tbuckley/cabot-search huggingface dataset:
Rictor/mTORC2 signaling mediates TGFβ1-induced fibroblast activation and kidney fibrosis
Authors: Jianzhong Li, Jiafa Ren, Xin Liu, Lei Jiang, Weichun He, Weiping Yuan, Junwei Yang, Chunsun Dai
Journal: Kidney International (2015)

The mammalian target of rapamycin (mTOR) was recently identified in two structurally distinct multiprotein complexes: mTORC1 and mTORC2. Previously, we found that Rictor/mTORC2 protects against cisplatin-induced acute kidney injury, but the role and mechanisms for Rictor/mTORC2 in TGFβ1-induced fibroblast activation and kidney fibrosis remains unknown. To study this, we initially treated NRK-49F cells with TGFβ1 and found that TGFβ1 could activate Rictor/mTORC2 signaling in cultured cells. Blocking Rictor/mTORC2 signaling with Rictor or Akt1 small interfering RNAs markedly inhibited TGFβ1-induced fibronection and α-smooth muscle actin expression. Ensuing western blotting or immunostaining results showed that Rictor/mTORC2 signaling was activated in kidney interstitial myofibroblasts from mice with unilateral ureteral obstruction. Next, a mouse model with fibroblast-specific deletion of Rictor was generated. These knockout mice were normal at birth and had no obvious kidney dysfunction or kidney morphological abnormality within 2 months of birth. Compared with control littermates, the kidneys of Rictor knockout mice developed less interstitial extracellular matrix deposition and inflammatory cell infiltration at 1 or 2 weeks after ureteral obstruction. Thus our study suggests that Rictor/mTORC2 signaling activation mediates TGFβ1-induced fibroblast activation and contributes to the development of kidney fibrosis. This may provide a therapeutic target for chronic kidney diseases.
Abstract 18311: Lipid Composition of Gold Nanoparticle-Templated High-Density Lipoprotein Analogs Dictates Cholesterol Efflux Function
Authors: R. Kannan Mutharasan, Amritha T Singh, Kaylin M McMahon, C. Shad Thaxton
Journal: Circulation (2013)

Background: Reverse cholesterol transport, the process by which cholesterol is effluxed from cells to high-density lipoproteins (HDL) and is delivered to the liver for clearance, is a promising pathway to augment for treatment of atherosclerosis. Though structure-function relationships between nascent, discoidal HDL and cholesterol efflux have been well studied, how the lipid composition of spherical HDL species, which varies in pathophysiological conditions, impacts their ability to mediate cholesterol efflux has not been investigated. Methods and Results: Spherical gold nanoparticles (5 nm) were used to synthesize spherical HDL analogs (HDL-NP) by adding ApoAI protein and various lipids to the particle surface. With this strategy a panel of HDL-NP varying in lipid content was generated. HDL-NP designs tested include: dipalmitylphosphatidylcholine (DPPC, saturated fatty acid), dioleoylphosphatidylcholine (DOPC, unsaturated fatty acid), sphingomyelin, lysophosphatidylcholine (LPC), and mixtures thereof. All of these lipids are found in natural HDL. After characterizing the purified HDL-NP, these HDL-NP designs were tested in the cellular reverse cholesterol transport assay using J774 mouse macrophages. These studies demonstrate that all HDL-NP designs mediate more efflux than equimolar amounts of ApoAI protein control, and further demonstrate that HDL-NP designs incorporating unsaturated phospholipid (DOPC), sphingomyelin, and LPC--each of which can increase disorder in the lipid membrane and thus give rise to opportunity for cholesterol to intercalate and bind--enhance cholesterol efflux compared to the saturated phospholipid (DPPC) design. Conclusion: In summary, these results demonstrate that lipid content of HDL-NP,analogs of spherical HDL, dictates cholesterol efflux function, a finding which sheds light on the functional importance of lipid content variation seen in mature, spherical HDL species.
In vitro predictors of therapeutic response in melanoma patients receiving tumor-infiltrating lymphocytes and interleukin-2.
Authors: D J Schwartzentruber, S S Hom, R Dadmarz, D E White, J R Yannelli, S M Steinberg, S A Rosenberg, S L Topalian
Journal: Journal of Clinical Oncology (1994)

