tbuckley/cabot-search huggingface dataset:
Breast cancer phenotype in patients with hereditary gene mutations other than BRCA1 and BRCA2.
Authors: Banu Arun, Nisreen Elsayegh, Heather Y. Lin, Katherine Clifton, Angelica M. Gutierrez-Barrera, Jennifer Keating Litton, Constance T. Albarracin
Journal: Journal of Clinical Oncology (2017)

e13121 Background: Use of multi-gene panel (MGP) testing for hereditary breast cancer (BC) has increased significantly. Unlike in case of TNBC diagnosed before age 60 and ordering BRCA testing; for MGP testing, healthcare providers depend on personal and/or family history of cancer as tumor phenotype and on patient characteristics for non-BRCA hereditary BC genes which are not well described. Therefore, we planned to evaluate tumor phenotype of BCs associated with hereditary gene mutations other than BRCA 1 and BRCA2. Methods: Consecutive patients with invasive BC who are in a prospective cohort study and who underwent MGP testing based on published criteria as clinically indicated were included in the study. All patients’ breast pathology slides were reviewed by breast pathologists at our institution. For statistical analysis: Patients’ demographic and clinical characteristics were summarized using descriptive statistics such as frequency distribution, mean (± s.d.) and median (range). SAS version 9.4 and S-Plus version 8.04 were used to carry out the computations for all analyses. Institutional IRB approval was obtained. Results: Between 2013 and 2017, 1607 patients underwent MGP testing and 347 were found to be positive for a pathogenic variant. For the study purposes we included only patients with invasive breast cancer (N = 146). Median age was 45.1 yrs (Range: 25-78). Genetics testing results were as follows: BRCA1: 38 (26%), BRCA2: 37 (25%), CHEK2 15 (10%), PALB2: 12 (8%) , ATM: 12 (8%), TP53: 9 (6%), CDH1 : 5 (3%), PTEN: 3 (2%), BRIP1: 3 (2%), and 12 patients (8%) positive for other genes (CDKN2A, MUTYH, PMS2, APC, BARD1, MLH1, NBN, RAD51C, and SDHD). Tumor phenotype by gene mutation in shown in table 1. Conclusions: Several hereditary BC genes are associated with ER positive BC which could have implications for chemoprevention, while others associated with ER neg/TNBC that could have therapeutic implications. These findings and implications need to be further studied in larger cohorts. [Table: see text]
The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers.
Authors: David Michael Hyman, Theodore Willis Laetsch, Shivaani Kummar, Steven G. DuBois, Anna F. Farago, Alberto S. Pappo, George D. Demetri, Wafik S. El-Deiry, Ulrik Niels Lassen, Afshin Dowlati, Marcia S. Brose, Valentina Boni, Brian Turpin, Ramamoorthy Nagasubramanian, Scott Cruickshank, Michael Craig Cox, Nora C. Ku, Douglas S. Hawkins, David S. Hong, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2017)

