tbuckley/cabot-search huggingface dataset:
NCCTG (Alliance) N0572: A phase II trial of sorafenib and temsirolimus in recurrent glioblastoma (GBM) patients who progress following prior RT/temozolomide (TMZ) and VEGF inhibitors (VEGFi).
Authors: Kurt A. Jaeckle, David Schiff, S. Keith Anderson, Evanthia Galanis, Philip J. Stella, Patrick J. Flynn, Jann Nagina Sarkaria, Caterina Giannini, Bradley J. Erickson, Jan C Buckner
Journal: Journal of Clinical Oncology (2013)

2014 Background: PFS6 is low (2.3%) and med OS brief (4 mos) for recurrent GBM pts who progress after prior RT/TMZ and bevacizumab (Bev), and then receive non-Bev containing regimens (Reardon et al, Br J Canc 2012). Following VEGFi exposure, tumor cell resistance potentially may result from activation of Ras/Raf/MEK/ERK (MAPK) and PI3K/Akt/mTOR signaling pathways. Temsirolimus (mTOR inhibitor) and sorafenib (Raf, PDGFR, VEGFR inhibitor) have previously shown limited single agent activity in GBM. Methods: Recurrent GBM pts who showed radiographic progression despite prior surgery, RT + temozolomide, and VEGFi (initially or at recurrence) received sorafenib 200 mg PO bid and temsirolimus 20 mg IV weekly (the NCCTG N0572 phase I MTD) until progression. All pts had received &lt; 2 prior chemo regimens. A two-stage design was used, with 90% power to detect an increase in PFS6 from 8% to 23%, requiring 41 evaluable pts. The primary endpoint was PFS6; secondary endpoints included OS, TTP, and ORR. Toxicity (TOX) was assessed using CTC ver 3.0. Results: 44 evaluable pts were accrued. Four of the first 40 (10%) reached PFS6, but this did not meet the pre-study threshold for success. Median TTP was 1.8 mos. (40 events, 95% CI: 1.5 – 2.3); median OS was 5 mos. (36 events, 95% CI: 6.6 – 3.1), and no objective responses were reported. Eight pts are alive; 4 have not progressed (median F/U 3.1 mos.; max, 12.2 mos.). Grade 3+ non-heme AE were observed in 51% (23/45; fatigue-5, hypophosphatemia-7, hypercholesterolemia-5, hypertriglyceridemia-5). One grade 4 hematologic AE (thrombocytopenia) occurred. 13.3% (6/45 pts) went off due to TOX, and 71.1% (32/45) due to disease progression. Conclusions: Sorafenib plus temsirolimus was tolerable, but the primary endpoint threshold for success (PFS6) was not met in post-VEGFi recurrent GBM patients. Nevertheless, PFS6 (10%) and OS (5 mos.) compared favorably to contemporary series of Bev-refractory, recurrent GBM pts who are subsequently treated with a non-Bev containing regimen. Supported by NCI CA-25224. Clinical trial information: NCT00329719.
Propagation and Behavior in Chicken Kidney Cultures of the Agent Associated With Classical Marek's Disease&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J. M. Sharma, S. G. Kenzy, A. Rissberger
Journal: JNCI Journal of the National Cancer Institute (1969)

A classical isolate (WSU-GF) of Marek's disease herpesvirus (MDHV), isolated from the kidneys of a chicken with clinical symptoms of the disease, was successfully propagated in chicken kidney (CK) cultures. The cytopathic effect (CPE) was similar to that produced by the herpesviruses of group B and could be inhibited by 5-iododeoxyuridine. With continued serial passage of MDHV in CK cultures, the character of CPE was changed in that the polykaryocytes became much larger and the type-A inclusions more frequent. Based on the specific CPE, a tissue culture assay system for MDHV was standardized. It was found that a cell was the unit of infection. A pH of 7.5 and an incubation temperature of 37°C in CO2 atmosphere were optimal for the expression of CPE by MDHV. A minimum contact of 12 hours was necessary between the infected and the normal CK cells to obtain a maximum number of foci of infection. It appeared that the cells of infected cultures became infectious before attaining a rounded, refractile state.
The role of HIV integration in viral persistence: no more whistling past the proviral graveyard
Authors: Frank Maldarelli
Journal: Journal of Clinical Investigation (2016)

