tbuckley/cabot-search huggingface dataset:
Abstract 563: Identification of a novel biomarker to predict pathologic complete response for neoadjuvant chemoradiotherapy in locally advanced rectal cancer
Authors: Jong Gwang Kim, In Hee Lee, Soo Jung Lee, Yee Soo Chae, Byung Woog Kang
Journal: Cancer Research (2018)

Abstract Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Good pathologic response to CRT is associated with better outcome. However, there is a lack of effective methods to select rectal cancer patients who would or would not have a benefit from CRT. Therefore, we aimed to perform whole-exome sequencing (WES) for rectal cancer to identify the novel genetic variations predicting CRT benefit in LARC. Two independent sets were used to evaluate the genetic differences between the good response group and poor response group to CRT. Fifteen patients who achieved pathologic complete response were divided into the good response group and 15 patients with pathologic stage III were classified as poor response group. Among these 30 patients, WES was examined. To validate discovery set, additional samples (n=67) were genotyped for candidate variants using TaqMan SNP genotyping assays or Sanger sequencing. Overall, the current study included a total of 97 LARC patients who were treated with neoadjuvant CRT followed by curative surgery at Kyungpook National University Medical Center. We found 5 candidate variants significantly associated with pathologic complete response (BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, RAET1L rs912565) using WES. In the dominant model, patients with GC/CC genotype of DLC1 rs3816748 (p=0.032), AC/CC genotype of DNAH14 rs3105571 (p=0.009) and TT genotype of RAET1 rs912565 (p&amp;lt;0.0001) showed higher rate of pCR compared to those of other genotype patients. In the recessive model, the BCL2L10 rs2231292 (p=0.036) and ITIH5 rs3824658 (p=0.003) were significantly associated with pathologic CR. Four SNPs (DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, RAET1L rs912565) found to be significantly correlated with pCR in codominant model. However, none of the SNPs was associated with the relapse-free survival or overall survival. The present results suggest that the genetic variation of the BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565 genes can be used as biomarkers predicting CRT response for patients with LARC. Citation Format: Jong Gwang Kim, In Hee Lee, Soo Jung Lee, Yee Soo Chae, Byung Woog Kang. Identification of a novel biomarker to predict pathologic complete response for neoadjuvant chemoradiotherapy in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 563.
Abstract 5847: A histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth with apoptosis in triple-negative breast cancer cells
Authors: Hisako Ono, Yoshihiro Sowa, Yosuke Iizumi, Mano Horinaka, Tetsuya Taguchi, Toshiyuki Sakai
Journal: Cancer Research (2018)

Abstract Purpose: Triple negative breast cancer (TNBC) is the most aggressive subtype in breast cancer. Eribulin is one of the well-tolerated chemotherapeutic drugs for the treatment of metastatic breast cancer. We usually administer eribulin or eribulin with anti-HER2 antibodies. Eribulin was approved for metastatic breast cancer refractory to anthracyclins and taxanes through EMBRACE trial, and the subgroup analysis indicated the efficacy of eribulin was effective in patients with TNBC. However, the prognosis of patients with TNBC is still poor because of the various molecular characteristics. Therefore, there is an urgent need for more effective treatment for the management of TNBC. Methods: We investigated the effect of eribulin in several TNBC cell lines. Eribulin inhibited the cell growth of TNBC cells in a dose-dependent manner. However, eribulin increased the expression of survivin, known to inhibit apoptosis. To counteract the up-regulation of survivin by eribulin, we used OBP-801, a novel histone deacetylase (HDAC) inhibitor, because HDAC inhibitors were reported to suppress the expression of survivin. Results: Co-administration of OBP-801 with eribulin showed a synergistic inhibition of cell growth in TNBC cells. The mechanism of this combination is due to the enhancement of apoptosis. The apoptosis was partially dependent on caspase, and it was via the suppression of not only survivin as expected, but also Bcl-xL. OBP-801 could suppress the survivin expression induced by eribulin at both protein and mRNA level. Interestingly, the combination more potently suppressed a MAPK pathway than each agent. Conclusion: We found that the combination of eribulin and OBP-801 synergistically inhibits the growth with apoptosis in TNBC cells, raising the possibility that the combination might be a novel promising strategy against TNBC patients. Citation Format: Hisako Ono, Yoshihiro Sowa, Yosuke Iizumi, Mano Horinaka, Tetsuya Taguchi, Toshiyuki Sakai. A histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth with apoptosis in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5847.
Abstract 5868: Preclinical testing of 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1): A potent protein kinase C-ι inhibitor as a potential anticancer drug
Authors: Christopher Apostolatos, Andre H. Apostolatos, Wishrawana S. Ratnayake, Marie Bourgeois, Mildred Acevedo-Duncan
Journal: Cancer Research (2018)

