tbuckley/cabot-search huggingface dataset:
Correlation between mismatch repair deficiency (MMRd), microsatellite instability (MSI) and survival in MAGIC.
Authors: Elizabeth Catherine Smyth, Andrew Wotherspoon, Clare Peckitt, Matthew Guy Nankivell, Zakaria Eltahir, Sanna Hulkki Wilson, David Gonzalez de Castro, Alicia Frances Clare Okines, Ruth E Langley, David Cunningham
Journal: Journal of Clinical Oncology (2016)

4064 Background: MMRd and MSI are prognostic for survival in many cancers and predict resistance to fluoropyrimidines in colon cancer. We examined the relationship between MMRd, MSI and survival in patients (pts) with resectable gastroesophageal cancer randomised to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. Methods: For MMR, tumour sections were assessed for expression of MMR proteins MLH1, MSH2, MSH6 and PSM2. MSI status was determined using the Promega MSI Analysis System (NR-21, BAT-26, BAT-25, NR-24, MONO-27). MMR status was correlated with MSI and the relationship between MMR status and survival was assessed. Results: MMRd results were available for 302 pts (66% resected pts). Sixteen (5%), 3 (1%), 2 (1%) and 18 (6%) pts were deficient in MLH1, MSH2, MSH6 and PMS2 respectively. Fourteen of 16 MLH1-ve tumours (88%) with available MSI results had MSI compared to 2/269 (1%) MLH1+ve tumours. Pts with MLH1-ve tumours treated with chemotherapy plus surgery had inferior median survival compared to MLH1+ve pts (7.2m vs 22.3m) whereas for pts treated with surgery alone the effect was in the opposite direction; median survival for MLH-ve pts was not reached, that for MLH1+ve pts was 20.3m. The interaction test between MHL1 and treatment was significant p=0.01. MSH2, MSH6 and PMS2 did not demonstrate similar relationships. Conclusions: In MAGIC, 88% of MLH1-ve pts demonstrated MSI and MLH1 deficiency was associated with a positive prognostic effect in pts treated with surgery alone and a differentially negative prognostic effect in pts treated with chemotherapy. These results are consistent with those reported for MSI status in this dataset. If independently validated, either MSI or MMRd (specifically MLH1) status on pre-operative biopsies could be used to select patients for peri-operative chemotherapy. MLH1 status and overall survival in MAGIC. Chemotherapy patients Surgery patients MLH1 +ve MLH1 -ve MLH1 +ve MLH1 -ve Patients 122 8 148 6 Events 77 7 101 1 Median OS (months) 95% CI 22.3 (16.1, 35.7) 7.2 (0.1, NR) 20.3m (16.7, 27.8) NR (4.9, NR) HR 95% CI 2.73 (1.25, 5.96) 0.17 (0.02, 1.27) p-value 0.012 0.085 *only patients with date of surgery included in survival analysis
Abstract LB-057: 1-Benzylquinazoline-2,4(1H,3H)-diones as potent PARP inhibitors. SAR of the quinazoline group and in vivo efficacy of clinical candidate IMP4297
Authors: Sui Xiong Cai, Qingbing Xu, Xiuhua Hu, Yangzhen Jiang, Guoxiang Wang, Ed Tian
Journal: Cancer Research (2016)

Abstract Poly (ADP-ribose) polymerase (PARP) is a critical enzyme for DNA repair and PARP-1 inhibitors have been found to be efficacious against cancers with BRCA mutations. Olaparib (AZD2281) has been approved as the first PARP-1 inhibitor for the treatment of ovarian cancers with BRCA mutations. In this presentation, we will report the SAR studies of 1-benzylquinazoline-2,4(1H,3H)-diones (BQD) as potent PARP inhibitors. We will present data for substituents at the quinazoline group of BQD, as well as in vivo efficacy data of IMP4297 which has been selected as clinical candidate for development. In a human triple negative breast cancer PDX model (BR-05-0028) with BRCA1 mutations, IMP4297 is highly efficacious against tumor growth with potency that is about 20-fold that of AZD2281. An IND for IMP4297 has been filed in China recently. Citation Format: Sui Xiong Cai, Qingbing Xu, Xiuhua Hu, Yangzhen Jiang, Guoxiang Wang, Ed Tian. 1-Benzylquinazoline-2,4(1H,3H)-diones as potent PARP inhibitors. SAR of the quinazoline group and in vivo efficacy of clinical candidate IMP4297. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-057.
Abstract 1537: The biological role of BAT-1 in prostate cancer
Authors: Aileen M. Garcia-Vargas, Maylein C. Juan-Rivera, Milaris M. Sánchez-Cordero, Maria Sánchez-Vázquez, Krizia Rohena, Magaly Martínez-Ferrer
Journal: Cancer Research (2016)