A substantial research effort has been directed to identifying strategies to eradicate or control HIV infection without a requirement for combination antiretroviral therapy (cART). A number of obstacles prevent HIV eradication, including low-level viral persistence during cART, long-term persistence of HIV-infected cells, and latent infection of resting CD4+ T cells. Mechanisms of persistence remain uncertain, but integration of the provirus into the host genome represents a central event in replication and pathogenesis of all retroviruses, including HIV. Analysis of HIV proviruses in CD4+ lymphocytes from individuals after prolonged cART revealed that a substantial proportion of the infected cells that persist have undergone clonal expansion and frequently have proviruses integrated in genes associated with regulation of cell growth. These data suggest that integration may influence persistence and clonal expansion of HIV-infected cells after cART is introduced, and these processes may represent key mechanisms for HIV persistence. Determining the diversity of host genes with integrants in HIV-infected cells that persist for prolonged periods may yield useful information regarding pathways by which infected cells persist for prolonged periods. Moreover, many integrants are defective, and new studies are required to characterize the role of clonal expansion in the persistence of replication-competent HIV.
Specific Reactivation of Latent HIV-1 by dCas9-SunTag-VP64-mediated Guide RNA Targeting the HIV-1 Promoter
Authors: Haiyan Ji, Zhengtao Jiang, Panpan Lu, Li Ma, Chuan Li, Hanyu Pan, Zheng Fu, Xiying Qu, Pengfei Wang, Junxiao Deng, Xinyi Yang, Jianhua Wang, Huanzhang Zhu
Journal: Molecular Therapy (2016)

HIV-1 escapes antiretroviral agents by integrating into the host DNA and forming a latent transcriptionally silent HIV-1 provirus. Transcriptional activation is prerequisite for reactivation and the eradication of latent HIV-1 proviruses. dCas9-SunTag-VP64 transcriptional system has been reported that it can robustly activate the expression of an endogenous gene using a single guide RNA (sgRNA). Here, we systematically investigated the potential of dCas9-SunTag-VP64 with the designed sgRNAs for reactivating latent HIV-1. We found dCas9-SunTag-VP64 with sgRNA 4 or sgRNA 5 targeted from -164 to -146 or -124 to -106 bp upstream of the transcription start sites of HIV-1 could induce high expression of luciferase reporter gene after screening of sgRNAs targeting different regions of the HIV-1 promoter. Further, we confirmed that dCas9-SunTag-VP64 with sgRNA 4 or sgRNA 5 can effectively reactivate latent HIV-1 transcription in several latently infected human T-cell lines. Moreover, we confirmed that the reactivation of latent HIV-1 by dCas9-SunTag-VP64 with the designed sgRNA occurred through specific binding to the HIV-1 LTR promoter without genotoxicity and global T-cell activation. Taken together, our data demonstrated dCas9-SunTag-VP64 system can effectively and specifically reactivate latent HIV-1 transcription, suggesting that this strategy could offer a novel approach to anti-HIV-1 latency.
A randomized trial of pentoxifylline and vitamin E versus standard follow-up after breast irradiation to prevent breast fibrosis, evaluated by tissue compliance meter (TCM)
Authors: G. M. Jacobson, B. J. Smith
Journal: Journal of Clinical Oncology (2008)

597 Background: Radiation induced fibrosis (RIF) is a common side effect of therapeutic radiation. The combination of pentoxifylline (PTX) and vitamin E has been demonstrated to reverse long standing radiation fibrosis. We conducted an institutional randomized clinical trial to determine if pentoxifylline and vitamin E given orally for 6 months following breast or chest wall irradiation, was effective in preventing radiation induced fibrosis. Methods: 37 breast cancer patients with localized disease were randomized to treatment with oral pentoxifylline 400 mg. TID and 400 IU vitamin E daily for 6 months following radiation, or standard follow up. Baseline Radiation Therapy Oncology Group (RTOG) acute effects were documented. RTOG late effects were documented at follow-up visits. Measurements with tissue compliance meter (TCM) were obtained from the treated and untreated breasts/chest wall in subjects and controls at 18 months to evaluate tissue compliance as a surrogate objective measurement of fibrosis. Differences in RTOG late effects and TCM measurements were evaluated by the Wilcoxon rank sum test. 18 patients were randomized to PTX/vitamin E with 19 controls. One subject discontinued her medication at 1 month. 33 patients have been followed a minimum of 6 months, with evaluation of RTOG late effects in 32. 20 patients have been followed for 18 months, 18 have been measured with the TCM. Results: The average difference in the PTX/ vitamin E group was 0.78 mm; the average difference in the control group was 3.7 mm. According to the Wilcoxon rank sum test, the difference between the treated and control group was significant (p=0.0228). Late effects were modest in these patents: the average RTOG late effects score in the PTX/vitamin E group was 0.46 and 1.23 in the control group (p=0.0516). Conclusions: In this study of post-radiation therapy breast cancer patients randomized to treatment with PTX/vitamin E or standard follow-up; there was a significant difference in radiation fibrosis as measured by a tissue compliance meter, with decreased fibrosis in the treated group (p=0.0228). The differences in RTOG late effects were marginally non-significant, but late effects were modest in both groups. No significant financial relationships to disclose.
Abstract 20038: Maternal Pre-Pregnancy Overweight is Associated with Increased Cardiovascular Disease Mortality in the Framingham Heart Study
Authors: Michael Mendelson, Asya Lyass, Sarah D de Ferranti, Charlotte Andersson, Caroline Fox, Chris O’Donnell, Matthew Gillman, Ralph B D’Agostino, Dan Levy
Journal: Circulation (2014)

