tbuckley/cabot-search huggingface dataset:
Abstract 2412: Reconstructing intratumor heterogeneity: lessons from therapeutic intervention in patient-specific models
Authors: Dirk Schumacher, Karsten Boehnke, Marlen Keil, Alessandra Silvestri, Maxine Silvestrov, Jens Hoffman, Iduna Fichtner, Reinhold Schaefer, Christian RA Regenbrecht
Journal: Cancer Research (2016)

Abstract Precision medicine approaches seeking to predict individual susceptibility to single or combinatorial drugs for advanced and/or metastasized solid cancers heavily depend on biological model systems that maintain key morphological, phenotypic and genomic features of the original tumor. Here, we present a case study of a female patient with metastasized colorectal cancer. Using tissue from five distinct areas of the primary tumor and its metastasis of the synchronously removed primary tumor and liver metastasis, we generated cell cultures. To address cell morphology and phenotypic features we performed immunohistochemistry (IHC) and immunofluorescence imaging showing that these cell cultures express colon-specific marker proteins/combinations CDX2 and CK20+/CK7-. Ultra-deep panel sequencing of original tumor tissue samples revealed damaging mutations in KRAS (G12D), PIK3CA (H1047R) and TP53 (C242F). Two cell cultures showed an additional SNP in the tumor suppressor SMAD4 (R361H), which was not detected in the original tissue, thus hinting at the existence of a small sub-population of cancer cells with a divergent mutation pattern. In parallel we established patient-derived xenografts (PDX) models from each region and investigated the response to targeted therapeutics, aiming at key molecules of the MAPK, PI3K/AKT and mTOR pathways in these genetically heterogeneous populations. drug response in single and mixed cell populations to address differential growth characteristics and response to mono- and combinatorial drug treatment. To distinguish the cells-of-origin and to calculate distributions/contribution of each population to the in vivo tumor growth in this model, sub-populations were color-coded using lentiviral constructs, expressing either a green or red tag. FACS analyses after treatment were performed and ratios of SMAD4mut(green) vs. SMAD4wt(red) were determined for each PDX tumor. These analyses, together with confirmatory IHC staining for the respective tag, showed significant effects on both tumor growth and population distributions in a treatment-dependent manner, advocating for systematic evaluation of combinatorial treatment in patients. Citation Format: Dirk Schumacher, Karsten Boehnke, Marlen Keil, Alessandra Silvestri, Maxine Silvestrov, Jens Hoffman, Iduna Fichtner, Reinhold Schaefer, Christian RA Regenbrecht. Reconstructing intratumor heterogeneity: lessons from therapeutic intervention in patient-specific models. [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 2412.
Perinatal mortality: a continuing collaborative regional survey.
Journal: BMJ (1984)

A collaborative survey of perinatal mortality in each district of the Northern region set up in July 1980 was able to obtain information on 99% of all the registered perinatal deaths among babies born in 1981-2 to mothers resident in the region. There were 12.4 perinatal deaths/1000 births over this two year period, but 41% of the stillbirths and early neonatal deaths were of babies with a lethal malformation or weighing less than 1000 g at birth (or both). All causes of perinatal mortality had become less common than they had been at the time of the National Birthday Trust survey in 1958, though there had been a relatively small decrease in the number of deaths due to malformation (in the absence of any neural tube defect) and in the number of stillbirths of normally developed fetuses: 36% of the antepartum stillbirths among non-malformed singleton fetuses were associated with poor fetal growth (weight below the fifth centile at birth) and 21% were due to sudden unexplained placental abruption.
Abstract 3659: DIRAS1 and DIRAS2 are novel ovarian cancer tumor suppressors that regulate cell growth, motility and autophagy
Authors: Margie N. Sutton, Zhen Lu, Hailing Yang, Gilbert Huang, Yan Wang, Weiqun Mao, Robert C. Bast
Journal: Cancer Research (2016)