Abstract Prostate cancer is the most common cancer in men in the United States and is the second cause of cancer death in men. In Puerto Rico, prostate cancer is the most common type of cancer and the leading cause of cancer death in men. The current available biomarkers are unable to predict malignant outcomes such as recurrence. Thus, there is a critical demand for the development of innovative diagnostic and prognostic tools for the management of prostate cancer. In the current study, we evaluated the biological role of BAT-1 in prostate cancer. Preliminary data from patients who had prostate cancer recurrence identified that HLA-B associated transcript 1 (BAT-1) was down-regulated in patients with prostate cancer recurrence when compared with non-recurrent patients. We down-regulated BAT-1 in PC3 and 22RV1 prostate cancer cell lines using small interfering RNA (siRNA). In vitro assays were performed to measure de-differentiation, proliferation, apoptosis, migration and invasion. Flow cytometry analysis using the cell Viability/Annexin V cell staining kit showed that down-regulation of BAT-1 significantly increased the proliferation of PC3 cells (P&amp;lt;0.05) but decreased apoptosis. Down-regulation of BAT-1 showed no significant change in the expression of vimentin, desmin, and alpha-smooth muscle actin (α-SMA). Wound healing and Boyden assays showed that cells treated with BAT-1 siRNA significantly increased migration and motility at 12h and 24h of PC3 cells when compared to control (P&amp;lt;0.05). Our results showed that BAT-1 down-regulation increased migration and cell motility. Cells also tend to proliferate more, but have reduced apoptosis. These results were expected due to its down-regulation in recurrent prostate cancer patient samples, suggesting that BAT-1 down-regulation promotes aggressiveness in prostate cancer recurrence. A possible mechanism of action for BAT1 is the modulation of cell proliferation and migration. Citation Format: Aileen M. Garcia-Vargas, Maylein C. Juan-Rivera, Milaris M. Sánchez-Cordero, Maria Sánchez-Vázquez, Krizia Rohena, Magaly Martínez-Ferrer. The biological role of BAT-1 in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1537.
Abstract 3986: Diagnostic significance of cathepsin L and cathepsin B expression in human gallbladder cancer - A pilot study
Authors: SIDDHARTH MEHRA, MANISH KUMAR, RAJESH PANWAR, NIHAR RANJAN DASH, RATNAKAR SINGH, RAJNI YADAV, SIDDHARTHA DATTA GUPTA, PEUSH SAHNI, SHYAM S. CHAUHAN
Journal: Cancer Research (2016)

