tbuckley/cabot-search huggingface dataset:
Parkinson Disease and Autoimmune Disorders—What Can We Learn From Genome-wide Pleiotropy?
Authors: Nikolaus R. McFarland, Karen N. McFarland, Todd E. Golde
Journal: JAMA Neurology (2017)

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French comment on article Duodenal endoscopic submucosal dissection is feasible using the pocket-creation method1 La dissection sous-muqueuse duodénale est réalisable avec la méthode de la poche
Journal: Endoscopy (2017)

La dissection sous-muqueuse (ESD) duodénale requiert une technique aboutie, car le taux de perforation est élevé. Afin d’essayer de contourner cette difficulté a été créée la méthode de la poche (PCM). Le principe est de réaliser, à partir d’une petite incision muqueuse, une poche sous-muqueuse en utilisant un cap de dissection de petit calibre, puis de terminer la dissection par l’incision des contours de la lésion. Elle aurait pour avantage de surmonter les difficultés liées à une fibrose sous-muqueuse importante ou à une localisation difficile. Le but de cette étude était donc d’évaluer cette nouvelle technique adaptée pour l’ESD de tumeurs superficielles duodénales extra-ampullaires.
Abstract 031: β-Adrenergic Receptor-Mediated Transactivation Of Epidermal Growth Factor Receptor Decreases Cardiomyocyte Apoptosis Through Differential Activation Of ERK1/2 and Akt
Authors: Laurel A Grisanti, Rhonda L Carter, Justine E Yu, Ashley R Repas, Douglas G Tilley
Journal: Circulation Research (2013)

β-adrenergic receptors (βAR) are critical regulators of cardiac function whose dysregulation during heart failure are associated with diminished function. However, βAR-mediated EGFR transactivation has been shown to relay cardioprotection in a mouse model of heart failure via unknown mechanisms. We hypothesized that transactivation of EGFR promotes survival via distinct cardiomyocyte signaling responses leading to decreases in apoptosis. To test this hypothesis, C57BL/6 mice were injected with isoproterenol (Iso) in the presence or absence of the EGFR antagonist AG1478 and ERK1/2 and Akt phosphorylation and subcellular distribution were assessed. Following 10 min Iso stimulation, increases in ERK1/2 and Akt phosphorylation were observed in cytosolic, plasma membrane and nuclear fractions. Phosphorylation of ERK1/2 were AG1478 sensitive in all three fractions while Akt phosphorylation occurred through EGFR-transactivation only in plasma membrane and nuclear fractions, which was confirmed in rat neonatal cardiomyocytes (RNCM). Additionally, EGFR-transactivation by βAR decreased apoptosis, as measured via caspase 3 activation/activity and TUNEL assay, which was sensitive to inhibition of both ERK1/2 and Akt signaling pathways. Increased phosphorylation of ERK1/2 and Akt in the nucleus and the ability to inhibit Iso-mediated changes in apoptosis with the transcriptional inhibitor Actinomycin D suggested that the cardioprotective effects of Iso-mediated EGFR transactivation may be influenced by changes in gene transcription. An Apoptotsis RT2 PCR Array was used to identify changes in transcript levels of 84 apoptotic genes. Of these, 12 were found to be altered in response to EGFR inhibition in the presence of Iso. These results demonstrate that βAR-mediated EGFR transactivation in the heart induces differential subcellular activation of ERK1/2 and Akt and leads to the promotion of cell survival, in part through the modulation of apoptotic gene expression in cardiomyocytes. Further understanding the downstream consequences of these effects in response to βAR-mediated EGFR transactivation could lead to improved therapies for the treatment of heart failure.
A phase 1b study of safety and immune response to PVX-410 vaccine alone and in combination with durvalumab (MEDI4736) in HLA-A2+ patients following adjuvant therapy for stage 2/3 triple negative breast cancer.
Authors: Steven J. Isakoff, Sara M. Tolaney, Nadine M. Tung, Sylvia Adams, Hatem Hussein Soliman, Elena F Brachtel, Karleen R. Habin, Louisa J Bauer, Leif W. Ellisen, Mariano Severgnini, William Thomas Barry, Doris Peterkin
Journal: Journal of Clinical Oncology (2017)

