tbuckley/cabot-search huggingface dataset:
Phase I evaluation of orally-administered CYT997, a novel cytotoxic vascular-disrupting agent, in patients with advanced cancer
Authors: A. Francesconi, D. Kotasek, M. Burge, G. Smith, J. Lickliter
Journal: Journal of Clinical Oncology (2009)

3568 Background: CYT997 is a novel, small-molecule vascular disrupting agent which binds tubulin and inhibits microtubule assembly. The compound demonstrates potent antitumour and vascular-disrupting activity in preclinical models. A phase I study of CYT997 given by intravenous infusion showed favourable safety and tolerability, pharmacokinetics and preliminary evidence of pharmacodynamic activity. Unlike most other VDAs, CYT997 is orally available and a phase I dose-ranging study with oral capsule dosing is underway. Methods: CYT997 was administered orally every 2 weeks to patients with advanced solid tumours. Doses were escalated using an accelerated phase I design to cohort 6 and thereafter with a standard 3+3 design. Pharmacodynamic effects on tumour vasculature were assessed with DCE-MRI scans, circulating endothelial cell (CEC) assays and von Willebrand factor (vWF) plasma levels. Results: 21 patients (M/F: 16/5; median age 63, range 48–77) have been treated on study. A total of 56 cycles of CYT997 have been administered (median 2/patient, range 1–7) over 8 dose levels (15 - 164 mg/m 2 ). Doses up to 118 mg/m 2 were well tolerated. However, dose-limiting toxicities were observed at 164 mg/m 2 , consisting of grade 3 hypoxia in one patient and grade 3–4 asthenia in two patients. The grade 3 hypoxia was reversible. PK profiles revealed favourable oral absorption which was generally dose-linear. DCE-MRI assessments indicating significant changes in tumour K trans values consistent with vascular disruption were observed in 6 of 10 currently evaluated patients. No objective tumour responses were seen; however, disease stabilisation for six weeks or greater was observed in 13 patients. vWf and CEC analysis is currently ongoing. Conclusions: Orally-administered CYT997 is well tolerated at doses associated with vascular targeting activity. Moreover, its good oral bioavailability suggests the potential for novel administration schedules, including metronomic dosing. [Table: see text]
P12.20 Meningiomas invading the major dural sinuses: long term results of attempted radical resection and adjuvant treatment after subtotal resection
Authors: S. Park, K. Sung
Journal: Neuro-Oncology (2017)

PURPOSE: Radical resection of meningiomas invading the major dural sinuses remains controversial. In particular, whether the fragment invading the sinus must be resected and whether the venous system must be reconstructed continue to be issues of debate. The aims of this study are to evaluate results of patients with a meningioma infiltrating the major dural sinuses and to discuss our management strategy. Materials and Methods: Between 2003 and 2015, 103 patients (75 women and 28 men; mean age, 54.0 ± 13.5 (18-83) year-old) underwent surgery for meningiomas originating at the superior sagittal sinus in 82, the transverse sinus in 12, the sigmoid sinus in 13, and the confluence of sinuses in 6. Meningiomas even if it was adjacent to the sinus and not invading its wall, as well as any tumor potentially detachable from the lateral wall without requiring resection of at least its outer layer, were excluded from this series. Median follow-up duration was 50.4 ± 44.2 (1.3-153.4) months. Results: Total and nearly total resection (grossly total resection) was achieved in 49 (47.5%) of cases. In grossly total resection group, 19 patients with a meningioma totally occluding the major dural sinus had complete resection of the encased portion of the sinus. In the remaining 30 patients, the opened sinus was closed with hemostatic materials or was sutured for repair of sinus wall after the resection of the tumor. The grossly total resection group was better than subtotal resection group in terms of progression free survival. In the subtotal resection group of grade I meningioma patients, performing adjuvant stereotactic radiosurgery (SRS) was effective than follow-up group without adjuvant treatment in considering progression free survival and recurrence rate. Conclusions: On the basis of our results, we conclude that if the sinus is completely obstructed, the portion of the sinus involved can be resected completely. However, if the sinus is incompletely occluded or adjacent drainage vein could not be dissected from tumor, subtotal resection of the tumor followed by SRS may be a good alternative treatment option. To decide whether resects tumors totally or subtotally, type and location of sinus invasion and pattern of cortical draining veins adjacent to tumors should be considered.
Collateral damage during antibiotic treatment of<i>C. difficile</i>infection in the aged host: Insights into why recurrent disease happens
Authors: Jae Hyun Shin, Cirle A. Warren
Journal: Gut Microbes (2017)