LBA2501 Background: Larotrectinib is the first selective small-molecule pan-TRK inhibitor. TRK fusions appear oncogenic independent of tumor lineage, are widely distributed across cancers, and affect all ages. We present an integrated dataset from 3 studies intended to support regulatory approval. Methods: All NTRK fusion pts with RECIST measurable disease enrolled to the adult (NCT02122913, n=8) and pediatric (NCT02637687, n=12) phase I trials and adult/adolescent phase 2 trial (NCT02576431, n=35) were analyzed. TRK fusion status was determined by local testing prior to enrollment. Pts were dosed predominantly at 100mg BID on a continuous 28-day schedule. Primary objective was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DOR) and safety. Data were cut on 31-JAN-2017. Results: 55 TRK fusion pts (12 peds, 43 adult, range: 4 mo.-76 yrs) were enrolled (median priors=2). Fusions involved NTRK1 (n=25), NTRK2 (n=1), and NTRK3 (n=29), and 14 unique partners. 13 discrete tumor types were treated: salivary (12), sarcoma (10), infantile fibrosarcoma (7), lung (5), thyroid (5), colon (4), melanoma (4), cholangio (2), GIST (2), and other (4). For the 46 pts evaluated to date, the ORR was 78% (95% CI: 64%–89%) with responses in 12 unique tumor types. Responses are ongoing in 29/33 (88%) pts, excluding 3 peds pts whose DOR was censored at attempted curative resection. A median DOR has not been reached as the majority of responders remain on treatment without progression. The longest responder remains on treatment at 23 mos., 8 pts remain in response at &gt;12 mos., and 16 pts at &gt;6 mos. NTRK solvent front mutations were detected in all 4 pts to develop acquired resistance. The most common TEAEs were fatigue (30%), dizziness (28%), and nausea (28%). 5 (11%) pts required dose reductions. Conclusions: Larotrectinib has demonstrated consistent and durable antitumor activity in TRK fusion cancers, across a wide range of ages and tumor types, and was well-tolerated. Larotrectinib could be the first targeted therapy developed in a tissue type-agnostic manner, and the first developed simultaneously in adults and pediatrics. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.
MAPK pathway activation in low-grade astrocytomas by BRAF gene duplications and activating mutations
Authors: Stefan Pfister, Wibke Janzarik, Marc Remke, Aurelie Ernst, Wiebke Werft, Andreas Kulozik, Christel Herold-Mende, Astrid Gnekow, Guido Reifenberger, Andrey Korshunov, Wolfram Scheurlen, Heymut Omran, Peter Lichter
Journal: Cancer Research (2008)

1624  Astrocytomas WHO grade I and II comprise the most frequent brain tumors in childhood. However, the molecular mechanisms of pathogenesis and tumor recurrence are still poorly understood. Here, we investigated 66 pediatric astrocytomas of World Health Organization (WHO) malignancy grades I and II by using array-based comparative genomic hybridization (array-CGH). The most frequent genomic aberration was a circumscribed duplication of the BRAF locus at 7q34 present in 30/66 (45%) of cases. Screening the same tumor sample for activating mutations of the BRAF gene, we identified such mutations in 4/66 (6%) tumors, exclusively affecting cases without BRAF duplication, indicating different mechanisms for BRAF activation. Tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and CCND1 as compared to tumors without duplication. Fluorescence in situ hybridization (FISH) analysis of 36 low-grade astrocytomas from adult patients also revealed a high frequency of duplications restricted to the BRAF locus (24%), as well as larger gains of chromosome arm 7q (35%). In adult patients, elevated BRAF protein expression in the tumor was associated with favorable prognosis. Proliferation of cultured tumor cells derived from low-gradegliomas was effectively blocked by pharmacological inhibition of MEK1/2, the immediate downstream target of BRAF as well as by stable knockdown of the BRAF gene using lentivirus-mediated transduction of BRAF-specific shRNAs. Cell cycle analysis revealed a G2/M arrest in cells treated either with MEK1/2 inhibitors or shRNAs targeting the BRAF gene. Taken together, our findings implicate aberrant activation of the Mitogen-Activated Protein Kinase (MAPK) pathway due to gene duplication or activating mutation of BRAF as a common molecular pathomechanism in low-grade astrocytomas and provide a promising novel target for future treatment strategies.
The Mutational and Signaling Landscape of Multiple Myeloma Varies Dependent upon Translocation Cyclin D (TC) Subgroup
Authors: Caleb K. Stein, Charlotte Pawlyn, Shweta S. Chavan, Niels Weinhold, Brian A Walker, Adam Rosenthal, Ola Landgren, Peter Leif Bergsagel, Gareth J Morgan
Journal: Blood (2016)
The brains of the bones: how osteocytes use WNT1 to control bone formation
Authors: Frank Rauch
Journal: Journal of Clinical Investigation (2017)

WNT proteins drive the development and maintenance of many tissues, including bone. It is less clear which of the many WNT proteins act on bone or where these WNTs act in the skeleton; however, loss-of-function mutations in WNT1 cause bone fragility in children and adults. In this issue of the JCI, Joeng and colleagues demonstrate that bone formation is under the control of WNT1 produced by osteocytes, the cells that reside deep in the bone matrix and form dendritic networks. The implication of WNT1 in the control of bone formation identifies a potential new target for the treatment of low bone mass disorders, such as osteoporosis.
Passive Immunisation of Hamsters against Clostridium Difficile Infection using Antibodies against Surface Layer Proteins
Authors: JB O'Brien, MS McCabe, DB Ní Eidhin, DP Kelleher
Journal: Endoscopy (2004)