To correlate in vitro characteristics of tumor-infiltrating lymphocytes (TIL) with clinical response to TIL immunotherapy in patients with metastatic melanoma.Forty-one melanoma patients undergoing 43 separate treatment courses with TIL and interleukin-2 (IL-2) from December 1990 through November 1992 were studied prospectively. Multiple patient and treatment characteristics were evaluated for response correlates. In addition, TIL were assayed within 7 days of infusion for characteristics such as doubling time, cell-surface phenotype, autologous tumor lysis in 4-hour chromium-51 release assays, and cytokine secretion following autologous tumor stimulation.Nine patients experienced complete or partial tumor regressions. Clinical parameters such as age, sex, sites of disease, performance status, and prior therapies were similar in responders and nonresponders. Treatment variables such as the cumulative IL-2 dose and concomitant administration of cyclophosphamide or interferon (IFN)-alpha were not predictive of response, although responders received 33% more TIL. However, statistically significant differences in favor of clinical response were noted for extranodal source of TIL (v lymph node), shorter culture duration (mean, 38 v 47 days), shorter TIL doubling time (2.6 v 3.7 days), greater autologous tumor lysis by TIL (30% v 15%; effector-to-target [E:T], 40:1), and secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) by TIL following autologous tumor stimulation (six of nine responders v eight of 32 nonresponders).The associations of TIL lysis of autologous tumor and younger TIL age with clinical response observed in this study are supportive of previous reports, and these findings will be useful in designing future clinical trials. The new observation correlating GM-CSF secretion by TIL with clinical response is interesting and needs further substantiation.
One cycle of induction chemotherapy (IC) in advanced oropharyngeal cancer (SCCOP) to select patients for organ preservation (OP)
Authors: F. P. Worden, S. Urba, C. Bradford, T. Carey, D. Chepeha, M. Prince, T. Teknos, A. Eisbruch, J. Lee, C. Tsien, G. Wolf
Journal: Journal of Clinical Oncology (2005)

5512 Background: A previous trial at the University of Michigan using 1 cycle of IC to select pts with advanced laryngeal cancer for OP resulted in improved survival & high rates of OP. To determine if selecting a subset of pts for chemoradiation (CRT) could improve survival rates, reduce surgical morbidity & yield high rates of OP in pts with advanced SCCOP, we tested a similar approach. Methods: Pts with advanced SCCOP received 1 cycle of cisplatin & 5-fluorouracil. Those who achieved 50% reduction of their tumor received concurrent CRT; those with < 50% response underwent planned definitive surgery. CRT consisted of 70 Gy (2 Gy fraction daily x 7 weeks) with concurrent cisplatin 100 mg/m2 every 3 weeks x 3 cycles. After CRT, pts with a complete histologic response (CHR) received 2 cycles of paclitaxel (TXL) 175 mg/m2; those with residual tumor had salvage surgery. Endpoints were survival & rate of OP. Results: From 1/20/2000 to 11/12/2002, 68 pts were enrolled, (76% male, 24% female). Mean age was 58 (range 37–87). Stage III -25% & stage IV -75%. One pt died during IC. After 1 cycle of IC, 53 pts (79%) had a > 50% response & received CRT. Fifty-two underwent evaluation for histologic response; 1 died during treatment. Four pts had persistent disease: 2 had salvage surgery, 1 was surgically unresectable due to distant metastases, & 1 refused surgery. Forty-eight pts (90%) had a CHR after CRT. Thirty-three with CHR underwent planned elective neck dissections. Adjuvant TXL was given to 24 (50%) with CHR - 13 received 2 cycles & 11 received 1 cycle. Thirteen pts (19%) had < 50% response to IC. Of these, 10 had surgical resection; 3 refused surgery. The OP rate is 80%. Only 8% of pts are G-tube dependent. Median follow-up is 30 months. Seventeen pts are dead, 10 from distant metastases, 5 from L/R disease, & 2 from non-cancer related causes. The 3-year overall survival is 67% (95% CI [53.5%, 80.6%]) & the 3-year disease-free survival is 80.5% (95% CI [68.9, 92.1]). Conclusion: One cycle of IC can be an effective selection factor for targeted CRT in pts with advanced SCCOP. The high rates of OP & survival, which are better than previously published results, suggest the need for prospective randomized testing of this treatment strategy. No significant financial relationships to disclose.
Amplification and pyrosequencing of near-full-length hepatitis C virus for typing and monitoring antiviral resistant strains
Authors: P. Trémeaux, A. Caporossi, C. Ramière, E. Santoni, N. Tarbouriech, M.-A. Thélu, K. Fusillier, L. Geneletti, O. François, V. Leroy, W.P. Burmeister, P. André, P. Morand, S. Larrat
Journal: Clinical Microbiology and Infection (2016)
Weekly bolus topotecan as secondary therapy in extensive stage small cell lung cancer: A Minnie Pearl Cancer Research Network phase II trial
Authors: N. W. Peacock, J. D. Hainsworth, A. B. Switzer, H. A. Burris, C. Barrett, M. F. Nicolau, F. A. Greco
Journal: Journal of Clinical Oncology (2004)

