tbuckley/cabot-search huggingface dataset:
SWOG 0012, a randomized phase III comparison of standard doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T) versus weekly doxorubicin and daily oral cyclophosphamide plus G-CSF (G) followed by weekly paclitaxel as neoadjuvant therapy for inflammatory and locally advanced breast cancer
Authors: G. K. Ellis, W. E. Barlow, C. A. Russell, M. E. Royce, E. A. Perez, R. B. Livingston
Journal: Journal of Clinical Oncology (2006)

LBA537 Background: Between 10-1-02 and 12-01-05, SWOG 0012 accrued patients to a two-arm randomized trial, with formal participation from NCCTG and CTSU participation by other cooperative groups. Arm 1 gave A at 60 mg/m 2 and C at 600 mg/m 2 q 3 wk IV for 5 cycles, arm 2 A at 24 mg/m 2 /wk × 15 IV and C at 60 mg/m 2 /day PO for 15 wk with G at 5 mcg/kg/day × 6/7 weekly. Both groups then received T at 80 mg/m 2 /wk × 12, and proceeded to surgery with pCR by NSABP criteria at the primary site as the endpoint. A total of 372 were randomized, and we report here on 265 patients (pts) evaluable for outcome, including those who did not proceed to surgery. In arm 1, pCR was seen in 17% vs 27% in arm 2 (p = .06); when adjusted for hormone receptor status (ER-PR- in 49% on arm 1, 41% on arm 2) and disease type (locally advanced vs inflammatory), the odds ratio in favor of arm 2 is 1.98 (95% CI 1.05–3.74, p = .034). For ER- PR- pts, pCR rates for Arm 1 vs 2 were 26 vs 43%, while for those with ER or PR+, pCR rates were 9 vs 14%. Inflammatory pts showed a striking difference in pCR rates for arm 1 vs arm 2 (12 vs 33%, p = .033). HER 2 status (+ in 29%) did not predict response or interact with treatment. Grade 3/4 toxicities (arm 1 vs 2, %) were as follows: hand-foot syndrome (0 vs 13), neutropenia (47 vs 16), neutropenic infection (1.8 vs 0.6), stomatitis (2 vs 11), and nausea/vomiting (11 vs 5). Toxicity from T was grade 3 neuropathy in 10%, with grade 3 or 4 neutropenia in 12%. There were no treatment-related deaths. Continuous or “metronomic” chemotherapy with AC is superior to standard intermittent AC, and the pCR rate reported for the continuous arm is the highest reported in a cooperative group experience for this patient population. [Table: see text]
Prophylactic clipping for the prevention of bleeding following wide-field endoscopic mucosal resection of laterally spreading colorectal lesions: an economic modeling study
Authors: Farzan Bahin, Khalid Rasouli, Stephen Williams, Eric Lee, Michael Bourke
Journal: Endoscopy (2016)

Clinically significant bleeding (CSPEB) is the most common adverse event following endoscopic mucosal resection (EMR) of large sessile and laterally spreading colorectal lesions (LSLs), and is associated with morbidity and resource utilization. CSPEB occurs more frequently with proximal LSLs. Prophylactic clipping of the post-EMR defect may be beneficial in CSPEB prevention. The aim of this study was to determine the cost-effectiveness of a prophylactic clipping strategy. We hypothesized that prophylactic clipping in the proximal colon was cost-effective.An economic model was applied to outcomes from the Australian Colonic Endoscopic Mucosal Resection (ACE) Study. Clip distances of 3, 5, 8, and 10 mm were analyzed. The cost of treating CSPEB was determined from an independent costing agency. The funds needed to spend (FNS) was the cost incurred in order to prevent one episode of CSPEB. A break-even analysis was performed to determine cost equivalence of the costs of clipping and CSPEB.Outcomes of 1717 LSLs (mean size 35.8 mm; 52.6 % proximal colon) that underwent EMR were analyzed. The overall rate of CSPEB was 6.4 % (proximal 8.9 %; distal 3.7 %). Endoscopic management was required in 45 % of CSPEB episodes. With a clip distance of 3 mm, the expected cost of prophylactic clipping was € 1106 per lesion compared with € 157 per lesion for the expected cost of CSPEB without clipping. At 100 % clipping efficacy, the FNS was € 14 826 (proximal and distal lesions € 9309 and € 29 540, respectively). A clip price of € 10.35 was required for the cost of clipping to offset the cost of CSPEB.A prophylactic clipping strategy is not cost-effective and at present cannot be justified for all lesions or selectively for lesions in the proximal colon.ClinicalTrials.gov (NCT01368289).
The Public Health Crisis in Emergency General Surgery
Authors: Martin G. Paul
Journal: JAMA Surgery (2016)