Abstract Background: Gallbladder cancer (GBC) is the most common biliary tract malignancy worldwide. Cancer of gallbladder usually refers to as an Indian disease as it is more common in Indian subcontinent especially in north and central India. Incidence rate of GBC in women in Delhi is as high as 21.5 per 100,000 population. It is an aggressive malignancy, which spreads locally to liver, adjacent organs and lymph nodes as well as to distant organs. Cathepsin L (CTSL) and B (CTSB) are lysosomal cysteine proteases implicated in protein turnover and tissue remodeling. Deregulated expression of these proteases has been associated with invasion and metastasis in several solid tumors. Objective: To assess the expression and clinical significance of CTSL and CTSB in human gallbladder cancer. Methods: We assayed the activities of CTSL and CTSB via spectroflurometrically in whole tissue lysates of gallbladder cancer patients (N = 23) and normal gall bladder tissue samples with gallstones (N = 31) / without gallstones (N = 34), which served as controls. Activities of these proteases were correlated with several clinic pathological parameters in GBC patients. CTSL and CTSB mRNA levels were determined in tissues samples by Real time PCR. Furthermore serum levels of these proteases were also assayed using sandwich based ELISA in GBC patients and controls. Results: Significant increase in the enzymatic activities of CTSL+B, CTSL and CTSB was observed in gallbladder cancer tissue samples in comparison to normal gall bladder both with and without gallstones (p &amp;lt; 0.001). ROC analysis confirmed the diagnostic relevance of CTSL and CTSB analysis with area under the curve 0.791 and 0.840 respectively for gallbladder cancer patients with respect to controls. Over expression of CTSB was also significantly associated with involvement of lymph node (p = 0.05) in gall bladder carcinoma. Secretory levels of CTSL and CTSB in serum were significantly elevated in GBC patients (p &amp;lt;0.01). Increased expression of these cysteine proteases were also confirmed at the mRNA level by Real time PCR. Conclusion: Our study for the first time demonstrated a significant increase in the levels of cathepsin L and B in GBC patients as compared to controls. Elevated levels of these proteases may serve as potential biomarkers for human gall bladder cancer. Citation Format: SIDDHARTH MEHRA, MANISH KUMAR, RAJESH PANWAR, NIHAR RANJAN DASH, RATNAKAR SINGH, RAJNI YADAV, SIDDHARTHA DATTA GUPTA, PEUSH SAHNI, SHYAM S. CHAUHAN. Diagnostic significance of cathepsin L and cathepsin B expression in human gallbladder cancer - A pilot study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3986.
瞬時血流予備量比(iFR)の被検者内再現性及び心筋血流予備量比と比較した血液動態依存性
Authors: Murai Tadashi, Kakuta Tsunekazu, Lee Tetsumin, Kuroi Akio, Kanadi Yoshihisa, Masuda Ryo, Araki Makoto, Ichihara Noboru, Takagi Takamitsu, Iwasawa Jin, Komatsu Yuki, Nakamura Hiroaki, Miyazaki Shinsuke, Taniguchi Hiroshi, Hachiya Hitoshi, Iesaka Yoshito, Fujiwara Hideomi, Isobe Mitsuaki
Journal: Circulation (2014)
Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): Results from the BELIEF trial.
Authors: Owen A. O'Connor, Tamás Masszi, Kerry J. Savage, Lauren C. Pinter-Brown, Francine M. Foss, Leslie Popplewell, Amanda F. Cashen, Jeanette Doorduijn, Shanta Chawla, Poul Knoblauch, Pier Luigi Zinzani, Peter Brown, Georg Hess, Achiel Van Hoof, Steven M. Horwitz, Andrei R. Shustov
Journal: Journal of Clinical Oncology (2013)