TPS1126 Background: Stage 2-3 triple negative breast cancer (TNBC) remains at high risk for recurrence despite modern adjuvant therapy. An important role for the immune system in TNBC has recently emerged. Tumor infiltrating lymphocytes (TILs) are correlated with improved prognosis and several PD-1/PD-L1 checkpoint inhibitors, including Durvalumab (DUR), demonstrated activity in metastatic TNBC. Vaccines are a promising approach to further enhance the immune response in many cancers including TNBC. PVX-410 (PVX) is a novel tetra-peptide vaccine against XBP1 (2 splice variants), CD138 and CS1 that was safe and induced immune responses in a phase 1b study in smoldering myeloma. XBP1 and CD138 are also over-expressed in TNBC. Methods: This Phase 1b multi-center, single arm study will enroll 20 HLA-A2+ female patients (pts) following completion of all adjuvant therapy for stage 2-3 TNBC. Pts will receive 6 doses of 800ug PVX (emulsified in Montanide (SC) and co-administered with Hiltonol (IM)) at 2-week intervals, and 2 doses of DUR 1500mg IV at the 4 th and 6 th vaccine visits. Eligible pts must be between 1-6 months from completing adjuvant therapy, have no prior autoimmune disease, and have residual disease if neoadjuvant therapy was used. The primary objective is to determine the safety and tolerability of the combination, and the key secondary objective is to determine the immune response to PVX + DUR. If ≤1 pt in the first 6 has a protocol defined dose limiting toxicity within 4 weeks after the first DUR dose, accrual will continue to 20 pts. Immune response will be assessed at baseline, pre-dose 4 PVX/dose 1 DUR, and 4 weeks after completing protocol therapy. Paired data in 20 pts provides 90% power to see a shift of 0.75 standardized units from baseline to 4 weeks post treatment with the signed rank test. Immune response will be determined by a FACs based assay of antigen specific CD3+CD8+ T lymphocyte response and IFN-γ production (intracellular staining) in patient PBMCs. Additional correlative studies, including T-cell PD-1 and tissue PD-L1, XBP1, and CD138, are planned. Currently 4 pts are enrolled. Clinical trial information: NCT02826434.
Efficacy of taxanes followed by anthracyclines as neoadjuvant therapy in HER2-negative breast cancer (BC): Analysis of everyday clinical practice.
Authors: Enrique Alanya Rodríguez, Catalina Falo Zamora, Miguel J. Gil Gil, Petit Anna, Raul Ortega, Adela Fernandez, Idoia Morilla, Agostina Stradella, Sara Cobo, Sonia Pernas Simon
Journal: Journal of Clinical Oncology (2017)

e12112 Background: Pathological complete response (pCR) after neoadjuvant chemotherapy for BC has been related with survival, and the sequence of anthracyclines followed by taxanes (AT) has been the strategy to achieve this response. Some studies suggest that the reverse sequence (TA) might improve cancer outcomes. The aim of our study was to compare clinical response, toxicity and efficacy in terms of pCR rate (ypT0/pTis, ypN0) between both sequences Methods: A retrospective cohort study was designed. TA cohort received Docetaxel (100 mg/m2) x 4, followed by AC (60/600 mg/m2) x 4. AT cohort received the reverse sequence at the same doses. To be included, it was necessary to have received at least one cycle in the planned sequence. Logistic regression analysis was performed to obtain a model adjusted by age, menopausal status, tumor size, nodal status, grade, estrogen receptor (ER), progesterone receptor, and Ki67 Results: From June 2008 to December 2015, 135 consecutive patients with stage II – III HER2 negative BC were treated: TA (n = 48) and AT (n = 87). No significant differences in patient characteristics between groups were found, except for histological grade 3 (63.2% to AT vs. 35.4% to TA), and ER negative (41.4% to AT vs. 22.9% to TA). The pCR rate for TA was 16.7% (8 of 40) vs. 14.9% (13 of 74) for AT. Multivariate logistic regression analysis found OR = 3.65 to achieve pCR for TA (95%CI 1.03 – 12.94; p = .045). We also performed the same analysis for two clinical parameters of response: Neoadjuvant response index (NRI) with cut-off &gt; 0.5 (OR 3.96, 95%CI 1.42-11.08; p = .009) and Clinical response (CR) &gt; 50% (OR 3.65, 95%CI 1.03 – 12.94; p = .045). These parameters were correlated in our series with DFS (p = .011 to NRI and p = .00023 to CR) and OS (p = .034 to NRI and p = .0014 to CR) using the Kaplan-Meier method. No significant differences between rates of either, hospitalizations, neutropenia or dose intensity were found Conclusions: Sequence of T followed by A was slightly significantly more effective to achieve pCR as well as better clinical outcomes in our series of HER2 negative BC than classical sequence of A followed by T, and support the design of large prospective studies to confirm these results
Phase II trial with letrozole as neoadjuvant treatment in postmenopausal and premenopausal patients with highly endocrine responsive operable breast cancer.
Authors: Min-Yi Cheng, Yi-Fang Zhang, Ci-Qiu Yang, Liu-Lu Zhang, Teng Zhu, Hong-Fei Gao, Fu-Long Chen, Qian-Qian Xiong, Yi Zhang, Kun Wang
Journal: Journal of Clinical Oncology (2017)