Aims: Clostridium difficile is the primary cause of antibiotic-associated diarrhoea and a frequent cause of pseudomembranous colitis. We assessed the ability of high specificity, high-titre rabbit anti-C. difficile surface layer protein (SLP) antibodies to protect against infection in a lethal hamster model.
Coronin 1A, a novel player in integrin biology, controls neutrophil trafficking in innate immunity
Authors: Robert Pick, Daniela Begandt, Thomas J. Stocker, Melanie Salvermoser, Sarah Thome, Ralph T. Böttcher, Eloi Montanez, Ute Harrison, Ignasi Forné, Alexander G. Khandoga, Raffaele Coletti, Ludwig T. Weckbach, Doris Brechtefeld, Rainer Haas, Axel Imhof, Steffen Massberg, Markus Sperandio, Barbara Walzog
Journal: Blood (2017)
PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer
Authors: Jennifer H. Yearley, Christopher Gibson, Ni Yu, Christina Moon, Erin Murphy, Jonathan Juco, Jared Lunceford, Jonathan Cheng, Laura Q.M. Chow, Tanguy Y. Seiwert, Masahisa Handa, Joanne E. Tomassini, Terrill McClanahan
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1–directed immunotherapy. However, PD-L1–negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated. Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab. Results: PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P = 0.0012–&amp;lt;0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2–positive than PD-L2–negative patients. Conclusions: Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients. Clin Cancer Res; 23(12); 3158–67. ©2017 AACR.
Reply to Orlando and Lirussi
Authors: I. Helmreich-Becker
Journal: Endoscopy (2003)

The letter from Orlando and Lirussi makes the important point that laparoscopy combined with liver biopsy improves the diagnosis of cirrhosis. In their review of 1003 patients undergoing conventional laparoscopy combined with liver biopsy, a positive diagnosis of cirrhosis was confirmed by at least one or both procedures in 42 % (411 of 981) of patients and confirmed by histology alone in only 33 % (324 of 981) [1].
Abdominal Aortic Calcification Among Individuals With and Without Diabetes: The Jackson Heart Study
Authors: Justin B. Echouffo-Tcheugui, Matthew Allison, Rita R. Kalyani, Mario Sims, Alain G. Bertoni, Sherita H. Golden
Journal: Diabetes Care (2017)

Diabetes increases mortality by two- to fourfold from atherosclerosis-related causes, including coronary artery disease, stroke, and peripheral artery disease (1). There is a paucity of population-based data on subclinical atherosclerotic disease in arterial beds other than the coronary arteries in persons with diabetes (2).

In the Jackson Heart Study (JHS), we examined the association of diabetes with abdominal aortic calcification (AAC) among African Americans. Among included individuals ( n = 1,664), the mean age was 57 (± 11) years, 69% were female, and 18.3% had diabetes (based on fasting blood glucose [FBG], HbA1c, use of glucose-lowering medications, or physician diagnosis). The median AAC and coronary artery calcification (CAC) scores were 904.15 (interquartile range 0–1093.10) and 0 (0–96.19), respectively. The prevalence of any AAC or CAC was 69% and 49%, respectively. Individuals with diabetes were older, had higher BMI, had higher systolic blood pressure and prevalence of hypertension, had lower …
Assessment of Matrix Metalloprteinases (MMP) 1, 3 and 9 in Gluten Sensitive Enteropaty
Authors: B Mohamed, C Feighery, J Kelly, U O'Shea, M Abuzakouk
Journal: Endoscopy (2004)