7278 Background: Topotecan given intravenously for 5 consecutive days every 3 weeks is standard secondary therapy for patients with relapsed small cell lung cancer, but the average objective response rate from multiple studies is less than 20%. Weekly bolus topotecan appears to be active in relapsed ovarian cancer and is associated with significantly less myelosuppression than the 5 day schedule. Methods: A phase II trial as secondary therapy for relapsed small cell carcinoma is currently ongoing. Topotecan 4mg/m2 IV over 30 minutes for 12 consecutive weeks was planned. Doses were held or reduced based on toxicity. Patients were evaluated for response after 4 weeks; at least 3 weeks of therapy were required to be evaluable for response. Results: Thirty evaluable patients of the required 100 patients have been enrolled; 19 with sensitive relapse and 11 with resistant relapse. None of the 11 patients with resistant relapse have had partial responses; 3 patients had stable disease and 8 patients progressive disease. One of 19 patients (5%) with sensitive relapse had a partial response, 7 patients had stable disease and 11 patients progressive disease. A total of 213 weeks of therapy have been administered. There were 25 weeks of treatment delays and 8.5% dose modifications. Grade 3/4 toxicities: neutropenia (17.5%); thrombocytopenia (5%); fatigue (17.5%). Grade 2 fatigue was seen in 42.5%. There were no treatment-related deaths. Conclusions: Weekly bolus topotecan produces less severe myelosuppression than seen with the standard 5 day schedule, and fatigue is an important toxicity which might be reduced by planned rest weeks. This is an ongoing trial, but weekly topotecan appears to have minimal activity in this setting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Back to the basics: the importance of concentration x time in oncology.
Authors: S D Weitman, E Glatstein, B A Kamen
Journal: Journal of Clinical Oncology (1993)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1993.11.5.820 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 8487045 Back to the basics: the importance of concentration x time in oncology. S D WeitmanxS D WeitmanSearch for articles by this author , E GlatsteinxE GlatsteinSearch for articles by this author , B A KamenxB A KamenSearch for articles by this author https://doi.org/10.1200/JCO.1993.11.5.820 PDF "Back to the basics: the importance of concentration x time in oncology.." Journal of Clinical Oncology, 11(5), pp. 820–821© 1993 by American Society of Clinical Oncology
Pazopanib (GW786034) is active in women with advanced epithelial ovarian, fallopian tube and peritoneal cancers: Initial results of a phase II study
Authors: M. Friedlander, K. C. Hancock, B. Benigno, D. Rischin, M. Messing, C. A. Stringer, E. H. Tay, S. Kathman, G. Matthys, J. J. Lager
Journal: Journal of Clinical Oncology (2007)

5561 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth &amp; inhibits angiogenesis. Clinical studies have demonstrated activity of anti-angiogenesis agents in ovarian carcinoma. Methods: Pts with epithelial ovarian, fallopian tube or primary peritoneal carcinoma; ECOG PS 0–1 with complete CA-125 response to initial platinum-based chemotherapy with subsequent rise to = 42 U/mL; no disease on CT; or non-bulky disease (masses ≤ 4 cm) were eligible. All pts must have received 1–2 prior regimens. Treatment consisted of pazopanib 800mg QD until PD, withdrawal due to AEs, or withdrawal of consent. Two-stage Green-Dahlberg design was employed requiring 2 CA-125 responses in Stage I (20 pts) to proceed to Stage II (15 pts). Primary endpoint was CA-125 response (= 50% decrease from 2 baseline samples, confirmed ≥ 21 d after initial response sample). Results: Data were available from 15/17 pts enrolled. Median age was 60 yrs (46–79). Majority of pts had platinum-sensitive disease to first line therapy (74%) and had 1 prior line of therapy (60%). 40% of pts relapsed &lt; 6 mos, 27% relapsed 6–12 mos; 27% relapsed &gt; 12 mos. CA-125 responses were seen in 7 pts (47%) with a median time to response of 29 d (5 pts have continuing response of 56–140 d and 2 pts had response duration of 56 &amp; 112 d). SD was observed in 4 pts (27%) and PD in 4 pts (27%). Most common AEs were fatigue, diarrhea, nausea, vomiting, and headache. Most common Gr 3/4 AEs were diarrhea (n=2) and ALT elevation (n=2). Five pts (33%) withdrew due to an AE; 1pt (7%) withdrew due to a potentially disease-related AE (Gr 3 ascites) and 4 pts (26%) withdrew due to toxicity (Gr 3 fatigue, Gr 2 vomiting, Gr 3 double vision, Gr 3 AST/ALT elevations). Conclusions: Preliminary review of Stage I suggests that pazopanib monotherapy demonstrates biologic activity in pts with ovarian cancer with biochemical relapse following prior platinum chemotherapy. The study has met the response criteria to proceed to stage II of enrollment. No significant financial relationships to disclose.
Differential Expression of Two Distinct Endogenous Retrovirus Genomes in Developing Tissues of the Domestic Cat&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: H L Niman, M Akhavi, M B Gardner, J R Stephenson, P Roy-Burman
Journal: JNCI Journal of the National Cancer Institute (1980)
DHAIS (Diagnosis-Helping-Accuracy-Imaging-Study) study: Combined endorectal MR and MR spectroscopic imaging in the diagnosis of prostate cancer
Authors: G. Pomara, M. Simone, L. Fontana, S. Giusti, C. Bartolozzi, F. Francesca
Journal: Journal of Clinical Oncology (2006)