Abstract Protein Kinase C iota (PKC-ι) is an oncogene overexpressed in many cancer cells including prostate, breast, ovarian, melanoma and glioma. Previous In- vitro studies have shown that ICA-1 a PKC-ι specific inhibitor, is effective against some cancer cell lines by decreasing cell growth and inducing apoptosis {Pillai et al. Int. J. Biochem. Cell Biol. 43 (2011) 784-794. To assess ICA-1 as a possible therapeutic, In- vivo studies using a murine model were performed. ICA-1 was tested for stability in blood serum and results demonstrated that ICA-1 was stable in human plasma at 25oC and 37oC over a course of two hours. Toxicity of ICA-1 was tested for both acute and sub-acute exposure. The acute exposure showed subject surviving after 48 hours of doses ranging from 5mg/kg to 5000 mg/kg. Sub-acute tests exposed the subjects to 14 days of treatment and was followed by serum and tissue collection. AST, ALK-P, GGT, Troponin, and CR-P serum levels were measured to assess organ function. Heart, liver, kidney, and brain tissues were analyzed for accumulation of ICA-1. Finally athymic nude mice were xenografted with DU-145 prostate cancer cells. After tumors reached approximately 1 cm2, they were either treated with ICA-1 or left as control until the tumor reached 2 cm2. Results showed tumors in treated mice took almost double the time to reach the experimental end point, showing a significant growth reduction. In conclusion, ICA-1 is stable, shows low toxicity, and is a potential therapeutic for some carcinoma tumors. Citation Format: Christopher Apostolatos, Andre H. Apostolatos, Wishrawana S. Ratnayake, Marie Bourgeois, Mildred Acevedo-Duncan. Preclinical testing of 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1): A potent protein kinase C-ι inhibitor as a potential anticancer drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5868.
Abstract 2654: Immunologic and prognostic correlates of WISP1 in prostate cancer
Authors: Pierre-Olivier Gaudreau, Sylvie Clairefond, Pierre-Luc Boulay, Pavel Chrobak, Bertrand Allard, Sandra Pommey, Fred Saad, Marian Young, John Stagg
Journal: Cancer Research (2018)

Abstract Background: Avoidance of immune destruction and tumor-promoting inflammation are equally important cancer hallmarks. In the context of prostate cancer, inflammatory markers and high levels of immune infiltrates have been associated with shorter biochemical recurrence (BCR)-free survival. WNT1 Inducible Signaling Pathway (WISP1) has been implicated in prostate cancer metastasis and the regulation of inflammation in diverse benign diseases. Thus, the objectives of this study were: 1) to assess the prognostic value of WISP1 in human prostate cancer, and 2) to determine the association of WISP1 to the inflammatory landscape specific to this disease. Methods: A tumor microarray (TMA) was constructed with radical prostatectomy specimens of 285 prostate cancer patients. Multicolor manual immunofluorescence (IF) was performed to simultaneously detect WISP1, CD8 and cytokeratins 8 and 18. WISP1 expression levels were determined by the mean fluorescence intensity (MFI) in stromal, epithelial, cytoplasmic and nuclear (DAPI) areas in each core, and CD8+ cell density was determined for each compartment by dividing cell count by the percentage of the core occupied by the compartment. Finally, the prostate cancer TCGA dataset (n = 548) was used to validate the prognostic value of WISP1 mRNA expression, as well as its association to CD8+ lymphocytes using previously validated gene signatures (Becht et al., 2016). Results: IF analyses of our TMA revealed that high levels of WISP1 in normal adjacent epithelium are significantly associated with shorter BCR-free survival in Kaplan-Meier (log-rank = 4.246, p = 0.039) and univariate Cox regression analyses (hazard ratio = 1.477; p = 0.042), but not in multivariate Cox regression analyses (hazard ratio = 1.381; p = 0.101). Furthermore, a significant correlation was found between WISP1 expression and CD8+ cell density. Gene expression analyses further showed that WISP1-high prostate tumors are associated with a CD8+ lymphocyte gene enrichment profile, and confirmed that patients with WISP1-high prostate tumors have reduced BCR-free survival (Wilcoxon rank, p = 0.003). Conclusions: Overall, our results support a negative prognostic association for WISP1 as well as a proinflammatory role. WISP1 may represent a relevant target for the improvement of prostate cancer immunotherapy. Citation Format: Pierre-Olivier Gaudreau, Sylvie Clairefond, Pierre-Luc Boulay, Pavel Chrobak, Bertrand Allard, Sandra Pommey, Fred Saad, Marian Young, John Stagg. Immunologic and prognostic correlates of WISP1 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2654.
An ulcer that will not heal
Authors: Arthur Clegg, Charlotte Hall, Diana Lockwood
Journal: BMJ (2018)

