tbuckley/cabot-search huggingface dataset:
Attenuated kallikrein‐related peptidase activity disrupts desquamation and leads to stratum corneum thickening in human skin equivalent models
Authors: J.A. McGovern, C. Meinert, S.J. de Veer, B.G. Hollier, T.J. Parker, Z. Upton
Journal: British Journal of Dermatology (2016)

Epidermal homeostasis is maintained through the balance between keratinocyte proliferation, differentiation and desquamation; however, human skin equivalent (HSE) models are known to differentiate excessively. In native tissue, proteases such as kallikrein-related peptidase (KLK) 5 and KLK7 cleave the extracellular components of corneodesmosomes; proteins corneodesmosin, desmocollin 1 and desmoglein 1, loosening the cellular connections and enabling desquamation. The actions of KLK7 are tightly controlled by protease inhibitors, skin-derived antileucoproteinase (SKALP) and lymphoepithelial Kazal-type-related inhibitor (LEKTI), which also inhibits KLK5, localizing protease activity to the stratum corneum.To investigate the mechanisms that inhibit the desquamation cascade in HSE models.Human skin tissue and HSE models were investigated using gene microarray, real-time polymerase chain reaction (PCR), immunohistochemistry and Western blot analysis to examine key components of the desquamation pathway. To elucidate proteolytic activity in HSEs and native skin, in situ and gel zymography was performed.Histological analysis indicated that HSE models form a well-organized epidermis, yet develop an excessively thick and compact stratum corneum. Gene microarray analysis revealed that the desquamation cascade was dysregulated in HSE models and this was confirmed using real-time PCR and immunohistochemistry. Immunohistochemistry and Western blot indicated overexpression of LEKTI and SKALP in HSEs. Although KLK7 was also highly expressed in HSEs, zymography indicated that protease activation and activity was lower than in native skin.These findings demonstrate that stratum corneum thickening is due to inhibited KLK5 and KLK7 activation and a subsequent lack of corneodesmosome degradation in the HSE model epidermis.
Primary Pulmonary Mucinous Adenocarcinoma Was Better Visualized on Delayed FDG PET/CT Imaging
Authors: Na Zheng, Xia Bai, Ruilong Niu, Xuemei Wang
Journal: Clinical Nuclear Medicine (2016)

A 36-year-old man underwent FDG PET/CT to evaluate a lung mass in the right middle lobe. The mass on the early PET images that were acquired 50 minutes post-FDG injection had only minimally increased FDG activity with uptake ratio between the mass and mediastinal blood pool of 0.93. However, on the delayed images acquired 230 minutes post-FDG administration, this ratio increased to 3.0, which enabled better notion of the lesion. Pathological examination demonstrated a primary pulmonary mucinous adenocarcinoma.
Abstract 4161: Bortezomib enhances expression of effector molecules in antitumor CD8+ T lymphocytes by modulating Notch-NF-kB-miR-155 crosstalk
Authors: Ariana N. Renrick, Menaka C. Thounaojam, Duafalia F. Dudimah, Portia Thomas, Samuel T. Pellom, Roman V. Uzhachenko, Anil Shanker
Journal: Cancer Research (2016)