14562 Background: The DHAIS study is a prospective, three-step investigation, consisting in an initial two-step phase (Diagnosis-Accuracy) followed by an extension phase (Helping). The purpose was to compare endorectal MRI and MR spectroscopic imaging (MRSI) results with biopsy results (Diagnosis) and definitive histology after radical retropubic prostatectomy (RRP) (Accuracy). The helping extension will investigate the ability of combined MRI and MRSI to detect prostate cancer foci in men with prior negative prostate biopsy. Methods: MRI and MRSI were performed in 37 consecutive pts for increased PSA and/or abnormal rectal examination. A dedicated radiologist identified areas of interest as normal, equivocal or suspicious on MRI and MRSI separately. All pts underwent prostate biopsy (TRUS 10-core biopsy) by the urologist who was blind to imaging results. Patients with positive biopsies underwent RRP. MRI and MRSI results were compared to biopsy and step-section histology. Those pts with negative biopsies will underdo a second set of 10-core prostate biopsy with up to 4 additional biopsies targeted at the equivocal or suspected sites (Helping-phase). Results: Prostate cancer was detected in 8 of 37 subjects (21.6%). Six pts underwent RRP. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) and the accuracy of MRI, MRSI and combined MRI/MRSI are shown in the Table. Conclusions: MRI and MRSI have the potential to identify cancer foci and potentially direct TRUS in patients undergoing TRUS biopsy. The third phase of this study could demonstrate the utility during repeated biopsies. Further larger studies are required to quantify the amount of benefit. [Table: see text] No significant financial relationships to disclose.
Carboplatin (CBDCA), 5-fluorouracil (5-FU) and mitoxantrone (DHAD): An effective and well tolerated regimen for metastatic breast cancer
Authors: O.F. Hidalgo, F.G. Gonzalez, J.M. Vieitez, J. Rebollo, E. Tangco, P. Herranz
Journal: Annals of Oncology (1992)
Structure-function relationships associated with extracellular matrix alterations in diabetic glomerulopathy.
Authors: S Adler
Journal: Journal of the American Society of Nephrology (1994)

Proteinuria and progressive renal insufficiency are the primary manifestations of diabetic nephropathy. Accumulating evidence suggests that these clinical features can be linked, at least in part, to pathologic changes in the glomerular extracellular matrix. Most evidence suggests that glomerular basement membrane thickening and mesangial matrix expansion consist of at least three elements. These are (1) an accumulation of normal extracellular components; (2) an increase in the novel peptide chains of the normal components of Type IV collagen; and (3) an increase in matrix elements not normally expressed in the glomerulus. The pathogenetic features underlying these changes include increased synthesis and decreased degradation of matrix. Abnormal physico-chemical interactions among these matrix elements likely contribute to alterations in three-dimensional structure, leading to proteinuria and loss of glomerular basement membrane filtering surface area. Many of these changes may be explained in whole or in part by direct or secondary effects of hyperglycemia, as well as by hemodynamic changes.
A Cell Culture System for the Assessment of Tumor-Promoting Activity&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: A. Sivak, B. L. van Duuren
Journal: JNCI Journal of the National Cancer Institute (1970)