A 26 year old British man presented with a seven week history of an ulcer over his left elbow that was slowly increasing in size (fig 1). It had not improved with a course of oral flucloxacillin prescribed by his general practitioner. The man was otherwise systemically well with no fever, night sweats, or weight loss, and he had no skin lesions elsewhere. He did not recall any bites or trauma to the area.



Fig 1 
Ulcer over the left elbow



His medical history included an overactive bladder and removal of a bot fly from his scalp. He had acquired the fly during a five week trip to the Peruvian Amazon three months before his attendance.

On examination, he had a 2×3 cm ulcer over his left elbow with indurated edges and associated lymphangitis ascending to the axilla. No other clinical signs were evident.

Full blood count, liver function tests, urea and electrolytes, and C reactive protein were within the normal ranges.

Punch biopsy of the ulcer showed “florid acute and chronic inflammation including foci of granulomatous inflammation” as well amastigotes of leishmaniasis, which were found to be of the L viannia complex on polymerase chain reaction testing. A diagnosis of new world cutaneous leishmaniasis …
Bifunctional Role of Protein Tyrosine Kinases in Late Preconditioning Against Myocardial Stunning in Conscious Rabbits
Authors: BuddhadebDawn, Yu-TingXuan, YuminQiu, HitoshiTakano, Xian-LiangTang, PeipeiPing, SupratimBanerjee, MichaelHill, RobertoBolli
Journal: Circulation Research (1999)

Abstract—Although protein tyrosine kinases (PTKs) have been implicated in late preconditioning (PC) against infarction, their role in late PC against stunning is unknown. Furthermore, it is unknown whether PTK signaling is necessary only to trigger late PC on day 1 or also to mediate it on day 2. Thus, conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3). In the control group (group I, n=7), the recovery of systolic wall thickening after the 6 occlusion/reperfusion cycles was markedly improved on days 2 and 3 compared with day 1, indicating the development of late PC against stunning. Administration of the PTK inhibitor lavendustin-A (LD-A, 1 mg/kg IV) before the first occlusion on day 1 (group II, n=7) completely prevented the late PC effect against stunning on day 2. Late PC against stunning was also abrogated when LD-A was given before the first occlusion on day 2 (group III, n=7); however, in these rabbits, the ...
John Godfrey Fairer
Authors: Joan Robinson
Journal: BMJ (2018)

Educated at the Wyggeston School, Leicester, Worksop, and King’s College London, John Godfrey Fairer—universally known as “Dickie”—was on holiday in the south-west of England. just after qualifying and was taken ill and was admitted to hospital. While he was recovering, the consultant in charge offered him a job as his houseman. So began a period of junior doctor posts in Devon and Cornwall. His two oldest children were born in Devon, and this was also where he spent most of the last 18 years of his life.