8507 Background: Therapies approved in US for R/R PTCL have overall response rates (ORR) of 25%-27%. The need for new therapies persists. BELIEF is a pivotal, single-arm study of belinostat in patients with R/R PTCL after failure of ≥1 prior systemic therapies. Methods: Entry criteria were measurable PTCL, platelets ≥ 50,000/µL, no prior HDACi therapy, and adequate organ function. PTCL was confirmed by central pathology review (CPRG). Belinostat 30 min IV infusion at 1000 mg/m 2 was administered on days 1–5 of a 3 week cycle until progression or unacceptable toxicity. Tumor response was assessed by Cheson 2007 criteria. The primary endpoint was ORR. Results: Patients with R/R PTCL (N=129, 53% male, median age 63 y) received belinostat a median of 2 cycles (range 1–33). The median number of prior therapies was 2 (1-8) including CHOP/CHOP-like (96%) and stem cell transplant (23%). The median administered dose intensity was 98%. One and two dose reductions of 25% occurred in 12% and 1% of patients, respectively, due to adverse events (AEs). For patients with CPRG confirmed PTCL (N=120), the ORR was 26% (n=31; 10% CR; 16% PR). The median time to response was 5.6 weeks (range 4.3-50.4). The median duration of response (DoR) was 8.3 months; longest DoR was 29.4 months. Seven patients remain on study in response. For the subgroup of patients with CPRG confirmed PTCL and baseline platelets ≥100,000/μL (N=100) ORR was 28% (CR 11%; PR 17%). The most frequent (≥ 5%) grade 3-4 treatment emergent AEs were thrombocytopenia (13%), neutropenia (13%), anemia (10%), dyspnea (6%), pneumonia (6%), and fatigue (5%). Patients with platelets &lt;100K tolerated belinostat, with 98% dose intensity. Belinostat was well tolerated with a low incidence of myelosuppression. Discontinuations were due to PD (64%), death (11%), AEs (7%), patient request (8%), and other (4%). Conclusions: Belinostat demonstrated a 26%-28% ORR in BELIEF and was well tolerated with a favorable safety profile in patients with R/R PTCL including those with low platelets. The low incidence of myelosuppression observed warrants further investigation of belinostat combination therapy to develop new treatment paradigms for R/R PTCL. Clinical trial information: NCT00865969.
Anatomical Segmentectomy and Wedge Resections Are Associated with Comparable Outcomes for Patients with Small cT1N0 Non–Small Cell Lung Cancer
Authors: Nasser K. Altorki, Mohamed K. Kamel, Navneet Narula, Galal Ghaly, Abu Nasar, Mohamed Rahouma, Paul C. Lee, Jeffery L. Port, Brendon M. Stiles
Journal: Journal of Thoracic Oncology (2016)
Practical Anatomy, Including a Special Section on the Fundamental Principles of Anatomy.
Journal: JAMA (1899)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Abstract 2949: REV3L, the catalytic subunit of pol ζ, is involved in the progression and chemoresistance of esophageal squamous cell cancer
Authors: Jundong Zhou, Sitao Zou, Wei-Qun Ding, Jinchang Wu
Journal: Cancer Research (2016)

Abstract REV3L, the catalytic subunit of DNA ploymerse zeta, is well known to participate in error-prone translesion synthesis (TLS) with less stringent and lower processivity. Recent evidence demonstrated that REV3L is involved in carcinogenesis and tumor progression. However, the function of REV3L remains unclear in esophageal squamous cell cancer (ESCC). In this study, we examined REV3L expression in ESCC tissues and its association with clinicopathological parameters. REV3L was found to be significantly up-regulated in ESCC tissues, which is correlated with lymph node metastasis and clinical stages of the patients. To further investigate the potential role of REV3L in esophageal cancer, stable ESCC cell lines with the suppression of REV3L expression were established. Down regulation of REV3L expression led to a decrease in cell proliferation and invasive tendency partly through suppressing cyclinD1 and survivin expression, and an increase in cellular sensitivity to 5-Fu by inducing G1 phase arrest and apoptosis. Therefore, REV3L plays an important role in ESCC progression and chemoresistance, and is a potential diagnostic marker and therapeutic target for ESCC. Citation Format: Jundong Zhou, Sitao Zou, Wei-Qun Ding, Jinchang Wu. REV3L, the catalytic subunit of pol ζ, is involved in the progression and chemoresistance of esophageal squamous cell cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2949.
Abstract 2643: Discovery and characterization of a selective TrkA inhibitor for the treatment of TrkA-driven cancers
Authors: Vijaya G. Tirunagaru, Kumaragurubaran Nagaswamy, Sayan Mitra, Srinivas Maddi, Ram Sudheer Adluri, Hemant Joshi, Jang B. Gupta
Journal: Cancer Research (2016)