Abstract The immunosuppressive tumor microenvironment usurps host antitumor immunity by multiple mechanisms including interference with the Notch system, which is important for various metazoan cell fate decisions and hematopoietic cell differentiation and function. We observed that treatment with the proteasome inhibitor bortezomib in mice bearing various solid tumors resulted in an upregulated expression of various Notch signaling components in lymphoid tissues, thereby increasing CD8+T-lymphocyte IFNγ secretion and expression of effector molecules, perforin and granzyme B, as well as the T-box transcription factor eomesodermin. Bortezomib also neutralized TGFβ-mediated suppression of IFNγ and granzyme B expression in activated CD8+T-cells. Of note, bortezomib reversed tumor-induced downregulation of Notch receptors, Notch1 and Notch2, as well as increased the levels of cleaved Notch intracellular domain (NICD) and downstream targets Hes1 and Hey1 in tumor-draining CD8+T-cells. Moreover, bortezomib promoted CD8+T-cell nuclear factor-κB (NF-κB) activity by increasing the total and phosphorylated levels of the IκB kinase and IκBα as well as the cytoplasmic and nuclear levels of phosphorylated p65. Even when we blocked NFκB activity by Bay-11-7082, or NICD cleavage by γ-secretase inhibitor, bortezomib significantly increased expression of Notch Hes1 and Hey1 genes as well as perforin, granzyme B and eomesodermin in activated CD8+T-cells. Data suggest that bortezomib can rescue tumor-induced dysfunction of CD8+T-cells by its intrinsic stimulatory effects promoting NICD-NFκB crosstalk. We are also elucidating components of microRNA regulation affecting NICD-NFκB crosstalk. Our preliminary data suggest that miR-155 plays a role in bortezomib-induced regulation of T cell function. These findings provide novel insights on using bortezomib not only as an agent to sensitize tumors to cell death, but also to provide lymphocyte-stimulatory effects, thereby overcoming immunosuppressive actions of tumor on anti-tumor T-cell functions. Citation Format: Ariana N. Renrick, Menaka C. Thounaojam, Duafalia F. Dudimah, Portia Thomas, Samuel T. Pellom, Roman V. Uzhachenko, Anil Shanker. Bortezomib enhances expression of effector molecules in antitumor CD8+ T lymphocytes by modulating Notch-NF-kB-miR-155 crosstalk. [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 4161.
Treatment of Del(5q) Myelodysplastic Syndrome with All-Trans-Retinoic Acid and Tocopherol-α.
Authors: Aristoteles A.N. Giagounidis, Sabine Haase, Ulrich Germing, Claudia Schoch, Brigitte Schlegelberger, Ludwig Wilkens, Guntram Büsche, Hans H. Kreipe, Manuel Aivado, Michael Lübbert, Arnold Ganser, Carlo Aul
Journal: Blood (2004)
A randomized phase II multicenter trial on the effects of budesonide on cabazitaxel-induced diarrhea: CABARESC.
Authors: Sander Bins, Annemieke J.M. Nieuweboer, Anne-Joy M. de Graan, Robert J. van Soest, Paul Hamberg, Robbert Jeroen Van Alphen, Andre M. Bergman, Aart Beeker, Henk Van Halteren, Albert J. Ten Tije, Johanna Maria Zuetenhorst, Nelly van der Meer, Dana A. Chitu, Ronald De Wit, Ron H.J. Mathijssen
Journal: Journal of Clinical Oncology (2016)

5073 Background: Cabazitaxel (CBZ) is registered for the treatment of patients with metastatic castration resistant prostate cancer (mCRPC). Diarrhea is a common adverse effect, reported in 47% of the patients in the TROPIC trial, with grade 3 or 4 events in 6% of patients (De Bono et al, Lancet 2010). We studied if co-administration of the oral corticosteroid budesonide (BUD) would decrease the incidence and severity of CBZ-induced diarrhea. Previously, we showed that BUD co-administration has no effect on CBZ plasma exposure (de Graan et al, PIII-41, ASCPT 2012). Methods: From Dec 2011 to Oct 2015, we performed a multicenter randomized phase II open-label trial in mCRPC patients [NTR2991]. After written informed consent, patients scheduled to receive standard of care CBZ 25 mg/m2 Q3W plus prednisone 5 mg BID were randomized to receive CBZ plus prednisone alone (control arm) or to receive concomitant BUD 9 mg QD during the first 2 treatment cycles (BUD arm). Patients reported the frequency and consistency of stools in a diary. The primary endpoint was the incidence of grade 2-4 diarrhea. To detect a decrease in incidence from 25% to 10% (2-sided α = 0.05 and β = 0.20) 113 evaluable patients per arm were needed. Results: Of the 246 included patients, 227 were evaluable for the primary endpoint. Median number of cycles was 6 for both arms. No grade 4 diarrhea was observed. The incidence of grade 3 diarrhea was 4% in both arms. In the BUD arm, 21 of the 114 patients (18%) had grade 2-3 diarrhea, compared with 14 of the 113 (12%) in the control arm (p = 0.208). Median number of stools per day at baseline was 1 in both arms and was maximally 3 (range 1-40) in the BUD arm and 3 (range 1-13) in the control arm. Two patients in the BUD arm and 5 patients in the control arm were hospitalized for diarrhea. In 3 patients diarrhea was one of the reasons for treatment discontinuation. Main other grade 3 adverse events were neutropenia (49%), nausea (1%) and vomiting (1%). Conclusions: BUD had no significant effect on CBZ induced diarrhea. Interestingly, the incidence of grade 3-4 diarrhea was slightly lower than that observed in the TROPIC trial, and diarrhea was never the sole reason for treatment discontinuation. Clinical trial information: NTR2991.
Impact of prognostic genomic classification of melanoma with a 31-gene expression profile on clinical decision-making in a retrospective cohort.
Authors: Adam C. Berger, Alexander R. Miller, Indy Chabra, Robert S. Davidson, Richard Hope, Amy Brackeen, J. Kevin Poitras, Kristen M. Oelschlager, Robert W. Cook, Clare Johnson, Federico A. Monzon
Journal: Journal of Clinical Oncology (2016)