e12125 Background: Neoadjuvant endocrine therapy (NET)is effective in postmenopausal patients with breast cancers expressing oestrogen receptor. However, the therapeutic benefit of NET in premenopausal population is not fully characterized. We aimed to assess the efficacy and safety of endocrine therapy between the postmenopausal and premenopausal patients with highly endocrine responsiveoperable breast cancer for primary systemic therapy. Methods: Previously untreated patients with operable breast cancer and highly endocrine responsive breast cancer (ER/PR≥50% and Her2-) were recruited. Patients were assigned to receive letrozole 2.5mg daily (combined with triptorelin in premenopausal patients) for a period of at least 6 months. The primary end point of the study was the objective response rate (ORR) measured by breast ultrasound. Secondary end points included safety, pathologically complete response (pCR) rate, breast conservative surgery (BCS) rate. Results: Between September 2012 and December 2016, 41 patients were enrolled in the study (16 postmenopausal, 25 premenopausal ). The total ORR of this study was 73.2% (30 of 41). No significant differences were seen in the ORR, 76.0% (19 of 25 premenopausal patients) and 68.8% (11 of 16 postmenopausal patients) (P = 0.723). The pCR rate was 8% (2 of 25) for the premenopausal and 0%(0 of 16) for the postmenopausal (p=0.512). The BCS rate was 40% (10 of 25) for the premenopausal and 37.5%(6 of 16) for the postmenopausal (P = 0.873). No treatment-related grade 3/4 adverse events were recorded in both groups. Conclusions: Letrozole shows a high activity and excellent tolerability as neoadjuvant therapy in both postmenopausal and premenopausal patients with highly endocrine responsive operable breast cancer.
microRNA expression analysis for biomarker discovery in formalin-fixed-paraffin-embedded tissues
Authors: Sylvie Beaudenon, Martina Doleshal, Amber Magota, Bhavna Choudhury, Carl Morisson, Scott Jewell, Anna Szafranska, Emmanuel Labourier
Journal: Clinical Cancer Research (2007)