A tissue culture system was developed to aid in the identification of tumor-promoting agents from tobacco leaf extracts and to study their mechanisms of action. Growth of clones of either viral or chemically transformed cells was enhanced in a mixed culture system, containing a large excess of contact-inhibited cells, by tumor-promoting agents from tobacco leaf extracts, by phorbol esters from croton oil, and by other chemicals. Without toxicity, the enhancement of outgrowth of transformed clones was related directly to the dose of the tumor-promoting agent and the density of the contact-inhibited cell overlay.
Common and Dissociable Mechanisms of Executive System Dysfunction Across Psychiatric Disorders in Youth
Authors: Sheila Shanmugan, Daniel H. Wolf, Monica E. Calkins, Tyler M. Moore, Kosha Ruparel, Ryan D. Hopson, Simon N. Vandekar, David R. Roalf, Mark A. Elliott, Chad Jackson, Efstathios D. Gennatas, Ellen Leibenluft, Daniel S. Pine, Russell T. Shinohara, Hakon Hakonarson, Ruben C. Gur, Raquel E. Gur, Theodore D. Satterthwaite
Journal: American Journal of Psychiatry (2016)

Disruption of executive function is present in many neuropsychiatric disorders. However, determining the specificity of executive dysfunction across these disorders is challenging given high comorbidity of conditions. Here the authors investigate executive system deficits in association with dimensions of psychiatric symptoms in youth using a working memory paradigm. The authors hypothesize that common and dissociable patterns of dysfunction would be present.The authors studied 1,129 youths who completed a fractal n-back task during functional magnetic resonance imaging at 3-T as part of the Philadelphia Neurodevelopmental Cohort. Factor scores of clinical psychopathology were calculated using an item-wise confirmatory bifactor model, describing overall psychopathology as well as four orthogonal dimensions of symptoms: anxious-misery (mood and anxiety), behavioral disturbance (attention deficit hyperactivity disorder and conduct disorder), psychosis-spectrum symptoms, and fear (phobias). The effect of psychopathology dimensions on behavioral performance and executive system recruitment (2-back > 0-back) was examined using both multivariate (matrix regression) and mass-univariate (linear regression) analyses.Overall psychopathology was associated with both abnormal multivariate patterns of activation and a failure to activate executive regions within the cingulo-opercular control network, including the frontal pole, cingulate cortex, and anterior insula. In addition, psychosis-spectrum symptoms were associated with hypoactivation of the left dorsolateral prefrontal cortex, whereas behavioral symptoms were associated with hypoactivation of the frontoparietal cortex and cerebellum. In contrast, anxious-misery symptoms were associated with widespread hyperactivation of the executive network.These findings provide novel evidence that common and dissociable deficits within the brain's executive system are present in association with dimensions of psychopathology in youth.
miR-508-3p concordantly silences NFKB1 and RELA to inactivate canonical NF-κB signaling in gastric carcinogenesis
Authors: Tingting Huang, Wei Kang, Bin Zhang, Feng Wu, Yujuan Dong, Joanna H. M. Tong, Weiqin Yang, Yuhang Zhou, Li Zhang, Alfred S. L. Cheng, Jun Yu, Ka Fai To
Journal: Molecular Cancer (2016)

NF-κB signaling pathway plays an important role in gastric carcinogenesis. The basic expression and functional role of NFKB1 and RELA (components of canonical NF-κB pathway) in gastric cancer (GC) have not been well elucidated. In this study, the role of NFKB1 and RELA in gastric tumorigenesis will be investigated and their regulation by microRNAs (miRNAs) will be deeply explored. The mRNA and protein expression of NFKB1 and RELA were investigated by qRT-PCR and Western blot in GC cell lines and primary tumors. The functional roles of NFKB1 and RELA in GC were demonstrated by MTT proliferation assay, monolayer colony formation, cell invasion and migration, cell cycle analysis and in vivo study through siRNA mediated knockdown. Identification of NFKB1 as a direct target of tumor suppressor miRNA miR-508-3p was achieved by expression regulation assays together with dual luciferase activity experiments. NFKB1 and RELA were up-regulated in GC cell lines and primary tumors compared with normal gastric epithelium cells and their upregulation correlation with poor survival in GC. siRNA mediated knockdown of NFKB1 or RELA exhibited anti-oncogenic effect both in vitro and in vivo. NFKB1 was further revealed to be a direct target of miR-508-3p in gastric tumorigenesis and their expression showed negative correlation in primary GC samples. miR-508-3p was down-regulated in GC cells compared with normal gastric epithelium samples and its ectopic expression in GC cell lines also exerts tumor suppressor function. NFKB1 re-expression was found to partly abolish the tumor-suppressive effect of miR-508-3p in GC. All these findings supports that canonical NF-κB signaling pathway is activated in GC at least by the inactivation of miR-508-3p and this might have therapeutic potential in GC treatment.