e21066 Background: DecisionDx-Melanoma is a 31-gene expression test that provides a binary classification for risk of cutaneous melanoma (CM) recurrence (Class 1 = low risk / Class 2 = high risk). This test has been validated in two multicenter studies, and has been in clinical use since 2013. Additional multi-center and independent single center studies have also been reported. We studied the impact of results from this genomic assay on changes in clinical management of CM patients. Methods: Medical records from consecutive CM patients tested with the 31-gene expression profile (DecisionDx-Melanoma) at 6 medical practices (3 Dermatology and 3 Surgical Oncology) from May 2013 to September 2015 were reviewed under an IRB-approved protocol. Clinical management plans encompassing frequency of visits, frequency and modality of imaging, use of laboratory tests and specialty referrals before and after receiving test results were collected and compared to assess impact of test results. Results: 153 CM patients met inclusion criteria with complete staging and management information: 44% were Stage I, 50% Stage II and 6% Stage III. 61% (94) had Class 1 results and 39% (59) Class 2. Test results prompted a change in clinical management in 52% of patients; 78% of Class 2 and 36% of Class 1 patients having management changes (p< 0.0001, Fisher’s Exact). Of the 80 cases with observed changes in management, 95% (76) were adjusted in a manner consistent with DecisionDx-Melanoma Class prediction (higher intensity management in Class 2 patients vs. lower intensity management in Class 1 patients) and the association between molecular class and change in management intensity was statistically significant (p< 0.0001, Fisher’s Exact with Freeman-Halton extension). Conclusions: Results from prognostic genomic classification of melanoma with a 31-gene expression profile that determines risk of recurrence changed clinical management in over half of the tested patients. Clinical impact was consistent with the expected use of results (i.e., increased surveillance in Class 2 and reduced surveillance in Class 1 patients) in most cases (95%).
Abstract 660: Modelling conventional and serrated colorectal tumorigenesis by altering the Wnt and MAPK signaling pathways
Authors: Vicki Whitehall, Winnie Fernando, Diane McKeone, Mark Bettington, Sally Pearson, Catherine Bond, Barbara Leggett
Journal: Cancer Research (2016)