Background. Matrix metalloprotenases (MMPs) are a group of proteolytic enzymes that degrade extracellular matrix (ECM) components. During inflammation MMPs are implicated in tissue destruction. Aim. To investigate the expression of matrix metalloproteinases in the small intestinal from patients with coeliac disease (CD) and dermatitis herpetiformis (DH).
Validation of Data-Mining in Identifying Novel Genes in the Colonic Polyp-Cancer Sequence
Authors: A Moss, S Madden, AM Mullian, C O'Keane, A Henger, M Kretzler, HR Brady, P Doran, P MacMathuna
Journal: Endoscopy (2004)

Background: We previously described identification of genes associated with colon cancer using a data-mining approach. We sought to validate this approach at a biological level, and determine their role in the polyp-cancer sequence.
Palbociclib's effect on estrogen receptor mutations in metastatic breast cancer.
Authors: Karthik Joshua Kota, Rekha Gyanchandani, Adam Brufsky, Adrian V. Lee, Steffi Oesterreich, Shannon Puhalla
Journal: Journal of Clinical Oncology (2016)

533 Background: An emerging resistance mechanism to endocrine therapy in metastatic breast cancer (MBC) is estrogen receptor mutations (ESR1-mut). Palbociclib (P) is a CDK4/CDK6 inhibitor with improved efficacy over endocrine therapy alone. Evaluation of initial ESR1-mut prevalence in MBC patients starting P and gain of ESR1-mut over time on P is understudied. We sought to determine ESR1-mut prevalence in plasma over time using circulating free DNA (cfDNA) in a diverse population starting therapy with P and letrozole (L) on an expanded access trial Methods: 17 patients with MBC were started on P and L and had serial plasma samples collected for evaluation of ESR1-mut (D538G, Y537C, Y537N, and Y537S) using digital droplet (dd)PCR. Twenty mL of blood was collected in 2 Streck tubes for the isolation of cfDNA at various time points after initiation of P and L Results: Median age was 50 (range 40-72), median number prior therapies was 8 (range 0-19), and median number prior endocrine therapies (ET) was 4 (range 0-9; 2 never with ET, 8 without adjuvant ET). 5/17 (29%) of patients had ESR1-mut (3/5 already mutated on initial draw; 2/5 developed mutations while on P and L treatment); D538G was the most common mutation (N = 3), followed by Y537N and Y537S (N = 2), and Y537C (N = 1); of note, 2/5 patients had multiple ESR1 mutations and 3/5 patients gained mutations on therapy. Median progression-free survival (PFS) was 129 days in ESR1-mut and 177 days in ESR-wt, not significant (p = 0.47); removal of two ESR-wt with rapid progression (9 and 22 days) changed ESR-wt median PFS to 312 days with a trend towards significance (p = 0.22) for faster progression in ESR1-mut Conclusions: P does not prevent ESR1-mut selection in the presence of an aromatase inhibitor (AI) when used in later lines of therapy. ESR1-mut prevalence in cfDNA in this study is similar to previous reports (29%). PFS on AI and palbociclib was similar in both ESR1-mut and ESR-wt with trend towards faster progression in ESR1-mut
An Age Distribution of D-Dimer Values in Normal Healthy Donor Population: An Indirect Verification of the Age-Adjusted D-Dimer Cutoffs for VTE Exclusion
Authors: Rachel Leger, Sandra c Bryant, Kelly Edwards, Julie I Tange, Kara A Fylling, Deepti M. Warad, Rong He, Dong Chen, Rajiv Pruthi
Journal: Blood (2016)
Molecular and cellular analyses of HPV 16/18-immortalized cervical cells exposed to Benzo[a]pyrene (B[a]P).
Authors: Joel L. Schwartz, Bogdan Prokopczyk, Neil Trushin, Amin Shantu, Dhimant Desai, Vikki Baker, Eric Larios, Karam El-Bayoumy
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2499 