Abstract DIRAS3 (also known as ARHI; Aplasia Ras Homolog Member I) is a potent tumor suppressor that has been well characterized for its role in ovarian cancer and autophagy. DIRAS3 is a maternally imprinted tumor suppressor gene that encodes a 26kDa GTPase which shares 60% homology to Ras and Rap. DIRAS3 is downregulated in many tumor types including ovarian cancer. DIRAS3 is downregulated by multiple mechanisms including loss of heterozygosity, transcriptional regulation by E2F1 and E2F4, hypermethylation of the second allele, and regulation by miRNAs 221 and 222. Re-expression of DIRAS3 at physiologic levels inhibits cancer cell growth, reduces motility, induces autophagy and promotes tumor dormancy. The mechanisms by which DIRAS3 induce autophagic cell death in vitro and tumor dormancy in vivo have been well characterized by previous work in our laboratory demonstrating that DIRAS3 is required for the induction of autophagy, and that upon inhibition of autophagy you can prevent outgrowth of dormant ovarian cancer cells in vivo. Interestingly, mice do not have DIRAS3 as it was lost during evolutionary rearrangement of murine chromosomes 3 and 6 nearly 60 million years ago, yet murine cells can still undergo autophagy. The DIRAS family members, DIRAS1 and DIRAS2 share 50-60% homology with DIRAS3 and are found in the murine genome. These 22kDa GTPases differ from DIRAS3 by the truncation of their N-terminal extension. Although DIRAS1 and DIRAS2 have not previously been characterized in ovarian cancer, TCGA analysis suggests that higher mRNA expression of these genes results in a survival advantage for patients with high grade serous ovarian cancer. In this study we demonstrate that re-expression of DIRAS1 and DIRAS2 inhibit ovarian cancer cell growth in vitro and induce autophagy in both human and murine cells. DIRAS1 and DIRAS2 are required for murine autophagy induced by rapamycin or amino acid starvation. Overexpression of DIRAS1 and DIRAS2 inhibits cancer cell growth and motility, and results in the inhibition of both the PI3K and Ras/MAPK signaling pathways. Thus DIRAS1 and DIRAS2 provide many of the functions of DIRAS3 in normal and malignant murine cells. Citation Format: Margie N. Sutton, Zhen Lu, Hailing Yang, Gilbert Huang, Yan Wang, Weiqun Mao, Robert C. Bast. DIRAS1 and DIRAS2 are novel ovarian cancer tumor suppressors that regulate cell growth, motility and autophagy. [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 3659.
Medical and Surgical Treatments for Usual-Type Vulvar Intraepithelial Neoplasia
Authors: Theresa A. Lawrie, Andrew Nordin, Manas Chakrabarti
Journal: JAMA Oncology (2016)

Which interventions are the most effective and tolerable for treating usual-type vulvar intraepithelial neoplasia?Provided cancer is not suspected, usual-type vulvar intraepithelial neoplasia treatment, including medical and surgical options, can be individualized to take into account the site, extent of disease, and a woman's preferences, with a commitment to long-term follow-up.
Abstract 4638: Targeted therapy of precancerous fields in the mucosal linings of the head and neck
Authors: D Vicky de Boer, Sanne R. Martens-de Kemp, Marijke Buijze, Marijke Stigter-van Walsum, Elisabeth Bloemena, C René Leemans, Boudewijn J.M. Braakhuis, Ruud H. Brakenhoff
Journal: Cancer Research (2016)