A44  Introduction/Background: Whether developing diagnostic tools or exploring novel therapeutic targets, cancer researchers are greatly dependent on tissue specimens that are typically available in limited quantities. Routine clinical practice worldwide includes preservation of virtually every resected biopsy and autopsy specimen. This has created valuable archived tissue collections that contain patient outcome data, such as disease progression, therapeutic response or toxicity and thus offer enormous potential for discovery and analysis of nucleic acid biomarkers with potential diagnostic and therapeutic value. However, widely used preservation methods, such as formalin-fixed paraffin-embedded (FFPE) preservation, are very harsh on a sample9s RNA. The recovery of quality RNA from FFPE tissues is challenging due to the cross-linking between nucleic acids and proteins and covalent modifications of RNA that occur during the fixation process. In this study, we have evaluated the suitability of microRNAs for molecular characterization of archived human specimens and for their use as potential biomarkers.  Materials and Methods: Total RNA was isolated from frozen and FFPE tissues using various commercial kits, and compared with respect to RNA yield, quality and recovery of microRNA. The best performing protocol was optimized and subjected to a more comprehensive characterization study, which included various tissues types, different block ages, process robustness, quantification of microRNA, rRNA and mRNA expression levels by qRT-PCR and microRNA expression profiling by microarray.  Results: The optimized procedure, including an Armored RNA® Quant internal process control, allowed reproducible extraction of high yields of RNA from various fixed tissues. Independently of RNA sample quality, microRNAs generated a qRT-PCR signal more robust and closer to the reference frozen samples than mRNAs. In addition, the same microRNAs were found differentially expressed by qRT-PCR and microarray between two tissue types whether using FFPE or frozen samples. Although lower abundance miRNAs became undetectable upon prolonged storage, miRNA profiling allowed for classification of tissue types from specimens up to 11 years old.  Conclusion: microRNA expression profiling and qRT-PCR are suitable platforms for retrospective molecular analysis and characterization of archived clinical samples provided that appropriate RNA isolation, quality controls and microarray methodologies are used.
The Metastatic Breast Cancer (MBC) project: Accelerating translational research through direct patient engagement.
Authors: Nikhil Wagle, Corrie Painter, Elana Anastasio, Michael Dunphy, Mary McGillicuddy, Dewey Kim, Esha Jain, Jorge Buendia-Buendia, Ofir Cohen, Erik Knelson, Jamie Holloway, Shawn Johnson, Katie Larkin, Viktor Adalsteinsson, Gavin Ha, Samuel Freeman, Greg Gydush, Sarah Reed, Eric Lander, Todd Golub
Journal: Journal of Clinical Oncology (2017)

1076 Background: The Metastatic Breast Cancer Project is a nationwide research study, launched in Oct 2015 in collaboration with patients (pts) and advocacy groups, that directly engages pts through social media and seeks to empower them to share their experiences, clinical information, and samples to accelerate research. Methods: MBC pts enroll by providing their information at mbcproject.org. Pts are sent a saliva kit and asked to mail back a sample which is used to extract germline DNA. We contact pts medical providers and obtain medical records (MRs) and stored tumor samples. Pts may also submit a blood sample, used to extract cell free DNA (cfDNA). Whole exome sequencing (WES) is performed on tumor, germline, and cfDNA; transcriptome sequencing is performed on tumor. Clinical and genomic data are used to generate genomic landscapes in pt subgroups and to identify mechanisms of response and resistance to therapies. Data are shared widely through public databases. Pts receive regular study updates. Results: In 12 months, 2908 MBC pts from 50 states enrolled. 95% completed the 16-question survey about their cancer, treatments, and demographics. 1730 (60%) completed the online consent form. 100-200 pts continue to enroll monthly. To date, 1539 saliva kits were mailed and 1120 samples were received (73%). 992 unique treating institutions were reported by pts, including 733 institutions reported by only 1 pt each and 5 institutions reported by more than 40 pts each. We have obtained MRs from 253 patients (67% yield) and tumor samples from 85 pts (67% yield). WES was successfully completed for 79 tumors of 88 attempted (90%). WES has been performed on initial cfDNA samples. Conclusions: A direct-to-patient approach enabled rapid identification of thousands of MBC pts willing to share MRs, saliva, and tumor samples, including many with rare phenotypes. Remote acquisition of MRs, saliva, tumor, and blood for pts located throughout the US is feasible. We estimate that for ~33% of consenting patients, we can obtain medical records, saliva, and tumor tissue. Genomic analysis of tumor and cfDNA from subgroups including young pts, pts with extraordinary responses, and pts with de novo MBC will be presented.
Bioinspired Collagen Scaffolds in Cranial Bone Regeneration: From Bedside to Bench
Authors: Justine C. Lee, Elizabeth J. Volpicelli
Journal: Advanced Healthcare Materials (2017)

