk, V. Rusch, R. Flores, B. Park, M. Shah, D. Kelsen, B. Miron, K. Goodman
Journal: Journal of Clinical Oncology (2009)

4573 Background: Preo chemoRT with weekly I/C and 5040 cGy followed by surgery is well tolerated [JCO 24: Abstract 4032; 2006]. ECOG trial E1201recently reported a median survival of 34 months with this preop regimen [JCO 26: Abstract 4532; 2008]. Bev + chemo improves response rate (RR) and time to progression (TTP) when added to weekly I/C in advanced esophagogastric cancer but does not increase chemo toxicity [JCO 24: 5201; 2006]. We are now combining in a Phase II trial Bev/I/C with concurrent radiotherapy (RT) in esophageal adenocarcinoma (EA) with the primary endpoint of safety. Methods: Patients (pts) with resectable Siewert's I or II EA were staged by EUS, PET, and CT. Induction chemo consisted of I-50–65 mg/m2 and C-30 mg/m2 weeks 1,2,4,5, Bev-7.5 mg/kg weeks 1 and 4; and, during RT (180 cGy daily to 5040 cGy), I/C was given weeks 7,8,10,11 and Bev weeks 7,10. Esophagectomy was 6–8 weeks after RT. A planned toxicity analysis was made in 10–15 pts completing chemoRT, and in 10 pts undergoing surgery: toxicity was acceptable if grade 3 / 4 hematologic toxicity remained &lt; 72% and non hematologic toxicity &lt; 40% during combined chemoRT (based on our prior phase II trial of I/C/RT [JCO 24: Abstract 4032; 2006]); and if pts undergoing surgery had no surgical complication related to Bev. Results: 18 pts have been enrolled, 12 male: 6 female; 7 Siewert I: 11 Siewert II; T3N1 12: T3N0 5: T2N0 1. 14 are evaluable for toxicity, 2 are too early, one progressed prior to RT, and one was taken off due to a CVA from a patent foramen ovale. Grade 3/4 neutropenia occurred in 4 pts (29%). Grade 3/4 non heme toxicity occurred in 5 pts (36%), including esophagitis 2 pts (14%), neutropenic fever 1 pt (7%), and pulmonary embolism 1 pt (7%). No grade 3 / 4 hypertension was seen, and 3 pts (21%) developed grade 1 proteinuria. Ten pts underwent surgery, and there were no unexpected surgical or wound complications; there were 2 anastomotic leaks. Pathologic responses: 1 pathologic CR and 1 T0N1. Conclusions: In a preliminary analysis of pts treated with Bev + preop chemoRT in EA, there was no increase in hematologic/non hematologic toxicity or Bev related surgical complications. Accrual will continue to 33 patients. Supported by Genentech. [Table: see text]
Toll-like receptor 3 signalling mediates angiogenic response upon shock wave treatment of ischaemic muscle
Authors: Johannes Holfeld, Can Tepeköylü, Christin Reissig, Daniela Lobenwein, Bertram Scheller, Elke Kirchmair, Radoslaw Kozaryn, Karin Albrecht-Schgoer, Christoph Krapf, Karin Zins, Anja Urbschat, Kai Zacharowski, Michael Grimm, Rudolf Kirchmair, Patrick Paulus
Journal: Cardiovascular Research (2015)

Shock wave therapy (SWT) represents a clinically widely used angiogenic and thus regenerative approach for the treatment of ischaemic heart or limb disease. Despite promising results in preclinical and clinical trials, the exact mechanism of action remains unknown. Toll-like receptor 3, which is part of the innate immunity, is activated by binding double-stranded (ds) RNA. It plays a key role in inflammation, a process that is needed also for angiogenesis. We hypothesize that SWT causes cellular cavitation without damaging the target cells, thus liberating cytoplasmic RNA that in turn activates TLR3. SWT induces TLR3 and IFN-β1 gene expression as well as RNA liberation from endothelial cells in a time-dependant manner. Conditioned medium from SWT-treated HUVECs induced TLR3 signalling in reporter cells. The response was lost when the medium was treated with RNase III to abolish dsRNAs or when TLR3 was silenced using siRNAs. In a mouse hind limb ischaemia model using wt and TLR3−/− mice (n = 6), SWT induced angiogenesis and arteriogenesis only in wt animals. These effects were accompanied by improved blood perfusion of treated limbs. Analysis of main molecules of the TLR3 pathways confirmed TLR3 signalling in vivo following SWT. Our data reveal a central role of the innate immune system, namely Toll-like receptor 3, to mediate angiogenesis upon release of cytoplasmic RNAs by mechanotransduction of SWT.
Joint Oncogenic Action of Antimetabolites and 3-Methylcholanthrene in Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Takiji Arata, Satoshi Tanaka, Chester M. Southam
Journal: JNCI Journal of the National Cancer Institute (1968)