Abstract Primary head and neck squamous cell carcinomas (HNSCC) and local relapses develop in preneoplastic fields in the mucosal linings of the upper aerodigestive tract. These fields are characterized by tumor-associated genetic changes, show frequently dysplastic features and are occasionally macroscopically visible as lesions. Currently, there are no adequate treatment options for these fields to prevent tumor development. To develop a targeted therapeutic approach we established four unique preneoplastic cell lines, derived from fields adjacent to HNSCCs. Next, we performed a screen with a selective panel of small interfering RNAs (siRNAs) that are lethal for HNSCC cells, to identify genes essential for survival of preneoplastic cells and not for normal cells. One of these selective essential genes was Polo-like kinase 1 (PLK1). Inhibition of PLK1, both with siRNAs as well as small molecule inhibitors, caused cell death of preneoplastic and HNSCC tumor cells, while primary fibroblasts and keratinocytes were hardly affected. Targeting PLK1 caused a strong G2/M cell cycle arrest in preneoplastic cells accompanied by formation of monopolar spindles during mitosis. Hence, PLK1 is a promising therapeutic target for chemopreventive eradication of preneoplastic fields in patients at high risk of developing HNSCC and local relapses. Citation Format: D Vicky de Boer, Sanne R. Martens-de Kemp, Marijke Buijze, Marijke Stigter-van Walsum, Elisabeth Bloemena, C René Leemans, Boudewijn J.M. Braakhuis, Ruud H. Brakenhoff. Targeted therapy of precancerous fields in the mucosal linings of the head and neck. [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 4638.
The incidence of clonal T-cell receptor rearrangements in B-cell precursor acute lymphoblastic leukemia varies with age and genotype
Authors: Caren Brumpt, Eric Delabesse, Kheira Beldjord, Frederic Davi, Jean-Michel Cayuela, Corinne Millien, Patrick Villarese, Pierre Quartier, Agnes Buzyn, Françoise Valensi, Elizabeth Macintyre
Journal: Blood (2000)
Abstract 1910: Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly regulate metastasis-promoting LOXL2 in prostate cancer
Authors: Mayuko Kato, Akira Kurozumi, Yusuke Goto, Ryosuke Matsushita, Ichiro Fukumoto, Atsushi Okato, Rika Nishikawa, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki
Journal: Cancer Research (2016)

Abstract BACKGROUNDS: Most patients with prostate cancer (PCa) initially respond to androgen-deprivation therapy, but eventually becomes hormone-insensitive and progress to castration-resistant prostate cancer (CRPC). CRPC is difficult to treat, and most clinical trials for advanced PCa have shown limited benefits, with disease progression and metastasis to the skeleton or other sites. Therefore, understanding the molecular mechanisms of CRPC and the metastatic pathways underlying PCa using genomic approaches would help to prevent and improve therapies for the disease. Our previous studies showed that three tumor-suppressive microRNAs (miRNAs), miR-26a/b, miR-29a/b/c and miR-218, significantly inhibited cancer cell migration and invasion. Therefore, we hypothesized that these miRNAs-regulated target genes deeply contributed to cancer metastasis. METHODS: Genome-wide gene expression analysis and in silico analysis were applied to investigate molecular targets regulated by miR-26a/b, miR-29a/b/c and miR-218 in PCa cells. A luciferase reporter assay was carried out to determine whether 3’ UTR of target genes have actual biding sites for these miRNAs. To investigate the functional role of target genes in PCa cells, loss-of-function studies by using siRNAs of targets genes were performed. RESULTS: Our in silico analysis and luciferase reporter assays showed that lysyl oxidase-like 2 (LOXL2) was directly regulated by tumor-suppressive miR-26a/b, miR-29a/b/c and miR-218 in PCa cells. Overexpression of LOXL2 was observed in PCa clinical specimens by immunohistochemical staining. Moreover, downregulating the LOXL2 gene significantly inhibited cell migration and invasion in PCa cells. The function of the LOXL2 is covalent crosslinking of collagen and/or elastin in the ECM. Aberrant expression of LOXL2 has been reported in several diseases, including cancers. CONCLUSIONS: Our present data showed that the gene promoting metastasis, LOXL2, was epigenetically regulated by tumor-suppressive microRNAs, miR-26a/b, miR-29a/b/c and miR-218 providing important insights into the molecular mechanisms of PCa metastasis. Elucidation of tumor-suppressive miRNAs regulated molecular pathways and targets could provide new information on potential therapeutic strategies in PCa. Citation Format: Mayuko Kato, Akira Kurozumi, Yusuke Goto, Ryosuke Matsushita, Ichiro Fukumoto, Atsushi Okato, Rika Nishikawa, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki. Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly regulate metastasis-promoting LOXL2 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 1910.
Abstract 2236: Long lasting CR status of stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine (AFTV)
Authors: Fumito Kuranishi, Yusuke Sumi, yoij Uemae, Tadao Ohno
Journal: Cancer Research (2016)