Clostridium difficile infection (CDI) is one of the most common causes of healthcare-associated infections but an even bigger problem for the aging population. Advanced age leads to higher incidence, higher mortality, and higher recurrences. In our study, recently published in the Journal of Infectious Diseases, we investigated the effect of aging on CDI using a mouse model. We were able to demonstrate that aging leads to worse clinical outcomes, as well as lead to changes in microbiota composition and lower antibody production against C. difficile toxin A, but not toxin B. An association between advanced age and lower antibody production against C. difficile is a new finding which would explain the effect of aging on CDI outcome. Vancomycin, an anti-C. difficile antibiotic, led to similar changes in antibody response, suggesting a connection between microbiome and antibody response in the context of aging, which would require a much more nuanced look at the treatment of CDI.
Erroneous Sentence in Cancer Care Chronicles Article
Authors: Reshma Jagsi
Journal: JAMA Oncology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
OS06.6 Optimized radiotherapy protocols delay the malignant transformation of low-grade gliomas in-silico
Authors: A. Henares-Molina, S. Benzekry, P. Lara, M. García-Rojo, V. Pérez-García, A. Martínez-González
Journal: Neuro-Oncology (2017)

Introduction: The optimal management of grade II gliomas (LGGs) remains controversial, and only limited definitive data is available to guide recommendations. Radiation therapy is currently offered to LGG patients with certain combinations of risk factors. However, its benefit on initial tumor control may be outweighed by late toxicities. Mathematical modeling has the potential of helping in selecting patients who may benefit from radiotherapy and in developing optimal fractionation schemes for patient subgroups. Materials and methods: LGG growth was described in-silico using a previously validated mathematical model incorporating accelerated repopulation and growth saturation. Tumor response to radiation and normal tissue toxicity was accounted for by a classical linear-quadratic (LQ) model. An optimization problem was posed to determine the optimal fractionation protocol (dose per fraction, number of doses and time between fractions) delaying the most the tumor’s malignant transformation (MT) while at the same time maintaining the toxicity on or below the level of the standard fractionation (30 daily fractions of 1.8 Gy). Results: The optimal protocols were found to be metronomic with 0.5 Gy/fraction and dose interspacing ranging from one week to one month depending on tumor’s growth rate. The MT was found to be delayed from 1 (fast growing LGGs) to 7 years (slowly growing LGGs). A robust protocol was found to provide a sub-optimal gain for all tumor growth rates. Other non-standard radiotherapy fractionations were found to provide survival advantages: (i) Protracted schemes with 1.8 Gy/fraction and time interval between doses ranging from one to three months (ii) Hypoprotracted schemes with dose per fraction of 3.2 Gy and larger interdose time spacings. In all cases the potential time delay of the MT, was of up to several years with the advantage over metronomic schemes of being more feasible from the practical point of view. Some fractionations were proven to provide a substantial survival advantage while at the same time reducing the toxicity in comparison with the standard fractionation. The concepts are being validated in biomimetic devices (microfluidic chips) and the results will be also reported at the conference. CONCLUSION: A substantial survival benefit could be achieved by using non-standard radiotherapy fractionation schemes together with a reduction in treatment toxicity. Thus, mathematical modelling techniques may complement the use of highly conformal techniques in order to improve treatment efficacy and reduce neurotoxicity. FUNDING: Ministerio de Economía y Competitividad/FEDER, Spain [MTM2015-71200-R], Junta de Comunidades de Castilla-La Mancha, Spain [PEII-2014-031-P] and James S. Mc. Donnell Foundation 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer [Collaborative award 220020450].
OS07.8 Adult infiltrating giomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT
Authors: M. Pekmezci, T. Rice, A. M. Molinaro, H. M. Hansen, L. S. McCoy, T. Tihan, C. Giannini, J. E. Eckel-Passow, D. H. Lachance, J. K. Wiencke, R. B. Jenkins, M. R. Wrensch
Journal: Neuro-Oncology (2017)

The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: 1-Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; 2- Astrocytoma, IDH-mutant; 3- Glioblastoma, IDH-mutant; 4- Glioblastoma, IDH-wildtype; and 5-Diffuse glioma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations with overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95%CI: 1.05–7.04, p=0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI: 0.17–0.81, p=0.01). Among Group 5, IDH-wildtype diffuse gliomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI: 0.27–0.87), p=0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information.
Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years: a cross-sectional study
Authors: Clifford R Jack, Heather J Wiste, Stephen D Weigand, Terry M Therneau, David S Knopman, Val Lowe, Prashanthi Vemuri, Michelle M Mielke, Rosebud O Roberts, Mary M Machulda, Matthew L Senjem, Jeffrey L Gunter, Walter A Rocca, Ronald C Petersen
Journal: The Lancet Neurology (2017)
Abstract P042: Loss of Mcl-1 in the Heart Leads to Rapid Mitochondrial Dysfunction and Development of Heart Failure
Authors: Robert L Thomas, Youngil Lee, Chengqun Huang, Shivaji Rikka, Kimberlee Fisher, Aleksander Andreyev, Anne N Murphy, Mark A Sussman, Åsa B Gustafsson
Journal: Circulation Research (2011)