More mice developed skin papillomas from application of 3-methylcholanthrene (MCA) if they simultaneously received high doses of iododeoxyuridine, fluorodeoxyuridine, or chloramphenicol, than if they received MCA only. The increase in skin papilloma incidence in the groups given these antimetabolites was approximately twofold. The phenomenon was reproducible in repeated experiments. The differences were statistically significant in the total experience, although they might readily have occurred by pure chance in the individual experiments.
Antiandrogen (AA), vaccine (V), and combination therapy in D0.5 prostate cancer (CaP) patients (Pts)
Authors: P. M. Arlen, J. L. Gulley, N. Todd, K. Y. Tsang, J. Schlom, W. L. Dahut
Journal: Journal of Clinical Oncology (2005)

2518 Background: The appropriate treatment (tx) of CaP pts who have received hormonal therapy, but develop a rising PSA without radiographic evidence of metastasis (mets) remains controversial. We have developed the first V in which an admixture containing the vaccinia vector with the gene for PSA (rV-PSA) is combined with vaccinia containing the costimulatory molecule B7.1 (rV-B7.1) as a priming V. As part of this therapeutic V strategy, pts receive monthly boosts of fowlpox-PSA as well as the cytokines GM-CSF and IL-2 with all vaccinations. Methods: Pts must have a rising PSA despite castrate levels of testosterone, and a bone scan and CT scan without mets. 42 pts have been randomized to V (n=21) vs. AA therapy with nilutamide (N) (n=21). After 6 months (mo) pts with a rising PSA and no mets may receive a combination of both tx. Results: The pts age and Gleason score were similar in the 2 arms. The treatment was tolerated well with only grade 2 or less toxicity related to the V itself. 3 patients randomized to N were removed from study secondary to grade 3 toxicities. The mean PSA velocity was calculated for patients enrolled on V prior to and after 6 mo of V tx. The median pre tx PSA velocity was 6.63ng/mL per month and decreased following 6 mo of V therapy to 4.50ng/mL per mo (p=.25). The median time to tx failure was 9.9 mo in the V arm vs. 7.6 mo in the N arm (p=0.28). 2 pts continue on the N arm to date without evidence of disease progression (>30 mo). 12 pts on the V arm had N added at the time of PSA progression. The median time for tx failure with the combined therapy was 13.9 mo, for a total of 25.9 mo from initiation of therapy. In contrast, 8 patients from the N arm had V added at the time of PSA progression. The median time on study with the combined therapy was 5.2 mo, with a total duration from onset of study of 15.9 mo. Conclusions: To our knowledge this is the first randomized trial specifically devoted to treating patients with D0.5 prostate cancer. Both V and N appeared to have clinical activity in this pt population. Furthermore, pts appeared to respond better to N after receiving V. We plan to investigate the role of combining V with AA therapy versus sequential V followed by AA therapy to determine if there is indeed a role for combination therapy in this pt population. No significant financial relationships to disclose.
Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization
Authors: Alexandre Dubrac, Gael Genet, Roxana Ola, Feng Zhang, Laurence Pibouin-Fragner, Jinah Han, Jiasheng Zhang, Jean-Léon Thomas, Alain Chedotal, Martin A. Schwartz, Anne Eichmann
Journal: Circulation (2015)

Sprouting angiogenesis is a key process driving blood vessel growth in ischemic tissues and an important drug target in a number of diseases, including wet macular degeneration and wound healing. Endothelial cells forming the sprout must develop front-rear polarity to allow sprout extension. The adaptor proteins Nck1 and 2 are known regulators of cytoskeletal dynamics and polarity, but their function in angiogenesis is poorly understood. Here, we show that the Nck adaptors are required for endothelial cell front-rear polarity and migration downstream of the angiogenic growth factors VEGF-A and Slit2.Mice carrying inducible, endothelial-specific Nck1/2 deletions fail to develop front-rear polarized vessel sprouts and exhibit severe angiogenesis defects in the postnatal retina and during embryonic development. Inactivation of NCK1 and 2 inhibits polarity by preventing Cdc42 and Pak2 activation by VEGF-A and Slit2. Mechanistically, NCK binding to ROBO1 is required for both Slit2- and VEGF-induced front-rear polarity. Selective inhibition of polarized endothelial cell migration by targeting Nck1/2 prevents hypersprouting induced by Notch or Bmp signaling inhibition, and pathological ocular neovascularization and wound healing, as well.These data reveal a novel signal integration mechanism involving NCK1/2, ROBO1/2, and VEGFR2 that controls endothelial cell front-rear polarity during sprouting angiogenesis.