Abstract (INTRODUCTION) The prognosis of advanced (stage IV) cancer is very poor. However, we have already reported two cases of eradication of advanced breast cancer with bone metastasis (AACR 2013 and AACR 2015) after combined treatments including AFTV. We here additionally report successful cases of gall bladder cancer (stage IV, liver metastasis) and colon cancer (stage IV, lung metastasis). (CASE 1) A 61-year-old female with stage IV gall bladder cancer (T3N1M1: liver metastasis) was operated in May 2011 including partial resection of liver. She was treated with, as the first-line adjuvant therapy, AFTV followed with conventional chemotherapy. This patient is still alive without any recurrence confirmed by CT etc. (CASE 2) A 60 year-old male with stage IV (N3, H0, P1, M1: lung, lt. adrenal gland, abdominal wall) was operated in August 2009. Then conventional chemotherapy, 2 courses of AFTV and radiation were applied sequentially. No recurrence was observed for more than 5 years. (DISCUSSION) We diagnosed both patients staying at long lasting complete remission. The prognoses of stage IV gall bladder cancer and abdominal wall-metastasized colon cancer are very poor despite of conventional treatments. Adverse effects of AFTV were less than grade 2, therefore combination therapies including AFTV are worth to consider, although larger scale clinical trial is essential. Citation Format: Fumito Kuranishi, Yusuke Sumi, yoij Uemae, Tadao Ohno. Long lasting CR status of stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine (AFTV). [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 2236.
Abstract 2170: Molecular modeling of novel peptide-receptor interaction for targeted drug delivery of prostate cancer
Authors: Ahmad Salam, Vincent Hembrick, Jesse Jaynes, Timothy Turner, Mohamed Abdalla
Journal: Cancer Research (2016)

Abstract Prostate Cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Due to the harsh side effects of conventional chemo- and radiotherapies, targeted drug delivery is now gaining the focus of cancer researchers. The key for success of any newly developed targeted drug delivery systems is the novel design of targeting peptides which have high binding affinities to differentially over-expressed receptors on the surface of PCa cells. Two over-expressed such receptors, which can be targeted to the cell surface of PCa cells are: Gonadotropin Releasing Hormone Receptor (GnRH-R), and Prostate Specific Membrane Antigen (PSMA). The analysis done from molecular dynamics simulation data gave an important information about each interaction; such as RMSD, The number of contacts between receptor and peptide within a cutoff distance of 5 Å and the binding free energies, ΔGGBSA of the interactions. In all systems, the back bone RMSD deviation of the receptor was calculated using the last 10 ns of the sampling process and averaged over all trajectories. The RMSD data deviated between 1.22 - 2.51 Å. The free binding energies or ΔGGBSA was calculated from the last 10 ns of the sampling process. The QH1 system has the more negative ΔGGBSA -36.15 kcal mol-1 and the QH4 system has the least negative ΔGGBSA of -18.4 kcal mol-1 among the eight systems of GnRH-R. QH2 system exhibits a highly interactive hydrogen bond (bond distance is 2.65 Å) between 134th position of the receptor amino acid sequence GLU and 5th position of the qh2 peptide's TYR. The ΔGGBSA is for the qh2 system is – 34.92 kcal mol-1. In the PSMA and its targeting peptide interactions, T2IA has the least negative ΔGGBSA of -47.37 kcal mol-1. A salt bridge was observed between the 10th position of the T2IA peptide sequence ARG and the 328 position of the 3RBU receptor's GLU. Based on our molecular modeling studies, we have determined the best targeting peptides among all the newly designed peptides. The binding efficiency of the targeting peptides with the lowest binding energies will be further investigated surface plasmon resonance (SPR) in near future. Citation Format: Ahmad Salam, Vincent Hembrick, Jesse Jaynes, Timothy Turner, Mohamed Abdalla. Molecular modeling of novel peptide-receptor interaction for targeted drug delivery of 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 2170.
Prevention of everolimus/exemestane (EVE/EXE) stomatitis in postmenopausal (PM) women with hormone receptor-positive (HR+) metastatic breast cancer (MBC) using a dexamethasone-based mouthwash (MW): Results of the SWISH trial.
Authors: Hope S. Rugo, Lasikas Seneviratne, J. Thaddeus Beck, John A. Glaspy, Julio Antonio Peguero, Timothy J. Pluard, Navneet Dhillon, Leon C. Hwang, Chaitali Singh Nangia, Ingrid A. Mayer, Timothy F. Meiller, Mark Steven Chambers, Ghulam Warsi, Robert William Sweetman, J. Randy Sabo, Jennifer Keating Litton
Journal: Journal of Clinical Oncology (2016)