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 Surgery 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 Surgery journal
Alpha-1 Antitrypsin Regulates Transcriptional Levels of Serine Proteases in Blood Mononuclear Cells
Authors: Nupur Aggarwal, Janine Koepke, Nerea Matamala, Beatriz Martinez-Delgado, Maria Teresa Martinez, Heiko Golpon, Jan Stolk, Sabina Janciauskiene, Rembert Koczulla
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
A phase IB study evaluating BSI-201 in combination with chemotherapy in subjects with advanced solid tumors
Authors: J. J. Mahany, N. Lewis, E. I. Heath, P. M. LoRusso, M. M. Mita, J. Rodon, A. W. Tolcher, B. M. Sherman, C. R. Bradley, K. P. Papadopoulos
Journal: Journal of Clinical Oncology (2008)

3579 Background: BSI-201 is a small molecule believed to achieve its anti-neoplastic effect by covalently binding and inhibiting PARP-1, and thus expected to potentiate the damage induced by chemotherapeutic agents. The primary study objective was to assess safety and establish the MTD of the combination of BSI-201 with topotecan (TOP), Gemcitabine (GEM), temozolomide (TMZ), and carboplatin/paclitaxel (C/T). A secondary objective was to evaluate the clinical response in subjects with measurable disease. Methods: Eligible subjects were ≥ 18 years old with an advanced solid tumor, had ECOG PS of ≤ 2, and had adequate hematological, renal, and hepatic function. Subjects were assigned to one of 4-study arms (BSI-201 plus TOP, GEM, TMZ, or C/T in a non-randomized manner dependent on physician decision. Within each arm, cohorts of 3 to 6 subjects were treated until the MTD was identified. Chemotherapy was started on study day 1, with BSI-201 administered I.V. twice weekly (days 1 and 4 of each week) for the duration of the study. Modified RECIST criteria were used to assess tumor response every 6–8 weeks. Results: To date, 55 subjects with advanced solid tumors have been treated with BSI-201 doses of 1.1 thru 8.0 mg/kg, in combination with cytotoxic chemotherapy. All dose combinations were well tolerated with a total of 21 serious adverse events reported for 10 trial participants, none of which were deemed related to study drug. A Complete Response (CR) at 6 months was reported for 1 subject with ovarian cancer, and 5 subjects with renal, breast (2), uterine, and sarcoma experienced a Partial Response (PR). An additional 19 subjects had Stable Disease (SD) for 2 months or more. Significant PARP inhibition was attained at doses of BSI-201 of 2.8 mg/kg or higher. Conclusions: BSI-201 is safe and well tolerated with all tested combinations over all BSI-201 doses studied. Adverse events were consistent with the known safety profiles of the standard regimens. These results suggest potential clinical benefit of BSI-201 in combination with chemotherapy in multiple tumor types and encourage future investigations. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration BiPar Sciences, Inc BiPar Sciences, Inc BiPar Sciences, Inc BiPar Sciences, Inc BiPar Sciences, Inc
Genetic alterations associated with acquired temozolomide resistance in SNB-19 a human glioma cell line and xenografted tumor
Authors: Auger Nathalie, Joëlle Thillet, Marie-Emmanuelle Legrier, Bernard Dutrillaux, Marc Sanson, Marie-France Poupon
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1255 