Mcl-1 is an anti-apoptotic Bcl-2 family protein that is expressed at high levels in the heart. However, the functional importance of Mcl-1 in the heart has not been investigated. To study the function of Mcl-1 in cardiac myocytes, we generated inducible, myocyte-specific Mcl-1 knock-out mice using a tamoxifen-driven loxP/α-MHC-Cre-recombinase system. We found that deletion of Mcl-1 by tamoxifen injections resulted in rapid development of cardiac hypertrophy, pulmonary edema and cardiac dysfunction in adult mice. Although Mcl-1 is known to inhibit apoptosis in cells, Mcl-1 deficient hearts were TUNEL negative and showed no activation of caspase-3. The anti-apoptotic proteins Bcl-2 and Bcl-X L have also been reported to inhibit autophagy, but we found no increase in autophagy upon loss of Mcl-1. Western blot analysis of other Bcl-2 family members revealed that Bcl-2 was significantly increased in Mcl-1 deficient hearts, suggesting a compensatory mechanism. Interestingly, ultrastructural analysis revealed the presence of swollen mitochondria, ruptured cells, and intracellular contents in the extracellular space. These signs are characteristics of necrotic cell death. Mcl-1 deficient hearts also exhibited reduced mitochondrial respiration and significantly lower cellular ATP levels compared to wild type, suggesting that the loss of Mcl-1 impairs mitochondrial function. Moreover, mitochondria isolated from Mcl-1-/- hearts showed pronounced swelling at baseline that could be alleviated by polyethylene glycol-induced shrinkage. Calcium release experiments also showed higher baseline Ca 2+ levels in mitochondria from Mcl-1-/- hearts compared to wild type, suggesting that Mcl-1 deletion increases permeability to Ca 2+ . Our data suggest that loss of Mcl-1 in cardiac myocytes leads to rapid mitochondrial impairment and necrotic cell death. Thus, in addition to its anti-apoptotic role, Mcl-1 has an essential but unidentified role in maintaining mitochondrial function in cardiac myocytes.
P18.05 Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): Preliminary Data on Clinical Utility within the Brain Tumor Population
Authors: A. R. Loughan, A. Lanoye
Journal: Neuro-Oncology (2017)

OBJECTIVE: The detrimental effects of brain tumors and related treatments on cognitive capacity are well documented. Since sustaining or improving quality of life is a goal of equal importance to prolonged survival rates, neurocognitive assessments have become integral to comprehensive neuro-oncology care. Existing screening tools are criticized because they are insensitive to cognitive changes caused by medical treatments. One measure that may offer unique utility is the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Research supports the clinical value and psychometric properties of the RBANS in various medical populations; however, there is minimal evidence for its use in the brain tumor population. The purpose of this study was to determine RBANS utility in a sample of brain tumor patients by assessing the incidence of cognitive impairment relative to normative data, as well as to an estimate of pre-morbid intelligence. Participants. Data was collected on 38 patients (53% male; mean age 51, range 27-81) with primary brain tumors, confirmed by histopathological diagnosis. Eighty-Two percent had received surgery as initial treatment, and 45% had undergone radiation, chemotherapy or both prior to assessment. METHODS: All patients were administered the RBANS and the Test of Premorbid Functioning (TOPF, an estimate of pre-morbid intelligence) according to standardized instructions. Composite and Index Standard Scores (SS) from the RBANS were compared to a normal distribution (SS ≤85 indicative of impairment) and TOPF (≥1 SD difference indicative of impairment) per patient. Correlations were completed to identify cognitive relationships within this cohort. RESULTS: Descriptive profiling of RBANS will be presented. Regarding demonstrated deficits, comparison with standardization norms (RBANS; 47% compositely impaired, 68% on at least one index, and 53% on multiple indexes) was strikingly similar compared to self (TOPF; 50%, 71%, 53%). However, patients had an increased likelihood of global impairment when compared to self (4 to 5 indexes impaired; 32% vs 8%). There was a positive correlation between quantity of deficits and TOPF (r = .636, p = .000), whereas there was a negative correlation when compared to RBANS normative distribution (r = -.351, p = .031). CONCLUSIONS: Accuracy and interpretation of neuropsychological assessment is crucial within the brain tumor population to correctly identify impairment, its influences on perception of illness, level of support, and recommendations for management. Our preliminary research demonstrates the utility of RBANS as an efficient tool to assess cognitive impairment in patients with primary brain tumors. Our data also supports the importance of comparison to self and estimated premorbid intelligence, rather than normative distribution, to ensure precision in estimation of impairment.
Errata
Authors: Anke Wahlers, Olga Kustikova, Peter F. Zipfel, Katsuhiko Itoh, Markus Koester, Christoph Heberlein, Zhixiong Li, Bernd Schiedlmeier, Christine Skerka, Boris Fehse, Christopher Baum, Maria T. Vlachaki, Andres Hernandez-Garcia, Michael Ittmann, Madhu Chhikara, Laura K. Aguilar, Xiaohong Zhu, Bin S. Teh, E.Brian Butler, Shiao Woo, Timothy C. Thompson, Hugo Barrera-Saldana, Estuardo Aguilar-Cordova
Journal: Molecular Therapy (2002)