Abstract Background. The majority of conventional colorectal adenomas are initiated by activation of the Wnt signal, whilst activation of the MAPK pathway is associated with progression to cancer. In contrast, sessile serrated adenomas are initiated by activation of the MAPK signaling pathway due to mutation of the BRAF oncogene, whilst the Wnt pathway is activated at the transition to dysplasia. We hypothesised that whilst both the Wnt and MAPK pathways play key roles in colorectal tumorigenesis, the order in which these signaling pathways are activated would determine the morphology of the lesion arising. Methods. To test this hypothesis, we utilised a conditional BRAF mutant mouse model crossed with an inducible Cre driven by the murine Villin gene promoter, to restrict Cre expression and induction of the BRAF mutation to the intestine. The MAPK pathway was activated two weeks after birth, whilst activation of the Wnt signal was achieved using APCMin mice or the intestinal carcinogen azoxymethane. Morphology and number of lesions was confirmed by histologically examination. Nuclear β-catenin immunostaining provided a surrogate for activation of the Wnt signal. Results. Induction of the BRAF mutation resulted in the rapid and sustained development of widespread intestinal hyperplasia. Murine serrated adenomas (mSA) mimicking the morphology of human traditional serrated adenomas were observed by 5 months and by 10 months 8/18 (44.4%) mice had developed mSA, primarily in the duodenum. Activation of the Wnt pathway using azoxymethane dramatically accelerated the serrated phenotype in both the small intestine (2.9 mSA per mouse, P&amp;lt;0.01) and colon (3.1 mSA per mouse, P&amp;lt;0.05) by 3 months. The MAPK and Wnt pathways also synergized in APCMin mice, increasing the average number of conventional adenomas per mouse from 2.1 to 78.8 (P&amp;lt;0.001). Conclusion. The rapid induction of hyperplasia and exclusive development of serrated lesions demonstrates that BRAF mutation is a key molecular event underlying initiation of serrated neoplasia. Importantly, we have demonstrated that activation of the MAPK pathway through BRAF mutation is sufficient for commitment to the serrated pathway and that whilst subsequent activation of the Wnt signal can accelerate tumorigenesis, it is not sufficient to override the existing serrated morphology. Citation Format: Vicki Whitehall, Winnie Fernando, Diane McKeone, Mark Bettington, Sally Pearson, Catherine Bond, Barbara Leggett. Modelling conventional and serrated colorectal tumorigenesis by altering the Wnt and MAPK signaling pathways. [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 660.
Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer
Authors: T. Kinoshita, R. Muramatsu, T. Fujita, H. Nagumo, T. Sakurai, S. Noji, E. Takahata, T. Yaguchi, N. Tsukamoto, C. Kudo-Saito, Y. Hayashi, I. Kamiyama, T. Ohtsuka, H. Asamura, Y. Kawakami
Journal: Annals of Oncology (2016)
Results of a randomized controlled study of personalized care plans in breast cancer survivors from a single institution.
Authors: Rashida Haq, Christine Brezden-Masley, Ronita Lee, Suzanne Richter, Ralph L. George, Jory Simpson, Julia Rackal, Fok Han Leung, Aleksandra Jovicic, Amy Kong, Benjamin Li, Pauline Gulasingam, Tara Jainudeen
Journal: Journal of Clinical Oncology (2015)

109 Background: In 2006, Institute of Medicine recommended care plans for coordination of care of cancer survivors. Our pilot study of multifaceted care plans met information and communication needs of breast cancer (BC) survivors and their primary care providers (PCP). In this study, a Personalized Multifaceted Care Plan (PMCP) was developed, implemented and evaluated. Methods: This was a randomized study with mixed methods design. Upon REB approval, 78 women diagnosed with invasive BC for adjuvant treatments were recruited from the breast clinic from June 2013 to March 2015. After informed consent, participants were randomized to the control or the intervention group and stratified to chemotherapy (CT) vs. endocrine therapy (ET). The intervention group received a PMCP (paper based treatment and care plans (TP &amp; CP) with information on breast pathology, treatment sequence, supportive care and follow-up guidelines with access to a website). CT arm patients received a TP at the start of therapy and a CP at completion. ET patients received the CP upfront. Quantitative outcomes were assessed by 3 standardized questionnaires at baseline and following treatment. Within-group baseline and post-intervention scores were compared using paired t-tests. The post-intervention control group and intervention group’s scores were compared using unpaired t-tests. In the intervention group, qualitative analysis was done through focus groups of BC survivors &amp; PCP interviews. Results: Baseline scores in the mean intervention and control groups were similar. In the CT arm of the intervention group, post-intervention scores on Communication and Efficacy Scale showed statistically significant increase (p &lt; 0.05, 95% CI). Results in the control group and in the intervention group of patients on ET were not significantly different. Focus group participants commented that the PMCP helped them feel ‘educated’ and engaged in their cancer treatment and their PCPs found the PMCP contained useful, concise medical summaries. Conclusions: Upfront PMCP improves self-efficacy scores in patients on CT. Qualitative analysis substantiates the benefits of PMCP. PMCP should be standard of care in BC survivors receiving CT.
Abstract 1504: Identification of novel kinase fusion transcripts in endometrial cancer
Authors: Ryo Tamura, Kosuke Yoshihara, Kazuaki Suda, Kaoru Yamawaki, Tatsuya Ishiguro, Sosuke Adachi, Takayuki Enomoto
Journal: Cancer Research (2016)