Around 1956-57 Dickie was …
Negative Inotropic Effect of Basic Fibroblast Growth Factor on Adult Rat Cardiac Myocyte
Authors: YujiIshibashi, YoshitoshiUrabe, HiroyukiTsutsui, ShintaroKinugawa, MasaruSugimachi, MasaruTakahashi, ShimakoYamamoto, HirofumiTagawa, KenjiSunagawa, AkiraTakeshita
Journal: Circulation (1997)

Background Basic fibroblast growth factor (bFGF) is highly expressed in the myocardium in some cardiac disorders, such as ischemia-reperfusion and cardiac allograft rejection. However, whether bFGF has any effects on myocardial contraction is unknown. Methods and Results We examined the effects of bFGF on myocardial contractility using isolated adult rat cardiac myocyte preparations. bFGF exerted a direct negative inotropic effect that was concentration and time dependent. The pretreatment of myocytes with a neutralizing anti-bFGF antibody (100 ng/mL) abolished the negative inotropic effects of bFGF (100 ng/mL). Platelet-derived growth factor (12.5 ng/mL) and transforming growth factor-β (1 ng/mL) did not exert such effects, which indicated that bFGF-induced negative inotropism was considered to be specific for this growth factor. bFGF decreased the peak intracellular Ca2+ transient by 46% during systole. The enhanced production of nitric oxide was unlikely to be responsible for the bFGF-induced negative ...
Cl−-HCO3− Exchange in Developing Neonatal Rat Cardiac Cells
Authors: IrinaKorichneva, MichelPucéat, RobertCassoly, GuyVassort
Journal: Circulation Research (1995)

Abstract The Cl−-HCO3− exchanger is the main anionic exchanger (AE) that alleviates alkaline loads in cardiac cells. We recently identified in adult ventricular cells two membrane proteins (80 and 120 kD) immunologically related to the erythroid band 3 and likely to mediate the anion exchange. In the present study, we further investigated the Cl−-HCO3− exchanger activity concomitantly with the expression and intracellular localization of the band 3–like proteins during the development of neonatal rat cardiac cells maintained in culture for 17 days. Microspectrofluorometric measurements of pHi in single cells show that neonatal rat cardiomyocytes display a fully functional DIDS-sensitive Cl−-HCO3− exchanger at early stages of development. Neither basal pHi nor the anion exchange activity changes with different stages of the culture. In Western blotting with an anti–whole erythroid band 3 antibody, we found both the 80- and the 120-kD band 3–like proteins in whole heart and cultured neonatal cardiac cells. ...
Transient Triglyceridemia Decreases Vascular Reactivity in Young, Healthy Men Without Risk Factors for Coronary Heart Disease
Authors: PiaLundman, MariaEriksson, KarinSchenck-Gustafsson, FredrikKarpe, PerTornvall
Journal: Circulation (1997)

Background Hypertriglyceridemia is now accepted as a risk factor for coronary heart disease, although the mechanism behind the increased risk is not well understood. The present study was undertaken to investigate the effects of triglyceridemia on endothelial function, because impaired endothelial function is considered a marker of atherogenesis. Methods and Results Flow- and nitroglycerin-induced dilatation of the brachial artery was investigated noninvasively by high-resolution ultrasound technique in seven young, healthy men without risk factors for coronary heart disease. Transient triglyceridemia was induced by infusion of a triglyceride emulsion, Intralipid, which raised free fatty acid concentrations twofold and triglyceride levels fourfold. Flow-induced vasodilatation decreased from 7.1±3.0% to 1.6±2.6% (P<.0002), whereas nitroglycerin-induced vasodilatation decreased from 20.5±5.8% to 11.5±3.2% (P<.002) before and after 1 hour of infusion of Intralipid, respectively. Conclusions Transient triglyc...
Abstract 3608: Molecular fingerprint sequencing for minimal residual disease detection in breast cancer
Authors: Iñaki Comino-Mendez, Ros Cutts, Isaac García-Murillas, Neha Chopra, Maria Afentakis, Abigail Evans, Duncan Wheatley, Anthony Skene, Simon Russell, Mohini Varughese, Mitch Dowsett, Ian E. Smith, Nick Turner
Journal: Cancer Research (2018)