Temozolomide (TMZ) is a recent alkylating agent that has shown a significant benefit in the treatment of high-grade gliomas. However, chemo-resistances occur frequently, either de novo or acquired, and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase (MGMT) or to loss of MMR capacity. Yet very few gliomas over-express MGMT or are MMR deficient, suggesting that other mechanisms are involved in TMZ resistance. The purpose of the present study was to generate TMZ-resistant variants from a human glioma cell line and the xenografted model of the same cell line (SNB-19) and use large-scale genomic and transcriptional analyses to study the molecular basis of acquired TMZ resistance. The four independently obtained TMZ-resistant variants showed no cross-resistance with other alkylating agents and shared common genetic modifications, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of resistant cells pre-existing within the parental SNB-19 cell line. Microarray analysis showed that among differentially expressed genes between parental cells and TMZ-resistant variants. Several genes involved in differentiation were down regulated. None were implicated in known resistance mechanisms, such as DNA repair or MGMT activity. No modification of MGMT methylation was detected. The data suggest that in this model the acquisition of TMZ resistance resulted from the selection of less differentiated pre-existing resistant cells within the parental tumor.
PTH-317 The effect of trendelenburg positioning during laparoscopic colorectal surgery on intra-ocular pressure (IOP)
Authors: P Vitish-Sharma, AG Acheson, C Maxwell-Armstrong, K Mohiuddin, B Bharathan, K Thomas, R Stead, JA Sharp, A King
Journal: Gut (2015)

<h3>Introduction</h3> Laparoscopic colorectal surgery is the preferred approach for colorectal resections. It often requires extreme positioning for many hours, including extreme head-down tilts. The incidence of perioperative visual loss after colorectal surgery is quoted as 1.24 per 10,000 in USA<sup>1</sup>and is thought to be due to raised IOP leading to reduced optic nerve head perfusion.<sup>1,2</sup> <h3>Aim</h3> This study assesses the effect of head-down tilt on IOP during laparoscopic colorectal surgery. <h3>Method</h3> Patients undergoing laparoscopic colorectal resections are included in this study. It is hypothesised that right-sided resections generally spend less time in the head-down position compared to left-sided and sub-total resections. Therefore, Group 1 included those undergoing right-sided resections and Group 2 included left-sided and sub-total resections. Baseline eye examination and IOP measurements using a Tonopen® XL applanation tonometer were carried out every hour during surgery and each time when the operating table was tilted. <h3>Results</h3> There were 30 patients (16 males, 14 females) in the study with an average age of 63 years (Range 25–78); with Group 1’s mean age 63.5 years (SD 14.35) and Group 2 had a mean age of 62.3 years (SD 17.68), (p &gt; 0.05). Group 1 had 14 patients and Group 2 had 16 patients. The mean length of surgery (LOS) for Group 1 was 2 hrs. 27 mins (SD 0.73) and for Group 2 mean LOS was 4 hrs. 7 mins (SD 1.63) with P = 0.001. The baseline IOP was similar in both groups with the mean baseline IOP in Group 1 being 16.69mmHg, and in Groups 2 it was 16.87 mmHg (p &gt; 0.05). The median IOP rise from baseline during surgery was 10.5 mmHg (IQR = 4.5) in Group 1 and 18 mmHg (IQR = 4.4) in Group 2 (p &lt; 0.05). The median maximum degree of head down tilt during surgery in Group 1 was 9.3<sup>°</sup>(IQR = 7.2) and Group 2 was 18.3° (IQR = 8.4), (p &lt; 0.05). <h3>Conclusion</h3> A rise in IOP occurs during laparoscopic colorectal surgery and it appears to be more pronounced in those with a greater degree of head down tilt for a prolonged time. This may have important implications for those patients undergoing prolonged surgery and for those with a history of glaucoma. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Molloy BL. Implications for postoperative visual loss: steep Trendelenburg position and effects on intraocular pressure. AANA J. 2011;79(2):115–121 Awad H, Santilli S, Ohr M, Roth A, Yan W, Fernandez S, Roth S, Patel V. The effects of steep trendelenburg positioning on intraocular pressure during robotic radical prostatectomy. Anesth Analg. 2009;109(2):473–8
TCTAP A-041 Effect of Polymer-Free Drug-Eluting Stent Coated with Everolimus Using Nitrogen-Doped TiO2 Film Deposition in a Porcine Coronary Restenosis Model
Authors: Doo Sun Sim, Myung-Ho Jeong, Dae Sung Park, Jung Ha Kim, Kyung Seob Lim, In Ho Bae, Zhehao Piao, Woo-jin Kim, Min Chul Kim, Hyun Kuk Kim, Jae Yeong Cho, Ki Hong Lee, Nam Sik Yoon, Hyun Ju Yoon, Kye Hun Kim, Young Joon Hong, Hyung Wook Park, Ju Han Kim, Youngkeun Ahn, Jeong Gwan Cho, Jong Chun Park
Journal: Journal of the American College of Cardiology (2016)
Targeting TDP-43 phosphorylation by Casein Kinase-1δ inhibitors: a novel strategy for the treatment of frontotemporal dementia
Authors: Carolina Alquezar, Irene G. Salado, Ana de la Encarnación, Daniel I. Pérez, Fermín Moreno, Carmen Gil, Adolfo López de Munain, Ana Martínez, Ángeles Martín-Requero
Journal: Molecular Neurodegeneration (2016)