Introduction: In the U.S., obesity among women of childbearing age is highly prevalent. Maternal obesity is associated with offspring obesity and cardiovascular disease (CVD) risk factors, potentially through epigenetic and early developmental mechanisms. There is limited evidence on the association of maternal overweight with offspring CVD events and mortality. Methods: We analyzed prospectively collected data from 1971 to 2012 on 879 Framingham Heart Study Offspring cohort participants with either directly measured pre-pregnancy maternal body mass index (BMI) (n=361) or offspring-reported maternal pre-pregnancy overweight status (n=518). Our outcomes included a composite measure of any CVD event or mortality, CVD mortality and all-cause mortality. Cox proportional hazard models were conducted, initially age and sex adjusted, and then additionally adjusted for potential mediators including traditional CVD risk factors. Pharmacologic treatments for diabetes, hypertension, and/or dyslipidemia were included as time-varying covariates. Results: Maternal pre-pregnancy overweight (BMI &gt;= 85th percentile or self-report) was available for 879 Framingham Offspring Study participants (mean age [SD] at baseline 30 [5] years; 49% female; mean follow-up [SD] 32 [8] years). There were 193 CVD events, 28 CVD deaths, and 138 total deaths among the offspring. Maternal overweight was associated with an increased hazard ratio (HR) with CVD mortality (HR 10.5 [2.6-43]; p=0.001), all-cause mortality (HR 3.1 [1.5-6.4]; p=0.002), and marginally associated with the composite endpoint of CVD events and mortality (HR 1.7 [95% CI 0.99-2.8]; p=0.05). Adjustment for offspring BMI, diabetes, hypertension, and dyslipidemia attenuated the associations. In sensitivity analyses restricted to only those with directly measured maternal pre-pregnancy BMI, effect estimates remained robust (similar hazard ratios but larger confidence intervals). Conclusions: Maternal pre-pregnancy overweight is associated with offspring CVD mortality. The association is likely mediated in part through classical CVD risk factors such as offspring obesity, hypertension, diabetes, and dyslipidemia.
L1 repeat elements in the human epsilon-G gamma-globin gene intergenic region: sequence analysis and concerted evolution within this family.
Authors: Peter Rogan, Julian Pan, Sherman Weissman
Journal: Molecular Biology and Evolution (1987)

We have deduced the sequence of a composite long interspersed repeated DNA in primates and herein describe its relationship to a complex repeat element (L1Heg) located in the interval linking the human epsilon- and G gamma-globin genes. The main element of L1Heg is 3' truncated and interrupted by the insertion of the 3' end of a second L1 element. Transposition of L1Heg into this intergenic locus generated a 62-bp duplication of flanking sequences. In contrast, insertion of the second repeat may have been mediated by homology between donor and target sequences. The main repeat represents a novel class of abundant elements whose sequences have diverged from other rodent and primate LINES approximately 1.3 kb downstream from the 5' terminus of L1Heg. Comparison of L1Heg with the sequences of two other related L1 members revealed a complex set of rearrangements confined within a region that resembles the long terminal repeats of other types of retroposons. The boundaries of conversion-like events were defined on the basis of the clustering of nucleotide sequence variants common to two or more nonallelic 3' L1H elements. Several of these events are apparently initiated or resolved within a common 150-bp region that coincides with the 3' terminus of a pan-mammalian open reading frame. This analysis showed that concerted genetic interactions and random drift both contribute appreciably to sequence variation within this set of L1H members.
Abstract 17359: Slow-release Prostacyclin Agonist using New Regional Drug Delivery System Promise Therapeutic Angiogenesis in a Porcine Chronic Myocardial Infarction
Authors: HIroki Mizoguchi, Shigeru Miyagawa, Satsuki Fukushima, Atsuhiro Saito, Yoshiki Sakai, Yukiko Imanishi, Akima Harada, Koich Toda, Yoshiki Sawa
Journal: Circulation (2013)