525 Background: Stomatitis is a significant complication associated with mTOR inhibition. In BOLERO-2 patients (pts) receiving EVE/EXE, all grade (Gr) stomatitis was 67%; 33% had Gr ≥ 2 and 8% Gr 3. The median time to ≥ Gr 2 onset was 15.5 days, the incidence of new stomatitis (Gr ≥ 2) plateaued at 6 wks. In a meta-analysis, 89% of first stomatitis events occurred within 8 wks. Topical steroids are used to treat aphthous ulcers; anecdotal use as prophylaxis has been reported. Methods: Eligibility included PM women with HR+ MBC prescribed EVE/EXE. Treatment included EVE 10 mg and EXE 25 mg QD, with 10 mL of commercially available 0.5 mg/5 mL dexamethasone oral solution to swish x 2 min, and spit QID for 8 wks, starting day 1. Pts completed a daily adherence log, including an oral pain (range 0-10) and normalcy of diet score. The primary endpoint was to compare the incidence of Gr ≥ 2 stomatitis at 8 wks with BOLERO-2 results. Secondary endpoints included: MW use by average times/day, EVE/EXE dose intensity, incidence of all Gr stomatitis and time to resolution to Gr ≤ 1. Results: 92 women were enrolled; 86 are evaluable for efficacy. Median age was 61 yrs (range 34-87); 38% were treated with EVE/EXEin the ≥ 2nd-line setting. Median dose intensity was 10 (range 3-14) and 25 mg (range 8-25) for EVE and EXE. 95% of pts used the MW 3-4 times/day (median MW use/d = 3.95, range 1.9-4). The rate of ≥ Gr 2 stomatitis at 8 weeks was 2.4% (2 pts) with a Gr 1 rate of 17.4%; there were no ≥ Gr 3 events. A comparison of stomatitis incidence by grade between BOLERO-2 and SWISH is shown in the Table. Mean pain scale score was < 1 at all visits; 86% of pts reported a normal diet at 8 wks. 12% discontinued EVE/EXE due to suspected related adverse events (most common: rash [2%], hyperglycemia [2%], stomatitis [1%] and pneumonitis [1%]). Conclusions: Prophylactic use of 0.5 mg/5 mL dexamethasone oral solution markedly decreases the incidence and severity of stomatitis in patients receiving EVE/EXE for MBC and should be considered a new standard of care in this setting. Clinical trial information: NCT02069093.Study Stomatitis Grade (%) All 1 2 3 4 BOLERO-2 (total) 67 34 25 8 0 SWISH (at 8 weeks) 19.8 17.4 2.4 0 0
A multicenter, randomised, phase 3 trial comparing fixed dose versus toxicity-adjusted dose of cisplatin + etoposide in advanced SCLC patients (pts). The STAD-1 trial
Authors: G. Daniele, A. Morabito, A. Favaretto, V. Filipazzi, A. Rossi, V. Gebbia, F. Castiglione, L. Cavanna, E. Maiello, G. Valmadre, R. Costanzo, A. Manzo, L. Bonanno, E. Piazza, P. Maione, G. Mancuso, M. Di Maio, M.C. Piccirillo, C. Gallo, F. Perrone, C. Gridelli
Journal: Annals of Oncology (2015)
Response to: ‘The role of infrapatellar fat pad resection in total knee arthroplasty’ by White<i>et al</i>
Authors: Weiyu Han, Faming Pan, Zhenhua Liu, Zhaohua Zhu, Xia Wang, Shuang Zheng, Benny Antony, Changhai Ding
Journal: Annals of the Rheumatic Diseases (2016)

We thank White and Melhuish1 for their interest in our original paper2 and our response3 to Bai et al. 4

There is moderate level evidence in a recent systematic review showing that infrapatellar fat pad (IPFP) preservation improves clinical outcomes post total knee arthroplasty (TKA), whereas IPFP resection increases post-TKA knee pain.5 This is contradictory with a previous systematic review suggesting that there were no differences in function, range of motion and anterior knee pain between preservation and resection groups after TKA in knee osteoarthritis (OA).6 This new evidence is consistent with our findings that the IPFP maximal area was associated with reduced …