Mutations in the progranulin gene (GRN) are the most common cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). TDP-43 pathology is characterized by the hyperphosphorylation of the protein at Serine 409/410 residues. Casein kinase-1δ (CK-1δ) was reported to phosphorylate TDP-43 directly. Previous works from our laboratory described the presence of CDK6/pRb-dependent cell cycle alterations, and cytosolic accumulation of TDP-43 protein in lymphoblast from FTLD-TDP patients carriers of a loss-of function mutation in GRN gene (c.709-1G > A). In this work, we have investigated the effects of two brain penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27) designed and synthetized in our laboratory on cell proliferation, TDP-43 phosphorylation and subcellular localization, as well as their effects on the known nuclear TDP-43 function repressing the expression of CDK6. We report here that both CK-1δ inhibitors (IGS-2.7 and IGS-3.27) normalized the proliferative activity of PGRN-deficient lymphoblasts by preventing the phosphorylation of TDP-43 fragments, its nucleo-cytosol translocation and the overactivation of the CDK6/pRb cascade. Moreover, ours results show neuroprotective effects of CK-1δ inhibitors in a neuronal cell model of induced TDP-43 phosphorylation. Our results suggest that modulating CK-1δ activity could be considered a novel therapeutic approach for the treatment of FTLD-TDP and other TDP-43 proteinopathies.
Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials
Authors: Nadja B. Kristensen, Thomas Bryrup, Kristine H. Allin, Trine Nielsen, Tue H. Hansen, Oluf Pedersen
Journal: Genome Medicine (2016)