Infections of human cervix with human papillomaviruses types 16 and 18 (HPV 16/18) and exposure to tobacco smoking are important factors in development of cervical cancer. However, it is unclear which cellular events are required for the normal cervical cell to become malignant. Therefore, several cervical cell lines immortalized with HPV (Z173, Z183, and SK-ECTO) were exposed to B[a]P for 24, 48 hours, 3 days and 1 week at concentrations ranging from 0.001 to 3.0 μM. The following analysis utilizing immunofluoresecent and laser scanning and flow cytometry were performed: DNA damage (N2-deoxyguanosine adduct derived from B[a]P-diol epoxide and the 8-OhdG), DNA repair; glycosylase expression (fpg, OGG1, and NTH1); additional markers of cell proliferation and apoptosis were also assessed. Increased responses with varied degrees were observed in cells exposed to B[a]P at levels ranging from 0.01 1.0 μM. Cells exposed to B[a]P for 24 h showed increased DNA damage and decreased DNA repair. Cells exposed for 1 week manifested increased DNA damage but contrary to 24 h exposure, the extent of repair has also increased. Exposure to B[a]P for 24 h resulted in decrease of population of cells in S phase, however, after 1 week the number of cells in S phase has increased. Finally, exposure of cervical cells for 24 h produced an insignificant number of aneuploid cells, whereas, a significant increase in aneuploidy was evident after 1 week. Following 24 h exposure the levels of markers related to apoptosis increased, but decreased after 1 week. Taken together the results of this study indicate that exposure of immortalized cervical cells to physiological doses of B[a]P resulted in a series of events that are associated with malignant transformation.
Opportunities and Challenges in Addressing Maternal Depression in Community Settings
Authors: Robert T. Ammerman
Journal: JAMA Psychiatry (2017)

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Heme-oxygenase-1 Production by Intestinal CX3CR1+ Macrophages Helps to Resolve Inflammation and Prevents Carcinogenesis
Authors: Giulia Marelli, Marco Erreni, Achille Anselmo, Valentina Taverniti, Simone Guglielmetti, Alberto Mantovani, Paola Allavena
Journal: Cancer Research (2017)

CX3CR1+ macrophages in the intestinal lamina propria contribute to gut homeostasis through the immunomodulatory interleukin IL10, but there is little knowledge on how these cells or the CX3CR1 receptor may affect colorectal carcinogenesis. In this study, we show that CX3CR1-deficient mice fail to resolve gut inflammation despite high production of IL10 and have increased colitis and adenomatous polyps in chemical and genetic models of colon carcinogenesis. Mechanistically, CX3CL1-mediated engagement of the CX3CR1 receptor induced upregulation of heme-oxygenase-1 (HMOX-1), an antioxidant and anti-inflammatory enzyme. CX3CR1-deficient mice exhibited significantly lower expression of HMOX-1 in their adenomatous colon tissues. Combining LPS and CX3CL1 displayed a strong synergistic effect in vitro, but HMOX-1 levels were significantly lower in KO macrophages. Cohousing of wild-type and CX3CR1-/- mice during the AOM/DSS treatment attenuated disease severity in CX3CR1-/- mice, indicating the importance of the microbiome, but did not fully reinstate HMOX-1 levels and did not abolish polyp formation. In contrast, pharmacologic induction of HMOX-1 in vivo by cobalt protoporphyrin-IX treatment eradicated intestinal inflammation and fully protected KO mice from carcinogenesis. Taken together, our results establish an essential role for the receptor CX3CR1 in gut macrophages in resolving inflammation in the intestine, where it helps protects against colitis-associated cancer by regulating HMOX-1 expression. Cancer Res; 77(16); 4472-85. ©2017 AACR.
Outcome of patients with refractory/relapsed aml salvaged with the mec (mitoxantrone etoposide cytarabine) regimen
Authors: C. Castagnola, E. P. Alessandrino, G. Pagnucco, P. Bernasconi, M. Lunghi, A. Colombo, E. Brusamolino, M. Bonfichi, A. Corso, M. Lazzarino, C. Bernasconi
Journal: Blood (2000)
Characterization of Cinnamyl Alcohol Dehydrogenase
Authors: B Mee, H Windle, D Kelleher, R Malone, G Henehan
Journal: Endoscopy (2004)

Aims: It has been proposed that some of the pathogenesis of H. pylori – mediated damage of the gastric mucosa occurs through the production of toxic aldehydes by H. pylori alcohol dehydrogenases. The alcohol dehydrogenases of H. pylori have not been thoroughly characterized.