Calvarial defects are common reconstructive dilemmas secondary to a variety of etiologies including traumatic brain injury, cerebrovascular disease, oncologic resection, and congenital anomalies. Reconstruction of the calvarium is generally undertaken for the purposes of cerebral protection, contour restoration for psychosocial well‐being, and normalization of neurological dysfunction frequently found in patients with massive cranial defects. Current methods for reconstruction using autologous grafts, allogeneic grafts, or alloplastic materials have significant drawbacks that are unique to each material. The combination of wide medical relevance and the need for a better clinical solution render defects of the cranial skeleton an ideal target for development of regenerative strategies focused on calvarial bone. With the improved understanding of the instructive properties of tissue‐specific extracellular matrices and the advent of precise nanoscale modulation in materials science, strategies in regenerative medicine have shifted in paradigm. Previously considered to be simple carriers of stem cells and growth factors, increasing evidence exists for differential materials directing lineage specific differentiation of progenitor cells and tissue regeneration. In this work, we review the clinical challenges for calvarial reconstruction, the anatomy and physiology of bone, and extracellular matrix‐inspired, collagen‐based materials that have been tested for in vivo cranial defect healing.
The assessment of chemotherapy risk in elderly cancer patients: Validation of the CRASH score in an Italian cohort.
Authors: Andrea Luciani, Antonella Brunello, NicolÃÂ² Battisti, Giovanna Romanato, Sarah Caldiera, Francesca Bergamo, Anna Roma, Vittorina Zagonel, Paolo Foa
Journal: Journal of Clinical Oncology (2015)

e20521 Background: Older cancer people receiving chemotherapy (CT) are an increasing proportion of patients (pts). Some clinical elements are predictive of toxicity from CT. The CRASH score (Extermann et al) is based on clinical and laboratory parameters are predictive of grade 3/4 hematological (Heme) and non-hematological (non-Heme) toxicity. We performed a multicenter validation of CRASH score in Italy. Methods: Clinical records of pts aged 70 years or older with advanced or localized solid tumors seen in two centers and treated with CT were reviewed. Data on tumor type, stage, performance status (PS), diastolic blood pressure (DBA), albumin, lactate dehydrogenase (LDH) and Comprehensive Geriatric Assessment (CGA) [CIRSG index and score, Mini Nutritional Assessment (MNA), Activities of daily living (ADL) and Instrumental activities of daily living (IADL), Mini Mental State Examination (MMSE), body mass index (BMI)] were collected. The outcome variables, Heme and non-Heme grade 3/4 toxicity, were assessed according to Common Terminology Criteria for Adverse Events v 4.0. CRASH score was calculated using the online formula at Moffitt Cancer Center website. Heme score, non-Heme score and combined score were obtained. Logistic regression models were used. Results: Eligible pts were 599 (203 female), mean age was 76,4 yrs (range 70-91), CIRS-G score and index were 3,4 and 1,4 (0-12; 0-2,6). Mean BMI and MMSE score were 24 and 27,3 (17-30). The most prevalent diagnoses were lung (233 pts, 37,2%), colorectal (126 pts, 26%). 560 pts (93,6%) had PS 0 or 1, 564 pts (94,2%) had a caregiver. Treatment was given as adjuvant in 129 pts (21,5%) and first line metastatic in 396 pts (66,1%). In 87 pts (14,5%) dose was reduced for toxicity. 86 pts (14,4%) and 69 (11,5%) had Heme and non-Heme toxicity respectively. At regression analysis CRASH combined score was significantly associated with Heme toxicity (p 0,005, OR 1,12 CI 1,03-1,22) and together with CIRS-G score was significantly associated with non-Heme toxicity (p 0,0001, OR 1,26 CI 1,15-1,39; p 0,001, OR 0,78 CI 0,68-0,90). Conclusions: Our results confirm the validity of CRASH score in predicting the risk of toxicity in Italian elderly patients receiving CT.
Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia
Authors: Miyuki Yokoro, Yosuke Nakayama, Sho-ichi Yamagishi, Ryotaro Ando, Miki Sugiyama, Sakuya Ito, Junko Yano, Kensei Taguchi, Yusuke Kaida, Daisuke Saigusa, Masumi Kimoto, Takaaki Abe, Seiji Ueda, Kei Fukami
Journal: Journal of the American Society of Nephrology (2017)

Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice via suppression of erythropoietin receptor expression.