The effects of probiotic supplementation on fecal microbiota composition in healthy adults have not been well established. We aimed to provide a systematic review of the potential evidence for an effect of probiotic supplementation on the composition of human fecal microbiota as assessed by high-throughput molecular approaches in randomized controlled trials (RCTs) of healthy adults.The survey of peer-reviewed papers was performed on 17 August 2015 by a literature search through PubMed, SCOPUS, and ISI Web of Science. Additional papers were identified by checking references of relevant papers. Search terms included healthy adult, probiotic, bifidobacterium, lactobacillus, gut microbiota, fecal microbiota, intestinal microbiota, intervention, and (clinical) trial. RCTs of solely probiotic supplementation and placebo in healthy adults that examined alteration in composition of overall fecal microbiota structure assessed by shotgun metagenomic sequencing, 16S ribosomal RNA sequencing, or phylogenetic microarray methods were included. Independent collection and quality assessment of studies were performed by two authors using predefined criteria including methodological quality assessment of reports of the clinical trials based on revised tools from PRISMA/Cochrane and by the Jadad score.Seven RCTs investigating the effect of probiotic supplementation on fecal microbiota in healthy adults were identified and included in the present systematic review. The quality of the studies was assessed as medium to high. Still, no effects were observed on the fecal microbiota composition in terms of α-diversity, richness, or evenness in any of the included studies when compared to placebo. Only one study found that probiotic supplementation significantly modified the overall structure of the fecal bacterial community in terms of β-diversity when compared to placebo.This systematic review of the pertinent literature demonstrates a lack of evidence for an impact of probiotics on fecal microbiota composition in healthy adults. Future studies would benefit from pre-specifying the primary outcome and transparently reporting the results including effect sizes, confidence intervals, and P values as well as providing a clear distinction of between-group and within-group comparisons.
Case 42-1963
Authors: William F. McNeely, Benjamin Castleman
Journal: New England Journal of Medicine (1963)

Presentation of Case First admission. A seventy-three-year-old woman was admitted to the hospital because of dyspnea and weakness.The patient had had the gradual onset of dyspnea on exertion and paroxysmal nocturnal dyspnea during the previous year. Ten weeks before entry left hemiparesis developed suddenly; it cleared in a few days, but weakness persisted. Her physician recorded systolic-blood-pressure levels as high as 180 and treated her with veratrum alkaloids, which lowered the level to 130; the medication was discontinued two days before admission. Nine weeks before admission she was given penicillin and chlortetracycline (Aureomycin) because of a persistent, nonproductive cough . . .
Large-scale assessment of the gliomasphere model system
Authors: Dan R. Laks, Thomas J. Crisman, Michelle Y. S. Shih, Jack Mottahedeh, Fuying Gao, Jantzen Sperry, Matthew C. Garrett, William H. Yong, Timothy F. Cloughesy, Linda M. Liau, Albert Lai, Giovanni Coppola, Harley I. Kornblum
Journal: Neuro-Oncology (2016)

Gliomasphere cultures are widely utilized for the study of glioblastoma (GBM). However, this model system is not well characterized, and the utility of current classification methods is not clear. We used 71 gliomasphere cultures from 68 individuals. Using gene expression-based classification, we performed unsupervised clustering and associated gene expression with gliomasphere phenotypes and patient survival. Some aspects of the gene expression-based classification method were robust because the gliomasphere cultures retained their classification over many passages, and IDH1 mutant gliomaspheres were all proneural. While gene expression of a subset of gliomasphere cultures was more like the parent tumor than any other tumor, gliomaspheres did not always harbor the same classification as their parent tumor. Classification was not associated with whether a sphere culture was derived from primary or recurrent GBM or associated with the presence of EGFR amplification or rearrangement. Unsupervised clustering of gliomasphere gene expression distinguished 2 general categories (mesenchymal and nonmesenchymal), while multidimensional scaling distinguished 3 main groups and a fourth minor group. Unbiased approaches revealed that PI3Kinase, protein kinase A, mTOR, ERK, Integrin, and beta-catenin pathways were associated with in vitro measures of proliferation and sphere formation. Associating gene expression with gliomasphere phenotypes and patient outcome, we identified genes not previously associated with GBM: PTGR1, which suppresses proliferation, and EFEMP2 and LGALS8, which promote cell proliferation. This comprehensive assessment reveals advantages and limitations of using gliomaspheres to model GBM biology, and provides a novel strategy for selecting genes for future study.
Calcium release channel RyR2 regulates insulin release and glucose homeostasis
Authors: Gaetano Santulli, Gennaro Pagano, Celestino Sardu, Wenjun Xie, Steven Reiken, Salvatore Luca D’Ascia, Michele Cannone, Nicola Marziliano, Bruno Trimarco, Theresa A. Guise, Alain Lacampagne, Andrew R. Marks
Journal: Journal of Clinical Investigation (2015)

The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a “leaky” RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.