Molecular Therapy 6: 313–320 (2002). doi:10.1006/mthe.2002.0671 Upstream Conserved Sequences of Mouse Leukemia Viruses Are Important for High Transgene Expression in Lymphoid and Hematopoietic Cells Anke Wahlers, Olga Kustikova, Peter F. Zipfel, Katsuhiko Itoh, Markus Koester, Christoph Heberlein, Zhixiong Li, Bernd Schiedlmeier, Christine Skerka, Boris Fehse, and Christopher Baum The Abstract contained a misspelling of Yin-Yang1 (YY1). The correct sentence follows. Sequence analysis and electrophoretic mobility shift assays revealed the presence of a highly conserved binding site for NFAT (nuclear factor of activated T cells) proteins that immediately neighbors a known binding site for the transcription factor Yin-Yang1 (YY1). Also, a passage in the Introduction contained a mispelling which altered the meaning of a sentence. The correct text follows. We investigated the contribution of the NCR to retroviral enhancer activity in distinct cell types of fibroblastic, hematopoietic, and lymphoid origin, strictly relying on a retroviral reporter system previously shown to detect the impact of individual mutations on retroviral enhancer function in vitro and in vivo [8]. Surprisingly, deletion of the NCR resulted in a significant reduction of enhancer activity. This finding could in part be explained by identifying a novel binding site for NFAT transcription factors within this region [28]. Molecular Therapy 6: 342–348 (2002). doi:10.1006/mthe.2002.0669 Impact of Preimmunization on Adenoviral Vector Expression and Toxicity in a Subcutaneous Mouse Cancer Model Maria T. Vlachaki, Andres Hernandez-Garcia, Michael Ittmann, Madhu Chhikara, Laura K. Aguilar, Xiaohong Zhu, Bin S. Teh, E. Brian Butler, Shiao Woo, Timothy C. Thompson, Hugo Barrera-Saldana, and Estuardo Aguilar-Cordova An author's name was misspelled in this article. Above is the author list as it should have appeared. Also, a sentence in the Discussion section contained an error. The correct text follows: However, it is not clear how intratumoral doses translate to systemic doses where a dose of ∼ 3 × 1013 vp was fatal [4].)
Role of p53 in the regulation of stathmin (Op18) in human colon carcinoma cells
Authors: Mamatha S. Nayak, Jin-Ming Yang, William N. Hait
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2825 

Stathmin (Op18) regulates the polymerization state of microtubules and is frequently upregulated in human tumors. Previous studies indicate that the expression of stathmin is regulated by p53 ( Murphy et. al., Genes Dev. 1999 Oct 1;13(19):2490–501 ). Our laboratory demonstrated that activated p53 is capable of repressing the expression of the microtubule-stabilizing protein, MAP4, and this changes the sensitivity to anti-microtubule drugs ( Zhang et. al., Cancer Res. 1999 Aug 1;59(15):3663-70 ). In the present study we explored the ability of p53 to repress stathmin in paired isogenic colon carcinoma cell lines, HCT116 p53+/+ and HCT116 p53-/-(kindly provided by Dr. Bert Vogelstein). We report that in unperturbed HCT116 p53+/+ cells, there was a reciprocal relationship between p53 and stathmin expression over a 72 h time interval as indicated by Western blot analysis. There was a gradual decrease in p53 (5-fold) over this interval and this coincided with decreased p21 (3-fold) and increased stathmin (3-fold). Further, stimulation of wild-type p53 in HCT116 p53+/+ cells by the DNA-damaging agent doxorubicin caused an increase in p53 and a decrease in stathmin in a dose- and time-dependent manner as compared to vehicle-treated HCT116 p53+/+ cells. In addition, siRNA against wild-type p53 caused decreased expression of p53 and increased expression of stathmin. Similar experiments were performed in HCT116 p53-/- cells that do not express p53. HCT116 p53-/- had equivalent amounts of stathmin as compared to HCT116 p53+/+ cells in unstimulated conditions. Unexpectedly, following treatment with doxorubicin, stathmin decreased to the same extent as that seen in HCT116 p53+/+. The two cell lines did not express p73 and there was no difference in p63 levels between the two cell lines. These studies suggest that stathmin can be regulated by a p53-independent manner in certain colon carcinoma cells. Further studies are in progress to investigate the possible mechanisms involved.