Background: Although prostacyclin is an endogenous factor for protection and regeneration of damaged tissue, the use of clinically available prostacyclin analogues for treating chronic pathological...
The retrospective analysis of reasons of prolonged air leakage after pulmonary resection
Authors: Armen Benyan, Evgeny Korymasov, Sergey Pushkin
Journal: European Respiratory Journal (2012)

Objective. Prolonged air leak is the one of most frequent complications after pulmonary resections.  The aim of our study is to identify the reasons of prolonged air leak by carrying out a retrospective analysis of cases with such complication.  Materials and methods. We have studied 878 case reports of patients, who underwent pulmonary resection, for last 10-year period (2002-2011). The patients had: chronic non-specific lung diseases – 266 (30,3%), interstitial lung diseases – 192 (21,9%), tumours – 182 (20,7%), purulent diseases of lung – 112 (12,7%), parasitic diseases – 71 (8,1%), tuberculosis – 55 (6,3%). We have performed: 218 lobectomies, 25 segmentectomies, 271 open and 364 VATS wedge resections.  Results. Prolonged air leak we have observed at 85 patients (9,7%). The reasons of prolonged air leak were integrated into 3 groups: a) reasons due to inadequate drainage functioning – 21 patient (2,4%); b) reasons due to thoracic wall – 2patients (0,2%); c) reasons due to operated lung – 62 patients (7,1%).  At 68 patients the problem was eliminated with use of different therapeutic and auxiliary methods. Re-operation was needed at 18 patients (2,0%). During re-operation we have also revealed: migration of drainage – at 3 patients, pulmonary fistula on resection line – at 9, unnoticed bulla on previous operation – at 1, lung destruction with bronchopleural fistula – at 2, lung laceration because of pleural adhesions – at 2, perforation of lung tissue with drainage – at 1 patient. The pathological reason of prolonged air leak was eliminated in every case.  Conclusion. Identification of reasons of prolonged air leak assists to timely application of different curative methods for its elimination.
Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial.
Authors: D H Mahoney, J Shuster, R Nitschke, S J Lauer, N Winick, C P Steuber, B Camitta
Journal: Journal of Clinical Oncology (1998)

To determine whether early intensification with 12 courses of intravenous methotrexate and intravenous mercaptopurine (IVMTX/IVMP) is superior to 12 courses of repetitive, low-dose oral MTX with I.V. MP (LDMTX/IVMP) for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL).Seven hundred nine patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction. Patients were randomized to receive intensification with either IVMTX 1,000 mg/m2 plus IVMP 1,000 mg/m2 (regimen A) or LDMTX 30 mg/m2 every 6 hours for six doses with IVMP 1,000 mg/m2 (regimen B). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy (TIT) was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and TIT every 12 weeks for 2 years.Six hundred ninety-nine (99%) patients achieved remission. Three hundred forty-nine were assigned to regimen A and 350 to regimen B. The estimated 4-year continuous complete remission (CCR) rate for patients treated with regimen A is 80.3% (SE = 2.9%) and with regimen B is 75.9% (SE = 3.1%). By log-rank analysis, regimen A demonstrated superior CCR (P = .013). Transient neutropenia/thrombocytopenia, bacterial sepsis, neurotoxicity, stomatitis, and hospitalizations were more frequent among patients treated on regimen A.Intensification with IVMTX/IVMP is more effective than LDMTX/IVMP for prevention of relapse in children with B-precursor ALL at lower risk for relapse.
Serum beta 2-microglobulin in the initial staging and subsequent monitoring of monoclonal plasma cell disorders.
Authors: H Garewal, B G Durie, R A Kyle, P Finley, B Bower, R Serokman
Journal: Journal of Clinical Oncology (1984)