Abstract The prognosis of patients with advanced stage or recurrent endometrial cancer remains poor and there is at present no effective therapeutic molecular target for this disease. Our aim is to identify therapeutic targetable targets in endometrial cancer. We focused on fusion transcripts whose inhibitors show impressive activity in some tumors and have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts. We have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications but have not detected recurrent fusion transcripts. We performed Sanger sequencing of RT-PCR amplification products and validated 27 (93.1%) of the 29 fusion transcripts that were randomly selected. As targetable fusion candidates, we extracted three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. Western blotting did not show the detectable protein level of the CPQ-PRKDC similar to CAPZA2-MET, and VGLL4-PRKG1. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. In conclusion, we have described the landscape of fusion transcripts in endometrial cancer by using RNA-sequencing data. We could not identify therapeutically targetable kinase fusions in a small set of 25 endometrial cancer cell lines. Our findings suggest that the transcript allele fraction is a good predictor for determining bona fide targetable fusion transcripts when applying fusion detection methods that use RNA-sequencing data. Citation Format: Ryo Tamura, Kosuke Yoshihara, Kazuaki Suda, Kaoru Yamawaki, Tatsuya Ishiguro, Sosuke Adachi, Takayuki Enomoto. Identification of novel kinase fusion transcripts in endometrial 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 1504.
Exploring the Potential Benefits and Risks of Anticoagulation for Atrial Fibrillation During Hospitalization for Sepsis
Authors: Gregg C. Fonarow
Journal: JAMA Cardiology (2016)

Allan J. Walkey, MD, MSc; Emily K. Quinn, MS; Michael R. Winter, MPH; David D. McManus, MD, MSc; Emelia J. Benjamin, MD, ScM
A randomized trial of quilizumab in adults with refractory chronic spontaneous urticaria
Authors: Jeffrey M. Harris, Christopher R. Cabanski, Heleen Scheerens, Divya Samineni, Mary S. Bradley, Colette Cochran, Petra Staubach, Martin Metz, Gordon Sussman, Marcus Maurer
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract 151: Modeling the rise of intratumoral heterogeneity in growing, static, and regressing human colorectal polyps
Authors: Chelsie K. Sievers, Luli Zou, Perry J. Pickhardt, Kristina A. Matkowskyj, Dawn Albrecht, David H. Kim, Fouad J. Moawad, Brooks D. Cash, Mark Reichelderfer, Michael A. Newton, Richard B. Halberg
Journal: Cancer Research (2016)

Abstract Benign adenomatous colon polyps are thought to be transformed into cancers through the stepwise accumulation of mutations. However, not all polyps progress. A significant number remain static in size, regress, or resolve completely. The mechanisms underlying these differential fates are unknown, and currently there are no biological characteristics that can reliably predict which polyps will grow or progress into invasive cancer. To determine the mutational landscape, targeted next generation sequencing was performed on a unique collection of small (6-9mm) colorectal polyps with known growth rates based on interval imaging with CT colonography. To determine spatial location of identified mutations within a polyp, micro-dissection was performed followed by quantitative PCR to validate low frequency mutations. The mutational landscape of small polyps is varied both within and among individual polyps. Polyps carried 0-3 pathogenic mutations with the most frequent being in APC (67%, 32/48), KRAS/NRAS (17%, 8/48), BRAF (17%, 8/48), FBXW7 (10%, 5/48), and TP53 (8%, 4/48). Additionally, 13% (6/48) contained driver mutations at varied mutant allele frequencies, indicating the presence of subclonal populations. In silico modeling of tumor growth was used to determine the likely size at which additional driver mutations arose in order to observe those varied frequencies. This model of colon tumor growth was adapted so that mutations occur with a given probability of 10−5, which may change the fitness positively or negatively, and the lineage from these mutant subpopulations was tracked during tumor growth. In silico polyps were sectioned and mutant allele frequency was recorded and compared to the frequencies observed from the targeted sequencing of human polyps. Contrary to the slow step-wise accumulation of mutations theory, these data indicate small colonic polyps can have multiple pathogenic mutations in crucial driver genes that arise early in a tumor's existence. Understanding the molecular pathway of tumorigenesis and clonal evolution in polyps that are at risk for progressing to invasive cancers will allow us to begin to better predict which polyps may be more likely to progress into adenocarcinomas and which patients are predisposed to developing advanced disease. Citation Format: Chelsie K. Sievers, Luli Zou, Perry J. Pickhardt, Kristina A. Matkowskyj, Dawn Albrecht, David H. Kim, Fouad J. Moawad, Brooks D. Cash, Mark Reichelderfer, Michael A. Newton, Richard B. Halberg. Modeling the rise of intratumoral heterogeneity in growing, static, and regressing human colorectal polyps. [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 151.