Abstract Kinase gene fusions have been implicated as oncogenic drivers promoting cell survival and proliferation. TrkA gene fusions have been reported in a number of cancer types including lung, colorectal, papillary thyroid, sarcoma, cholangiocarcinoma and other tumors. We have identified novel, potent, selective and orally bioavailable TrkA inhibitors for the treatment of TrkA-driven cancers. One of the inhibitors, GVK-TrkI showed potent activity with an IC50 of 0.8 nM and 1.5 nM in the cell based assays for WT TrkA (AD293 cells expressing TrkA) and TPM3-NTRK1 fusion (KM12 cells) respectively. Potent activity of 12.5 nM IC50 was observed in TrkA Z-lyte kinase assay. Significant change in TrkA Z-lyte kinase IC50 was not observed at multiple ATP concentrations ranging from 100 uM to 1 mM suggesting non-ATP competitive mode of inhibition. Excellent selectivity (&amp;gt;1000x) was observed towards TrkB and TrkC in the cell based assays. GVK-TrkI inhibited TrkA autophosphorylation in a concentration dependent manner up to 24 h in KM12 cells in vitro. GVK-TrkI inhibited cell proliferation in KM12 cells with a GI50 of 34 nM while exhibiting no activity in cell lines without TrkA fusion. Comparable activity was observed in Ba/F3 cell line expressing MPRIP-NTRK1 fusion, demonstrating inhibition of TrkA driven cell proliferation irrespective of the N-terminal fusion with a different gene, MPRIP. In the KM12 xenograft model, treatment with GVK-TrkI at various doses and dosing regimens of 20 mpk bid, 50 mpk bid and 100 mpk qd resulted in dose dependent inhibition with almost 100% tumor growth inhibition (TGI) at 100 mpk qd with 3 out of 8 mice showing complete tumor regression. Besides, at 50 mpk in various dosing regimens of qd, bid and bid alternate day showed good correlation of TGI with compound exposure. GVK-TrkI was well-tolerated, causing no weight loss or death compared with vehicle control. Based on the evidence of ATP binding site mutations contributing to clinical resistance with kinase inhibitor drugs, GVK-TrkI is predicted to be effective as a second generation TrkA inhibitor with a non-ATP binding site mechanism compared to pan-Trk inhibitors currently being pursued in clinic. These results suggest that GVK-TrkI is an effective therapeutic option in TrkA driven cancers with TrkA gene fusions, activating mutations and cancers with NGF/TrkA overexpression resulting in constitutive activation of TrkA pathway. Citation Format: Vijaya G. Tirunagaru, Kumaragurubaran Nagaswamy, Sayan Mitra, Srinivas Maddi, Ram Sudheer Adluri, Hemant Joshi, Jang B. Gupta. Discovery and characterization of a selective TrkA inhibitor for the treatment of TrkA-driven cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2643.
Abstract 3364: Adaptive mechanisms upon LRP1 repression: Impact on sphingosine-1-phosphate-mediated signalling and migration of brain endothelial cells
Authors: Amélie Vézina, Cyndia Charfi, Alain Zgheib, Borhane Annabi
Journal: Cancer Research (2016)

Abstract Switches in the sphingolipid metabolism have recently been associated with oncogenic transformation, and a role for the low density lipoprotein receptor related protein (LRP1) in the sphingosine-1-phosphate (S1P) proangiogenic signalling inferred. Although S1P is a key determinant of blood-brain barrier (BBB) permeability, the interdependent signalling crosstalk with LRP1 in brain endothelial cells (EC) remains unclear. Here, we tested whether any adaptive LRP1/S1P interdependence mechanisms are required in a SV40-immortalized human brain microvascular EC (HBMEC) model which closely mimics the brain tumor endothelium phenotype. Transient LRP1 silencing and stable LRP1-/- HBMEC were generated and increased expression of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor which regulates the transcription of all five S1P receptors members, was observed upon stable but not transient LRP1 repression. Migration of EC isolated from Lrp1(EC)-/- mice and of stable LRP1-/- HBMEC became unresponsive to S1P, in part explained by altered ERK and p38 MAPK pathways, whereas it remained unaltered in transient in vitro LRP1 repression. Adaptive diminished expressions of S1P1, S1P3, and S1P5, and increased S1P2 were observed in stable LRP1-/- HBMEC and in brain EC isolated from Lrp1(EC)-/- mice. Finally, gene silencing strategies highlighted the need for S1P3 for proper S1P-mediated HBMEC migration. Collectively, our study highlights an unexpected adaptive transcriptional crosstalk between LRP1 and specific S1P receptors which accounts for S1P signalling in brain EC. Targeting of the LRP1/S1P signalling axis at the BBB may thus be considered in future therapeutic strategies. Citation Format: Amélie Vézina, Cyndia Charfi, Alain Zgheib, Borhane Annabi. Adaptive mechanisms upon LRP1 repression: Impact on sphingosine-1-phosphate-mediated signalling and migration of brain endothelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3364.
Orange Sweater
Authors: Thomas B. Cole
Journal: JAMA (2013)

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