Abstract Introduction: The substantial majority of breast cancers present with early-stage disease, although micro-metastatic disease may be established at the time of diagnosis and may ultimately result in metastatic disease recurrence. Prior studies have shown that analysis of circulating tumour DNA (ctDNA) can detect micro-scopic minimal residual disease (MRD) serving as biomarker to anticipate future cancer recurrence, although sensitivity of current assays is limited. We present a novel molecular fingerprint ctDNA assay that exploits tumour whole genome sequencing (WGS) to develop highly personalised assays. Methods: WGS was conducted on paired tumor and germline DNA from 11 early breast cancer patients to identify tumour specific small indels (SIs) to track in plasma as individual molecular fingerprints. Patient-specific amplicon-based panels were designed and validated to identify somatic reporters with no sequencing background. DNA was extracted from plasma samples taken at pre-surgery (baseline), post-surgery, and every 3 months until 1 year and every 6 months thereafter, and sequenced to 100,000X. Results: Molecular fingerprint assays were demonstrated to detect less than a single cancer genome, with undetectable background in control samples. Using plasma samples from patients with early stage breast cancer, we detected ctDNA in 80% of the baseline plasma time-points with 100% specificity (95% confidence limits (CI) 98.7%-100%). ctDNA was detected in all patients prior to relapse, with an observed lead-time of 15.5 months, substantially improved compared with previous techniques, detecting residual disease that was not detectable by tracking mutations using digital PCR. Conclusions: This proof-of-principle study demonstrates that tumor-specific molecular fingerprints combined with ultra-deep plasma DNA sequencing have the potential to transform MRD detection. Identifying those patients who have undetectable recurrence would pave the way for identifying who is cured by surgery alone and who requires further therapy. Citation Format: Iñaki Comino-Mendez, Ros Cutts, Isaac García-Murillas, Neha Chopra, Maria Afentakis, Abigail Evans, Duncan Wheatley, Anthony Skene, Simon Russell, Mohini Varughese, Mitch Dowsett, Ian E. Smith, Nick Turner. Molecular fingerprint sequencing for minimal residual disease detection in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3608.
Abstract 13747: Phase 1a/1b Study of EP-7041: A Novel, Potent, Selective, Small Molecule FXIa Inhibitor
Authors: Neil J Hayward, Dennis I Goldberg, Eric M Morrel, Phillip M Friden, Paula M Bokesch
Journal: Circulation (2017)

Introduction: Bleeding risk is the dose-limiting concern with available anticoagulant/antithrombotic therapies. Inhibition of Factor XIa decreases thrombin generation in the amplification phase, bu...
Abstract 750: Modular coiled-coil masking domains for tumor-specific antibody activation
Authors: Vivian H. Trang, Xinqun Zhang, Melissa M. Dominguez, Weiping Zeng, Julia H. Cochran, Ivan J. Stone, Peter D. Senter, Matthew R. Levengood
Journal: Cancer Research (2018)

Abstract The power of monoclonal antibody therapeutics arises from their remarkable selectivity for a particular antigen. However, antibody therapies can still be limited by serious side effects that result from target-mediated toxicity when the antigen is also expressed on non-diseased tissue. An emerging concept in the field of therapeutic antibodies is to restrict antibody binding in healthy tissues while empowering the antibody at sites of disease. This has previously been accomplished by fusing masking groups to the antibody through cleavable sequences that can be activated upon hydrolysis by disease-associated proteases. Here, we present a novel approach to mask antibodies utilizing a variety of leucine zipper coiled-coil peptides fused to the N-termini of antibody heavy and light chains. An optimized heterodimeric coiled-coil masking domain was identified that significantly impaired the binding of multiple antibodies to their cognate receptors with no antibody-specific optimization required. Protease-cleavable linkers were introduced between the coiled-coil peptides and antibody termini, and protease-catalyzed removal of the coiled-coil domains restored antibody binding affinity to that of the unmasked parent antibody. The coiled-coil mask did not impair production of antibody-drug conjugates (ADCs) of varying drug-to-antibody ratios, and masked antibodies and ADCs had similar stability and pharmacokinetic profiles to unmasked counterparts. However, coiled-coil masked ADCs and antibodies displayed decreased functional activity in biological assays, commensurate with the decrease in affinity afforded by masking, and this activity could be restored upon cleavage of the mask. Lastly, coiled-coil masked antibodies and ADCs had been tested in vivo and had demonstrated improved safety benefits as well as equivalent antitumor activity compared to the unmasked counterparts. Coiled-coil masked antibodies represent an advance in the field of antibody pro-drugging, as this modular domain can be rapidly applied to an array of therapeutic antibodies and ADCs. Citation Format: Vivian H. Trang, Xinqun Zhang, Melissa M. Dominguez, Weiping Zeng, Julia H. Cochran, Ivan J. Stone, Peter D. Senter, Matthew R. Levengood. Modular coiled-coil masking domains for tumor-specific antibody activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 750.