Serum beta 2-microglobulin (beta 2-M) measurements were carried out in 97 patients with monoclonal plasma cell disorders. Twenty-six (87%) of 30 patients with monoclonal gammopathy of undetermined significance (MGUS) had increased beta 2-M levels and serial follow-up in seven patients showed a progressive increase with time. Of the 63 patients with active myeloma, pretreatment serum beta 2-M values were available in 25 for correlation with pretreatment stage. Stage III beta 2-M levels were significantly higher than stages I and II (p less than 0.001). Four patients with smoldering myeloma had beta 2-M values similar to stage I disease. There was, therefore, excellent correlation between beta 2-M and myeloma tumor burden. Levels of beta 2-M decreased with response to chemotherapy induction and low levels in stable remission (plateau phase) were associated with unusually good prognosis. Median survival for stage III patients in stable remission with low serum beta 2-M was greater than 48 months. Conversely, at relapse very high beta 2-M levels were associated with a very fulminant and refractory course. Serum beta 2-M, therefore, appears to be an extremely useful marker in initial stratification and follow-up of myeloma patients.
Analysis of safety profile of thalidomide in multiple myeloma: A multicenter Indian experience
Authors: R. Arora, A. Mukhopadhyay, K. Patel, V. P. Gangadharan, M. Chandy, S. Patil, P. P. Bapsy, S. H. Advani, A. Arora, S. Ganguly
Journal: Journal of Clinical Oncology (2005)

6709 Background: Thalidomide has been used for the treatment of multiple myeloma as a single agent, in combination with dexamethasone and other chemotherapeutic agents. This open labeled, non randomized, multicentric study was conducted across 8 centers in India to assess any difference in the safety and efficacy profile of the molecule in ethnic Indian population. Methods: Thalidomide (THALIX, Dabur Pharma Ltd.) was given either as a single agent at a dose of 100–200mg, or in combination with dexamethasone at a dose of 40 mg (oral) on days 1–4,9–12, 17–20 of a 28 days cycle of the odd cycles and days 1–4 of the even cycles. A minimum of 4 such cycles was needed to qualify for assessment. Responses were assessed as per SWOG criteria (Paraprotein levels in serum and plasma cells in the marrow). Toxicities were graded as per the NCI CTC (version 2.0). Results: Of the 108 patients recruited, 99 were evaluable for safety & efficacy. 36/99 (36.4%) patients received Thalidomide as first line therapy either as single agent (5/36, 13.9%) or in combination with dexamethasone (31/36, 86.1%). Of the relapsed cases (63/99, 63.6%), 28/63 (44.4%) received Thalidomide as monotherapy. The most commonly observed toxicities were peripheral neuropathy in 44/99 (44.4%), sedation 38/99 (38.4%), constipation 28/99 (28.3%), rashes 14/99 (14.1%) and neutropenia 10/99 (10.1%). All the adverse reactions were more common in the combination arm. Only 2 patients had Grade 3 neuropathy and one patient had a Grade 3 rash. No Grade IV toxicity was observed. Interestingly, no case of deep vein thrombosis (DVT) was reported. 32/36 (88.9%) patients had an objective response in the first line setting and 33/63 (52.4%) relapsed cases responded to the therapy. Conclusions: Thalidomide shows excellent tolerability in the Indian population and has responses similar to that reported in the western literature. More extensive studies using investigational modalities like color doppler will be carried out to confirm the low incidence of DVT in the Indian population especially in combination with dexamethasone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Dabur Research Foundation
Weighting sequence variants based on their annotation increases power of whole-genome association studies
Authors: Gardar Sveinbjornsson, Anders Albrechtsen, Florian Zink, Sigurjón A Gudjonsson, Asmundur Oddson, Gísli Másson, Hilma Holm, Augustine Kong, Unnur Thorsteinsdottir, Patrick Sulem, Daniel F Gudbjartsson, Kari Stefansson
Journal: Nature Genetics (2016)
Air—Water and Ether—Water Distribution of N—Nitroso Compounds: Implications for Laboratory Safety, Analytic Methodology, and Carcinogenicity for the Rat Esophagus, Nose, and Liver 2
Authors: Sidney S. Mirvish, Phillip Issenberg, Halvor C. Sornson
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article Air—Water and Ether—Water Distribution of N—Nitroso Compounds: Implications for Laboratory Safety, Analytic Methodology, and Carcinogenicity for the Rat Esophagus, Nose, and Liver Get access Sidney S. Mirvish, Sidney S. Mirvish Search for other works by this author on: Oxford Academic PubMed Google Scholar Phillip Issenberg, Phillip Issenberg Search for other works by this author on: Oxford Academic PubMed Google Scholar Halvor C. Sornson Halvor C. Sornson Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 56, Issue 6, June 1976, Pages 1125–1129, https://doi.org/10.1093/jnci/56.6.1125 Published: 01 June 1976 Article history Received: 11 June 1975 Accepted: 13 December 1975 Published: 01 June 1976